Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1.Cl>CN(C)C=O.O>[NH2:10][C:11]1[CH:16]=[C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C(=NOC)c1nc(N)cc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NOC)c1nc(N)cc(Sc2ccccc2)n1
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of thiophenol (2.55 g) in N,N-dimethylformamide (20 ml) was added 50% sodium hydride (1.1 g) under cooling in an ice bath and the mixture was stirred for 20 minutes at 0° C. to 5° C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature. The resultant mixture was poured into cold water, adjusted to pH7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by valume) as an eluent. The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg), mp 154°-156° C.
Reaction SMILES: [NH2:1][CH:2]([CH:15]([CH3:17])[CH3:16])[C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:18]([C:21]1[C:22]([CH:34]=O)=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][CH:26]=1)([O-:20])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.ClCCl>[CH3:16][CH:15]([CH3:17])[CH:2]([NH:1][CH2:34][C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:26][N:25]=[C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)[C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)C(N)C(=O)N(C)CCc1ccccc1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C(=O)N(C)CCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 2-amino-3,N-dimethyl-N-phenethyl-butyramide (1.5 g, 6.48 mmol), 5-nitro-2-phenoxy-pyridine-4-carbaldehyde (1.5 g, 6.1 mmol), dichloromethane (75 mL), and THF (75 mL) was stirred for 5 hrs. Sodium triacetoxyborohydride (3.0 g, 14.25 mmol) was then added and the resulting mixture was stirred 16 hrs. Sodium hydroxide solution ([0.1 N], 100 mL) was added, the organic layer was separated, treated with MgSO4, filtered and the solvent evaporated to yield an oil. The oil was purified by column chromatography (10%-40% ethyl acetate/heptane) to yield a residue.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15]O)=[CH:14][C:9]=2[N:8]=[N:7]1>C(OCC)C.O>[Br:2][CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH3:5])[N:7]=[N:8][C:9]=2[CH:14]=1
Reactant: BrP(Br)Br
Reactant: Cn1nnc2cc(CO)ccc21
Solvent: CCOCC
Solvent: O
Product: Cn1nnc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus tribromide (0.230 ml, 2.45 mmol) is added to a stirred solution of (1-methyl-1H-1,2,3-benzotriazole-5-yl)methanol (0.4 g, 2.45 mmol) in diethyl ether (25 ml) under an inert atmosphere of Argon. After stirring overnight at room temperature, the reaction mixture is diluted with water (5 ml) and stirred vigorously for 10 minutes. The organic portion is separated, washed with water (2×5 ml), brine (2×5 ml) and concentrated in vacuo to yield the titled product which is used crude in the next step. (MH+ 226).
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Cl[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: COC(=O)C(C)Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (25.0 g, 0.14 mol) in dimethylformamide (DMF) (100 mL) is added methyl 2-chloropropanoate (24.5 g, 0.20 mol) over 30 minutes and stirred at 85°-90° C. for 3 hours under nitrogen. The reaction is filtered to remove KCl and the filtrate is concentrated under reduced pressure to remove DMF and the product analyzed by GLC. The product is dissolved in ethyl acetate (300 mL) and extracted with 2N NaOH (2×100 mL) and water (100 mL). The organic phase is dried and concentrated to give pure methyl 2-(4-acetylphenoxy)propanoate (25 g) (yield 64%).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.C(Cl)Cl>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][CH2:12][NH:11][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirring solution of salicylic acid (2.0 g, 14.5 mmol) and t-butyl N-(2-aminoethyl)carbamate (2.32 g, 14.5 mmol) in dry THF (15 mL) was added a solution of 1,3-dicyclocarbodiimide (3.29 g, 16.0 mmol) in CH2Cl2 (5 mL) dropwise at 0° C. The reaction was stirred for 18 h and then filtered. The filtrate was conc in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 5% NaHCO3, dried with MgSO4, and conc in vacuo to a white solid. The solid purified by silica gel chromatography (gradient: 0-70% EtOAc in hexanes) to yield 2.88 grams (71%) of the product as white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[OH:1][C@H:2]1[CH2:6][N:5]([CH:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)[CH2:4][C@@H:3]1[NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1
Reactant: COc1ccc(N2CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CNC[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCC(N3C[C@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@@H](O)C3)CC2)cn1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of rac-N-(2-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.152 mmol; prepared according to WO2004/050024A2), 1-(6-methoxypyridin-3-yl)piperidin-4-one (31 mg, 0.151 mmol) in methanol (4 mL) was added sodium triacetoxyborohydride (37 mg, 1.74 mmol) and stirred overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3S,4S)-4-hydroxy-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (73 mg, 93%) as a white solid. 1H-NMR (CD3OD) δ: 1.56-1.70 (m, 1H), 1.95-2.06 (m, 1H), 2.20-2.30 (m, 1H), 2.54-2.75 (m, 5H), 3.05-3.14 (m, 3H), 3.30-3.37 (m, 3H), 3.45-3.54 (m, 2H), 3.80-3.86 (s, 3H), 4.03-4.09 (m, 2H), 4.10-4.20 (m, 2H), 6.70-6.76 (in 1H), 7.40-7.50 (m, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.70-7.78 (m, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.21 (s, 1H). MS m/z: 522 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:38]=[C:39]=[O:40])(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:39](=[O:40])[NH2:38])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Example 66 (488 mg, 1.00 mmol) in dichloromethane (10 ml) was added trimethylsilylisocyanate (2.00 ml), and the mixture was stirred at room temperature for 3 days. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (20 ml), and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (20 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the mixture was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (353 mg, 0.66 mmol, Yield 66%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@H:28]2[CH3:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)#[N:2].CS(C)=[O:44].OO.[OH-].[Na+]>CO.CC#N>[C:1]([C:3]1[N:4]=[CH:5][C:6]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C@H:28]2[CH3:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:44])[NH2:2]
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C(N)=O)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
tert-Butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (312) (430 mg, 0.74 mmol) was dissolved in MeOH (25 mL), DMSO (4.4 mL), and TEA (0.22 mL, 1.6 mmol). The solution was cooled to 0° C., and a pre-mixed solution of 30% H2O2 (175 μL, 1.5 mmol) and 4N NaOH (384 μL, 1.5 mmol) was added. The reaction was stirred for 1 hour at 0° C. An additional amount of the pre-mixed solution 30% H2O2 (175 μL, 1.5 mmol) and 4N NaOH (384 μL, 1.5 mmol) was added, and the reaction was stirred for an additional hour at 0° C. MeCN (10 mL) was then added and the solution was stirred for 10 minutes at room temperature. The solvents were removed under reduced pressure, and the residue was subjected to silica flash column chromatography (MeOH/DCM) to give tert-butyl (2R,3R)-1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (313) (430 mg, 0.74 mmol, 97% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:6])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(-c2ccccc2)c(O)c1
Reactant: BrCCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCc1ccc(-c2ccccc2)c(OCCCCOCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 26.5 h

Procedure:
To a solution of 3-hydroxy-4-phenylbenzonitrile (0.600 g) in N,N-dimethylformamide (4.1 mL) was added potassium carbonate (0.850 g). Then 4-benzyloxy-1-bromobutane (0.703 mL) was added, and the resulting mixture was stirred at 50° C. for 26.5 hours. The reaction mixture was cooled to room temperature and then partitioned between diethyl ether (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (1.25 g) was dissolved in tetrahydrofuran (13 mL) and added to an ice-cold suspension of lithium alminiumhydride (0.175 g) in tetrahydrofuran (18 mL), and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and then quenched by sequential addition of water (0.175 mL), 15% aqueous sodium hydroxide (0.175 mL) and water (0.175 mL). After addition of anhydrous sodium sulfate (10.4 g), the mixture was stirred at room temperature for 13 hours and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure to give the title compound (1.21 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]4[CH2:30][CH2:29]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].N1C=CC=CC=1.CO>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]4[CH2:29][CH2:30]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C2CC2)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCOc1nc(C2CC2)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Compound A (1.21 g, 2.60 mmol), hydroxylamine hydrochloride (181 mg, 2.6 mmol), pyridine (10 mL, 100 mmol), and MeOH (10 mL, 300 mmol) were combined and stirred at room temperature overnight. Additional hydroxylamine hydrochloride (20 mg) was added and the mixture evaporated to dryness. The solids were dissolved in DCM (50 mL), washed with water (2×20 mL) and saturated aqueous NaCl (10 mL), dried over Na2SO4, and evaporated to dryness to afford compound B as a white solid (1.0 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[P:5]([CH2:10][CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[NH4+:21]>C(O)C>[NH2:21][C:12](=[O:13])[CH:11]([F:17])[CH2:10][P:5]([CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9]
Reactant: CCOC(=O)C(F)CP(=O)(OCC)C(OCC)OCC
Reactant: [NH4+]
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(F)C(N)=O)OCC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluoropropanoate (16.0 g, 51.1 mmol) in ethanol (22 mL) was added concentrated ammonium hydroxyde (14.8 N, 3.5 mL, 51.1 mmol). The solution was stirred for 16 h and evaporated. The residue was purified by chromatography on a wet-packed silica gel column (7×37 cm) eluting with 96.5:3.5 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 3.43 g (27%) of ethyl (3-amino-2-fluoro-3-oxopropyl)(diethoxymethyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 5.70 (s, 1H), 5.21–5.49 (dm, 1H), 4.7 (dd, 1H),4.18–4.31 (m, 2H), 3.65–3.91 (m, 4H), 2.21–2.81 (m, 2H), 1.30–1.40 (m, 3H), 1.20–1.28 (m, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([OH:24])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([OH:24])=[O:23])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)[C@H](c2ccc(Cl)cc2)C1
Agent: Cl
Product: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)[C@@H](c2ccc(Cl)cc2)C1
Yield: 199.5 %

Procedure:
The residue obtained from the evaporation of the mother liquors obtained from the crystallisation of (S)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid with Brucine was treated with EN HCl as described above for obtaining the free acid. After evaporating the organic phase 21.86 g of a mixture with a theoretical composition of 20 mmoles (S)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid and 39.9 mmoles of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were obtained. A suspension of 13.82 g (39.9 mmoles) of (+)-cinchonine in 1000 ml of acetonitrile were added and the mixture was heated to reflux. More acetonitrile was added until dissolution was complete (total volume of acetonitrile 4000 ml). The mixture was then slowly cooled to room temperature to obtain crystals. After a few hours a white solid was obtained, which was filtered off and dried to give 22.42 (yield 84.5% related to the salt of (R)-5-(4-chlorophenyl)-1-(2,4dichlorophenyt)-4,5-dihydro-pyrazole-3-carboxylic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1Br.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][NH:25][CH2:26][C@H:14]23)[CH:20]=1
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@H]2C1
Product: Clc1ccc(Cl)c(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)c1

Procedure:
Using 2,5-dichloro-1-bromobenzene and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis-tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate, from EXAMPLE 17, Part A, was converted to the title compound of EXAMPLE 19. 1H NMR (CDCl3): δ 7.18 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=2.2 Hz), 6.74 (s, 1H), 6.70 (s, 1H), 6.62 (dd, 1H, J=8.4, 2.6 Hz), 5.87 (s, 1H), 3.48-3.30 (m, 2H), 3.21 (q, 1H, J=7.6 Hz), 3.13-3.05 (m, 2H), 2.99 (dd, 1H, J=11.0, 4.7 Hz), 2.92-2.83 (m, 1H), 2.81-2.70 (m, 4H), 2.69-2.58 (m, 1H), 2.08-1.98 (m, 2H). LRMS (ES)+: 374.3 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=O.CCN=C=NCCCN(C)C.[NH2:38][C@@H:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1[NH:48][C:49]([C:51]1[NH:52][C:53]2[C:58]([CH:59]=1)=[CH:57][C:56]([Cl:60])=[CH:55][CH:54]=2)=[O:50]>C(Cl)Cl>[Cl:60][C:56]1[CH:57]=[C:58]2[C:53](=[CH:54][CH:55]=1)[NH:52][C:51]([C:49]([NH:48][C@@H:40]1[CH2:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:39]1[NH:38][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH3:20])=[O:50])=[CH:59]2
Reactant: COCCC(=O)O
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), 3-methoxypropanoic acid (46 μL, 0.5 mmol) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-5-chloro-1H-indole-2-carboxamide (Method 5, 220 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue triturated (DCM), collected by filtration, washed with hexane (2×5 mL) and dried to give the title compound (84 mg, 41%) as a brown solid.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH:40]=O>>[CH3:16]/[C:15](/[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]2([CH3:14])[CH3:13])=[CH:40]\[C:39]1[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:38]=1[CH3:37]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C/C(=C\c1ccc(C)cc1C)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 2,4-dimethyl-benzaldehyde there can be obtained 6-[(E)-α,2,4-trimethylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 54°-56° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]23[CH2:19][CH2:18][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[C:20]1([C:15]23[CH2:18][CH2:19][C:12]([CH2:11][C:27]#[N:28])([CH2:17][CH2:16]2)[CH2:13][CH2:14]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4)(CC2)CC3)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC12CCC(c3ccccc3)(CC1)CC2
Temperature: 100 °C
Yield: 92 %

Procedure:
A stirred mixture of 4-phenylbicyclo[2.2.2]oct-1-ylmethyl toluene-4-sulfonate (2.5 g, 6.75 mmol) and sodium cyanide (0.5 g, 10.20 mmol) in DMSO (20 mL) was heated at 100° C. under nitrogen for 5 h. After cooling overnight the mixture was poured into water (100 mL) then extracted with DCM (2×100 mL) then methyl t-butyl ether (3×100 mL). The DCM and methyl t-butyl ether phases were separately combined, washed with water (50 mL) and dried (MgSO4). The organic phases were then combined and the solvents evaporated to give the crude product which was purified by silica column chromatography (silica 40-63 micron) eluting with hexane:ethyl acetate 19:1 to give the title compound as a white solid (1.4 g; 93%).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]([O:21]CC)=[CH2:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:26])[C:9]([O:24][CH3:25])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>C(O)C.O>[C:19]([C:14]1[C:15](=[O:18])[CH2:16][CH2:17][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=1[C:12]1[C:7](=[C:8]([Cl:26])[C:9]([O:24][CH3:25])=[CH:10][CH:11]=1)[CH2:6]2)(=[O:21])[CH3:20]
Reactant: C=C(OCC)C1=C2c3ccc(OC)c(Cl)c3CC2(CCCC)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCC12CCC(=O)C(C(C)=O)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 80 °C

Procedure:
The product from step 1 in ethanol (1.0 mL), water (0.2 mL) and aqueous 2N HCl (0.2 mL) was stirred and heated in an oil bath at 80° C. for 40 minutes. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide 4-acetyl-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (54 mg) as an oil.