Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][O:11][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO[Si](C)(C)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
To a solution of 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentylpyridine (3.14 g, 8.78 mmol) (Example 1, Step H) in methylene chloride (45 mL) were added imidazole (0.9 g, 13.17 mmol, 1.5 eq) and t-butyl-dimethylsilyl chloride (2.0 g, 13.17 mmol, 1.5 eq). A white precipitate began to form immediately. The mixture was stirred for 14 h at 25° C. and was then diluted with methylene chloride (100 mL) and washed sequentially with 10% hydrochloric add (20 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (20 mL). The organic layer was concentrated under reduced pressure and the resultant residue was recrystallized from methanol to provide the product (3.27 g, 79%) as a white fluffy crystalline solid. 1H NMR (300 MHz, CDCl3): δ −0.10 (s, 6 H), 0.79 (t, J=6.9 Hz, 3 H), 0.83 (s, 9 H), 1.07-1.20 (m, 4 H), 1.29-1.32 (m, 14 H), 2.23-2.30 (m, 2 H), 3.21 (sept, J=6.6 Hz, 1 H), 3.35 (sept, J=6.6 Hz, 1 H), 4.24 (s, 2 H), 7.05-7.18 (m, 4 H). Anal. calc. for C29H46NOFSi: C, 73.83; H, 9.83; N, 2.97. Found: C, 73.82; H, 9.95; N, 2.86.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1.[C:19]1([NH:25][C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[NH:27])=[CH:12][CH:13]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1
Reactant: N#CNc1ccccc1
Reactant: Nc1ccc(-n2c(N)nc3ccccc32)cc1
Agent: Cl
Solvent: CC#N
Product: N=C(Nc1ccccc1)Nc1ccc(-n2c(N)nc3ccccc32)cc1

Procedure:
A mixture of 2-Amino-1-(4-aminophenyl)benzimidazole hydrochloride (1.58 g, 6.06 mmol), phenylcyanamide (2.79 g, 23.6 mmol) and acetonitrile (10 ml) was refluxed for 3 days. The solid product was filtered off. The product was recrystallized from acetonitrile (300 ml). Yield 1.3 g, 57%. M.p. 265-267° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[F:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:19]=1.C(N(CC)CC)C>CN(C)C=O>[F:17][C:18]1[C:23]([NH:24]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:19]=1
Reactant: CN1CCN(c2ccc(N)c(F)n2)CC1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(F)n2)CC1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
(4E)-6-Iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.26 g, 0.80 mmol), 2-fluoro-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine (contaminated with triethylammonium trifluoroacetate, approximately 0.80 mmol) were coupled in N,N-dimethylformamide (10 mL) with triethylamine (0.66 mL). The mixture is heated in a 100° C. oil bath for one hour. The reaction mixture is purified by reverse phase HPLC and then flash silica gel chromatography (methanol/chloroform) to give (4Z)-4-({[2-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione (0.20 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].Cl.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=4)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Reactant: Cn1ccc(CCN)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4ccn(C)c(=O)c4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.265 mmol), 4-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochloride (16 mg, 0.132 mmol), 1-methyl-1H-imidazole (118 mg, 1.45 mmol) and EDCI (276 mg, 1.45 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (5 mL×2), then brine (5 mL×2). After drying and concentration, the residue was purified by chromatography (silica gel, 5 g, 200˜300 mesh, methanol:dichloromethane=1:30) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (27 mg, 21%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.94 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.03-7.94 (m, 4 h), 7.66 (s, 1H), 7.58 (d, 1H, J=6.6 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.23 (s, 1H), 6.13 (d, 1H, J=7.2 Hz), 4.01 (s, 3H), 3.77 (s, 3H), 3.53-3.47 (m, 2H), 3.36 (s, 3H), 2.69 (t, 2H, J=6.6 Hz). LC-MS: [M+H]+, 526, tR=1.367 min, HPLC: 98.9% at 214 nm, 99.36% at 254 nm, tR=4.615 min.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(OCC)(=O)C>[CH2:24]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](NCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in THF (2 mL) was added benzyl bromide (0.036 mL) at 50° C., and the mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([O:21]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[NH3:29]>C(O)(C)C>[C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([NH2:29])=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Reactant: N
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-Benzamido-2-carboethoxyindole (3.0 g) and phosphorous oxychloride (20 mL) was refluxed for 30 min. The reaction mixture was concentrated in vacuo and the residue was triturated with ether to afford a white solid. This solid was treated with 40 mL of isopropanol which had been previously saturated with ammonia and heated in a sealed tube at 120° C. for 40 min. The reaction mixture was again concentrated in vacuo and the residue was triturated with ether to afford 3-Benzamido-indole-2-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]([C:21]([F:24])([F:23])[F:22])[CH3:20])[N:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[C:2]([N:1]2[CH:27]=[CH:31][CH:30]=[CH:29]2)=[N:3][C:4]([CH:19]([C:21]([F:24])([F:23])[F:22])[CH3:20])=[N:5]1
Reactant: COC1CCC(OC)O1
Reactant: CC(c1nc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(c1nc(-n2cccc2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)C(F)(F)F
Reaction time: 1 h
Yield: 67.7 %

Procedure:
3.9 g (0.01 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1-trifluoromethylethyl)-1H-1,2,4-triazole and 1.3 g (0.01 mol) of 2,5-dimethoxytetrahydrofuran were dissolved in 15 ml of acetic acid, and the solution was refluxed under stirring for one hour. After cooling, the reaction solution was poured into water and neutralized with sodium hydrogencarbonate. Then, precipitates were extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 3 g (yield: 68%) of the desired compound having a melting point of from 73.5° to 75° C. as white powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:29](O)=[O:30]>>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][N:5]=[N:6]2)=[CH:13][C:12]=1[CH:29]=[O:30]
Reactant: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O

Procedure:
A solution of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol (45 mmol) in trifluoroacetic acid (200 ml) and hexamethylenetetramine (186.9 mmol) was heated at 100°, under nitrogen for 16 h. The reaction mixture was quenched with 2N sulphuric acid (250 ml) and extracted with ether (3×250 ml)). The combined organics were dried (Na2SO4) and evaporated to give a dark yellow oil. Purification by FCC (hexane/ether (2:1)) afforded the title compound (8.8 g) as a pale yellow solid. T.I.c. (hexane/ether (2:1)) Rf 0.36
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:21]([C:22]([OH:24])=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][N:11]2[N:10]=1.CN(C(O[N:33]1[N:41]=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:21]([C:22]([O:24][N:40]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[N:41]2)=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)On1nnc2ccccc21
Temperature: 50 °C

Procedure:
Triethylamine (994.9 mg, 1.370 mL, 9.832 mmol) was added to a suspension of 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5d (2.2 g, 8.938 mmol) in chloroform (22 mL). TBTU (2.870 g, 8.938 mmol) was added to the solution and the reaction mixture was heated at 50° C. for 20 min, during which time a yellow precipitate formed. The reaction mixture was cooled to ambient temperature. The precipitate was isolated by filtration and washed with chloroform to leave the product (benzotriazol-1-yl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate) 6d as an off white solid (2.8 g, 86% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:12][CH2:11][CH2:10][Br:9])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 13.1 %

Procedure:
To a solution of 3-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed by Cs2CO3 (0.246 g, 0.756 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0137 g, 13.2%). EI-MS Rt (2.28 min).
Reaction SMILES: [CH:1]([N:4]1[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]2[C:6]([CH2:7][C:8]([CH3:25])([CH3:24])[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11]2)=[N:5]1)([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:13]2[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]3[C:12]=2[CH2:11][C:10]([CH3:22])([CH3:23])[NH:9][C:8]([CH3:24])([CH3:25])[CH2:7]3)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CC(C)(C)NC(C)(C)C2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CC(C)(C)NC(C)(C)C2
Yield: 59.4 %

Procedure:
The title compound (100 mg) was prepared as in Example 296 using 196 mg of trifluoro-methanesulfonic acid 2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester and 100 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C20H28FN3, 329.23. found, m/z 330.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.27 (m, 4H), 4.31 (m, 1H), 3.10 (s, 2H), 2.70 (s, 2H), 1.47-1.34 (m, 18H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH:14]=1)=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH:14]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1F
Reactant: NCCCN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1NCCCN1CCOCC1
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-fluorobenzamide was reacted with 3-morpholinopropylamine to give the title compound in 33% yield; m.p. 239-240° C.; NMR Spectrum: (DMSOd6) 1.7 (m, 2H), 2.17 (s, 3H), 2.31 (m, 6H), 2.95 (s, 6H), 3.15 (q, 2H), 3.53 (t, 4H), 6.6 (t, 1H), 6.72 (d, 1H), 6.89 (m, 1H), 7.2 (m, 3H), 7.3 (m, 2H), 7.54 (m, 1H), 7.65 (m, 1H), 7.75 (m, 2H), 9.69 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2ccc(OC)cc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: COc1ccc2c(c1)N=C(N1CCN(C)CC1)c1c(sc3ccccc13)N2

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-methoxy-anilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 9-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1)[CH3:2].C1C=CC(O[C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=CC=1.O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[C:40]1=[N:41][C:42]#[N:43])[CH3:2]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CCOC(=O)C[C@H](NCCNCCCc1ccc2c(n1)NCCC2)c1ccc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=NC#N
Temperature: 75 °C

Procedure:
A solution of the diamine 1-2 (120 mg, 0.27 mmol), diphenyl cyanocarbonimidate (65 mg, 0.27 mmol) and K2C03 (94 mg, 0.68 mmol) in EtOAc (10 mL) and water (5 mL) was stirred at room temperature for 16 hours then heated to 75° C. for 6 hours. After cooling, the mixture was poured into saturated Na2CO3, extracted with EtOAc and washed successively with water and brine. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to give 1-3 an oil which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 3-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CCCCCC.[CH3:19][C:20](=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:20]([CH3:21])([CH3:19])[CH2:1][C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)=[CH:23]1
Reactant: Cc1csc(C)n1
Reactant: CC(C)=C1C=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1csc(CC(C)(C)C2=CCc3ccccc32)n1
Temperature: -78 °C
Reaction time: 14 h

Procedure:
A solution of 2,4-dimethyl-1,3-thiazole (3.2 g, 28.1 mmol) in 20 ml of tetrahydrofuran was cooled to −78° C. and 15% n-butyl-lithium in hexane (17.5 ml, 28 mmol) was added during 15 min with stirring. The resulting yellow suspension was stirred for 20 min and then a solution of 1-(1-methylethylidene)-1H-indene (4.6 g, 29 mmol) in 5 ml of tetrahydrofuran added with vigorous stirring while the temperature was maintained at −78° C. The reaction mixture was allowed to reach room temperature and for 14 h. The resulting mixture was hydrolyzed with a saturated ammonium chloride solution.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Br)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]>O>[CH3:6][CH2:5][CH2:4][CH2:3][Sn:7]([O:1][Sn:7]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH3:6])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](Br)(CCCC)CCCC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Temperature: 60 °C
Yield: 92.8 %

Procedure:
The same apparatus as used in Example 1 was employed. To the flask were continuously fed 450 g of 30% aqueous sodium hydroxide solution and 300 g of tri-n-butyltin bromide containing 3.5% di-n-butyltin dibromide, with stirring and heating at 60° C., to perform hydrolysis for 60 minutes. To the resulting reaction mixture was added 260 g of water for specific gravity adjustment. The same precipitation as in Example 1 took place, and the reaction mixture split into three distinct phases. The specific gravity of the aqueous phase was measured and was found to be 1.25. Thereafter, the upper phase was treated in the same manner as in Example 1 to give 224.4 g (92.8% yield) of bis(tri-n-butyltin) oxide. Analysis revealed that the product was of high quality, its purity being 98.3% and the content of di-n-butyltin oxide dissolved therein being 300 ppm.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].Cl[C:14]1[N:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCO>[Cl:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[N:22]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(=O)Cc2nc(Cl)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
Elemental sodium (173 mg, 7.5 mmol) was added to 40 mL of absolute EtOH stirring under nitrogen. After all of the sodium reacted, 4-methoxyacetophenone (1.44 g, 7.5 mmol) was added, and the reaction stirred an additional 15 minutes . 2,6-Dichloronicotinic acid (1 g, 5.2 mmol) and copper acetate (80 mg, 0.65 mmol) was added and the reaction was stirred at reflux for 16 hours. The reaction was cooled to room temperature and quenched with 1 mL concentrated acetic acid. The mixture was concentrated to a solid, and redissolved in EtOAc. A small portion of fine inorganic precipitate was filtered off. The organic layer was extracted with 3×100 mL 1N NaOH. This was acidified with 1 N HCl to a pH of ˜4. A precipitate formed and was collected by vacuum filtration, yielding 6-chloro-2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid (1 g, 63%) as a tan solid.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:13][Li].Cl>C(OCC)C>[C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)(=[O:12])[CH3:13]
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled suspension of 2,3-dihydrobenzofuran-7-carboxylic acid (D1) (2 g) in dry diethyl ether (100 ml) was added dropwise under argon, methyllithium (16.2 ml of a 1.5M solution in diethyl ether). The mixture was stirred at room temperature for 18 h, added to 5N hydrochloric acid (50 ml) and extracted into ethyl acetate. The organic phase was washed with potassium carbonate, then water and dried (Na2SO4). The solvent was evaporated under reduced pressure to leave the title compound as a plate lemon solid (1.5 g, 76%)