Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:10]=2[NH:26][C:27]2[C:28]3[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[N:33][C:29]=3[N:30]=[CH:31][N:32]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1.C(OCC)(=O)C>[CH:37]([C:34]1[CH:35]=[CH:36][C:28]2[C:27]([NH:26][C:10]3[CH:11]=[C:12]([CH:24]=[CH:25][C:9]=3[S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:3][CH:4]=3)[C:13]([NH:15][C@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])=[O:14])=[N:32][CH:31]=[N:30][C:29]=2[N:33]=1)([CH3:39])[CH3:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NS(C)(=O)=O)cc3)ncnc2n1

Procedure:
A solution of the product of Example 385G (50 mg, 0.094 mmol) and triethylamine (0.030 mL, 0.215 mmol) in THF (1.0 mL) at 0° C. under N2 was treated with methanesulfonyl chloride (0.008 mL, 0.103 mmol) added dropwise then reacted at room temperature for 1 hour. The reaction was recooled to 0° C., followed by additional methanesulfonyl chloride (0.004 mL, 0.052 mmol) added dropwise and reaction at room temperature for 0.5 hours. The mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with dichloromethane and ending with ethyl acetate (25 mg, 44%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 1.46 (d, J=6.99 Hz, 3 H) 3.03 (s, 3 H) 3.15-3.28 (m, 1 H) 5.04-5.31 (m, 1 H) 7.09 (d, J=8.09 Hz, 2 H) 7.13-7.27 (m, 3 H) 7.26-7.45 (m, 7 H) 7.62 (d, J=8.46 Hz, 1 H) 7.77 (dd, J=8.27, 1.65 Hz, 1 H) 7.95 (s, 1 H) 8.57 (s, 1 H) 8.82 (d, J=8.46 Hz, 2 H) 10.00 (s, 1 H) 10.20 (s, 1 H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=3)[N:41](C3CCCCO3)[N:40]=2)[CH:36]=[CH:37][CH:38]=1.OC1C=C(C2C3[C:66](=CC=C(C#N)C=3)[N:65]([CH:74]3CCCCO3)N=2)C=CC=1.Cl>O1CCCC1>[CH3:66][N:65]([CH3:74])[CH2:2][CH2:1][CH2:6][O:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=3)[NH:41][N:40]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(O)c1)nn2C1CCCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc(-c2n[nH]c3ccc(C#N)cc23)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 56.2 %

Procedure:
Triphenylphosphine (1.31 g, 5.00 mmol), tetrahydrofuran (4.00 mL), 3-N,N-dimethylaminopropanol (0.592 mL, 5.00 mmol) and diethylazodicarboxylate (0.788 mL, 5.00 mmol) were added to 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.25 mmol). The mixture was stirred at ambient temperature for 15.5 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ethyl acetate (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. Purification by flash chromatography on silica gel pretreated with 2% triethylamine/hexanes followed by 0–20% ethyl acetate/hexanes elution, sonication of the product in ethyl acetate (3 mL), addition of hexanes (20 mL) and filtration gave the title compound (0.225 g, 56% yield). ES-MS (m/z) 321 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27](Cl)=[O:28])[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([NH:12][C:10]1[N:11]=[C:7]2[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]2[N:9]=1)=[O:28]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Product: COc1cccc(C(=O)Nc2nc3c(-c4ccccc4)ccc(OC)n3n2)c1

Procedure:
According to example 6, the title compound was synthesized from 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and 3-methoxy-phenyl carboxylic acid chloride. (MS m/e (%): 374.4 (M+H+, 100).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11]([CH3:21])([CH3:20])[O:10][C:9]2=[O:22])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:12]2[C:11]([CH3:20])([CH3:21])[O:10][C:9](=[O:22])[N:8]2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C)OC(=O)N(C2CCC(N)CC2)[C@H]1c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a vial charged with (S)-3-(4-aminocyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.320 g, 1.044 mmol) were added ACN (3.48 mL), DIEA (0.365 mL, 2.089 mmol) and 4-chloro-3-nitropyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.166 g, 1.044 mmol) respectively. The vial was sealed and heated at 80° C. for 2 hours leading to ˜90% conversion to the desired product with starting amine present. Additional chloropyridine (0.2 eq) and DIEA (0.2 eq) were added, and the mixture was heated at 80° C. for an additional 15 hours. The dark mixture was dried under reduced pressure and purified with a 25 g HP spherical silica column ramping DCM:MeOH (90:10) in DCM from 0-50%, then isocratic at 50% (detection at 215 nm) leading to isolation of (S)-4-(4-fluorophenyl)-5,5-dimethyl-3-(4-((3-nitropyridin-4-yl)amino)cyclohexyl)oxazolidin-2-one (0.286 g, 0.668 mmol, 63.9% yield) as an orange/brown oil and as a mixture of cis/trans isomers. m/z (ESI) 429.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1sc(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of thiazole III (2.0 g, 6.6 mmol) and the phenyl boronic acid (9.9 mmol) in THF (10 mL) was added potassium fluoride (1.15 g, 19.8 mmol), palladium (II) acetate (74 mg, 0.33 mmol), and 2-(di-t-butylphosphino)biphenyl (197 mg, 0.66 mmol). This mixture was stirred at 25° C. for 24 h. Diethyl ether (100 mL) was then added and the mixture was washed with 1 N aqueous NaOH (2×50 mL), saturated aqueous NaCl (1×50 mL), dried over MgSO4 and concentrated in vacuo to give an off-white solid. Purification by flash chromatography (silica, 0-2.5% ethyl acetate/hexane) gave the product, generally in 60-90% yield.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[CH3:10][C:9]1[C:2]([NH:1][CH3:11])=[N:3][CH:4]=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(C#N)cnc1N
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNc1ncc(C#N)cc1C

Procedure:
6-Amino-5-methyl-nicotinonitrile (0.250 g, 1.88 mmol) was dissolved in 2.5 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 2.07 ml, 1.1 eq.) and, after 5 Min., 3 eq. of methyl iodide (0.35 ml). The mixture was allowed to react for 3 h at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=6/4) produced 0.225 g of the title compound as off-white solid.
Reaction SMILES: [CH3:1]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].[N+](=C)=[N-].CCOCC.[OH:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29]([C@H:35]2[S:39][C@H:38]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[CH2:37][S:36]2)=[CH:28][C:27]=1[O:52][CH3:53]>C(OCC)C.C(Cl)(Cl)Cl.CO>[CH3:53][O:52][C:27]1[CH:28]=[C:29]([C@H:35]2[S:39][C@H:38]([C:40]3[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=3)[CH2:37][S:36]2)[CH:30]=[C:31]([N+:32]([O-:34])=[O:33])[C:26]=1[O:25][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cc([C@@H]2CS[C@@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Reaction time: 5 h

Procedure:
Using the Aldrich diazald kit, diazald (13.0 g, 60.7 mmole) predissolved in 100 ml diethyl ether was added dropwise to an aqueous potassium hydroxide solution (ethanol, 27 ml; H2O, 21 ml; and potassium hydroxide, 13.3 g) at 65° C. The diazomethane/ether distillate was added at 0° C. to a solution of trans-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (1) (FIG. 20) predissolved in 25 ml chloroform and 50 ml methanol. The reaction was stirred to completely homogenize the solution and was then allowed to stand at room temperature under an argon atmosphere for 5 hours. The solvent was removed in vacuo and the remaining oil was dissolved in 10 ml diethyl ether. The product crystallized out of the ether solution to yield 3.285 g (98%) of light yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cncc(-c2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-phenyl-pyridine.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Cyclopentyl chloroformate was added to a stirred solution of the amino ester (A) (0.15 g.) and N-methylmorpholine (0.27 g.) in dichloromethane (3 ml.) at 0°-5° C., under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at 0°-5° C., the cooling bath removed, and stirring continued for 1 hour. The mixture was then poured into 1M hydrochloric acid (15 ml.), and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.18 g., 89%) as a colorless oil; NMR: 1.66 (m, 6 H), 1.82 (m,2 H), 3.83 (s,3 H, CO.OCH3), 3.92 (s,3 H, OCH3), 3.97 (s,2 H, CH2.Ar), 5.04 (m,1 H, --CHO--), 7.09 (m, 3 H), 7.22 (d,1 H), 7.42 (dd,1 H), 7.48 (d,1 H), 7.57 (br,1 H), 9.18 (br,1 H, CONH), 10.57 (s,1 H, H1 -indole).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH2:14][CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>C(O)(C)C.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH2:14][CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCc1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Twenty grams (0.123 mol) of isatoic anhydride were slowly added to a cold (0° C.) solution of 13.5 g (0.122 mol) of 2-(2-aminoethyl)imidazole in 220 ml isopropanol, under nitrogen. The reaction mixture was gradually warmed to room temperature and allowed to react. When the reaction was complete, as indicated by thin layer chromatography, the solution was reduced to dryness under reduced pressure and the resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated, the organic layer was washed with water and reduced to dryness to provide a solid. This solid was recrystallized from ethanol containing a small amount of hexane to provide 24.1 g of the desired subtitled intermediate (m.p. 180°-185° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][C:32]([OH:37])=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=3[O:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH:11]([O:37][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][O:27][C:28]=2[C:33]=1[CH2:34][CH2:35][CH3:36])[CH3:12]
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reactant: COC(=O)Cc1ccc(OCCCCBr)c(Cl)c1
Product: CCCc1c(OC(C)CCOc2ccc(CC(=O)OC)cc2Cl)ccc2c(-c3ccccc3)coc12

Procedure:
Using the method of Example 19, step E, using methyl 3-chloro-4-(4-bromobutyloxy)-phenylacetate (Example 8, Step 2) and 3-phenyl-6-hydroxy-7-propylbenzofuran (Example 5, Step B) as the starting material, the title compound was obtained.
Reaction SMILES: ClCCC([N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1)=O.N1C(=O)CCC2(CC3CC2CC3)C1=O.C(N(C(C)C)CC)(C)C>C1C=CC=CC=1>[NH:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1
Reactant: O=C(CCCl)N1CCCC2(CC3CCC2CC3)C1
Agent: O=C1CCC2(CC3CCC2C3)C(=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: C1CNCC2(C1)CC1CCC2CC1
Reaction time: 42 h

Procedure:
4.8 g (0.0178 mole) of 1'-(3-chloropropionyl)-spiro[bicyclo[2.2.2]octane-2,3'-piperidine] is dissolved in 50 ml of abs. benzene; an addition is then made of 3.0 g (0.018 mole) of (1RS, 2RS, 4SR)-spiro[norbornane-2,3'-piperidine] (see Example 2) and 3.5 g (0.0267 mole) of diisopropylethylamine, and the whole refluxed in a nitrogen atomosphere, with stirring, for 42 hours. The mixture is concentrated in vacuo under 12 Torr, and the residue distributed between 50 ml each of water and of chloroform. After separation of the chloroform extract, the aqueous phase is subsequently extracted again with 50 ml of chloroform. The chloroform extracts are washed separately twice with 50 ml of water each time; they are then dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr). There is thus obtained crude 1'-[3-(1RS,2RS,4SR)-spiro[norbornane-2,3'-piperidin]-1' -yl)-propionyl]-spiro[bicyclo[2.2.2]octane-2,3'-piperidine] as colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:14].C([O-])(=O)C.[Na+].[Br:20]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:20][CH:13]1[C:3]2([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: O=C1Nc2ccccc2C12CCCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12CCCC2Br
Yield: 105 %

Procedure:
A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm3) was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give the subtitled compound (0.37 g, 1.47 mmol, 96%) as an off-white solid which was used without further purification: 1H NMR (CDCl3) δ 1.8–2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H), 7.30–7.39 (m, 2H), 8.63 (br s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:12](=[O:13])[CH2:11][O:10][C:9]2[N:14]=[C:15]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:8]1=2>C(O)(C(F)(F)F)=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:12](=[O:13])[CH2:11][O:10][C:9]2[N:14]=[C:15]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4([NH2:34])[CH2:33][CH2:32][CH2:31]4)=[CH:28][CH:29]=3)[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:8]1=2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 1107.4 %

Procedure:
Tert-butyl (1-(4-(1-((1H-imidazol-2-yl)methyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (5 mg, 0.001 mmol) was dissolved in TFA (1 ml). The resulting mixture was stirred for 30 seconds at room temperature and evaporated under reduced pressure. The deprotected compound was taken back twice into diethyl ether and the solid formed was washed twice with DCM. The remaining solvent was removed under reduced pressure and dried to afford the title compound (5 mg, quantitative). LCMS (Method A): RT=2.80 min, M-NH2=435. 1H NMR (500 MHz, MeOD): 7.44 (1H, s), 7.41 (2H, s), 7.31-7.26 (4H,m), 7.18-7.16 (3H,m), 7.06-7.05 (2H, m), 5.44 (2H, s), 4.97 (2H, s), 2.66-2.60 (2H, m), 2.49-2.43 (2H, m), 2.14-2.10 (1H, m), 1.89-1.82 (1H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([I:22])[CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>C(O)(=O)C>[C:23]([O:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([I:22])[CH:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1ccc(CO)cc1I)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=CNc1ccc(COC(C)=O)cc1I)C(=O)OCC
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of diethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate (0.20 g) and acetic anhydride (0.054 mL) in acetic acid (0.24 mL) is heated at 80° C. overnight. The reaction is cooled to room temperature and poured into 50 mL of water. The resulting solid is filtered and dried to yield 0.19 g (87%) of diethyl 2-({4-[(acetyloxy)methyl]-2-iodoanilino} methylene)malonate as a white solid, m.p. 128-131° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (2.17 g), 2-fluoro-5-hexylbenzonitrile (1.23 g), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.11 g of desired compound (refractive index: 1.5608).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)cc1
Yield: 43 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-methylbenzenesulfonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 43% yield; m.p. 242-245° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.89 (s, br, 1H), 8.58 (s, br, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.33-7.17 (m, 7H), 4.32 (d, J=5.8 Hz, 2H), 2.32 (s, 3H), 2.31 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 166.2, 160.6, 143.0, 139.7, 139.6, 139.5, 129.9, 128.7, 127.8, 127.3, 126.2, 111.7, 43.1, 21.4, 13.6; MS (ES+) m/z 402.4 (M+1).
Reaction SMILES: C([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][N:21]=[C:16]3[C:15]([CH3:23])([CH3:22])[C:14]2=[O:24])[CH2:10]1)C1C=CC=CC=1>CO.O[Pd]O>[OH:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][N:21]=[C:16]3[C:15]([CH3:22])([CH3:23])[C:14]2=[O:24])[CH2:10]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@@H](OCc3ccccc3)C2)c2nccnc21
Agent: O[Pd]O
Solvent: CO
Product: CC1(C)C(=O)N([C@H]2C[C@@H](O)C2)c2nccnc21

Procedure:
A mixture of 5-(cis-3-(benzyloxy)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.205 g, 0.634 mmol), and dihydroxypalladium (0.092 g, 0.655 mmol) in MeOH (5 mL) was hydrogenated at room temperature under H, balloon overnight. The catalyst was filtered off, the filtrate was concentrated, and purified by ISCO (65% EtOAc/Hexanes) to give the title compound (55 mg, 37%). MS (M+1): 234.1.