Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2c(Cl)nccc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1ccc2c(Cl)nccc2c1
Temperature: 50 °C
Yield: 155.1 %

Procedure:
To a solution of 1-chloro-6-methoxy-isoquinoline (2 g, 10.3 mmol) in DCM (60 ml) was added BBr3 in (4.9 ml, 51.6 mmol) in 10 mL THF and the reaction was heated to 50° C. overnight. The reaction was cooled to 0° C. and 30 volumes of methanol was added as a quench. The solvent was removed to afford 2.87 g (>99%) of 1-chloro-isoquinolin-6-ol as a brown solid. LCMS found 180.36 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CO.[ClH:47]>C(O)(C)C>[ClH:47].[ClH:47].[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.29 g tert-butyl 4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylate are dissolved in 25 ml of a 5 M solution of HCl in isopropanol and stirred for 12 hours at ambient temperature. Then the solvents are eliminated in vacuo and the residue is twice taken up with 20 ml of methanol and this is then eliminated again in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][OH:46])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1.F[B-](F)(F)F.[H+].[CH3:53][Si](C=[N+]=[N-])(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][O:46][CH3:53])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4(CO)CCCC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: COCC1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(1-hydroxymethyl-cyclopent-1-yloxy)-benzyl]-benzene (0.56 g) in dichloromethane (4 mL) chilled in an ice-bath is added tetrafluoroboric acid (0.12 mL) and trimethylsilyldiazomethane (0.45 mL). The solution is stirred at ambient temperature for 1 h and then quenched with water. The resultant mixture is extracted with dichloromethane, the combined extracts are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0→2:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)[CH3:2].[H-].[Na+].N1C2C(=CC=CC=2C=O)C=C1>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc2cc[nH]c12
Agent: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(E)-3-(1H-Indol-7-yl)-acrylic acid ethyl ester (K-45). To a 100 mL round bottom flask which contained a suspension of NaH (60% in mineral oil, 320 mg, 8 mmol) in THF (20 mL) was added triethylphosphonoacetate (1.5 g, 6.6 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and stir at for 2 h and then cooled to 0° C. To this solution, 1H-indole-7-carboxaldehyde (K-44, 450 mg, 3 mmol) was added at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stir for 2 h, then heated and stirred at 78° C. for 14 h. The reaction mixture was cooled to 5° C. and was quenched with the addition of saturated aqueous NH4Cl (15 mL) followed by extraction of EtOAc (3×30 mL). The combined organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/hexane=1:20-1:8) to afford desired 3-(1H-indol-7-yl)-acrylic acid ethyl ester K-45 (450 mg, 68%) as a white solid. MS(ESI−) m/z(216.3, 100%). 1HNMR, 13CNMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(F)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-chloro-4-fluorophenol.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CN(C)CCNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 87.9 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 50 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]+.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O.CCOC(C)=O>[Si:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCN1C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), at room temperature, under a nitrogen atmosphere, was added NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol). The mixture was stirred at the same temperature for additional 15 min, a solution of (6-bromohexyloxy)-tert-butyldimethylsilane (177 mg, 0.6 mmol) in DMF (1 mL) was added and the resulting mixture microwaved at 150° C. for 10 min. The reaction mixture was cooled to room temperature and diluted with water (5 mL) and AcOEt (10 mL). The organic layer was separated and the aqueous layer extracted with AcOEt (2×10 mL). The combined organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuum. The residue was purified by flash column chromatography on silica gel (20% ethyl acetate-petroleum ether) to give 83.8 (89 mg, 45% yield), as a viscous liquid.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([CH:25]2[CH2:26][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:33][CH2:34][NH:24]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCNC(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
Following the procedure set out in Example 1, 3.0 parts of 3,3,3-triphenylpropionyl chloride and 2.0 parts of ethyl isonipecotate are reacted to provide 2-(3,3,3-triphenylpropionyl)-4-ethoxycarbonyl piperidine. Reduction of 5.0 parts of this material with 3.0 parts of lithium aluminum hydride in tetrahydrofuran provides 1-(3,3,3-triphenylpropyl)-4-hydroxymethylpiperidine, melting at 142.5°-144°. This compound has the following structural formula. ##STR47##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>C(#N)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][CH2:22][NH:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NCCCNC(=O)OC(C)(C)C)nc2ccccc12
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester (4.51 g, 14.7 mmol), tert-butyl N-(3-aminopropyl)carbamate (3.07 g, 17.6 mmol), and diisopropylethylamine (3.84 ml, 22.0 mmol) in anhydrous acetonitrile (35 ml) was heated at reflux for 6 days. The solution was cooled to ambient temperature then evaporated under reduced pressure to an oil. It was taken into water (35 ml) then extracted into ethyl acetate. The extracts were dried (sodium sulfate) then concentrated to an oil. Column chromatography on silica (1:1 ethyl acetate/hexanes) gave [3-(4-methoxyquinolin-2-ylamino)propyl]carbamic acid tert-butyl ester (3.10 g, 64%) as a colorless oil that solidified on standing. [M+H]+ 332.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:23])[N:10]=2)=[CH:5][CH:4]=1.[O:24]=[C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:28]2[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=2[NH:26]1>CO.C1COCC1>[Cl:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:33]3[CH2:32][CH2:31][CH:30]([N:29]4[C:28]5[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=5[NH:26][C:25]4=[O:24])[CH2:35][CH2:34]3)=[CH:4][CH:5]=2)[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (2-5; 0.078 g, 0.203 mmol) in MeOH (1 mL) and THF (1 mL) was added 4-(2-keto-1-benzimidazolinyl)-piperidine (0.066 g, 0.305 mmol; commercially available) and DIEPA (0.131 g, 1.02 mmol). The mixture was stirred at rt overnight and concentrated. The residue was treated with aqueous Na2CO3 solution (5 mL, 2 M) and extracted with with CH2Cl2 (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6). 1H-NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.31-7.37 (m, 4H), 7.25-7.29 (m, 4H), 7.17-7.19 (m, 2H), 7.05-7.09 (m, 3H), 4.31-4.36 (m, 1H), 3.54 (s, 2H), 2.97-2.99 (m, 2H), 2.41-2.47 (m, 2H), 2.12-2.17 (m, 2H), 1.78-1.80 (m, 2H). LRMS m/z (M+H) Calcd: 520.0, found: 520.0.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CN(C)C=O.[CH3:14][C:15]1[C:19]([C:20](OC)=[O:21])=[N:18][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1>CO.O.O1CCCC1>[ClH:1].[CH3:14][C:15]1[C:19]([C:20]([NH:4][C:3]([NH2:5])=[NH:2])=[O:21])=[N:18][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccc2)nc1C(=O)NC(=N)N
Temperature: 70 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Guanidine hydrochloride (2.42 g, 25.32 mmol) was dissolved in 20 ml of anhydrous methanol and then treated with sodium methoxide (1.50 g, 27.83 mmol), added in one portion at room temperature. The reaction mixture was stirred under nitrogen for 1 hour, then filtered under a nitrogen atmosphere. The solids were washed with anhydrous methanol (3×10 ml) and the filtrate concentrated under reduced pressure. Anhydrous benzene (60 ml) was added to the residue, the mixture reconcentrated in vacuo and the residue was dried under high vacuum. Anhydrous dimethylformamide (10 ml), anhydrous tetrahydrofuran (20 ml) and methyl 4-methyl-2-phenyl-2H-1,2,3-triazole-5-carboxylate (1.00 g, 4.60 mmol) were added to the solid residue and the resulting mixture was heated at 70° C. under nitrogen for 7 h, then stirred at ambient temperature overnight. The reddish colored solution was then diluted with water (90 ml) to give the free base corresponding to the title compound as a tan solid (0.53 g, 47% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+].[CH2:31]([CH:38]([C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][N:51]2[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:47][CH:46]=1)[C:39]([O:41]CC=C)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(Cl)Cl>[CH2:31]([CH:38]([C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][N:51]2[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:47][CH:46]=1)[C:39]([OH:41])=[O:40])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C=CCOC(=O)C(Cc1ccccc1)c1ccc2ccn(Cc3ccccc3)c2c1
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)c1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
6 mg of tetrakistriphenylphosphine palladium, 7 mg of triphenylphosphine and 65 mg of sodium 2-ethylhexanoate were added to a solution of 104 mg of allyl 2-benzyl-2-(1-benzylindol-6-yl)acetate, as obtained in Example 65, in 5 ml of methylene chloride, and the resulting mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was acidified by the addition of a 3% aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 5 g of silica gel with a 1:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 61 mg of the title compound as a solid material, melting at 148°-150° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:30]=1[NH2:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3[NH:31][C:30]1[CH:32]=[C:33]([O:37][CH3:38])[C:34]([F:36])=[CH:35][C:29]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCc5ccccc5)c(OC)cc4cc23)c(Cl)cc1F
Temperature: 80 °C
Yield: 36 %

Procedure:
A mixture of 8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile (1.00 g, 2.7 mmol), 2-chloro-4-fluoro-5-methoxyaniline (560 mg, 3.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (240 mg, 0.26 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (330 mg, 0.84 mmol) and K3PO4 (860 mg, 4.1 mmol) in 15 mL of ethylene glycol dimethyl ether is heated at 80° C. for 3 hours. An additional 5% of all reagents is added and the mixture is heated at 80° C. for 2 hours then cooled to room temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with 1:1 hexane/ethyl acetate yields 500 mg (36%) of 8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 248–250° C. dec.
Reaction SMILES: CC(C)(C)[C@H](NC(C1N=C(C2C=CC=CC=2)N2CCNCC=12)=O)C(NC)=O.[C:28]([C:36]1[N:40]2[CH2:41][CH2:42][N:43](C(OC(C)(C)C)=O)[CH2:44][C:39]2=[C:38]([C:52](=[O:63])[NH:53][C@@H:54]([C:59]([CH3:62])([CH3:61])[CH3:60])[C:55]([NH:57][CH3:58])=[O:56])[N:37]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([C:36]1[N:40]2[CH2:41][CH2:42][NH:43][CH2:44][C:39]2=[C:38]([C:52]([NH:53][C@@H:54]([C:59]([CH3:62])([CH3:61])[CH3:60])[C:55]([NH:57][CH3:58])=[O:56])=[O:63])[N:37]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CNCC2)C(C)(C)C

Procedure:
Intermediate 25C was synthesized in the same manner as described above for Compound 2 except that Compound 25B was used in place of Compound 1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:16][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1.[CH3:23][C:24](N(C)C)=[O:25].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C>O>[CH3:1][N:2]1[C:6]([C:7]2[S:16][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:24](=[O:25])[CH3:23])[C:9]=3[CH:8]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Reactant: CC(=O)N(C)C
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)cc12
Temperature: 25 °C
Yield: 76 %

Procedure:
6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)thieno[2,3-d]pyrimidine-4-amine (Example 8) (29 mg), DMA (2 mL), DIPEA (0.05 mL) and acetic anhydride (0.01 mL) were heated at 82° C. for 1 day. The reaction mixture was cooled to ambient temperature, water (2 mL) added and then preparative RPHPLC (eluting with a gradient of MeCN and water containing 0.1% TFA) afforded the title compound as a colourless solid (25 mg, 76%);
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](=O)[CH3:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:24][C:23]1([CH2:22][O:21][C:20]2[CH:26]=[CH:27][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH2:2][C:1](=[O:3])[C:4]2[C:12](=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=2)[O:13]1
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(C(=O)O)ccc2O1
Yield: 88.7 %

Procedure:
A procedure similar to that described in Preparation 1 was repeated, except that 10 g of 3-acetyl-4-hydroxybenzoic acid, 13 g of 4-nitrophenoxyacetone, 7.9 g of pyrrolidine, 2.6 g of p-toluenesulfonic acid monohydrate and 150 ml of benzene were reacted, to afford 17.6 g of the title compound as pale brown crystals, melting at 227°-235° C.
Reaction SMILES: C(C1N([CH2:14][C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)C2=NC(C)=CC(C)=C2N=1)C.C(N(CC)CC)C.CS([Cl:44])(=O)=O.[Cl-].[Li+]>C1COCC1.C(OCC)(=O)C>[Cl:44][CH2:14][C:15]1[CH:32]=[CH:31][C:18]2/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][CH2:23][C:17]=2[CH:16]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#C/C=C1\c2ccccc2CCc2cc(CCl)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (JP-B-2526005; 2.61 g, 10.0 mmol) was dissolved in THF (26 mL), triethylamine (2.09 mL, 15.0 mmol), methanesulfonyl chloride (1.16 mL, 15.0 mmol) and lithium chloride (0.636 g, 15.0 mmol) were added, and the mixture was stirred at 50° C. for 2 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl ether (30 mL) was added to the obtained residue, and the mixture was filtered to give the title compound (2.59 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:16][CH2:15][CH2:14][CH:13]3[C:8](=[N:9][N:10]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:11](=[O:17])[CH2:12]3)[C:6]=2[CH:7]=1.BrBr>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:16][CH2:15][CH2:14][C:13]3[C:8](=[N:9][N:10]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:11](=[O:17])[CH:12]=3)[C:6]=2[CH:7]=1
Reactant: O=C1CC2CCSc3ccc(Cl)cc3C2=NN1c1ccc(Cl)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(Cl)ccc1SCC2
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a mixture of 3.0 g of 10-chloro-2-(4-chlorophenyl)-4,4a,5,6,-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one obtained in Example 10 in 90 ml of acetic acid is added 0.4 ml of bromine at 40°-50° C. and stirred for 30 minutes at the same temperature. The mixture is concentrated under reduced pressure and to the residue is added water. The precipitated crystals are collected by filtration, dissolved in chloroform and the solution is washed with water. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The crude product obtained is purified by column chromatography and recrystallized from chloroformmethanol to give 2.4 g of 10-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 215°-217° C.