Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]4[C:2]([O:26][CH3:25])=[N:3][CH:4]=[CH:5][CH:6]=4)=[N:9][N:10]=3)[CH:13]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2ccc3nnc(-c4cccnc4Cl)n3c2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2ccc3nnc(-c4cccnc4OC)n3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A mixture of 3-(2-chloropyridin-3-yl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (178 mg, 0.53 mmol) and sodium methoxide (518 mg, 9.6 mmol) in methanol (60 mL) was heated to reflux for 16 h under Argon. The reaction mixture was cooled to room temperature and concentrated. The residue was mixed with DCM (60 mL) and water (60 mL), and it was separated and the organic layer was washed with brine (50 mL×2) and concentrated. The residue was stirred at room temperature for 0.5 h in petroleum ether (35 mL) and ethyl acetate (5 mL) and filtered. The solids were dried in vacuo to give the title compound (150 mg, 84.0% yield). 1H NMR (DMSO-d6): 8.47 (dd, J=4.8 and 1.8 Hz, 1H), 8.32 (m, 1H), 8.10 (dd, J=7.2 and 1.8 Hz, 1H), 7.94 (dd, J=9.6 and 0.9 Hz, 1H), 7.79 (dd, J=9.6 and 1.5 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.27 (dd, J=7.5 and 5.1 Hz, 1H), 7.05 (d, J=9.0 Hz, 2H), 3.95 (s, 3H), 3.80 (s, 3H). MS: m/z 333.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.[N+:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:34])=[O:33]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][CH:35]([N+:32]([O-:34])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1CCCC1CCC(c1ccccc1)[N+](=O)[O-]
Temperature: -2 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 200 mg (1.460 mmol) 2-(2-bromo-ethyl)-pyrrolidine-1-car boxylic acid tert-butyl ester (CAS: 958026-65-8) in 4.3 ml tetrahydrofuran over mol-sieves and 851.0 ul HMPA, was added drop-wise 1.92 ml (3.064 mmol) n-BuLi (1.6 M in hexane). After 45 minutes at −78° C., a solution of 406.2 mg (1.460 mmol) nitromethyl-benzene in 0.6 ml tetrahydrofuran over mol-sieves was added drop-wise. After 1 hour at −78° C., the reaction mixture was allowed to warm up slowly (during 5 hours) to −2° C. The mixture was then cooled again to −78° C. and quenched at this temperature with 0.4 ml of acetic acid, then with 8 ml saturated ammonium chloride. Back to room temperature, the aqueous phase was extracted 2 times with ethylacetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (993 mg) was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 15%) to provide 242 mg (y: 49.6%) of the title compound as a colorless oil. MS (m/e): 335.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-6-trifluoromethyl-pyrimidine (90 mg, 0.41 mmol) in n-butanol (1 mL), was added 4-chloro-phenylamine (52 mg, 0.416 mmol) and DIPEA (72 uL, 0.416). The mixture was stirred at 100° C. for overnight. The LC-MS showed the desired product mass [MS:(ESI), M/Z, 308 (M+1). Retention time: 2.70 min (FA-polar)]. This intermediate was used in situ without purification.
Reaction SMILES: NC1C=CC(OCC2C=CC(Cl)=CC=2)=CN=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=1>>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][O:33][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:30][CH:29]=1
Reactant: OCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Br)cc2)nc1

Procedure:
The substituted amino-pyridine compounds of formula (I) wherein W is oxygen can be prepared by the reaction of a hydroxy-nitropyridine with a substituted phenalkyl halide to obtain the corresponding substituted nitro-pyridine which is reduced to the desired substituted amino-pyridine of formula (I). For example, the reaction of 5-hydroxy-2-nitropyridine and 4-chlorobenzyl bromide gives 5-(4-chlorobenzyloxy)-2-nitropyridine which is then reduced to 2-amino-5-(4-chlorobenzyloxy)pyridine of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitropyridine with a substituted phenalkyl alcohol or substituted phenalkyl thiol followed by reduction of the nitro group. For example, the reaction of 2-chloro-5-nitropyridine and 4-bromobenzyl alcohol gives 2-(4-bromobenzyloxy)-5-nitropyridine which is then reduced using, for example, iron powder to give 5-amino-2-(4-bromobenzyloxy)pyridine of formula (I).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][CH:6]=1)=[O:4].[Br:16]NC(=O)CCC(N)=O.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][Br:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1ccc(C)c2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c2ccccc12
Yield: 69.4 %

Procedure:
To a stirred solution of 4-methyl-naphthalene-1-carboxylic acid methyl ester (Preparation 50, 10.85 g, 54.18 mmol) in CCl4 (500 mL) was added N-bromosuccinamide (9.93 gm, 55.81 mmol) followed by AIBN (0.1 g, 0.612 mmol) at room temperature. Resulting reaction mixture was refluxed for 3 hours. Progress of reaction was monitored by TLC using 5% EtOAc in hexane. Rf of new spot and starting material was 0.8 and 0.7 respectively. After consumption of starting material, reaction mixture was concentrated in vacuo to residue. Residue was dissolved in EtOAc (300 mL) and washed with water (2×300 mL), brine (300 mL), dried over sodium sulphate and evaporated in vacuo to get pale yellow semisolid. Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4% EtOAc in hexane to afford white solid (10.5 g, 69.39%). 1H NMR (400 MHz, CDCl3) δ: 4.00 (s, 3H), 4.93 (s, 2H), 7.56 (d, J=7.48 Hz, 1H), 7.62-7.68 (m, 2H), 8.06 (d, J=7.4 Hz, 1H), 8.17-8.20 (m, 1H), 8.90-8.93 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH:24][CH2:25][C@@H:26]1[N:30]([CH3:31])[C:29](=[O:32])[CH2:28][CH2:27]1>C(Cl)(Cl)Cl.O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:24][CH2:25][C@H:26]2[CH2:27][CH2:28][C:29](=[O:32])[N:30]2[CH3:31])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)CC[C@@H]1CO
Agent: CN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (5.26 mL), trimethylamine hydrochloride (1.07 g) and 4-methylbenzenesulfonyl chloride (5.6 g) were sequentially added to a solution of (R)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (2.93 g, 48.3 g, described in J. Med. Chem., 34(3), 1991, 887-900) in chloroform (40 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure to give (R)-(1-methyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate as a yellow amorphous (6.6 g).
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:10]#[N:11])[C:7]([NH2:9])=[O:8])SC.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[NH:21][NH2:22].O>CO>[NH2:11][C:10]1[N:21]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][C:15]=2[Cl:20])[N:22]=[C:3]([S:2][CH3:1])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CO
Solvent: O
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Yield: 81.5 %

Procedure:
A mixture of bis(methythio)methylenecyanoacetamide (7.800 g, 50 mmol) and 2,4,6-trichlorophenylhydrazine (10.575 g, 50 mmol) in 250 ml of methanol was heated at reflux for 2.5 hours. The mixture was cooled and water was added. Precipitate formed and filtered to give 14.323 g (81.5% yield) of the title compound as a white solid. 1H NMR(CDCl3): 2.6 (s,3H), 5.5(brs, 2H), 7.5(s,2H) ppm. Recrystallization of a small portion of the solid from chloroform gave white crystals; m. p. 198-199° C. Anal. Calc. for C11H9Cl3N4OS: C, 37.57; H, 2.58; N, 15.93; Found: C, 37.54; H, 2.51; N, 15.73.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(c(=O)n(COC(=O)C(C)(C)C)c(=O)n3COC(=O)C(C)(C)C)n2-c2ccccc2Cl)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
4-[7-(2-Chlorophenyl)-1,3-bis-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (2.227 g) was dissolved in tetrahydrofuran (10 ml) and methanol (20 ml), and 1,8-diazabicyclo[5,4,0]undec-7-ene (0.518 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, and 1 N hydrochloric acid was added. Deposited solid was collected by filtration and dried to give 1.025 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH:6]=[N:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11].[BH4-].[Na+]>CO>[CH3:20][O:19][C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13]
Reactant: COc1cc(C=NCC(OC)OC)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCC(OC)OC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Imine (11c, 14.47 g, 0.05112 mol) was dissolved methanol (100 mL) and NaBH4 (2 g×3) was added over 5 h while stirring the reaction mixture at room temperature. After 3 h the TLC indicated there still was starting material and more NaBH4 (2 g) was added. The reaction did not go to completion leaving 25% of the starting material unreacted. The reaction was quenched with methanol (200 mL) and the reaction mixture was concentrated and then diluted with chloroform (300 μL) and filtered to remove the precipitate. The filtrate was washed with water (4×200 mL), brine (200 mL), dried (Na2SO4), and concentrated. The mixture was dissolved in ethanol (100 mL) and NaBH4 (2.5 g) was added. The reaction was stirred at room temperature for 4 h and then it was heated for 12 h at 80° C. The reaction mixture was diluted with methanol (50 mL) and concentrated. It was then dissolved in chloroform (250 mL) and washed with water (2×300 mL), brine (250 mL), dried (Na2SO4), and concentrated to provide a yellow oil (14.57 g, 100%). 1H NMR (300 MHz CDCl3) 6.47 (s, 2H), 4.39 (t, J=5.4 Hz, 1H), 3.76 (s, 6H), 3.73 (s, 3H), 3.65 (s, 2H), 3.28 (s, 6H), 2.65 (d, J=5.4 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:62]=[CH:61][C:12]([C:13]([N:15]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:59]=[CH:58][C:35]4[N:36](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:37]=[N:38][C:34]=4[CH:33]=3)[CH:29]=[CH:28][C:27]=2[F:60])[CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH:36]1[C:35]2[CH:58]=[CH:59][C:32]([C:30]3[CH:29]=[CH:28][C:27]([F:60])=[C:26]([CH:31]=3)[CH2:25][N:15]([CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]3)[C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:62][CH:61]=3)=[CH:33][C:34]=2[N:38]=[N:37]1
Reactant: CC(C)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc4[nH]nnc4c3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
Trifluoroacetic acid (TFA, 0.25 mL) was added to a solution of 4-fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-(1-isopropyl-piperidin-4-yl)-benzamide (18 mg, 0.024 mmol) in 1 mL of dichloromethane and the resulting mixture stirred at ambient temperature for 3 h, when an additional 0.5 mL of TFA was added. This was stirred overnight and then the mixture was neutralized by the careful addition of 1M sodium carbonate. The layers were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and the volatiles were removed in vacuo to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 6.5 mg of product. LC/MS: Retention time, 2.25 min; (M+H)=490.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[O:7][CH:8]=[C:9]([C:11]([NH:13][CH2:14][C@@H:15]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=3)=[N:18]2)[CH3:16])=[O:12])[N:10]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([C@@H:15]([CH3:16])[CH2:14][NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[O:7][CH:8]=3)=[O:12])[N:18]=2)[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: CC(=O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Sodium borohydride (0.051 g, 1.352 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-2-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)oxazole-4-carboxamide (0.269 g, 0.676 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted below 7 and the mixture was evaporated. 5% of DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 84%. 1H-NMR (400 MHz; CDCl3): δ 1.58 (d, 3H), 1.61 (d, 3H), 2.40 (d, 1H), 3.79 (m, 1H), 3.89 (m, 1H), 4.62 (m, 1H), 4.94 (m, 1H), 6.61 (d, 1H), 7.46 (m, 1H), 7.49 (d, 1H), 7.69 (d, 1H), 7.85 (dd, 1H), 7.98 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Mg].II.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[C:28]([C:34]#[N:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[C:34]([CH:28]([CH:25]1[CH2:24][CH2:23][N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:27]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:26]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:35]
Reactant: Brc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1CCN(Cc2ccccc2)C(c2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
2-Bromonaphthalene (26 g) was dissolved in anhydrous diethyl ether (100 ml) and 1/5 of this solution added to a vigourously stirred mixture of magnesium turnings (3.3 g) and 2-3 iodine crystals under a nitrogen atmosphere. Gentle heating was applied to initiate formation of the Grignard reagent since it proved difficult to maintain spontaneous refluxing. The remainder of the 2-bromonaphthalene solution was added in 4 portions, allowing the refluxing to subside after each addition, and the mixture finally heated under reflux for 1 hour after which time two dark organic phases had formed. The mixture was cooled in an ice-bath and anhydrous tetrahydrofuran (50 ml) added followed by dropwise addition of a solution of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate (12 g) (see Preparation 2) in tetrahydrofuran (100 ml). The single phase mixture was stirred at 0° C. for 30 minutes before being left to stand at room temperature overnight. The mixture was then poured into saturated aqueous ammonium chloride solution (450 ml) and extracted twice with diethyl ether. The organic extracts were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 4:0 changing to 4:1, by volume, dichloromethane:diethyl ether to give the title compound (5.9 g) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1
Yield: 74.5 %

Procedure:
Reaction of 4-aminoacetophenone (74 mg, 0.55 mmol) in THF (6 mL) with p-anisoyl chloride (90 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-4-methoxy-benzamide (110 mg, 0.41 mmol, 75% yield) as a white powder after washing by dichloromethane.
Reaction SMILES: O[CH:2]([C:6]1[C:7]([O:12][CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH:4]=[CH2:5].[Cl:14]CCl.S(Cl)(Cl)=O>>[Cl:14][CH:2]([C:6]1[C:7]([O:12][CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCC(O)c1cccnc1OC
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCC(Cl)c1cccnc1OC
Yield: 93.8 %

Procedure:
56.5 g (0.32 mol) of the compound from Example I are stirred in 400 ml of anhydrous dichloromethane containing 277 ml (3.8 mol) of thionyl chloride overnight at 20°-30° C. Subsequently, dichloromethane and unreacted thionyl chloride are removed in a water pump vacuum at 20°-30° C. The residue is partitioned between dichloromethane and aqueous saturated sodium bicarbonate solution. The organic phase is separated off, dried and evaporated in vacuo. 59.3 g of the crude title compound are obtained as an oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([N:16](CC)CC)C.N#CBr>C1COCC1>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)CC
Agent: N#CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (25 g, 134.2 mmol) was taken into THF (100 mL) followed by addition of triethylamine (25 mL, 178 mmol). The solution was cooled to 0° C. follwed by addition dropwise addition of cyanogen bromide (15.6 g, 147.6 mmol) in THF (100 mL) and the resulting mixture was allowed to warm to room temperature then stirred an additional 12 hours. The reaction mixture was concentrated in vacuo and partitioned with ethyl ether and water. The organic layer was washed once with saturated aqueous NaCl then dried over anhydrous magnesium sulfate followed by concentration to afford 1,1-dimethylethyl 4-cyanopiperazine-1-carboxylate (24.5 g, 86% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 3.51 (tr, 4H), 3.19 (tr, 4H), 1.46 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3](=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[CH2:2]=[C:3]1[CH2:4][C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C=C1CC1(C(=O)OCC)C(=O)OCC
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
Compound 5 (43.4 g, 0.156 mol) from Example 1 was added to a vigorously stirred refluxing solution of potassium tert-butoxide (17.5 g, 0.156 mol) in tert-butyl alcohol (500 mL) under nitrogen. The stirring was continued for 15 min. and the mixture was immediately cooled in an ice bath. Acetic acid was then added, the solid portion was filtered off and thoroughly washed with ether. The filtrate was concentrated in vacuo, diluted with ether and the organic layer was washed several times with water. After drying with magnesium sulfate, the solution was evaporated in vacuo and the residue was distilled, bp. 99-93° C./0.3 torr, yield 14.8 g (47%) of a 1:1 mixture of 4+6. This mixture was chromatographed on a silica gel column using first hexanes-ether (40:1) and then (20:1) to give product 6 (7.3 g, 23%) as a colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH:1]=[CH:13][S:10]2(=[O:12])=[O:11])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Nc1ccccc1C=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CN2c3ccccc3C=CS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. To a solution of N-(2-formylphenyl)methanesulfonamide (2.0 g, 10 mmol) in anhydrous acetonitrile (45 mL) was added cesium carbonate (6.5 g, 20 mmol) and 4-methoxybenzylchloride (2.7 mL, 20 mmol). The mixture was heated to 50° C. and stirred for 48 hours, diluted with ethyl acetate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (50-100% methylene chloride in hexanes) to give the product (0.9 g, 31%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.32 (m, 2H), 7.28-7.24 (m, 3H), 7.16-7.11 (m, 2H), 6.85-6.81 (m, 3H), 5.15 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:9][CH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@@H:2]1[OH:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CNCc2ccccc2)[C@@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@@H](O)C1

Procedure:
A mixture of intermediate (60) (0.016 mol) in methanol (150 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst at a temperature of 50° C. After uptake of hydrogen (1 equivalent) the catalyst was filtered off and the filtrate was evaporated, yielding 1,1-dimethylethyl(3R-trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 61).