Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][O:44][CH2:45][CH2:46]O.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:46][CH2:45][O:44][CH3:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Yield: 80.9 %

Procedure:
In a manner similar to the method described in Example 7, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.4 mg, 0.163 mmol) was reacted with N,N′-carbonyldiimidazole (Aldrich, 69.2 mg, 0.414 mmol) and then, a mixture of 2-methoxyethanol (Sigma Aldrich, 38.6 mg, 0.506 mmol) and sodium hydride (9.7 mg, 0.384 mmol) in tetrahydrofuran to give chiral 2-methoxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (89 mg, 81% yield). MS (ES+) m/z calcd. for C34H37Cl2F2N4O4 [(M+H)+]: 674. found: 674.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3cccc(F)c3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5 Step A) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23ClFNO3+H: 404, observed: 404.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.Cl.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1)[CH:11]=[CH:10]2
Reactant: O[C@@H]1CCCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@@H](O)C3)ccc12
Temperature: 120 °C
Yield: 58.7 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (1 g), (3R)-3-piperidinol hydrochloride (0.424 g) and triethylamine (1.2 mL) were placed into a 10 mL microwave vial followed by the addition of acetonitrile (3 mL). The vial was sealed and heated at 120° C. in a single mode microwave for 45 minutes. On cooling a solid crystallised from the reaction mixture which was filtered and washed with acetonitrile (10 mL) to afford the sub-title compound (0.7 g).
Reaction SMILES: C(OC(=O)[N:7]([C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][OH:14])[CH3:8])(C)(C)C.Cl.[C:25](OCC)(=[O:27])[CH3:26]>>[C:25]([O:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[C@H:9]([NH:7][CH3:8])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(O)CCCO
Agent: Cl
Product: CN[C@H](Cc1ccccc1)C(O)CCCOC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
((1R)-1-Benzyl-2,5-dihydroxypentyl)methylcarbamic acid tert-butylester (560 mg, 1.52 mmol) was dissolved in ethyl acetate (10 mL). 3M Hydrogen chloride in ethyl acetate (2.0 mL, 6.08 mmol) was added. The solution was stirred at room temp. for 1 h. It was diluted with ethyl acetate (10 mL) and extracted with 1N sodium hydroxide solution (30 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (5 mL). The solution was cooled to 0° C. Trifluoroacetic acid (5 mL) was added. The solution was stirred at this temp. for 5 min. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate (10 mL). The solution was extracted with 1N sodium hydroxide solution (10 mL). The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g) with dichloromethane/methanol/25% aqueous ammonia 100:10:1 to give 136 mg of (5R)-4-hydroxy-5-(methylamino)-6-phenylhexyl acetate.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>>[CH3:28][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=23)=[O:18])[CH2:23][CH2:24]1
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: CN1CCC(N)CC1
Agent: Cl
Product: CN1CCC(NC(=O)c2cccc3oc(-c4ccccc4)nc23)CC1
Yield: 38 %

Procedure:
N-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 2-phenylbenzoxazole-4-carboxylic acid and 4-amino-1-methylpiperidine dihydrochloride using the conditions described for Step C in Example 1. This compound was obtained in 38% yield as a white solid; mp 126-128° C.; 1H NMR (300 MHz, CDCl3) δ 9.26 (d, J=7.5 Hz, 1H), 8.25 (m, 2H), 8.19 (d, J=7.7 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.63-7.53 (m, 3H), 7.46 (t, J=8.0 Hz, 1H), 4.20 (m, 1H), 2.86 (m, 2H), 2.37 (s, 3H), 2.33-2.13 (m, 4H), 1.85-1.73 (m, 2H); MS (APCI) m/z 336 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1.[CH2:17]([O:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24])[CH3:18]>O1CCCC1>[CH3:18][CH2:17][O:19][CH2:20][CH2:21][NH:22][C:23]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:24]
Reactant: CCOc1nc(O)ns1
Reactant: CCOCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCCNC(=O)n1sc(OCC)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
1 ml of triethylamine was added to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran and then 23 g of ethoxyethyl isocyanate were added dropwise. The mixture was stirred for 2 hours at 25° C and was concentrated to dryness. The residue was chromatographed over silica gel and elution with a 4-6 benzene-ethyl acetate mixture yielded 14 g of 2-(N-β-ethoxyethylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at <50° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5](OC)=[O:6].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=O)[O:20][C:19](=O)[N:18](C)[C:17]=2[CH:25]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:25]=[C:17]2[C:16]([C:21]([OH:20])=[C:4]([C:3]([O:10][CH3:11])=[O:9])[C:5](=[O:6])[N:18]2[CH3:19])=[CH:15][CH:14]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a 50 mL RBF was added sodium hydride (0.15 g, 3.7 mmol) and N,N-dimethylformamide (50 mL, 3.1 mmol) under nitrogen. The mixture was cooled with an ice-water bath for 10 min, and then dimethyl malonate (6.4 mL, 56 mmol) was added over 3 min. A mixture of 7-bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.80 g, 3.1 mmol) in DMF (5.0 mL) was added, and then the reaction was placed in oil bath at 120° C. for 3 hours. The reaction was cooled to room temperature, and water (25 mL) was added to the mixture. A white solid was collected by filtration and washed with water (100 mL), followed by ether (100 mL). The white solid was placed in vacuum oven at 50° C. for 6 h to afford the desired product as a white solid (0.65 g, 67%).
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH:7]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C>CCO>[CH:7]1([CH:13]([OH:14])[CH2:6][N+:3]([O-:5])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CC1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC(O)C1CCCCC1
Reaction time: 0.17 h

Procedure:
10 M aqueous NaOH (8.31 mL, 83 mmol) was added dropwise via addition funnel to a solution of nitromethane (4.46 mL, 83 mmol) and cyclohexanecarboxaldehyde (10 mL, 83 mmol) in EtOH (20 mL) at 0° C. with vigorous stirring. The resulting white slurry was stirred 10 minutes and became a white solid. Acetic acid (4.76 mL, 83 mmol) was added and the reaction was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo and dried under vacuum to afford 1-cyclohexyl-2-nitroethanol. The product was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1(C)C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[S:17])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN(CC(=O)O)C(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(CC(=O)O)C(=S)c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 67.7 %

Procedure:
To a slurry of 4.54 g of 4-chlorobenzoyl methyl glycine (20 mmol) in 60 ml of toluene under an atmosphere of nitrogen was added 0.89 g (20 mmol) of phosphorus pentasulfide. The reaction was heated to 90° C. for 3 hours. An additional 0.18 g of phosphorus pentasulfide was added, and the reaction was heated for an additional 1 hour, then cooled to room temperature. The product was filtered, the slurry was washed with ethyl acetate, and the combined filtrates were run through silica gel on Gelite, then stripped. The product was chromatographed on a silica gel column to give 3.3 g (68% yield) of 4-chlorothiobenzoyl methylglycine, melting point 72-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]/[CH:10]=[CH:11]\[CH:12]([OH:14])[CH3:13])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:14][CH:12]([CH3:13])/[CH:11]=[CH:10]\[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1ccc(S/C=C\C(C)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S/C=C\C(C)OC(C)=O)cc1

Procedure:
1 g (4.76 mmol) of rac-(Z)-4-[(p-methoxyphenyl)thio]-3-buten-2-ol are dissolved in 50 ml of methylene chloride. whereupon the solution is treated with 0.77 ml (9.5 mmol) of pyridine and cooled to 0° . There is added dropwise thereto a solution of 0.5 ml (7.1 mmol) of acetyl chloride in 10 ml of methylene chloride and the mixture is stirred at 0° for 1 hour. The reaction mixture is washed successively with 50 ml of 1N hydrochloric acid, 50 ml of 5 percent sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (9:1) there is obtained pure rac-4-[[(Z)-3-acetoxy-1-butenyl]thio]anisole; IR: 1735 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].I[CH:31]([F:33])[CH3:32].O>C(#N)C>[F:33][CH2:31][CH2:32][N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:19][CH2:20]1
Reactant: CC(F)I
Reactant: COc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (Example 89, step D) (0.958 g, 2.99 mmol) and Na2CO3 (0.470 g, 4.43 mmol) in acetonitrile (20 mL) was added iodofluoroethane (0.500 mL, 6.15 mmol) in one portion. The resultant mixture was heated at 70° C. for 48 h. When complete by TLC, the reaction was poured into H2O (150 mL), extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step A (0.972 g, 2.63 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H), 1.70 (d, J=15.0 Hz, 2H), 1.94 (t, J=12.5 Hz, 2H), 2.12-2.21 (m, 1H), 2.50 (t, J=5.0 Hz, 1H), 2.52-2.58 (m, 5H), 2.88 (d, J=10.4 Hz, 2H), 3.35-3.40 (m, 4H), 3.86 (s, 3H), 4.46 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 6.47 (d, J=2.4 Hz, 1H), 6.54 (dd, J=9.3, 2.1 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]>CN1CCCC1=O>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CCCCS(=O)(=O)Cl
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCS(=O)(=O)N1CCC(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)CC1
Reaction time: 12 h

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 436.62 (C22H36N4O3S); MS (ESI): 437 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:29]3[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]4[CH2:41][C:40]([CH3:42])([CH3:43])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]4)=[CH:31][CH:30]=3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)OB(c2ccc3ccnc(OCc4ccccc4)c3c2)OC1(C)C
Product: CN(c1ccc(-c2ccc3ccnc(OCc4ccccc4)c3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 94 %

Procedure:
The title compound (120 mg, 0.249 mmol, 94% yield) was prepared following GENERAL METHOD 1-4 for Suzuki reaction from 1-(benzyloxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (144 mg, 0.398 mmol) and (Intermediate 1-1, 75 mg, 0.265 mmol). LCMS Rt=0.57 min [Method Q]; MS (M+1)=482.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.81 (d, J=2.01 Hz, 1H), 8.39 (dd, J=8.41, 1.88 Hz, 1H), 7.99 (d, J=9.79 Hz, 1H), 7.76 (d, J=8.53 Hz, 1H), 7.72-7.74 (m, 1H), 7.46 (d, J=7.28 Hz, 1H), 7.26-7.37 (m, 5H), 7.24 (d, J=9.79 Hz, 1H), 6.76 (d, J=7.53 Hz, 1H), 5.29 (s, 2H), 3.01 (s, 3H), 1.71-1.78 (m, 2H), 1.61-1.70 (m, 2H), 1.44 (s, 6H), 1.29 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[Cl:14][C:6]1[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2occc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2occc2c(Cl)n1
Temperature: 100 °C
Yield: 96 %

Procedure:
A mixture of 6-methylfuro[3,2-c]pyridin-4(5H)-one (11.9 g, 0.08 mol) and phosphorus oxychloride (15.2 ml, 0.163 mol) was heated, under a nitrogen atmosphere, at 100° C. for 1.5 hours. The cooled blackish liquid was poured onto crushed ice and the solution made basic with sodium hydroxide solution. The precipitated product was extracted into methylene chloride. This solution was dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated. Pure product was collected by filtration after the residue was triturated with hexane to give 12.9 g (96% yield), mp: 64.5°-66° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:35])[N:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]([C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])=[N:14]2>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:21][C@H:19]([C:13]1[N:12]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:11](=[O:35])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[Cl:8])[N:14]=1)[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of (5)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate (1 g, 2.5 mmol) in dichloromethane (3 mL). The resultant was stirred at room temperature for 3 hours. The solvents was removed in vacuuo to afford (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one 2,2,2-trifluoroacetic acid salt. ES/MS m/z=300.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=2)[CH:8]=1)=[O:6]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1F
Yield: 85 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 150 mg (0.505 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-1H-quinolin-4-one, 145.3 mg (0.605 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, 24.2 mg (0.605 mmol, 60% dispersion in oil), and 1 mL of N,N dimethylformamide. Water was added and the solid was collected by filtration. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 195.9 mg of 3-(3-Fluoro-4-methoxy-benzoyl)-1-(6-trifluoromethyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C24H16F4N2O3 [M+H]: 457.11 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[C:26]2[CH:32]=[C:33]([CH2:40][CH3:41])[C:34]([C:36]([F:39])([F:38])[F:37])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[C:26]2[CH:32]=[C:33]([CH2:40][CH3:41])[C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Add 3,5-bistrifluoromethylbenzaldehyde (4.30 g, 24.22 mmol) to a solution of (S)-5-amino-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (4.91 g, 13.70 mmol) in dichloromethane (100 mL) and glacial acetic acid (6 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxyborohydride (6.01 g, 28.35 mmol) and stir the mixture for 2 h. Remove the solvents under reduced pressure and dilute the residue with dichloromethane (50 mL) and water (50 mL). Collect the organic layer and extract the aqueous layer with dichloromethane (3×30 mL). Wash the combined organic extracts with water (20 mL) and brine (20 mL) and dry over anhydrous sodium sulfate. Filter and remove the solvents under reduced pressure to provide the title compound as an amber oil (6.58 g, 75%), which is used in the next step without purification. 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 19H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 3H), 6.89-7.60 (m, 3H), 7.70-7.91 (m, 2H); APCI MS m/z 585 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](OCC)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[BH4-].[Li+].O.Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([CH2:15][OH:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2c(CO)ncn2-c2ccc(F)cc2C1=O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
15.0 g (49.5 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are dissolved under argon in 450 ml of boiling absolute tetrahydrofuran (filtered over Alox) and added dropwise at 50° C. to a solution of 1.1 g (49.5 mmol) of lithium borohydride in 50 ml of absolute tetrahydrofuran. The mixture is stirred at 40° C. for 4 hours and at the boiling point for 2.5 hours. Subsequently, the mixture is decomposed at 40° C. with 20 ml of water and 20 ml of concentrated hydrochloric acid/water (1:1) and stirred at room temperature overnight. After removal of the tetrahydrofuran in vacuo, the residue is treated with 14 ml of concentrated ammonia. The mixture is left to crystallise in the cold and separated material is filtered off under suction and washed with water. After recrystallisation from ethanol, there is obtained 8-fluoro-4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[ 1,5-a][1,4]benzodiazepin-6-one of melting point 221°-223° C.