Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C(=O)C.Br.[NH2:29][C:30]1[N:39]=[C:38]([NH2:40])[C:37]2[C:32](=[N:33][CH:34]=[C:35]([CH2:41]O)[N:36]=2)[N:31]=1.C1C=CC=CC=1>CCOCC>[Br:1][CH2:41][C:35]1[N:36]=[C:37]2[C:32](=[N:33][CH:34]=1)[N:31]=[C:30]([NH2:29])[N:39]=[C:38]2[NH2:40]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(N)c2nc(CO)cnc2n1
Agent: Br
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CBr)cnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To the solution of dibromotriphenylphosphine (2.4337 g, 5.76 mmol) of 2 ml anhydrous N,N-dimethylacetamide was added (2,4-Diamino-Pteridin-6-yl)-methanol hydrobromide (335.8 mg, 1.747 mmol). The mixture is the stirred at RT for overnight. The solution was treated with benzene. The filtered solid was then successively treated with benzene and ether and evaporate the remaining solid. The residue was dissolved in minimum 48% HBr at RT which then was added MeCN to give a tan solid precipitate. Collect the solid in ice water bath and wash it with MeCN and ether. 352 mg product was obtained. Yield 60%; 1H NMR (500 MHz, DMSO-d6): δ 4.86021(s, 2H), 9.01 (s, 1H), 9.15 (s, 2H), 9.22 (s, 2H); ESI-MS: 255, 257(M++1)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25]>C(O)C.CN(C)C=O.[Pd]>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25]
Reactant: CCCc1c(OCCOc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCc1c(OCCOc2ccc(N)cc2)ccc(C(C)=O)c1O
Reaction time: 2 h

Procedure:
1-{2-Hydroxy-3-propyl-4-[2-(4-nitrophenoxy)ethoxy]phenyl}ethanone (6.0 g) was dissolved in a mixture of ethanol (250 ml) and dimethylformamide (60 ml) to which was added, under nitrogen, a slurry of palladium on charcoal (500 mg, 5%) in ethanol (50 ml). The suspension was then hydrogenated on a Parr at 60 psi and room temperature for 2 hours. The suspension was filtered over Celite, washed with ethanol and the filtrate evaporated under reduced pressure to give a brown oil. The oil was triturated with water and filtered to give a brown solid. The solid was recrystallised from ethanol to give a cream solid, m.p. 73°-74° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH2:15][N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[BH4-].[Na+]>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:15][N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH2:10][CH2:9]1
Reactant: O=C1CCN(CCc2cccs2)CC1
Reactant: Nn1cccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: c1csc(CCN2CCC(Nn3cccc3)CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2-thienylethyl)-4-piperidone (24.6 g, 0.12 mole) and 1-aminopyrrole (12 g, 0.15 mole) in 200 ml of benzene was stirred at reflux for 4 hours. The resultant mixture was cooled and evaporated to an oil which in turn was dissolved in 200 ml of isopropanol and 50 ml of methanol. To the resultant solution was added NaBH4 (9.1 g, 0.24 mole). The mixture was stirred at 80° C. for 2 hours, cooled, evaporated, stirred with water and then extracted with ethyl acetate-ether. The organic extract was washed twice with water and saturated NaCl solution and was dried (anhydrous MgSO4), filtered and evaporated to 33 g of an oil of 1-[2-(2-thienyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)=[O:15])=[C:9]([O:23][CH3:24])[CH:8]=1)=[O:5].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[O:15])=[C:9]([O:23][CH3:24])[CH:8]=2)=[O:5])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(NC(=O)CCCl)ccc1NC(=O)Nc1cnccn1
Reactant: NC1CCCC1
Product: COc1cc(NC(=O)CCNC2CCCC2)ccc1NC(=O)Nc1cnccn1
Temperature: 80 °C

Procedure:
A mixture of 3-chloro-N-[3-methoxy-4-(3-pyrazin-2-yl-ureido)phenyl]-propionamide (Compound 8, Example 12) and cyclopentylamine (0.5 mL, large excess) was warmed at 80° C. for 1 h and cooled to room temperature. The product was precipitated from ether (10 mL), collected by filtration, washed with ether, and dried in vacuo (24 mg, 60%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.14 (s, 1H), 10.03 (s, 1H), 9.93 (s, 1H), 8.87 (d, J=1.1 Hz, 1H), 8.31 (dd, J=2.6, 1.5 Hz. 1H), 8.23 (d, J=2.7 Hz, 1H), 8.03(d, J=8.7 Hz, 1H), 7.47,(d, J=2.1 Hz, 1H), 7.04(dd, J=8.7, 2.1 Hz, 1H), 3.87 (s, 3H), 3.05 (quintet, J=6.3 Hz, 1H), 2.80 (t, J=6.6 Hz, 2H), 2.44 (t, J=6.6 Hz, 2H), 1.80-1.67 (m, 2H), 1.65-1.56 (m, 2H), 1.53-142 (m, 2H), 1.37-1.27 (m, 2H). LRMS (ESI, positive) m/e 399.1 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])C.[H-].C([Al+]CC(C)C)C(C)C>Cl>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH:6]=[CH:5][CH2:4][OH:3])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=CC1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: O=C(OCc1ccccc1)N1CCCC1C=CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 1.86 g of (±)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)acrylic acid ethyl ester in 15 ml of dry dichloromethane1, 12.9 ml of diisobutylaluminum hydride (1M toluene solution) was added dropwise under an argon atmosphere at −70° C. or lower, followed by stirring for one hour. To the reaction solution, 60 ml of 1N hydrochloric acid was added dropwise, and then the mixture was heated to room temperature and extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.75 g of the desired compound as a colorless oily substance.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[N:6][O:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13]>Br>[CH3:8][C:7]1[C:3]([CH2:2][S:13][CH2:12][CH2:11][NH2:10])=[N:4][O:5][N:6]=1
Reactant: Cc1nonc1CO
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1nonc1CSCCN
Reaction time: 40 h

Procedure:
A solution of 3-hydroxymethyl-4-methylfurazan (2.49 g; 21.8 mmoles) [prepared in Step A] and 2-aminoethanethiol hydrochloride (2.48 g; 21.8 mmoles) in 60 ml of 48% aqueous hydrobromic acid was stirred and heated at reflux temperature for 23 hours and then at ambient temperature for 40 hours. The excess hydrobromic acid was removed under reduced pressure, and the oil residue was dissolved in isopropyl alcohol, filtered though Celite and the product was crystallized from the filtrate. Recrystallization from isopropyl alcohol yielded the title compound as the hydrobromide salt, mp 142°-143°.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([F:47])[CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][C:42]=1[F:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[S:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccc(Cl)nc1
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: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2cc3ccccc3s2)nc1
Reaction time: 8 h
Yield: 56.4 %

Procedure:
In a 500 ml-three-necked flask, 12.6 g (85.2 mM) of 2,5-dichloropyridine, 15.2 g (85.4 mM) of benzothiophene-2-boronic acid, 75 ml of toluene, 37.5 ml of ethanol and 75 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 3.06 g (2.64 mM) of tetrakis(triphenylphosphine)palladium (0) was added thereto, followed by refluxing under stirring for 8 hours under nitrogen stream. After the reaction, the reaction mixture was cooled on an ice bath to precipitate a crystal, which was then filtered out and washed with water. To the crystal, 100 ml of methanol was added and washed under stirring at room temperature, followed by filtration to recover the crystal. The crystal was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from a mixture solvent of chloroform-methanol to obtain 11.8 g (Yield: 56.4%) of 5-chloro-2-(benzo[b]thienyl)pyridine (colorless crystal).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added methanesulfonyl chloride (24 μL, 0.307 mmol). Reation mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 55%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[O-:35][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(=O)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (6.30 g, 17.8 mmol, available from Step 3 of Example 15) by reaction with m-CPBA (13.1 g) to provide ethyl 6-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate followed by reaction with p-toluenesulfonyl chloride (4.58 g, 24.0 mmol) and ammonium hydroxide solution (60 mL) to provide ethyl 6-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate as a tan solid after recrystallization from aqueous methanol, mp 112-113° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2=[CH:9][S:10][N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]2=[CH:9][S:10][N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2nscc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2nscc12

Procedure:
A mixture of 6.3 g. 4-methoxy-2,1-benzisothiazole, 28.5 g. boron tribromide, and 180 ml. methylene chloride was heated at reflux temperature 17 hours to give 5.1 g. 4-hydroxy-2,1-benzisothiazole as a yellow solid, mp. 184.5°-186.5° after recrystallization from benzene. This structure was confirmed by nmr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18].Br[C:32]1[S:36][C:35]([C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[S:36][C:35]([C:37]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:38])=[CH:34][CH:33]=2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: O=C(c1ccc(Br)s1)N1CCCC1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)N3CCCC3)s2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone (408 mg, 0.98 mmol) and (5-Bromo-thiophen-2-yl)-pyrrolidin-1-yl-methanone (CAS 326875) (256 mg) MS 470.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C=Nc1ccccc1
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(C(=O)Nc2ccccc2)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 70% yield. LCMS for C30H30ClN8O3 (M+H)+: m/z=585.0.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@@H:17]([OH:19])[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:56][CH:57]=[C:58]([CH3:60])[CH3:59]>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([CH3:18])[O:19][CH2:56][CH:57]=[C:58]([CH3:60])[CH3:59])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)O)[C@@]1(C)CC3
Reactant: CC(C)=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)OCC=C(C)C)[C@@]1(C)CC3
Temperature: 70 °C

Procedure:
xvii)—A mixture of (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (17; 1.65 g), dry toluene (115 ml), potassium t-butoxide (5.68 g), 18-crown-6 (0.99 g) and 4-bromo-2-methyl-2-butene (4.44 ml) was heated at 70° C. for 1 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with water and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-22-oxacholesta-8,14,24-triene (compound 18; 2.30 g), which was used in the following step without further purification.
Reaction SMILES: [Si:1](Cl)([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.[OH:19][CH2:20][C:21](=[CH2:24])[CH2:22][OH:23]>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([O:19][CH2:20][C:21](=[CH2:24])[CH2:22][OH:23])([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
Reactant: C=C(CO)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of t-butyldiphenylsilylchloride (45 g, 165 mmol) in anhydrous dichloromethane (60 ml) is added dropwise to a stirred solution of 2-hydroxymethyl-2-propene-1-ol (12 g, 165 mmol) triethylamine (27.5 ml) and 4-dimethylaminopyridine (2 g) in anhydrous dichloromethane (300 ml) at 0° C. Then, the mixture is stirred at 20° C. overnight, washed with a saturated solution of ammonium chloride and brine. The title product is obtained by flash chromatography on silica gel (19.4 g, 40%).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH3:12].C([O-])(=O)C.[Na+].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH2:27])[CH3:23]>C(#N)C>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][N:27]1[CH:10]([CH:11]([N+:13]([O-:15])=[O:14])[CH3:12])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:16])[CH3:23]
Reactant: CCOC(CN)OCC
Reactant: COC(=O)c1ccccc1C=C(C)[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(CN1C(=O)c2ccccc2C1C(C)[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-nitro-1-propenyl)-benzoic acid methyl ester (1.6 g, described in Example 28), sodium acetate (1.1 g) and 2,2-diethoxyethanamine (1.25 ml) in acetonitrile (20 ml) is stirred at 25° C. for 18 hr and evaporated. The residue is dissolved in ethyl acetate. The organic solution is washed with 1 N hydrochloric acid and brine, dried and evaporated to give the title compound as a mixture of two isomers (2.5 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:19])([F:21])[F:20])=[O:39])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:30])([F:29])[CH:26]([F:27])[F:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
0.4 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2-tetrafluoroethoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.2 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.3 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,2-tetrafluoroethoxy)pyrazole.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[CH:7]=1)([OH:5])[CH3:4].[H-].[Na+].I[CH3:20].O>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([O:5][CH3:20])([CH3:4])[C:2]([F:15])([F:16])[F:1])=[CH:7][C:8]=1[CH3:14]
Reactant: CI
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(OC)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-methoxy-3-methylphenyl)-propane-2-ol (1 g) in DMF (20 ml) were added sodium hydride (60% in mineral oil, 205 mg) and iodomethane (727 mg). After stirring for 5 hours at room temperature, the reaction mixture was ice cooled, then water and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with brine, and dried over anhydrous magnesium sulfate. After removing the drying agent, the organic layer was concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]([CH2:8][O:9][CH3:10])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[Cl:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][C:17]([C:15]1[S:16][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:18])([CH2:8][O:9][CH3:10])[CH2:5][O:6][CH3:7]
Reactant: COCC(N)(CO)COC
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: C1CCOC1
Product: COCC(CO)(COC)NC(=O)c1ccc(Cl)s1
Temperature: 0 °C

Procedure:
1.14 g (6.16 mmol) 2-amino-3-methoxy-2-methoxymethyl-propan-1-ol are suspended in 9 ml THF, cooled in the ice bath and combined with 2.56 ml (18.4 mmol) TEA. 1.12 g (6.19 mmol) 5-chlorothiophene-2-carboxylic acid chloride are dissolved in 6 ml THF and added dropwise. After 1.5 h the mixture is filtered and the filtrate is concentrated by evaporation i.vac. Then it is purified by chromatography through RP material (Microsorb C18 Varian; eluant:water/acetonitrile/trifluoroacetic acid=90:10:0.1=>0:100:0.1).