Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]2[SH:16])=[CH:4][CH:3]=1.[CH3:17][NH:18][O:19][CH3:20].C(N=C=NCCCN(C)C)C.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([N:18]([O:19][CH3:20])[CH3:17])=[O:15])=[CH:11][N:10]=[C:9]2[SH:16])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(S)n1-c1ccc(F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylic acid (4) (2.2 g, 9.23 mmol), N,O-dimethylhydroxylamine (0.9 g, 9.23 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.77 g, 9.23 mmol) in pyridine was heated at 40° C. overnight. The reaction was cooled to room temperature, water was added and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-(4-fluorophenyl)-2-mercapto-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (5) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].S(OCC)(O[CH2:27][CH3:28])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:5]=1[N:6]([CH2:27][CH3:28])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2Cl)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(C#N)cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.07 g (1.75 mmol)) in 3.0 ml of DMF, 2′-chloro-4′-cyano-p-toluenesulfonanilide (0.50 g (1.63 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, diethyl sulfate (0.25 ml (1.91 mmol)) was added dropwise and the mixture heated at 100° C. for 2 hours with stirring. Then, after being left to cool to room temperature, water was added and the mixture was extracted with diethyl ether. The extract was washed with water and 1% aqueous solution of sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crystals were recrystallized from diethyl ether to give 0.33 g (61%) of the title compound as white crystals.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:38])[CH2:9]1>C(Cl)Cl>[CH3:39][N:7]([CH3:6])[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@H](N(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
A solution of acryloyl chloride (1M in CH2Cl2, 0.36 mL, 0.36 mmol) was added dropwise to a solution of 4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methy-lindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 148, 183 mg, 0.40 mmol) in CH2Cl2 (5 mL) at −10° C. over a period of 2 minutes under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 10 minutes and was then allowed to warm to r.t. over 20 minutes. The mixture was then washed with sat. NaHCO3 (2 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 3-25% CH3OH in CH2Cl2 gave an oil which later crystallised. This solid was triturated and washed with EtOAc (3 mL) to give the title compound (67 mg, 33%) as a pale yellow solid; 1H NMR: 1.77 (1H, m), 2.08 (1H, s), 2.18 (6H, s), 2.72 (1H, m), 3.17 (1H, s), 3.21 (2H, d), 3.32-3.45 (1H, m), 3.87 (3H, s), 3.89 (3H, s), 5.70 (1H, d), 6.22 (1H, d), 6.48-6.58 (1H, m), 6.59 (1H, s), 7.20 (3H, m), 7.51 (1H, d), 7.76 (1H, s), 8.17 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.39 (1H, s), 9.33 (1H, s); m/z: ES+ MH+ 512.7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][C:20](=[O:21])[C:11]=2[CH:10]=1)[C:16]1[N:22]=[C:23]([C:26]([O:28]CC)=[O:27])[CH:24]=[CH:25][C:15]=1[C:14]=3[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][C:20](=[O:21])[C:11]=2[CH:10]=1)[C:16]1[N:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:15]=1[C:14]=3[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCC(=O)c1cc(OCc2ccccc2)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCC(=O)c1cc(OCc2ccccc2)ccc1-3
Temperature: 60 °C
Yield: 43.7 %

Procedure:
To a solution of ethyl 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-carboxylate (50 mg, 0.10 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred with heating at 60° C. for 1 hr. The reaction mixture was allowed to cool to room temperature. 2N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the precipitated solid was collected by filtration and dried in vacuo to give 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-carboxylic acid (21 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH:9][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C(NC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
A mixture of 2-(p-chlorophenyl)glycine (37.1 g, 0.2 mol) in methanol is treated with triethylamine (20.2 g, 0.2 mol), stirred for 10 minutes, treated dropwise with ethyl trifluoroacetate (35.5 g, 0.25 mol), stirred for 4 days, diluted with methanol and treated with Dowex 50×8-100 ion exchange resin. The reaction mixture is stirred for 10 minutes and filtered. The filter cake is washed with methanol. The filtrates are combined and concentrated in vacuo to afford a yellow solid which is recrystallized from 1,2-dichloroethane to give the title compound as white crystals, 26.4 g (46.8% yield), mp 170-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].BrC[C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1>CC#N>[CH3:12][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[CH:30]=1)(=[O:9])=[O:10]
Reactant: Cc1nc2cc(CBr)ccc2s1
Reactant: Cc1c(Cl)cccc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2s1

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonamide (103 mg, 0.5 mmol) in CH3CN was added potassium carbonate (100 mg), followed 5-bromomethyl-2-methylbenzothiazole (121 mg, 0.5 mmol). The mixture was refluxed under N2 for 6 h, partitioned between ethyl acetate and water. The organic phase was washed brine, dried over sodium sulphate and concentrated in vacuo to give a yellow residue, which was separated with flash chromatography (ethyl acetate/DCM, gradient elution). STX1029 was obtained as white solid. TLC single spot at Rf 0.55 (10% EtOAc/DCM); HPLC purity >99% (tR 2.0 min in 10% water-methanol); 1HNMR (270 MHz, CDCl3) δ7.89 (1H, d, J=7.9 Hz, ArH), 7.66 (1H, d, J=7.9 Hz, ArH), 7.65 (1H, d, J=1.3 Hz, ArH), 7.49 (1H, d, J=7.9 Hz, ArH), 7.17 (1H, t, J=7.9 Hz, ArH), 7.13 (1H, dd, J=7.9, 1.5 Hz, ArH), 5.35 (1H, t, J=5.9 Hz, NH), 4.24 (2H, d, J=5.9 Hz, CH2), 2.79 (3H, s, CH3), 2.62 (3H, s, CH3); APCI-MS 367 (MH)+; FAB-HRMS calcd for C16H16ClN2O2S2 (MH+) 367.0342, found 367.0330.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1.[OH2:31].OO.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][CH:12]([OH:31])[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCC=CCC2)cc(C(F)(F)F)c1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (Z)-5-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-5-phenylcyclohept-1-ene (56 mg) from step E in THF (0.55 mL) at 0° C. was added borane-tetrahydrofuran complex (1.5 M solution, 0.17 mL) drop wise, and the resulting solution was warmed to room temperature and stirred at room temperature for 12 h. The reaction mixture was cooled to 0° C., and water (10.50 mL) was added slowly followed by 30% hydrogen peroxide (0.19 mL) and 1 N sodium hydroxide (0.30 mL). The resulting solution was stirred at room temperature for 5 min, and ethyl acetate (2.0 mL) was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 40% ethyl acetate/60% hexanes to give the title compound as an oily material (27 mg). 1H NMR (400 MHz, CDCl3) δ 1.3-2.4 (m), 3.40 (s), 3.44 (s), 4.43 (s), 7.32 (m), 7.56 (s), and 7.73 (s). HRMS m/z calcd for C23H23F6O2 (M−H)− 445.1602, found 445.1607.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[C:24]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:23]=3)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[C:24]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:23]=3)[CH2:20][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCN(C(C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(c2ccc(C(=O)O)c(Oc3ccccc3Cl)c2)CC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 110D (300 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) at 50° C. was treated with 10% NaOH (2085 μL), stirred overnight, neutralized with HCl and concentrated. The concentrate was taken up in water and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].I[CH3:39]>C(#N)C.[Ag]=O>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][CH3:39])[CH:20]=[C:19]1[C:33](=[O:37])[N:34]([CH3:35])[CH3:36])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](COC)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 120 h
Yield: 97.8 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(dimethylcarbamoyl)-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 139, 1.64 g, 3.03 mmol) and silver oxide (2.81 g, 12.13 mmol) were dissolved in acetonitrile (40 mL). To this solution was added iodomethane (1.897 mL, 30.34 mmol) under N2 and stirred over for 5 days protected from the light. The reaction mixture was then filtered through Celite, rinsed with EtOAc, and the crude product was loaded onto silica gel. The product was purified by flash chromatography (0-20% MeOH/DCM) to yield the desired product (1.643 g, 98%) as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36]CC3C=CC=CC=3)=[C:32]([NH:44][CH:45]=[O:46])[CH:31]=2)[OH:29])[CH3:25])=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)C>[Pd].CO>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:44][CH:45]=[O:46])[CH:31]=2)[OH:29])[CH3:25])=[CH:19][CH:20]=1
Reactant: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Yield: 53.7 %

Procedure:
A mixture of compounds 27 (029 g, 0.45 mmol), palladium catalyst (0.2 g, 10% Pd on carbon, 50% wet), ethanol (10 mL) and methanol (5 mL) underwent hydrogenation at room temperature for 4 h under one H2 pressure. The catalyst was vacuum filtered and washed with ethanol (3×5 mL). The filtrate and the washings were combined and concentrated. The residue was subjected to column chromatography, eluting with a mixture of methanol (0-22%), concentrated ammonium hydroxide (0-2.2%) and dichloromethane (100-75.6%), to afford the desired product 28 (0.10 g, 54%) as a colorless, glass solid: 1H NMR (300 MHz, CD3OD) δ 1.08 (d, 3H), 1.32 (m, 2H), 1.48-1.78 (m, 6H), 2.59 (m, 4H), 2.78 (m, 5H), 3.44 (m, 2H), 4.75 (m, 1H), 6.82 (m, 1H), 7.00 (m, 1H), 7.08 (m, 5H), 8.06 (s, 1H), 8.31 (s, 1H); m/z (ESI) 414 [C31H41N3O3+H]+. The diastereoisomer 29 (13 mg, 7%) was also isolated as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 1.26 (d, 3H), 1.48-1.90 (m, 8H), 2.50 (m, 4H), 2.82-3.08 (m, 3H), 3.50 (m, 2H), 4.60 (m, 1H), 6.82-6.82 (m, 2H), 7.10 (m, 5H), 8.00 (s, 1H), 8.28 (s, 1H); m/z (ESI) 414 [C31H41N3O3+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:24]([CH3:26])[N:16]=2)[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(Br)cn12

Procedure:
Under argon, 200 g (0.72 mol) of 3-(benzyloxy)-5-bromopyridine-2-amine, 590 g (3.58 mol) of ethyl 2-chloroacetoacetate and 436 g of 3 A molecular sieve were suspended in 6 l of ethanol and boiled at reflux for 72 h. The reaction mixture was filtered off through kieselguhr and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 9:1, then 6:4) and the product fractions were concentrated. This gave 221 g (79% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: Oc1nccc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A solution of 7-bromoisoquinolin-1-ol (2.5 g, 11.1 mmol) and POCl3 (10.4 mL, 111 mmol) was stirred at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, poured into ice water, and the solution was stirred overnight. The aqueous mixture was diluted with chloroform, washed with a saturated solution of NaHCO3, saturated NaCl, dried (MgSO4), filtered, and concentrated under reduced pressure to afford 7-bromo-1-chloroisoquinoline (2.3 g): 1H NMR (300 MHz, DMSO-d6) δ 8.39–8.36 (m, 2H), 8.09–8.02 (m, 2H), 7.95 (d, J=6 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[CH2:1]([C:5]1[N:6]=[C:7]([S:12][CH3:13])[N:8]=[C:9]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:10]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C1COCCN1
Reactant: C=CCCc1cc(Cl)nc(SC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CCCc1cc(N2CCOCC2)nc(SC)n1
Temperature: 80 °C

Procedure:
To a solution of 4-(3-buten-1-yl)-6-chloro-2-(methylthio)-pyrimidine (26.66 mmol) and DIPEA (5.1 mL, 29.33 mmol) in 1,4-dioxane (100 mL) at room temperature was added morpholine (2.6 mL, 29.33 mmol). The reaction mixture was stirred and heated at 80° C. overnight. After the reaction was completed, the volatiles were removed by evaporation in vacuo. The residue was purified by column chromatography (hexane/EtOAc=8:1 to 4:1) to provide the title compound. MH+266.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH2:15][N:14]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([OH:24])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:12][C@H:11]2[C@@H:10]([OH:9])[CH2:15][N:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:13]2)=[O:24])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Clc1ccc(-c2nc3c(o2)CN(C2CCCCC2)C3)cc1
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@@H]1O)c1ccc(Cl)cc1

Procedure:
Forty-one grams of 2-(4-chlorophenyl)-5-cyclohexyl-5,6-dihydro-4H-pyrrolo-[3,4-d]oxazole was dissolved in 500 ml. of 95% ethanol and the solution was heated at reflux for one hour. The solvent was evaporated under vacuum and replaced with methylene chloride. The methyl chloride was washed with dilute sodium hydroxide, dried and evaporated. The product was crystallized from benzene. Yield was 33.2 g (94.5%); m.p. 158°-160° C.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][CH2:17][CH:18]=[CH:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH:18]=[CH:19][CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:2][CH2:3]1
Reactant: ClCC=CCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: ClCC=CCN1CCN(c2nsc3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (1 g; 4.56 mmol), 1,4-dichloro-2-butene (2.9 g; 22.8 mmol), anhydrous potassium carbonate (0.79 g; 5.7 mmol) and dry dimethylformamide (10 ml) was stirred at a bath temperature of 90° to 100° C. for 2 hours. After completion of the reaction, toluene (100 ml) was added to the mixture, which was washed three times with water (50 ml). The toluene layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The crude oil thus obtained was purified by silica gel chromatography to give the objective compound. IR νmaxNujol (cm-1): 1590, 1560, 1490, 1450, 1420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH2:15][CH3:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[N+](=[CH2:29])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([O:19][CH3:29])=[O:18])[CH2:15][CH3:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: C=[N+]=[N-]
Reactant: CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Product: CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, 7-chloro-2-[(1-carboxypropylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine is treated with etheral diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[CH3:11][Li]>CCOCC>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1)(=[O:10])[CH3:11]
Reactant: [Li]C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CCOCC
Product: CC(=O)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To suspension of 20 gm. (142 mmoles) of 2-fluoro-5-pyridinecarboxylic acid (J. Am. Chem. Soc., 71, 1125 (1949)) in 750 ml. of ether, stirred and cooled in ice, was added 225 ml. of 1.6M methyl lithium (360 mmoles) in ether over 1 hr. The reaction was stirred for an additional 2 hr., then 300 ml. of ice water was added. The aqueous layer was washed with 2×100 ml. fresh ether, acidified and extracted with ether to give 5.0 gm. (25%) of unreacted starting acid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:25]([NH2:27])=[O:26])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34].C(O)C(N)(CO)CO.CCOC(C)=O>N1C=CC=CC=1>[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:25]([NH2:27])=[O:26])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)=[O:34]
Reactant: CN(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: NC(CO)(CO)CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Reaction time: 14 h
Yield: 44.1 %

Procedure:
To a stirred solution of 8-amino-1-{4-[(dimethylamino)sulfonyl]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (Example 46) (1.52 g, 3.70 mmol) in pyridine (25 mL) at RT was added 2-chlorobenzoic chloride (970 mg, 5.55 mmol). After 14 h, trisamine (1 g) was added and the mixture was stirred for 2 h. The mixture was filtered through a silica gel pad with EtOAc and concentrated. Column chromatography (silica gel, EtOAc) gave the title compound as a yellow solid (900 mg, 1.63 mmol, 44%). Its structure was confirmed by 1H NMR and MS (551, M+1). C27H24ClN5O4S, Calc.: C: 58.96; H: 4.40, N: 12.73; Found, C: 58.66; H: 4.65, N: 12.58.