Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4](=[CH:8][CH2:9][CH3:10])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:2][C:1]([C:4]1[CH:8]=[C:9]([CH3:10])[O:7][C:5]=1[CH3:6])=[O:3]
Reactant: CCC=C(C(C)=O)C(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cc(C)oc1C
Yield: 65.5 %

Procedure:
A mixture of 2.80 g (0.02 mole) 3-acetyl-3-hexen-2-one and 3.56 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 24 hours. After cooling, the succinimide was removed by filtration and the solution concentrated. Distillation of the crude product gave 1.81 g (66%) of 2,5-dimethyl-3-furyl methyl ketone, bp 84°-87° C (17 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH:25]3[CH2:27][CH2:26]3)[CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:28])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>C(Cl)Cl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CC=CCCC=C1.C1C=CN=CC=1.F[P-](F)(F)(F)(F)F.[Ir]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]([CH:22]3[CH2:24][CH2:23]3)[CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:28])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C1C=C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C(C1CC1)C1CC1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-5,6-dihydropyridin-2(1H)-one (Example 115, Step H, 0.826 g, 2.003 mmol) and (1,5-cyclooctadiene)(pyridine) (tricyclohexylphosphine)iridium (i) hexafluorophosphate (0.129 g, 0.160 mmol) in DCM (60.0 ml) was saturated with hydrogen. The resulting mixture was stirred at rt under a hydrogen atmosphere for 2 h, then another 66.0 mg of (1,5-cyclooctadiene)(pyridine) (tricyclohexylphosphine)iridium (i) hexafluorophosphate were added. Stirring under hydrogen atmosphere was continued until LCMS indicated complete saturation of the double bond. The solvent was removed and the crude mixture was purified by chromatography on silica gel (eluting with ethyl acetate:hexane, 10:90) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:38]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:32]=[CH:31]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][CH2:44][N:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([Cl:27])[CH:29]=4)[N:34]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc2nc(N3CCCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-[1.4]diazepan-1-yl-quinoline
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCN(C)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 133 (0.5 g, 1.31 mmol) in 1,4-dioxane (5 mL) was added slowly a solution of 1-methylpiperizine (0.13 g, 1.31 mmol) in 1,4-dioxane (5 mL) followed by 2.5 N sodium hydroxide solution (0.5 mL, 1.31 mmol) and water (1.2 mL). The mixture was heated to reflux for 2.5-3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. and diluted with water (10 mL). The mixture was then stirred for 10-15 min., the precipitated solid was filtered off and dried under vacuum to afford the title compound E18 as an off-white solid (0.5 g, 86%). mp 120-122° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns 65:35 [0.01 M KH2PO4 (0.1% TFA):CH3CN], 223 nm, Rt 10.23 min, 98.50% purity); MS (CI): m/z 446 (M+H, 100), 375 (25).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15]Br.[H-].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][O:9][CH2:15][CH2:14][O:13][CH3:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1CO
Reactant: COCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1cc(Br)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-2-methoxy-phenyl)-methanol (3.38 g, 14.8 mmol) and 2-bromoethyl methyl ether (2.06 g, 14.8 mmol) in DMF (30 mL) is added NaH (55% dispersion in oil; 1.36 g, 31.1 mmol) in three portions at room temperature, followed by stirring overnight. The mixture is poured into ice-cooled aqueous 2N HCl, the water phase is extracted with diethyl ether, the combined organic phase is washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexane/AcOEt 3:1) gives the title compound as liquid. TLC, Rf (hexane/AcOEt 1:1)=0.44. 1H-NMR (CDCl3): δ 3.45 (s, 3H), 3.64 (m, 2H), 3.71 (m, 2H), 3.83 (s, 3H), 4.60 (s, 2H), 6.76 (d, 1H), 7.37 (dd, 1H), 7.56 (d, 1H) ppm.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:16]([S:4][C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]=2)[C:17]([OH:19])=[O:18])=[CH:25][CH:24]=1
Reactant: Cn1c(S)nc2ccccc21
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(SC(C(=O)O)c2ccc(Cl)cc2)nc2ccccc21
Yield: 41 %

Procedure:
A methylene chloride solution of 3.3 g (0.02M) of 2-mercapto-1-methyl-1H-benzimidazole, 5.0 g (0.02M) of α-bromo-(p-chlorophenyl)acetic acid and 4.0 g (0.04M) of triethylamine is heated to reflux overnight. The reaction mixture is neutralized with a diluted HCL solution. The layers are separated and the organic layer is dried over anhydrous magnesium sulfate. After removal of methylene chloride the residue is recrystallized from acetonitrile. The recrystallized material weighs 4.1 g (41% yield) and has a melting point of 161°-3° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:16][C@:8]2([C:13]([CH3:15])([CH3:14])[C:9]32[CH2:12][CH2:11][CH2:10]3)[CH2:7][N:6]1[C:17](=[O:41])[C@@H:18]([NH:23][C:24](=[O:40])[C@@H:25]([NH:32]C(OC(C)(C)C)=O)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:4].Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:16][C@:8]2([C:13]([CH3:14])([CH3:15])[C:9]32[CH2:12][CH2:11][CH2:10]3)[CH2:7][N:6]1[C:17](=[O:41])[C@@H:18]([NH:23][C:24](=[O:40])[C@@H:25]([NH2:32])[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](N)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (5R,8S)-7-[(S)-2-((S)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid methyl ester (0.755 g; 1.31 mmol) and 4.9 mL HCl (4 M in dioxane) in 10 mL dioxane was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure to yield the title compound which was used in the next step without further purification. LC-MS (method E): Rt=1.47 min; M/z=476 [M+]; HPLC (method A3): Rt=4.27 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccc(F)cc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 38 and 2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for C22H22FN3O3S, 427.5; m/z found, 428.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:29])[F:28])=[CH:21][N:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:1][C:19]2[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:28])[F:29])=[CH:21][N:20]=2)=[CH:3][C:4]([CH3:17])=[C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: Cc1cc(N)c(Cl)cc1C(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C)c(C(=O)N3CCOCC3)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 53.3 %

Procedure:
A mixture of (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (79 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (71 mg, 53%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=430 at 3.47 min. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.21 (d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 5.30 (br s, 1H), 3.79 (br d, 4H), 3.60 (br s, 2H), 3.32 (br s, 2H), 3.11 (d, 3H), 2.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:14]([O:21][CH3:22])(=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1>ClCCl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:15]([C:14]([O:21][CH3:22])=[O:20])[C:16]([O:18][CH3:19])=[O:17])[CH:10]([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(c1ccc(F)c(F)c1)C(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)=C(c1ccc(F)c(F)c1)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Titanium tetrachloride (11.4 mL, 104.1 mmol) in dichloromethane (28 mL) was added dropwise to a flask containing tetrahydrofuran (205 mL) under a nitrogen atmosphere, cooled in icebath. Then 1-(3,4-difluorophenyl)-2,2-difluoro-ethanone (10 g, 52 mmol) and dimethyl malonate (5.93 mL, 52 mmol) were added both at once. The resulting mixture was stirred under nitrogen atmosphere for 60 minutes while cooling was continued. Then, pyridine (16.8 mL, 208 mmol) in tetrahydrofuran (37 mL) was added to the mixture and this was allowed to warm to room temperature and stirred overnight. Next, distilled water (40 mL) and diethylether (40 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted with diethylether (2×40 mL). The combined organics were washed with brine (60 mL), NaHCO3 (60 mL) (aq/sat) and again with brine (60 mL). The organic layer was dried on MgSO4, filtered and concentrated under reduced pressure yielding dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (15.6 g) as a clear oil. Dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (5 g) was dissolved in 1,4-dioxane (25 mL) and treated with 3,5-difluoropyridine-2-carboximidamide (3.1 g, 19.6 mmol). The resulting mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate-heptane 0:100 to 50:50) yielding methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate (5.45 g) as a yellow solid which was used as such. Methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate was treated with phosphorus oxychloride (10 mL, 107.6 mmol) and the mixture was stirred at reflux for 2 hours.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C.O>CN(C=O)C>[C:1]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18])(=[O:13])[CH2:2][NH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C[C@H](NC(=O)CNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material was synthesised as follows. To a solution of hippuric acid (0.90 g, 5×10-3 moles) and L-aspartic acid dibenyzl ester (2.31 g, 5×10-3 moles) in DMF (35 ml) was added 1-hyhdroxybenzotriazole (0.73 g, 5.5×10-3 moles), triethylamine (1.4 ml, 9.7×10-3 moles) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide, HCl salt (1.05 g, 5.5×10-3 moles). The mixture was stirred for 4 hours at room temperature then poured into water (450 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated sodium bicarbonate solution, water, 2N HCl and water. The organic phase was dried over MgSO4 and evaporated to dryness to obtain the desired starting material as a yellow oil. 1.90 g (80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccnc3)C2)cc(OC)c1OC
Product: CCOCCn1c(NC2CCN(CCC3(c4cccnc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (100 g, 398 mmol) and triethylamine (166 ml, 1.2 mol) are added to toluene (1 L) at room temperature. The mixture is heated to 60° C. Pivaloyl chloride (73.5 ml, 597 mmol) is added over 2 h. After a further 1 h, citric acid solution (237 g in 1 L) is added and the phases are separated. The water phase is washed with toluene (0.5 L). The organic portions are combined, washed with water (0.5 L) and then dried (MgSO4). The mixture is concentrated in vacuo. The residue is suspended in heptane (550 ml) and is heated to reflux. The mixture is then cooled to room temperature. After 1 h, the mixture is cooled to 0° C., and then filtered to give (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C(S(O[CH2:37][CH2:38][N:39]([CH3:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][N:39]([CH3:46])[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cc1ccccc1S(=O)(=O)OCCN(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)c1ccccc1
Temperature: 75 °C
Yield: 80 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (96 mg, 0.25 mmol, the preparation of which may be found in Example K1) in DMF was added 2-(methylanilino)ethyl toluenesulfonate (153 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and a 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (104 mg, 80%). 1H NMR (DMSO-D6) δ 3.01 (3H, s), 3.78 (5H, m), 4.18 (2H, t, J=3.7 Hz), 6.63 (1H, t, J=7.3 Hz), 6.78 (2H, d, J=7.2 Hz), 7.02-7.20 (5H, m), 7.60 (2H, d, J=8.6 Hz), 7.96 (3H, m), 8.39 (1H, s). LCMS m/z=518 (m+H+). Calcd. for C28H24ClN3O3S×1H2O: C, 62.74; H, 4.89; N, 7.84. Found: C, 62.76; H, 4.65; N, 7.82.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12](=[O:19])(=[O:18])[NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[N:20]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>Cl.O>[C:14]([NH:13][S:12]([C:4]1[CH:3]=[C:2]([NH:1][NH2:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:19])=[O:18])([CH3:16])([CH3:15])[CH3:17]
Reactant: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Product: COC(=O)c1ccc(NN)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
25.0 g (0.087 mol) of methyl 4-amino-2-(N-tert-butylsulfamoyl)benzoate are suspended in a mixture of 150 ml of concentrated HCl and 130 ml of water. A solution of 7.8 g (0.114 mol) of sodium nitrite is added dropwise at 0°-5° C. A small amount of undissolved constituents are filtered off cold and the still cold diazonium salt solution is allowed to run slowly at 0° C. into a suspension of 55.0 g (0.244 mol) of SnCl2.2H2O in 55 ml of concentrated HCl. The mixture is subsequently stirred for 30 minutes and is then left to stand for 15 hours, while cooling with ice. Most of the HCl is first neutralized by addition of 6N NaOH and the pH is then brought to about 6 with solid NaHCO3. The mixture is extracted several times with ethyl acetate, the extracts are dried and the solvent is removed in vacuo. After trituration of the residue with diisopropyl ether and drying, 18.3 g (70% of theory) of methyl 2-(N-tert-butylsulfamoyl)-4-hydrazinobenzoate of melting point 133°-136° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([C:9]3[O:10][C:11]([CH3:14])=[N:12][N:13]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:21][CH:20]=1)=[O:18].[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]([CH3:14])=[N:12][N:13]=2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2ccc(C)c(Br)c2)o1
Product: COC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
Methyl 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate Methyl 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate was prepared from 2-(3-bromo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole and [4-(methoxycarbonyl)phenyl]boronic acid using method D. NMR; δH CDCl3 8.12,(2H, d), 7.94, (1H, dd), 7.90,(1H, d), 7.43,(3H, m), 3.96,(3H, s), 2.61,(3H, s), 2.33,(3H, s). LCMS; retention time 3.37 min, MH+ 309.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]([OH:16])[CH2:14][CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2]
Reactant: CCC(O)c1ccc(OC)c(OC(C)C)c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1ccc(OC)c(OC(C)C)c1
Yield: 94 %

Procedure:
A magnetically stirred solution of alcohol 4 (500 mg, 2.23 mmol) in CHCl3 (15 mL) was treated with activated MnO2 (1.94 g, 22.3 mmol) and the resulting mixture heated at reflux under a nitrogen atmosphere for 17 h. The cooled reaction mixture was filtered through a pad of Celite™ that was then washed with CHCl3 (1×15 mL). The combined filtrates were concentrated under reduced pressure to afford the title compound 10 (466 mg, 94%) as a white solid, m.p. 58.1-58.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:13]([O:15]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:14]>C1(C)C=CC=CC=1.[Pd].CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:13]([C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:15])[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1cc(Br)cc2ccoc12
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)c1cc(C=O)c2occc2c1
Reaction time: 6 h
Yield: 72.4 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (2.00 g), 1-ethoxy-1-tributylstannanylethene (3.53 g)and bis(triphenylphosphine)palladium (II) chloride (63 mg) in dry toluene (4 ml) was heated at reflux under nitrogen for 18 h. A further portion of palladium catalyst (63 mg) was added and heating at reflux continued for a further 6 h. The reaction was allowed to cool, diluted with ether (40 ml) and filtered through a plug of Hyflo. The filtrate was washed successively with hydrochloric acid (50 ml; 2M) and brine (50 ml), then dried, and concentrated in vacuo to give an orange oil. Purification by FCC eluted with hexane to hexane:ethyl acetate (4:1) gave the title compound as a yellow powder (1.21 g), m.p. 91-93°.