Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH:10]=[N:11][O:12][CH3:13])[C@@H:7]([CH3:9])[S:8][C@H:3]12.CCN(CC)CC.[Cl:39][CH2:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:53]/[O:54][CH3:55])/[C:50](Cl)=[O:51])[N:48]=1)=[O:42]>C(Cl)Cl>[Cl:39][CH2:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:53]/[O:54][CH3:55])/[C:50]([NH:1][CH:2]2[C:30](=[O:31])[N:4]3[C:5]([C:14]([O:16][CH:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:15])=[C:6]([CH:10]=[N:11][O:12][CH3:13])[C@@H:7]([CH3:9])[S:8][C@H:3]23)=[O:51])[N:48]=1)=[O:42]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@@H]1C
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC(=O)CCl)n3)[C@H]2S[C@@H]1C
Yield: 81.7 %

Procedure:
To a solution of 656 mg of diphenylmethyl 7-amino-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 30 ml of CH2Cl2 were added, at -20° C., 0.2 ml of Et3N and 407 mg of 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetylchloride, and the mixture was stirred at from -20° C. to -15° C. for 1.5 hours. The reaction solution was washed with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl solution, successively, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (15:1) were collected to distill off the solvent under reduced pressure, thus yielding 783 mg (75%) of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH:8]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[C:9]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[O:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:8]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2O)C(=O)Nc2nccs2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
A solution of 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 26, 72.4 mg, 0.184 mmol) in methylene chloride (1.8 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 237.3 mg, 0.22 mmol). The resulting reaction mixture was stirred at 25° C. for 3 h, at which time, thin layer chromatography indicated a small amount of the 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide. The reaction mixture was then treated with an additional amount of pyridinium chlorochromate (20 wt. % on basic alumina, 237.3 mg, 0.220 mmol). The reaction mixture was allowed to stir at 25° C. for 4 h and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/7 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (10.2 mg, 14%) as a white solid: mp 228-230° C.; EI-HRMS m/e calcd for C18H20N2O4S2 (M+) 392.0865. found 392.0871.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH2:39](Br)[CH:40]=[CH2:41].C(O)C>CN(C=O)C>[CH2:41]([N:34]1[CH2:35][CH2:36][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([N:8]7[CH2:12][CH2:11][CH2:10][C:9]7=[O:13])=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:32][CH2:33]1)[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: C=CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3
Yield: 11 %

Procedure:
This was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and allyl bromide using a similar procedure to Example 19, except that DMF was used as solvent in place of ethanol. This gave the title compound as a white foam (11%) which was converted to its hydrochloride salt, crystallising from acetone as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:19]([CH2:36]C([O-])=O)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:36][CH:19]([O:7][C:6](=[O:5])[CH3:8])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.325 g (1.50 mmol) tert-butylindole-2-carboxylate is dissolved in 15 ml absolute DMSO, mixed with 0.184 g (1.64 mmol) potassium-tert-butylate and stirred at 110° C. for 15 min. A solution of 0.576 g (1.50 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO is added drop-wise. Following 30 minutes of heating at 110° C. and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 99:1) and yields the product as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:21]([S@:24]([N:26]=[C:1]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:6][CH:5]=1)[CH3:2])=[O:25])([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of tert-butyl 5-acetylpyrrolo[3,2-b]pyridine-1-carboxylate (2.0 g, 7.68 mmol) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.45 mmol) dissolved in anhydrous THF (50 mL) was added titanium (IV) ethoxide (3.2 mL, 15.37 mmol) at RT under a N2 atmosphere. The reaction mixture was stirred at 75° C. under N2 for 16 h. The solvent was removed in vacuo and the crude residue was diluted with EtOAc (ca. 100 mL). The reaction mixture was vigorously stirred while a saturated solution of brine (−20 mL) was added slowly. The reaction mixture was stirred for 15 min and filtered through a pad of Celite®. The organic layer from the filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/heptane to afford 1.50 g (53.7%) of (R)-tert-butyl 5-(1-(tert-butylsulfinylimino)-ethyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate as yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.88 (d, J=3.8 Hz, 1H), 6.83 (d, J=3.8 Hz, 1H), 2.94 (s, 3H), 1.69 (s, 9H), 1.35 (s, 9H); MS (ESI) m/z: 364.3 [M+1]+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: BrCCc1ccccc1
Product: CC(C)(C)N1C(=O)C(NC2CCN(CCc3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) and (2-bromoethyl)benzene in a similar manner as described for Example 104. 1H NMR (500 MHz CDCl3): δ 7.64-7.50 (m, 2H), 7.48-7.45 (m, 3H), 7.30-7.25 (m, 2H), 7.22-7.17 (m, 1H), 7.16-7.12 (m, 2H), 5.22 (d, 1H), 3.00-2.90 (m, 1H), 2.81-2.74 (m, 2H), 2.73-2.67 (m, 2H), 2.50-2.43 (m, 2H), 1.82-1.60 (m, 13H), 1.46-1.36 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.9, 140.2, 134.3, 131.9, 130.0, 128.9, 128.6, 126.3, 125.4, 106.9, 61.8, 60.2, 51.8, 50.2, 33.8, 32.4, 27.9; Mass Spectrum: M+H+ 468
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][C:29]([C:26]1[C:24]2=[N:25][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)[C:22]([Cl:34])=[C:23]2[O:28][N:27]=1)=[O:31])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCc4ccccc4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and benzylamine.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[CH3:20][O:19][N:18]([CH3:17])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1Sc1ccccc1
Reactant: CNOC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1Sc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 3.7 parts of 2-(phenylthio)-benzoylchloride in 50 parts of tetrahydrofuran was added to a cold (~5°) stirred solution of 1 part N,O-dimethyl hydroxylamine and 1.6 parts triethylamine in 75 parts of tetrahydrofuran. The mixture was stirred for 8 hrs. and the temperature was allowed to rise to room temperature. Removal of the precipitated triethylamine hydrochloride by filtration and concentration of the filtrate under vacuum gave 3.3 parts of N-methoxy N-methyl 2-(phenylthio)-benzamide as a very viscous oil. NMR (CDCl3) 3.3δ(S,3H,N-CH3), 3.5δ(S,3H,-O-CH3), 7.3δ(m,9H,Aromatic H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:11][C:9](=[O:10])[C:8](=[C:12]=[O:13])[CH2:7]1.O.[NH2:15][NH2:16]>C(O)C>[OH2:10].[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:11][C:9](=[N:15][NH2:16])[C:8](=[C:12]=[O:13])[CH2:7]1
Reactant: NN
Reactant: O=C=C1CC(c2ccc[nH]2)OC1=O
Solvent: O
Solvent: CCO
Product: NN=C1OC(c2ccc[nH]2)CC1=C=O

Procedure:
7.2 g (0.04 mol) of 4-(2-pyrrolyl)-carbonyl-γ-butyrolactone and 2.5 ml (0.05 mol) of hydrazine hydrate are stirred in ethanol at room temperature for 4 hours. The product which has crystallised out is filtered off with suction and rinsed with ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1ccccc1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1cc(-c3ccccc3-c3ccccc3)ccc1n2-c1ccccc1
Temperature: 100 °C
Yield: 42 %

Procedure:
A mixture of 40.1 g (100 mmol) of 3,6-dibromo-9-phenyl-9H-carbazole, 21.8 g (110 mmol) of biphenyl-2-ylboronic acid, 2.31 g (2 mmol) of Pd(PPh3)4, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica to give product (19.9 g, 42.0 mmol, 42%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>CC(O)C.CCN(C(C)C)C(C)C>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[N:7][CH:6]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Fc1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Yield: 117.8 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (239 mg, 1.80 mmol) and (R)-2-methylpiperazine (271 mg, 2.71 mmol) in iPrOH (1 mL) and DIEA (617 μL) was heated in MW at 130° C. for 30 min. Solvent was removed under reduced pressure and the crude (600 mg) was purified by chromatography on silica using DCM/methanol (9/1) as eluent to afford The title compound as a white solid (416 mg, quantitative). TLC-DCM/MeOH (8/2); Rf: 0.3. 1H NMR (DMSO-d6) δ 8.14 (s, 2H), 4.48 (d, J=13.2 Hz, 2H), 4.33 (brs, 1H), 2.98-3.13 (m, 2H), 2.83 (m, 2H), 2.67 (t, J=12.7 Hz, 1H), 1.20 (m, 3H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C@@H:19]2[OH:29])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:29][C@H:19]1[C@H:18]2[CH2:30][C@H:17]2[C@H:16]2[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C@:25]1([CH3:28])[C:12]([CH2:11][C@@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26]1)=[CH:13][CH2:14]3)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@@]43C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
6.5 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17β-ol, 13 ml of acetic anhydride, and 26 ml of pyridine were heated for 1.5 hours to 95° C. After ice water precipitation, the sediment was filtered off and taken up in methylene chloride. The solution was washed with water, dried, and evaporated, thus obtaining 6.9 g of crude 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androstene, used without further purification in the next stage.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10])#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.C(O)C>[ClH:41].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH:13]=[C:14]([CH2:25][NH:26][CH3:27])[CH:15]=[C:16]1[C:17]1[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:11])=[O:10])#[N:2]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
tert-Butyl {[1-[(2-cyanophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (239 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 185 mg, yield 89%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.67 ml benzylbromide are added dropwise to 1.73 g 3-hydroxy-4-chloro-benzoic acid and 3.04 g potassium carbonate in 10 ml N,N-dimethylformamide, and the reaction mixture is stirred overnight at ambient temperature. Then the reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic phases are dried on magnesium sulphate and evaporated down. The flask residue is taken up in 5 ml of methanol, combined with 3 ml of 10 M aqueous potassium hydroxide solution and stirred for 4 h at 50° C. gerũhrt. The reddish solution is diluted with water and acidified with 3 N aqueous hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][C:8]#[N:9].C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7](=[N:14][OH:15])[C:8]#[N:9]
Reactant: CN1CCN=C1CC#N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN=C1C(C#N)=NO
Reaction time: 2 h

Procedure:
12.3 g (0.1 mol) of 1-methyl-2-cyanomethyl-2-imidazoline are initially introduced into 50 ml of glacial acetic acid. A solution of 7.8 g (0.1 mol) of NaNO2 in 20 ml of water is added dropwise at about 15°, with cooling. The mixture is stirred for 2 hours, cooled and filtered and the residue is washed with a little cold water. This yields 11 g (=73% of theory) of end product, which is recrystallised from methanol; melting point 216.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:17]=[CH2:18])[CH:7]=[CH2:8].[C:20]([O-])(=[O:22])C.[Na+]>CN(C=O)C>[CH2:16]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:9]([CH2:6][CH:7]=[CH2:8])[CH3:19])[CH:20]=[O:22])[CH:17]=[CH2:18]
Reactant: C=CCc1ccccc1N(C)CC=C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCc1cc(C=O)ccc1N(C)CC=C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To dry DMF (25 ml) is added phosphorous oxychloride (15.4 g, 0.10 mol) at 0°-5° C. with mechanical stirring over 0.5 hours. N,2-Diallyl-N-methylaniline (18.7 g, 0.10 mol) in DMF (10 ml) is added in a slow stream with stirring. The mixture is heated to 100° C. with stirring for two hours. The mixture is cooled, poured into ice water (200 ml) and neutralized by slow addition of saturated sodium acetate (150 ml) with stirring. The mixture is extracted with ether two times. The extracts are washed with aqueous saturated sodium bicarbonate (50 ml), water, and then brine solution, dried over potassium carbonate, and concentrated to a solid. The solid is recrystallized from hexane-ethyl acetate to provide pure 3-allyl-4-(N-allyl-N-methylamino)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH2:44][C:45]2([CH3:49])[CH2:48][O:47][CH2:46]2)/[C:26]1=[O:50])=O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:50])[C:27]3([CH:35]([C:36]4[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=4[O:43][CH2:44][C:45]4([CH3:49])[CH2:48][O:47][CH2:46]4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:28]2=[CH:29][CH:30]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC1(COc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)COC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (7.1 mmol) in anhydrous toluene (7 mL) was added E/Z-6-Chloro-3-[5-chloro-2-(3-methyl-oxetan-3-ylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.7 g, 1.4 mmol). The solution was stirred under Ar in a sealed tube at 140° C. for 3 h. After the solution was cooled to room temperature and concentrated, the residue was purified by chromatography (DCM:CH3OH=50:1) to give crude product. The crude product was purified again by Prep-HPLC to give title compound as a white solid (12 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1c(C)ccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccnc(C)c1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 2,4-dimethyl-3-carboethoxypyridine (11.3 g, 63.1 mmol) in distilled THF (375 mL) under nitrogen was cooled to 0° C. and lithium aluminum hydride (1M in THF, 63.1 mL) was added dropwise. The reaction was stirred for 18 hours at room temperature then cooled to 0° C. and quenched with EtOAc (2.5 mL), then H2O (2.5 mL), then 15% NaOH (2.5 mL), followed by H2O (7.5 mL). The solution was filtered and the solvent removed under reduced pressure to give the desired 2,4-dimethyl-3-hydroxymethylpyridine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1(=O)[NH:11][C:10](=O)[CH:9]2[CH2:13][CH2:14][CH:15]=[CH:16][CH:8]12>C1COCC1>[CH:10]1[NH:11][CH:7]=[C:8]2[C:9]=1[CH:13]=[CH:14][CH:15]=[CH:16]2
Reactant: O=C1NC(=O)C2CCC=CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c[nH]cc2c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a suspension of LAH (22.80 g, 600 mmol) in THF (600 mL) at 0° C. was added tetrahydrophthalimide (39.45 g, 260.9 mmol) portionwise. After addition, the reaction mixture was stirred at 60° C. for 18 h, then cooled down to 0° C. and quenched carefully with water (25 mL) followed by 15% KOH aqueous solution (25 mL) and another 75 mL of water. The resulting mixture was stirred at rt for 1 h, and filtered through a pad of Celite, then washed with DCM (500 mL). The filtrate was concentrated in vacuo to give isoindole as yellow oil, which was used directly in the next reaction.