Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:25][C:24]4[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:23]=4[CH:22]=3)(=[O:20])=[O:19])[CH2:14][C:13]2=[O:31])[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:23]2[CH:22]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:8]4[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=4)[C:13](=[O:31])[CH2:14]3)(=[O:20])=[O:19])[S:25][C:24]=2[CH:26]=1
Reactant: CCOC(=O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Reaction time: 2 h

Procedure:
A solution of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid ethyl ester (75 mg, 0.15 mmol) is dissolved in THF/MeOH −3:1 (2 mL) and a solution of 1N NaOH is added (0.5 mL). The reaction is stirred for 2 h and then diluted with EtOAc and washed with 2N HCl. The organic phase is dried (MgSO4) and concentrated to yield 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (d, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.04 (d, 1H), 7.57 (dd, 1H), 4.74 (s, 2H), 3.87 (s, 2H), 3.49 (s, 4H); MS (Ion Spray) 471 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[N:3]=1.[NH2:13][C:14]1[S:15][C:16]([C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:24][C:23]=2[F:33])=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20]>>[F:33][C:23]1[CH:24]=[C:25]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:26]=[C:27]([F:28])[C:22]=1[C:16]1[S:15][C:14]([NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[CH:12]=[CH:11][N:10]=[N:9]3)[N:3]=2)=[C:18]([C:19]([NH2:21])=[O:20])[CH:17]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Clc1cccc(-n2ccnn2)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(-n4ccnn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-chloro-6-(1H-1,2,3-triazol-1-yl)pyridine (72 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[F:12][C:13]([F:20])([F:19])[CH2:14][C:15]1([OH:18])[CH2:17][CH2:16]1>>[F:12][C:13]([F:20])([F:19])[CH2:14][C:15]1([O:18][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:17][CH2:16]1
Reactant: OC1(CC(F)(F)F)CC1
Reactant: NS(=O)(=O)Oc1ccccc1
Product: NS(=O)(=O)OC1(CC(F)(F)F)CC1

Procedure:
Sulfamic acid 1-trifluoroethyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-trifluoroethylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234.) to obtain sulfamic acid 1-trifluoroethyl-cyclopropyl ester.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12]([NH:33][CH:34]([CH3:36])[CH3:35])=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[N:14]=2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[O:24][CH:21]1[CH2:20][CH2:19][N:18]([C:13]2[N:14]=[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]3=[N:11][C:12]=2[NH:33][CH:34]([CH3:36])[CH3:35])[CH2:23][CH2:22]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A mixture of 6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (6.43 g, 13.03 mmol) and 10% Pd/C (640 mg) in MeOH (86 mL) under H2 in a balloon was stirred at room temperature overnight. Removal of the solvent gave the title compound (4.4 g, 84%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.4 Hz, 6H), 1.89-1.99 (m, 2H), 2.09-2.17 (m, 2H), 2.74 (t, J=5.9 Hz, 2H), 2.95 (ddd, J=12.3, 8.7, 3.4 Hz, 2H), 3.11 (t, J=6.1 Hz, 2H), 3.82 (s, 2H), 4.14 (septet, J=6.4 Hz, 1H), 4.46 (tt, J=7.7, 3.5 Hz, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.4, 8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 404.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25](C)(C)C)=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:25][C:5]1[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:29])[CH2:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)=CCC3(C)C)cc1
Yield: 0.5 %

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 250 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (HPLC Partisil 10, 0.5% EtOAC-hexanes) using 70.2 mg (0.78 mmol) of cuprous cyanide, 33.2 mg (0.78 mmol) of lithium chloride and 34.5 mg (1.28 ml, 1.57 mmol) of methyl-lithium (1.22M solution in Et2O).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Br:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].C1COCC1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:12]([Br:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
26.63 g (86.3 mmol ) of ethyl 2-chloro-3-bromo-5-nitrobenzoate was dissolved in a mixture comprising 150 ml of ethanol and 80 ml. of THF, followed by the addition of 55 ml of a 2N aqueous solution of sodium hydroxide. The obtained mixture was stirred at room temperature for one hour, followed by the addition of water and 19 ml. of 6N hydrochloric acid. The obtained mixture was concentrated under reduced pressure and extracted with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous solution of common salt, dried and distilled to remove the solvent, giving 24.11 g of the title compound (yield: quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:8]([CH3:9])[N:17]([CH:14]3[CH2:16][CH2:15]3)[N:11]=2)[CH:7]=1
Reactant: NC1CC1
Reactant: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1c2cc(Br)ccc2nn1C1CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of 1-(5-bromo-2-nitrophenyl)ethanone (4.0 g) in toluene (41 ml) were added cyclopropylamine (2.3 ml) and titanium(IV) tetraisopropoxide (14.4 ml) at room temperature, and the mixture was stirred at 60° C. for 17 hr. The reaction mixture was concentrated, triethyl phosphite (8.4 ml) was added to the residue, and the mixture was stirred at 150° C. for 5 hr. The reaction mixture was cooled, and diluted with ethyl acetate, and 1 M aqueous sodium hydroxide solution was added. The resulting insoluble solid was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.6 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28](=[O:30])[NH2:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>[Pd].CO>[C:28]([C:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:30])[NH2:29]
Reactant: NC(=O)C(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: NC(=O)C(CC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
10% Palladium on charcoal (900 mg) was added portionwise over 10 minutes to a stirred, ice-cooled solution of 1-benzyl-4-(2-carbamoyl-2,2-diphenylethyl)piperidine (890 mg, 2.23 mmol) (see Example 17) and formic acid (1.0 ml) in methanol (19 ml) and the mixture stirred at room temperature for 24 hours, filtered and evaporated. The residue was partitioned between dichloromethane and saturated aqueous sodium carbonate solution and the organic layer was dried over magnesium sulphate and evaporated to give the title compound (600 mg, 87%) as a colourless foam which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH:19]([C:21]1[CH:22]=[C:23]([Cl:31])[C:24]([O:27][CH:28]([F:30])[F:29])=[N:25][CH:26]=1)[CH3:20]>>[Cl:31][C:23]1[CH:22]=[C:21]([CH:19]([N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH3:20])[CH:26]=[N:25][C:24]=1[O:27][CH:28]([F:30])[F:29]
Reactant: CC(Br)c1cnc(OC(F)F)c(Cl)c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1C(C)c1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(1-bromoethyl)-3-chloro-2-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min., [M+H]+: 441.23 g/mol; tR=0.91 min., [M+H]+: 441.22 g/mol (diastereomers).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1.O1CCOCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:19][CH:18]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Clc1ccc(Nc2ccc(C3CNCCO3)cc2)nc1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
To a stirred solution of (RS)-2-[4-(5-chloro-pyridin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (50 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.26 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford (RS)-(5-chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine (19 mg, 51%) as a white solid. MS (ISP): 292.1 ([{37Cl}M+H]+), 290.1 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:14])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([S:14][CH2:17][C:16]([F:30])([F:29])[F:15])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1S
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1SCC(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 3,4-dichloro-2-mercaptobenzoate (7.95 g), 2,2,2-trifluoroethyl-p-toluene-sulphonate (9.66 g) and potassium carbonate (6.56 g) in DMF was heated at 90° C. for 4.5 hours. After cooling, water was added and the reaction mixture extracted with ether. The organic extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography eluting with ether/n hexane to give ethyl 3,4-dichloro-2-trifluoroethylsulphenylbenzoate as a yellow oil, (3.53 g) NMR CDCl3 ; 1.4(t,3H), 3.5(q,2H), 4.4(q,2H), 7.45(d,1H), 7.55(d,1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[NH:12][C:11]2=[S:21])[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:31]([S:21][C:11]1[N:10]([C@@H:9]2[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OC[C@@H]1C[C@H](n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 65 %

Procedure:
A mixture of (±)-(1R*,2S*,3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.50 g, 1.05 mmol), benzyl bromide (0.3 mL, 2.5 mmol) and anhydrous potassium carbonate (0.145 g, 1.05 mequiv as 98%) in dioxane (5 mL) was stirred vigorously at ambient temperature for 2.5 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried(sodium sulfate) and concentrated to an oil which was stirred in ammonia-methanol (40 mL of half-saturated) for 18 hours. Volatiles were evaporated and the residue solidified from 3:1 methanol-water to give title compound as a white powder (300 mg, 65%), m.p. 160°-162° C.; 1H-NMR(DMSO-d6) δ: 8.04 and 7.89 (both s, 1 each, 2 aromatic CH), 7.5-7.2 (m, 5, C6H5), 5.06 (t, J=4.7 Hz, 1, OH), 4.98 (d, J=6.2 Hz, 1, OH), 4.75-4.55 (m overlapping d at 4.68, J=3.7 Hz, and s at 4.63, total 4, NCH, OH, and SCH2); mass spectrum(CI): 439 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:13]1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(NCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A solution of 4-fluorobenzylamine (5.48 g, 43.8 mmol) in a mixture of methanol and acetic acid (5:1, 60 mL) was added dropwise to a solution of benzyl 4-oxo-1-piperidine carboxylate (10.2 g, 43.8 mmol) in methanol (150 mL) at rt. To this mixture sodium cyanoborohydride (5.50 g, 87.5 mmol) was slowly added. After 20 hours stirring at rt the reaction mixture was neutralized and the solvent was removed by evaporation under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with 7% methanol in dichloromethane, afforded the desired compound (9.0 g, 60%).
Reaction SMILES: ClC1C=CC2CCN(C(=O)C(F)(F)F)CCC=2C=1OS(C(F)(F)F)(=O)=O.CC1(CCCN)OCCO1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:89][C:90]1[CH:106]=[CH:105][C:93]2[CH2:94][CH2:95][N:96]([C:99](=[O:104])[C:100]([F:103])([F:102])[F:101])[CH2:97][CH2:98][C:92]=2[C:91]=1[NH:107][CH2:108][CH2:109][CH2:110][C:111]1([CH3:116])OCCO1.Cl.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C(Cl)Cl.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[Cl:89][C:90]1[CH:106]=[CH:105][C:93]2[CH2:94][CH2:95][N:96]([C:99](=[O:104])[C:100]([F:101])([F:103])[F:102])[CH2:97][CH2:98][C:92]=2[C:91]=1[N:107]1[CH2:108][CH2:109][CH2:110][CH:111]1[CH3:116]
Reactant: CC1(CCCNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)OCCO1
Agent: [Pd]
Agent: CC1(CCCN)OCCO1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1CCCN1c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 95 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
Place 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 1) (3 g, 7.08 mmol) in toluene (60 mL) with 3-(2-methyl-[1,3]dioxolan-2-yl)-propylamine (prepared essentially as described in Preparation 38) (3.08 g, 21.24 mmol), tris(dibenzylideneacetone)dipalladium (1.3 g, 1.42 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (1.77 g, 2.84 mmol), and cesium carbonate (3.3 g, 9.91 mmol) and heat for 16 h at 95° C. in a sealed tube. Cool the reaction to RT, dilute with EtOAc (600 mL) and filter. Concentrate the filtrate and purify (silica gel chromatography, eluting with 10:90 to 25:75 EtOAc:hexanes) to give the crude product as an orange oil (1.72 g). Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[3-(2-methyl[1,3]dioxolan-2-yl)-propylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.72 g, 4.09 mmol) in DCM (20 mL) and add methanol (2 mL) and 2 N HCl in diethyl ether (20 mL) and stir at RT for 3 h. Concentrate and dissolve the residue in acetic acid (30 mL) and add sodium cyanoborohydride (1.28 g, 20.43 mmol). Stir the reaction at RT for 0.5 h then concentrate to remove the acetic acid. Dissolve the residue in DCM (200 mL) and extract with saturated aqueous sodium bicarbonate solution (400 mL), Extract the aqueous layer with DCM (100 mL) and combine the organic fractions, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound as a foam (1.2 g, 81%).
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]1[CH2:9][CH:8]([N:10]=[N+:11]=[N-:12])[CH2:7][N:6]1[C:13](=[O:15])[CH3:14])C.[BH4-].[Na+].Cl>C(O)C.C(=O)(O)[O-].[Na+]>[C:13]([N:6]1[CH2:7][C@@H:8]([N:10]=[N+:11]=[N-:12])[CH2:9][C@H:5]1[CH2:4][OH:3])(=[O:15])[CH3:14]
Reactant: CCOC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: CC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1CO
Yield: 101.8 %

Procedure:
644 g of N-acetyl-4-azido-L-proline ethyl ester dissolved in 700 ml of ethanol was added dropwise to a suspension of 2.5 L of ethanol and 162 g of sodium borohydride at not higher than 10° C. while cooling. After overnight reaction, 35% hydrochloric acid (594 g) was added dropwise to the above mixture at not higher than 20° C. while cooling, and the solution was neutralized with sodium bicarbonate (24 g). After filtration, the solution was concentrated under reduced pressure while the solvent was substituted with 1.3 L of isopropyl alcohol, thereby to obtain 534 g of (2S,4S)-N-acetyl-4-azido-2-hydroxymethylpyrrolidine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 582.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].CCO>Cl>[NH2:14][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Agent: Cl
Solvent: CCO
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 15 °C
Yield: 97.9 %

Procedure:
A suspension of N-(6-nitro-1-oxo-indan-5-yl)-acetamide (10 g, 0.042 mol) in HCl (200 ml, 2 N)) and EtOH (100 ml) was refluxed for 30 min. The reaction was cooled to 15° C. and the resulting precipitate was isolated and recrystallized from dilute ethanol to give 7.9 g (97.5%) of yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([S:13][C:14]1[N:15]=[C:16]([CH3:24])[NH:17][C:18]=1[C:19](OCC)=[O:20])[CH3:12].C(Cl)(=O)C.O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:11]([S:13][C:14]1[N:15]=[C:16]([CH3:24])[NH:17][C:18]=1[CH2:19][OH:20])[CH3:12]
Reactant: CCOC(=O)c1[nH]c(C)nc1SCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)Cl
Product: CCSc1nc(C)[nH]c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
11.64 cm3 of a 1.2M solution of diisobutylaluminium hydride in toluene is added over 10 minutes at -70° C. to a solution of 1 g of ethyl 4-(ethylthio)-2-methyl-1H-imidazole-5-carboxylate (obtained as in Preparation 1 using, in Stage B, acetyl chloride instead of pentanoyl chloride) in 100 cm3 of methylene chloride. The mixture is agitated for 3 hours at ambient temperature then hydrolyzed by the addition of 1 cm3 of water. After agitation for 15 minutes, then filtering, the insoluble part is washed with 20 cm3 of methylene chloride then 5 times with 20 cm3 of a methylene chloride - methanol mixture (9-1). After drying, the filtrate is brought to dryness under reduced pressure. The residue (760 mg) is impasted in 7.6 cm3 of methylene chloride and 614 mg of the expected product is obtained. M.p.=153° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[O:32][N:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[CH:34]=[C:33]([CH3:35])[O:32][N:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(CN2C[C@@H](C)n3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)no1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 3-(bromomethyl)-5-methylisoxazole, to give the desired product as a yellow oil (76%).