Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[C:16]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[S:15][C:14]=2[CH:36]=1.CN1CCOCC1.[CH2:44]([NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl>[CH2:44]([NH:51][C:26](=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]1[C:13]2[CH:12]=[CH:11][C:10]([OH:9])=[CH:36][C:14]=2[S:15][C:16]=1[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: O=C(O)CCCCCCCCc1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: CCCCCCCN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCCCNC(=O)CCCCCCCCc1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of isobutyl chloroformate (0.117 g.) in methylene chloride (5 ml.) was added to a stirred solution of 9-(6-hydroxy-2-p-hydroxyphenylbenzo[b]thien-3-yl)nonanoic acid (0.1 g.) and N-methylmorpholine (0.145 g.) in methylene chloride (10 ml.) which was cooled to -30° C., and the mixture was allowed to warm up to laboratory temperature. A solution of n-heptylamine (0.098 g.) in methylene chloride (5 ml.) was added and the mixture was stirred at laboratory temperature for 1 hour and then evaporated to dryness. The residue was dissolved in methanol (5 ml.), aqueous 40% sodium hydroxide solution (2 ml.) was added and the mixture was stirred for 5 minutes and then acidified with concentrated aqueous hydrochloric acid and extracted three times with diethyl ether (20 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 100:3 v/v mixture of methylene chloride and methanol as eluant. There was thus obtained as an oil N-n-heptyl-9-(6-hydroxy-2-p-hydroxyphenylbenzo[b]thien-3-yl)nonanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]=[C:19]([Cl:21])[N:18]=[C:17](Cl)[C:13]=3[NH:14][C:15]=2[CH:16]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]=[C:19]([Cl:21])[N:18]=[C:17]([O:3][CH2:2][CH2:1][OH:4])[C:13]=3[NH:14][C:15]=2[CH:16]=1
Reactant: OCCO
Reactant: Clc1nc(Cl)c2[nH]c3cc(Br)ccc3c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
397 mg (6.4 mmol) ethylene glycol was added to 115 mg (4.8 mmol) NaH in 20 ml THF and the mixture was stirred at room temperature for 30 min. Then, 500 mg (1.6 mmol) 7-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole (Example 4) was added and the mixture was refluxed for 5 h. Thereafter, the solvent was removed and the residue was taken up in acetic ester and washed with saturated NaCl solution, dried over Na2SO4 and filtrated. Having removed the solvent, 450 mg (88%) 2-(7-bromo-2-chloro-5H-pyrimido[5,4-b]indol-4-yloxy)ethanol was obtained. ESI-MS [m/z]: 342, 344 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:30]1(=O)[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:30]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH2:33][CH2:32][CH2:31]1
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
4-(4-Piperidinyloxy)benzonitrile trifluoroacetate (D22) (2.2 g) was dissolved in DCM (50 ml) and triethylamine (1.92 ml) was added followed by cyclobutanone (0.64 g). The mixture was stirred for 5 min, then sodium triacetoxyborohydride (1.94 g) was added and the reaction was stirred at rt under argon overnight. The reaction mixture was then washed with saturated potassium carbonate solution (3×30 ml) and brine (30 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D23) as a white solid (1.91 g). 1H NMR δ (CDCl3): 7.56 (2H, d, J=6.84 Hz), 6.93 (2H, d, J=6.80 Hz), 4.41 (1H, m), 2.77 (1H, m), 2.75 (2H, m), 2.30 (2H, m), 2.06 (4H, m), 1.87 (4H, m), 1.66 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1.[CH2:18]([O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[CH:3]=[C:2]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:30])=[CH:28][CH:27]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cc(Cl)cc(C3CC3)n2)c1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C3CC3)c2)cc1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyridine (0.300 g, 1.14 mmol), 4-aminophenyl acetic acid ethyl ester (0.203 g, 1.14 mmol), palladium acetate (0.013 g, 0.057 mmol), rac-BINAP (0.053 g, 0.085 mmol) and cesium carbonate (0.925 g, 2.84 mmol) in dioxane (6 mL) under argon. The reaction mixture was heated to 120° C. under microwave irradiation for 2 h. After this time, the reaction mixture was cooled, diluted with ethyl acetate (25 mL) and water (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL). The combined extract was washed with saturated sodium chloride (2×5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) to afford the title compound (0.152 g, 33%) as a colorless oil: MW=406.90. 1H NMR (CDCl3, 500 MHz) δ 7.94-7.92 (m, 1H), 7.80-7.76 (m, 1H), 7.34-7.31 (m, 2H), 7.31-7.27 (m, 2H), 7.18-7.15 (m, 2H), 6.66 (d, J=2.5 Hz, 1H), 5.96 (s, 1H), 4.18 (q, J=7.5 Hz, 2H), 3.61 (s, 2H), 1.99-1.92 (m, 1H), 1.28 (t, J=7.0 Hz, 3H), 1.13-1.08 (m, 2H), 0.96-0.91 (m, 2H); ESI MS m/z 407
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:15]C1C=CC=CC=1CBr.COP(OC)OC>>[Cl:15][C:13]1[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: Clc1ccccc1CBr
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccccc1Cl)OC

Procedure:
Following the procedure of Compound 11, 2-chlorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH2:6][OH:7].CCN(CC)CC.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[Si:22]([O:7][CH2:6][CH2:5][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:3][CH2:2][Cl:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: OCCC(O)(CCCl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a 0° C. solution of 5-chloro-3-phenylpentane-1,3-diol (4.3 g, 20 mmol) and Et3N (3.4 mL, 24 mmol) in 20 mL DMF, was added tert-butyldimethylsilyl chloride (3.3 g, 21 mmol). After stirring for 2 h at 0° C., the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4) and chromatographed (9:1 hex:EtOAc) to provide 1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol (5.2 g, 79%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.32 (m, 4H), 7.25 (m, 1H), 4.88 (s, 1H), 3.73 (dt, 1H, J=10.3, 4.0 Hz), 3.65 (ddd, 1H, J=11.5, 10.6,5.1 Hz), 3.44 (td, 1H, J=10.6, 2.7 Hz), 3.15 (ddd, 1H, J=11.3, 10.6, 5.1 Hz), 2.34 (ddd, 1H, J=13.3, 11.4, 5.1 Hz), 2.27-2.15 (m, 2H), 1.96 (dt, 1H, J=14.6, 3.2 Hz), 0.86 (s, 9H), −0.02 (s, 3H), −0.09 (s, 3H); ESI-MS 351 (M+Na).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:15]1([C@@H:3]2[C@H:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]2)[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)n23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 108.2 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (40 g, 78 mmol, Example #5 Step H) in 1,4-dioxane (160 mL) was added NaOH (1 N aqueous, 157 mL). The reaction was heated at about 60° C. for about 1 h. The reaction was allowed to cool to ambient temperature. The reaction was neutralized with aqueous HCl (4 N, 50 mL). The layers and extracted with DCM (2×300 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered then concd in vacuo. The product was purified by chromatography on silica gel (330 g) using 1-5% MeOH in DCM to give (3R,4R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (30 g, 99%): LC/MS (Table 1, Method b) Rt=2.00 min; MS m/z: 356 (M+H)+.
Reaction SMILES: C(=O)([O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:18])OCC.C([O-])([O-])=O.[K+].[K+]>CO>[OH:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:18]
Reactant: CCOC(=O)Oc1c(OC)ccc2c1CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2c(c1O)CCNC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed ethyl 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl carbonate (1.5 g, 5.65 mmol, 1.00 equiv), methanol (20 mL) and K2CO3 (2.34 g, 16.81 mmol, 3.00 equiv). The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate (100%). This resulted in 0.7 g (64%) of 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one as a off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 2.83 (m, 2H), 3.78 (s, 3H), 4.14 (s, 2H), 6.63-6.66 (2s, 1H), 6.88-6.91 (2s, 1H); MS (ESI) m/z 194 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.S1C=CC=C1>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nccc(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1cccc(-c2ccnc(N)n2)c1

Procedure:
4-(3-amino-phenyl)-pyrimidin-2-ylamine was prepared in an analogous manner: A solution of 4-(3-nitro-phenyl)-pyrimidin-2-ylamine (0.046 mol) in MeOH (250 ml) was hydrogenated at 50° C. with Pd/C 10% (2 g) as a catalyst in the presence of a solution of thiophene in DIPE (4% v/v, 1 ml). After uptake of H2 (3 equiv.), the catalyst was filtered off and the filtrate was concentrated and dried (vacuum 60° C.). Yield: 8.64g of 4-(3-amino-phenyl)-pyrimidin-2-ylamine (87%) (m.p.; 190-194° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a suspension of 60% sodium hydride (360 mg, 9 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (865 mg, 9.1 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A56. A solution of 6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (500 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B56. Solution B56 was added to Solution A56 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (270 mg, 45%) as a white solid: MS (ESI) M+1=462.1.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[Br:31][C:32]1[CH:40]=[C:39]([Br:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[Br:31][C:32]1[CH:40]=[C:39]([Br:41])[CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccc(Br)cc1Br
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(Br)cc1Br

Procedure:
1-(2,4-Dibromobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2,4-dibromobenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: Cl.ClC[CH:4](O)[C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21].[NH2:23][C@H:24]([C:28]([OH:30])=[O:29])[CH2:25][CH2:26][SH:27].[I-].[K+]>O>[C@@H:8]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:5]([CH2:4][S:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[NH2:23])[C@@H:6]([OH:21])[C@H:7]1[OH:20]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)CCl)[C@@H](O)[C@H]1O
Reactant: N[C@@H](CCS)C(=O)O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCC[C@H](N)C(=O)O)[C@@H](O)[C@H]1O

Procedure:
condensing 5′-chloromethyl adenosine hydrochloride with L-homocysteine in the presence of water and potassium iodide at 70 to 80° C. to obtain S-adenosyl-L-homocysteine (SAH), and
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([OH:13])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([O:13][C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: CON=C(C#N)C1=CCCN(O)C1
Reactant: O=C=Nc1ccccc1
Product: CON=C(C#N)C1=CCCN(OC(=O)Nc2ccccc2)C1
Yield: 33 %

Procedure:
α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (E2) (0.45 g, 0.0025 moles) was treated with phenyl isocyanate as in the method of Example 8. The residue obtained was chromatographed on silica gel eluting with 0-1% methanol/chloroform to give a crystalline solid. Recrystallisation from ethyl acetate/60-80 petrol gave the title compound (E9) as white crystals (0.245 g, 33%) m.p. 128°-130° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[CH:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.O>[Br:20][CH2:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[CH:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(=O)cc(-c3cccc(F)c3)oc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=c1cc(-c2cccc(F)c2)oc2c(CBr)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of 14.3 g of 8-methyl-2-(3-fluorophenyl)-4H-benzopyran-4-one, 17.2 g of N-bromosuccinimide and 3.5 g of azobisisobutyronitrile (AIBN) in 700 ml of carbon tetrachloride was refluxed for 6.5 hours, cooled to room temperature and stirred overnight and then diluted with 100 ml of water. The solvents were removed in vacuo and the residue recrystallized from hot ethyl acetate to give 16.5 g of 8-bromomethyl-2-(3-fluorophenyl)-4H-benzopyran-4-one which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@H]2O)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: CCc1nc(N[C@H]2c3ccccc3C[C@H]2O)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (1S,2R)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a tan solid. IR (diffuse reflectance) 3439, 2964, 1568, 1551, 1500, 1469, 1391, 1373, 1204, 1183, 1102, 1048, 819, 748, 741 cm−1; OAMS supporting ions at: ESI+ 427.9; MS (EI) m/z 427 (M+); HRMS (FAB) calcd for C23H23CL2N3O+H1 428.1296, found 428.1286. Anal. Calcd for C23H23Cl2N3O: C, 64.49; H, 5.41; N, 9.81. Found: C, 64.43; H, 5.54; N, 9.42.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:30])[CH2:28][OH:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:28][OH:29])=[CH:25][CH:26]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NC(CO)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2ccc(Br)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-bromo-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(4-bromo-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:37][CH2:36][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[CH:5]=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:11][CH2:10]4.[Cl:50]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:10][CH2:11][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[C:5]([Cl:50])=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:36][CH2:37]4
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Cl)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Methyl(2S)-2-[(22S)-8-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate (50 mg, 0.068 mmol, 1.0 equiv) was dissolved in acetonitrile (1357 μl). To this solution was added 1-chloropyrrolidine-2,5-dione (9.06 mg, 0.068 mmol, 1.0 equiv) and stirred for 3 hours. The mixture was diluted by 15 mL Ethyl Acetate, washed by NaHCO3 and brine. The organic layer was dried, concentrated, and purified on ISCO 12 g column (0-100% EtOAc [2% TEA]/Hexane) to give the product (30 mg, 0.039 mmol, 57.3% yield).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C([Li])CCC>O1CCCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([B:15]([OH:16])[OH:14])[C:7]1=2
Reactant: Brc1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2ccsc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 75218.4 %

Procedure:
Combine 7-bromobenzo[b]thiophene (300 g, 1.41 mmol) and triisopropylborate (403.6 g, 2.15 mmol) in anhydrous tetrahydrofuran (THF) (4000 mL) in a 12 L Morton flask fitted with a mechanical stirrer and cool under nitrogen in a dry-ice/acetone bath to −70° C. Add n-butyl lithium (1.6 M in hexane, 714 g, 1.68 mmol) dropwise at such a rate as to keep the internal temperature less than −67.5° C. After the addition is complete, allow the reaction mixture to stir at this temperature for 1 hour. Remove the cooling bath and slowly add 4 L of water. Add concentrated HCl (75 mL) until the pH of the solution is about pH=2. Allow the slurry to stir for 1 hour. Add sufficient 5 N aqueous NaOH to adjust the pH of the mixture to about pH=12. Separate the layers and save the aqueous layer. Dilute organic layer with 4 L of methyl-tert-butyl ether and extract with 1 L of 5 N aqueous NaOH. Separate the layers. Combine the aqueous layer with the previous aqueous extract. Wash the aqueous layer with additional methyl-tert-butyl ether (4 L). Separate the layers and transfer the aqueous layers to a 12 L 3-neck round bottom flask fitted with a mechanical stirrer. Cool the solution to +5° C. with an ice-water bath. Add concentrated HCl slowly until the pH of the solution is about pH=2. Stir the mixture for 30 min and filter off the resulting solid. Rinse the solid on the funnel twice with 2 L of water and allow to air-dry for 30 min. Place the solid in a vacuum oven at 50° C. and dry under vacuum overnight. Remove the yellow color by slurrying the dried solid with 2 L of n-heptane for 30 min. Again filter off the solid, air-dry for 30 min, and vacuum dry at 40° C. overnight to afford the title compound (188.8 g, 75%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=8 Hz, 1H), 7.49-7.57 (m, 2H), 7.30-7.39 (m, 2H).