Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[OH:11]>CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]([C:12]2[N:13]=[C:14]([CH3:17])[S:15][CH:16]=2)([OH:11])[CH2:9][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:19][CH:20]=1
Reactant: Cc1nc(C(O)(CBr)c2ccc(F)cc2)cs1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(O)(Cn2cncn2)c2ccc(F)cc2)cs1
Yield: 28.8 %

Procedure:
At 10° C., a solution of 4.1 g (0.06 mol) of 1,2,4-triazole in 30 ml of dimethylformamide is added dropwise and with stirring to a suspension of 1.8 g (0.06 mol) of sodium hydride in 20 ml of dimethylformamide, and, after an hour, a solution of 12.6 g (0.04 mol) of 2-bromo-1-(4-fluorophenyl)-1-(2-methylthiazol-4-yl)-ethanol in 30 ml of dimethylformamide is likewise added dropwise at 0° C. and with stirring. When the addition is complete, the mixture is stirred for an hour at 20° C., for a further two hours at 70° C., for two hours at 90° C. and for a further hour at 110° C. For working up, the reaction mixture is cooled and evaporated in vacuo, the residue is taken up in 300 ml of dichloromethane, the solution is washed twice using 200 ml of water each time, dried over sodium sulphate and concentrated in vacuo the residue is chromatographed over silica gel (eluent: dichloromethane/methanol 10:1), and the product thus obtained is crystallized by stirring with 150 ml of diisopropyl ether. 3.5 g (29% of theory) of 1-(4-fluorophenyl)-1-(2-methylthiazol-4-yl)-2-(1,2,4-triazol-1-yl)-ethanol of melting point 120° C. are obtained.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO.C(N(CC)CC)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:12][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([O:10][CH3:11])[CH:6]=3)[C:3]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (1.28 g, 4.94 mmol, 1.0 equiv) in methanol (9 mL) and triethylamine (0.83 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 5.19 mmol, 1.05 equiv; commercially available) and the reaction stirred at rt overnight. The reaction mixture was poured on crashed ice/diluted HCl, extracted with ethyl acetate, the combined organic phases washed with a sat. solution of NaHCO3 and water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (3:7) yielding 0.84 g (49%) of the title compound as white crystals. MS (ISP): 347.3 [M+H]+.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[CH3:2][C:1]1[NH:23][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [NH4+]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
Ethyl 2-acetyl-4-oxo-4-phenylbutanoate (3.0 g) and ammonium acetate (1.39 g) were added to acetic acid (20 mL), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown solid (yield 1.25 g, 45%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Br)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.72 (1H, s), 7.30-7.32 (2H, m), 7.41 (1H, d, J=0.8 Hz, J=5.2 Hz), 7.52-7.54 (2H, m), 7.56 (1H, d, J=0.8 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.0 Hz). [M+H] Calc'd for C16H11BrN4O, 355. Found, 355.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (170 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (251 mg).
Reaction SMILES: O.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:17]([NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a vigorously stirred solution of 2 g (0.013 mol) of L-asparagine monohydrate and 2.02 g (0.014 mol) of potassium carbonate in 15 ml of water, 1.51 ml (0.013 mol) of benzoyl chloride was added dropwise, over a period of 15 min., at room temperature. The stirring was continued for 2 hour, then the mixture was extracted with 10 ml of ether and the aqueous phase was acidified to pH 2 with concentrated hydrochloric acid. The white precipitate was filtered off, washed with water and purified by crystallization from isopropyl alcohol to give 2.1 g (68% yield) of the title compound at 190-192° C.; NMR (DMSO-d6): 2.62 (m, 2H, CH2); 3.32 (broad s, 1H, OH); 4.72 (m, 1H, CH); 6.64-8.0(m, 7H, aromatic, NH2); 8.6 (d, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:8])[NH:6][CH:7]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccccc1
Reactant: Cc1c[nH]c(=O)c(-c2ccccc2)c1
Product: Cc1cc(-c2ccccc2)c(=O)n(-c2ccccc2)c1
Yield: 77 %

Procedure:
5-Methyl-3-phenyl-2-(1H)-pyridone (B. E. Witzel, et al. Brit. Pat. 1,238,959) is reacted with iodobenzene as in Example 1 to give 1,3-Diphenyl-5-methyl-2-(1H)-pyridone in 77% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Cl)nc(Cl)c2)CCC1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirring solution of 2,4,6-trichloropyridine (1.00 g, 5.48 mmol) and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous THF (27 mL) at −78° C. and under nitrogen was added lithium bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M solution in THF). The cooling bath was removed and stirring continued for 1 h. The reaction was quenched by the addition of sat. aq. NH4Cl, extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the reaction residue was purified by flash column chromatography (100:0 heptanes/EtOAc 85:15 heptanes/EtOAc) to afford the title compound as a white solid (0.995 g, 76%); 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 2H), 2.92-2.80 (m, 2H), 2.68-2.40 (m, 3H), 2.23-2.08 (m, 1H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH:26]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30]([CH:26]5[CH2:29][CH2:28][CH2:27]5)=[O:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (26.6 mg, 78.9%), MS (ISP) m/z=413.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(=O)c1cc(C)c(OCC(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cc(Cl)c1OCC(F)F
Yield: 93 %

Procedure:
The title compound is prepared in 93% yield (0.85 g, yellow oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (0.65 g, 2.61 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:12]=2)[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.O.[H][H]>C(O)C.[Ni]>[C:1]1([CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:12]=2)[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N#CC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: NCC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1

Procedure:
To a solution of the product of Example 2 (70 mg, 0.256 mmol, 1.0 equiv) in ethanol (25 ml) was added concentrated ammonia (0.5 ml) and Raney Nickel (approximately 0.5 ml of the water suspension) and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through Celite® and the mother liquor was concentrated under reduced pressure to give the title compound which was purified by preparative liquid chromatography. (LC/MS: (PS-A) Rt 1.89 [M+H]+278.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]2[O:42][CH2:41][C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=2[CH:49]=1>>[CH3:48][O:47][CH2:46][CH2:45][CH2:44][N:39]1[C:38]2[CH:49]=[C:34]([CH2:33][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]3)[CH:35]=[CH:36][C:37]=2[O:42][CH2:41][C:40]1=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4)cc3)cc21

Procedure:
Analogously to Method D, 1.05 g of tert-butyl 3-hydroxy-4-[4-(3-phenoxypropoxy)phenyl]piperidine-1-carboxylate and 0.735 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.36 (1:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(NC(=O)CCCc2ccccc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (268 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.45 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (575 mg, 83%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(N(C)C)=O>[N:21]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(CBr)ccc1Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(CN=[N+]=[N-])ccc1Cc1ccc(F)cc1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of methyl 5-bromomethyl-2-(4-fluorobenzyl)benzoate (3.8 g), sodium azide (2.9 g) and dimethyl acetamide (50 ml) was stirred under an inert atmosphere for 16 hours. The dimethyl acetamide was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried, evaporated to dryness and purified by flash chromatography using iso-hexane/ethyl acetate (80:20) as eluant to give methyl 5-azidomethyl-2-(4-fluorobenzyl)benzoate (3.23 g) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([C:27]1[C:28]([CH:33]=O)=[N:29][CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)[CH2:33][C:28]2[C:27]([CH:24]([CH3:26])[CH3:25])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B: Reaction of 4-[(5-Chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 3-Isopropyl-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(C2C=CC=CC=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C@H:12]2[CH2:17][CH2:16][Si@H:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:13]2)=[C:4]([F:9])[CH:3]=1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: Oc1ccc(Cl)cc1F
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(Cl)cc2F)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-chloro-2-fluorophenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl>[CH3:31][S:32]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)(=[O:34])=[O:33]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.1 g) in dichloromethane (1 liter) under ice cooling are added triethylamine (52 ml) and then methanesulfonyl chloride (21.6 ml), and the mixture is stirred for 25 minutes. The reaction mixture is acidified with diluted hydrochloric acid and stirred. The organic layer is taken, washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2: 90.0 g) as an organge oil. This product can be used in the next step without further purification. IR ν (CHCl3) cm-1 : 1741, 1703, 1602. 1HNMR δ (CDCl3) ppm: 2.22 to 2.82(2H, m), 3.07(3H, s), 3.67, 3.78(3H, 2s), 3.75 to 4.03(2H, m), 4.55(1H, t, J=7.8 Hz), 5.08 to 5.39(3H, m), 7.43 to 7.58(2H, m), 8.23(2H, d, J= 8.6 Hz).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.S(C1C=CC(C)=CC=1)(O[CH2:12][C@@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1)(=O)=O>CN(C)C=O>[CH3:29][N:15]1[C@H:16]2[C@@H:26]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:28]=3[C:18]([CH2:17]2)=[CH:19][NH:20]4)[CH2:27][C@@H:13]([CH2:12][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH2:14]1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2cccn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
0.7 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.5 g of pyrazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.5 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration, washed with water and recrystallized from dichloromethane-isopropyl ether to obtain 1.7 g of the titled compound as colorless flakes having a melting point of 192°-194° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:47](=[O:71])[CH2:48][CH2:49][N:50]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=1)[C:51](=[O:60])[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[CH2:53]([O:52][C:51]([N:50]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=1)[CH2:49][CH2:48][C:47]([N:27]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:26][CH2:25][N:14]([CH2:13][CH2:12][C:5]1[C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[C:2]([OH:1])=[CH:3][CH:4]=1)[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:71])=[O:60])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(OCc1ccccc1)N(CCNC1CCOCC1)CCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(Cl)CCN(CCc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCOCC1)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of benzyl 2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(2-(tetrahydro-2H-pyran-4-ylamino)ethyl)carbamate (2.5 g), as prepared as in Example 23 step i), in dichloromethane (40 mL) was added triethylamine (2.95 mL) followed by chlorotrimethylsilane (2.69 mL). The reaction was allowed to stir for 30 min before a solution of the acid chloride of step i) (2.198 g) in dichloromethane (20 mL) was added. The reaction was stirred for 2 h before the mixture was diluted with dichloromethane (200 mL), washed with water (150 mL) and saturated sodium hydrogen carbonate (150 mL), and the organic layer was dried over sodium sulphate, filtered and evaporated to afford crude product. This was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (3.10 g) as a off-white foam.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.CI.[C:19]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:19][S:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCc2ccc(S)cc2O1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)C1CCc2ccc(SC)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of ethyl 7-mercaptochromane-2-carboxylate (3.4 g, 14.3 mmol), Methyliodide (3.03 g, 21.4 mmol) and K2CO3 (7.88 g, 57 mmol) in ACN (100 ml) was stirred for 2 h at RT. Filtration and evaporation of solvents gave the title compound (3.28 g). MS m/z (rel. intensity, 70 eV) 252 (M+, bp), 179 (94), 177 (40), 132 (55), 131 (63).