Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][O:11][C:12]([CH:14](P(OCC)(OCC)=O)[CH3:15])=[O:13].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([CH:39]=O)=[CH:31]2)[CH:25]=1>O1CCCC1>[CH2:10]([O:11][C:12]([C:14]([CH3:15])=[CH:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH:31]=1)=[O:13])[CH3:9]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cn(-c2cccnc2)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of lithium diisopropylamide (from 1.4 ml of diisopropylamine and 6.3 ml of 1.6M n-butyllithium in hexane) in 25 ml of dry tetrahydrofuran under nitrogen is cooled to -70° and 2.14 ml of triethyl 2-phosphonopropionate is added dropwise. The reaction mixture is stirred for 20 minutes at -70° and 2.0 g of N-(3-pyridyl)indole-3-carboxaldehyde is added. The reaction is allowed to warm to room temperature for 14 hours. The solvent is evaporated and the residue is partitioned between 20 ml of half saturated ammonium chloride solution and 30 ml of methylene chloride. The organic phase is separated, dried over sodium sulfate and evaporated to a solid which is recrystallized from methanol to yield 3-[2-(ethoxycarbonyl)prop-1-enyl]-N-(3-pyridyl)indole, m.p. 97°-99°.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:36](=[O:38])[NH2:37])=[CH:11][N:12]2[CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@H:19]2[C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])=[O:17])=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.O>[C:36]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@H:19]2[C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])=[O:17])[CH:11]=1)(=[O:38])[NH2:37]
Reactant: COC(=O)COc1ccc2c(C(N)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCC(=O)O)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3-carbamoyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxy)-acetic acid methyl ester Example 592 (18 mg, 0.032 mmol) in a mixture of THF (2 mL) and water (0.2 mL) was added 1N NaOH (0.064 mL), followed by stirring at RT for 4 h. The reaction mixture was partitioned between CH2Cl2 and water. The aqueous phase was adjusted to pH=2 by addition of 1N HCl, followed by extraction with CH2Cl2 (3×). The combined organics were dried (phase separator) and concentrated under reduced pressure to afford the title compound as a white solid. MS: 549 [M+H]+; tR (HPLC conditions c): 3.74 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].[Cl:36]C(OCC)=O>>[Cl:36][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]2[CH2:23][CH2:24][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: CCOC(=O)Cl
Reactant: CCCC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (2-chloro-phenyl)-amide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chlorformate. Wt.: 21 mg (27%). 1H NMR (300 MHz, CDCl3) δ 8.67 (m, 2H), 8.48 (d, 1H), 8.35 (d, 1H), 8.20 (s, 1H), 7.82 (d, 1H), 7.72 (m, 2H), 7.41 (m, 2H), 7.09 (m, 1H), 4.78 (d, 1H), 4.31 (m, 1H), 3.67 (m, 1H), 3.35 (m, 1H), 2.95 (m, 1H), 2.22 (m, 2H), 1.60 (4H), 1.27 (m, 2H), 0.92 (t, 3H); LC/MS m/z 515 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:44])([F:43])[C:4]1[CH:5]=[C:6]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]=CC2C=CC=CC=2O)[CH2:11][C@H:10]1[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:8].C(OCC)(=O)C.CO>O1CCOCC1>[ClH:1].[ClH:1].[NH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]2[CH:5]=[C:4]([C:3]([F:43])([F:44])[F:2])[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=2)[C@H:10]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)[CH2:11]1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCN=Cc2ccccc2O)C[C@H]1Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
Hydrochloric acid (0.22 ml) was added to a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[N-(2-hydroxybenzylidene)-2-aminoethyl]-2-(1H-indol-3-yl-methyl)piperazine (0.80 g), ethyl acetate (12 ml) and methanol (6 ml) at room temperature. The mixture was stirred at 50° C. for 4.5 hours and then concentrated in vacuo to give an oil. The oil was treated with 4N hydrogen chloride in dioxane solution (0.33 ml) to afford (2R)-4-(2-aminoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine dihydrochloride (0.57 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([F:14])[CH:8]=1.[C:15](=[O:17])=[O:16].O>CCOCC>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]([OH:17])=[O:16])=[CH:8][C:9]=1[F:14]
Reactant: Fc1cc(Br)ccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(Cl)c(F)c1
Temperature: -78 °C

Procedure:
n-Butyl lithium (2.5M in hexanes, 176 ml) was added to a stirred solution of 1-bromo-4-chloro-3-fluorobenzene (83.38 g) in dry ether. Stirring was maintained for a further 2.5 hours at -78° C., and the mixture poured onto excess solid carbon dioxide pellets, allowed to reach room temperature and water added. The mixture was washed with ether, acidified, extracted (ethyl acetate) and dried (magnesium sulphate). After evaporation the residue was triturated with petroleum ether to give 4-chloro-3-fluorobenzoic acid (66.4 g) as a white solid, m.p. 192°-192.5° C.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=[C:6]1[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cc5ccccc5o4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended benzofuran-2-yl borate (122 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (120 ml) to give colorless crystals of 7-(benzofuran-2-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 138) (188 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Al+3].[Cl-].[Cl-].[Cl-].ClC(Cl)(Cl)[C:17](Cl)=[O:18].[OH2:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17]([OH:18])=[O:22])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-7-azaindole (2.0 g, 10.1 mmol) in DCM (50 mL) was added AlCl3 (6.8 g, 51.0 mmol). The suspension was stirred at RT for 10 min and trichloroacetyl chloride (2.8 g, 15.40 mmol) was added slowly. The mixture was stirred at RT for overnight and then poured into iced-water. The aqueous solution was extracted with DCM three times, and organic layers were combined and evaporated. The crude solid was dissolved in THF (50 mL) and treated with water (25 mL) and triethylamine (5 mL) at RT for 6 h. The solvents were then removed by evaporation and the resulting solid was poured into 1N HCl solution. The crude product was collected by filtration and washed with water. After drying on the pump for over night, a white solid was obtained (2.4 g, 9.96 mmol). MS (ES+): m/e=241.0 (M+H); LC: 2.7 min.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH:4]([CH2:29][S:30]([OH:33])(=O)=[O:31])[CH2:3]1.C(Cl)[Cl:35].CN(C=O)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH:7]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH:4]([CH2:29][S:30]([Cl:35])(=[O:33])=[O:31])[CH2:3]1
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)O)CC4C)ncnc32)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)Cl)CC4C)ncnc32)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A mixture of (3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonic acid (0.400 g, 0.81 mmol), CH2Cl2 (10 mL), and DMF (50 uL) was treated with thionyl chloride and warmed to 40° C. After 1.5 h, the mixture was cooled, treated with toluene (5 mL) and concentrated. The resulting material was triturated with Et2O and dried to afford (3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonyl chloride that was used immediately without additional manipulation. MS for C22H27ClN4O4S2 (ESI) (MH)+ m/z=512.
Reaction SMILES: [C:1]([C:3]1([CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].CCOCC.[Cl:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH:6]3[CH2:7][CH2:8][C:3]([C:1]#[N:2])([CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:35]
Reactant: CC(C)C(Cl)C(=O)O
Reactant: CCC(C)CC1(C#N)CCC(c2ccc(-c3ccc(O)cc3)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCC(C)CC1(C#N)CCC(c2ccc(-c3ccc(OC(=O)C(Cl)C(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 5.3 g of p-[p-(4-cyano-4-(2-methylbutyl)-cyclohexyl)-phenyl]-phenol (obtainable by alkaline ether cleavage from r-1-cyano-cis-4-(4'-propyloxybiphenyl-4-yl)-1-(2-methylbutyl)-cyclohexane with potassium tert.-butylate in NMP at 180°), 1.9 g of optically active 2-chloro-3-methyl-butyric acid and 170 g of DMAP are suspended in 40 ml of CH2Cl2. 3.1 g of DCC in 5 ml of CH2Cl2 are then added dropwise and the mixture is stirred at room temperature for 12 hours. After removal of the dicyclohexylurea and customary working up, optically active 4'-(4-cyano-4-(2-methylbutyl)-cyclohexyl)-biphenyl-4-yl 2-chloro-3-methyl-butyrate is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CN(C)C=O.I[CH2:22][CH2:23][CH2:24][CH:25]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:25]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:24][CH2:23][CH2:22][N:8]2[CH2:7][CH2:6][N:5]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:4]([CH2:3][O:2][CH3:1])[CH2:9]2)=[CH:31][CH:30]=1
Reactant: COCC1CNCCN1C(=O)C(F)(F)F
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)C(F)(F)F
Reaction time: 4 h
Yield: 94 %

Procedure:
To a stirred mixture of 6.05 parts of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine, 5.25 parts of N,N-diethylethananamine and 36 parts of N,N-dimethylformamide were added 11 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene]. Stirring was continued for 4 hours at 75° C. The reaction mixture was cooled and poured onto 400 parts of water. The product was extracted twice with 140 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated, yielding 11.5 parts (94%) of 4-[4,4-bis(4-fluorophenyl)butyl]-2-(methoxymethyl)-1-(trifluoroacetyl)piperazine as a residue (intermediate 60).
Reaction SMILES: [Br:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Br:1][C:2]1[C:14]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[O:25])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2cc(Br)c(O)cc21
Product: CC1(C)OC(=O)Nc2cc(Br)c(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 7-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CCN1C(=O)OCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)OCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21

Procedure:
Following a procedure analogous to Example 1741e, 3-amino-5-ethyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide were converted to 2-[5-chloro-2-(5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide. HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.45 (dd, 2H), 7.30 (dd, 2H), 7.21 (d, 1H), 7.09 (dd, 1H), 4.39 (t, 2H), 3.67 (q, 2H), 2.94 (t, 2H), 2.84 (s, 3H), 1.05 (t, 3H); MS (m/e) 485 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:28][CH:29]([F:39])[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[F:39][CH:29]([F:28])[C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: FC(F)c1nc2ccccc2[nH]1
Product: CC(=O)N1CCC(Cc2ccc3nc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone from Example 148 (0.135 g) was reacted with 2-(difluoromethyl)-1H-benzo[d]imidazole via General Procedure D to produce 31.4 mg of 171 following reverse phase HPLC purification. MS (Q1) 522.2 (M)+
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CO>ClC1C(Cl)=C(Cl)C=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:4]2[CH:5]=[CH:6][C:1]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:2][CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Clc1cccc(Cl)c1Cl
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of biphenyl (10 g, 0.065 mol) and 4-chlorobenzenesulphonyl chloride (13.69 g, 0.065 mol) in trichlorobenzene (3 mL) was heated with stirring to 110° C. Anhydrous ferric chloride (0.05 g, 0.0003 mmol) was added and stirring was continued at 150° C. for 16 h. The cooled solid was stirred with methanol (200 mL). The product was filtered, washed with methanol, dried, and recrystallised from acetic acid to give 4-(4′-chlorobenzenesulphonyl)biphenyl (13.9 g, 65%); m.p. 169° C. (lit. 171-173° C.).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][CH:8]2[CH:9]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC=CC1=O
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CCC2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 7.5 g of 6-acetoxy-2-cyclohexenone and 16.83 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 150 cm3 of dichloromethane are added, at a temperature of 10° C., 12 drops of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 7 hours, then 2 g of potassium carbonate are added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (97.5-2.5 by volume) and collecting 60 cm3 fractions. Fractions 25 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.25 g of (3aRS,5RS,7aSR)-5-acetoxy-2-benzyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2cc(F)ccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1C(=O)N(NC(=O)[C@H](C)NC(=O)[C@@H](O)c2cc(F)cc(F)c2)c2ccccc2-c2cc(F)ccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-Q), the title compound was prepared. The reaction was monitored by tic (Rf=0.4, 10% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([N:13]([CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CS(=O)Nc1ccc(Cl)nc1
Product: CN(C)S(C)(=O)=Nc1ccc(Cl)nc1

Procedure:
The title compound is prepared from N-(6-chloropyridin-3-yl)methanesulfinamide and dimethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.78 min; Mass spectrum (ESI+): m/z=234 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.FC(F)(F)C(O)=O>C(OCC)(=O)C>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(C#N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C2CCCNCC2)cc1
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a vial containing tert-butyl 4-(4-cyanophenyl)azepane-1-carboxylate (compound 40.3, 77 mg, 0.257 mmol, 1.0 equiv) was added DCM (500 μL) and trifluoroacetic acid (198 μL, 2.57 mmol, 10 equiv) and the mixture was stirred vented for 90 min. The mixture was diluted into ethyl acetate (5 mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous was adjusted to pH 10-11 and extracted with addition ethyl acetate until no product remained. The combined organics were dried (Na2SO4), filtered and concentrated to obtain the title compound as a yellow oil (51 mg, theoretical). m/z (ES+) 201 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:18]2[C:5]3=[C:6]([CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]3[C:3]=1[CH2:19][CH2:20][NH:21][CH3:22].[Na].[Cl-:24].[NH4+]>O1CCCC1>[CH3:1][C@@H:2]1[C:18]2[C:5]3=[C:6]([CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]3[C@H:3]1[CH2:19][CH2:20][NH:21][CH3:22].[ClH:24]
Reactant: [Cl-]
Reactant: CNCCc1c(C)c2cccc3c2n1-c1ccccc1CC3
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Product: CNCC[C@H]1[C@H](C)c2cccc3c2N1c1ccccc1CC3
Product: Cl

Procedure:
7.4 g (0.0255 mol) of 6,7-dihydro-2-methyl-1-(2-methylaminoethyl)-indolo[1,7-ab][1]benzazepine were dissolved in 74 ml of tetrahydrofuran (freshly distilled from sodium) and 148 ml of liquid ammonia and reduced with 1.17 g (2 × 0.0255 mol) of sodium. Addition of a further 0.12 g (10% excess) of sodium caused formation of a permanent blue colour. After decomposition with 3 g of ammonium chloride, the mixture was worked up in the manner described in part B of Example 2. The basic product was distilled at ca 150° C (air-bath temperature)/10-5 mm Hg to give the trans-1,2,6,7-tetrahydro-2-methyl-1-(2-methylaminoethyl)-indolo[1,7-ab][1]benzazepine whose hydrochloride melted at 198°-200° C.