Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:5].C1COCC1.[Li]C(CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1CCCCC1>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:2]=[CH:17][CH:16]=[CH:15][C:14]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1NC(=O)c1c(Br)cccc1[Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1ccccc1[Si](C)(C)C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
The compound of Example 120 (0.0021 mol, 0.75 g) and 50 mL THF were cooled to −78° C. in a nitrogen atmosphere with magnetic stirring. 1.3M s-BuLi (0.0026 mol, 2 mL) in cyclohexane was added dropwise. After stirring for 30 min, 25 mL of 25% citric acid were added. The mixture was then extracted three times with ethyl acetate, the extracts combined and washed with brine and twice with water, dried (MgSO4) and concentrated. The title compound was recrystallized as a white solid from ethyl acetate/hexanes in 54% yield. m.p. 117-119° C.
Reaction SMILES: [CH2:1]([C:3]1OCC[N:7]=1)[CH3:2].[NH2:8][NH2:9]>O1CCCC1>[CH2:1]([C:3]1[NH:8][NH:9][C:3]([CH2:1][CH3:2])=[N:7][N:7]=1)[CH3:2]
Reactant: NN
Reactant: CCC1=NCCO1
Solvent: C1CCOC1
Product: CCC1=NN=C(CC)NN1
Temperature: 60 °C

Procedure:
In a nitrogen flushed flask were mixed 2-ethyl-2-oxazoline (99 g, 1 mole) and anhydrous hydrazine (32 g, 1 mole) in 150 ml of tetrahydrofuran. The mixture was heated 2 hours at 60° C. to obtain a yellow solution. The solvent was stripped to give a pale yellow oil. On standing, white crystals formed. They were recrystallized from 2-propanol to give 3,6-diethyl-1,2-dihydro-1,2,4,5-tetrazine as identified by mass spectroscopy, 13C NMR, and infrared analyses, mp 118.5°-119.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:21])=[O:13])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(=O)c1ccc(F)cc1
Yield: 84 %

Procedure:
To a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid (3.0 g, 14.3 mmol) in dry MeOH (50 ml) was added concentrated sulfuric acid (50 mg) and the mixture refluxed under nitrogen for 16 h. The bulk of the MeOH was removed by rotary evaporator and the residue treated with sodium bicarbonate solution (5%, 100 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water (1×100 ml), brine (1×100 ml), dried (Na2SO4) and evaporated to give methyl 5-(4-fluorophenyl)-5-oxopentanoate (2.69 g, 84%) as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 4-bromo-2,6-dimethylaniline (15 g, 75 mmol) (commercially available) and pyridine (16.1 ml, 200 mmol) in anhydrous tetrahydrofuran (150 ml) under an atmosphere of nitrogen was added the solution of 4-fluoro-3-nitrobenzoyl chloride (Step A). The reaction mixture was stirred at ambient temperature for 8 hours. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give N-(4-bromo-2,6-dimethyl-phenyl)-4-fluoro-3-nitro-benzamide (27.54 g, 67% yield) which was used without further purification. LC/MS (Method A): 369 (MH+), 410 (MH++CH3CN).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])=[O:4]>CN(C=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[C:3](=[O:4])[CH2:2][O:12][C:6]=2[CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
CsCO3 (5.36 g) was added in portions over 10 min to an ice cold solution of Example 1109A (3.2 g) in DMF (140 mL). The resulting mixture was stirred for 30 min then diluted with water and extracted with ether (3×). the combined extracts were dried (Na2SO4), and concentrated to give 1.6 g of the title compound. MS ESI(−) m/e 151.1 (M−H)−.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: OC1CCNCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-hydroxypiperidine and pyridine in chloroform. [α]D20=+29.4° (c=1.01, CHCl3), ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: [C:1]([CH:3]([O:33][CH3:34])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)#[N:2].[OH:35]O.[Li+].[OH-:38]>CO>[C:1]([C@@H:3]([O:33][CH3:34])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:35])[NH2:2].[C:1]([C@H:3]([O:33][CH3:34])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:19][CH2:20][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]4)[C:7]=3[C:6]1=2)(=[O:38])[NH2:2]
Reactant: COC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Reactant: OO
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: CO[C@@H](C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)C(N)=O
Product: CO[C@H](C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)C(N)=O
Reaction time: 2 h

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(2-cyano-2-methoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (360 mg, 0.74 mmol, 1.00 equiv) in methanol (10 mL) was added H2O2 (30%, 1 mL) and LiOH (36 mg, 1.50 mmol, 2.03 equiv) in a water/ice bath and the resulting mixture was stirred for 2 h. After completion, the reaction was quenched with saturated aqueous NaHSO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC (eluent with EtOAc/petroleum ether 1:1) to afford tert-butyl N-(4-[[(3R)-3-[(2S)-2-carbamoyl-2-methoxyethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (100 mg) as a colorless oil and tert-butyl N-(4-[[(3R)-3-[(2R)-2-carbamoyl-2-methoxyethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (140 mg) as a colorless oil, respectively. MS (ES): m/z 505 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].CC1C([O:43]CC(F)(F)F)=CC=NC=1CSC1NC2C=CC=CC=2N=1>>[CH3:24][C:8]1[C:9]([CH2:13][S+:14]([O-:43])[C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Yield: 75 %

Procedure:
The experiment described in example 2 was repeated using 48.8 g of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole as substrate instead of Lansoprazole sulfide. 38.3 g of crystallized Rabeprazole are isolated after crystallization and drying (yield 75%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a pressure tube was charged 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-9d, 5.36 g, 12.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.26 g, 13.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (510 mg, 0.62 mmol), 2M Na2CO3 (30 ml) and DME (60 ml). The tube was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was diluted with EtOAc and water, the organic layer was isolated, washed with brine and dried (MgSO4). After the solvent was removed under reduced pressure, the residue was purified on silica. Elution with EtOAc in hexanes (0-25%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Int-9e) (5.76 g, 80%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([O:6][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CCC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a cooled solution of cyclopent-3-enol (30.40 g, 0.36 mol) in THF (300 mL) at 0° C. was added NaH (18.82 g, 0.47 mol, 60% in mineral oil). After effervescence had ceased, benzyl bromide (80.45 g, 0.47 mol) was added dropwise at 0° C. over a 45 min period. The reaction mixture was allowed to warm to RT over a 6 h period. Excess NaH was quenched with MeOH (120 mL) at a temperature below 5° C. The mixture was warmed to RT, diluted with H2O, and the two layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, concentrated, and purified by column chromatography eluting with petroleum ether and EtOAc (PE/EA=40/1 to 30/1) to give the title compound as an oil (45.28 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.41 (m, 2H), 2.49-2.54 (m, 2H), 4.20-4.24 (m, 1H), 4.42 (s, 2H), 5.62 (s, 2H), 7.17-7.28 (m, 5H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[Cl:18].CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:3]([NH:2][CH3:1])=[S:4])=[CH:13][C:12]=1[Cl:18]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N)cc1Cl
Reactant: CN=C=S
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=S)Nc1ccc(C(=O)N[C@@H](Cc2ccc(-c3ccccc3OC)cc2)C(=O)OC)c(Cl)c1
Temperature: 90 °C

Procedure:
Methylisothiocyanate (43 μL) was added to a solution of N-(4-amino-2-chlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (55.1 mg) in anhydrous DMF (1 mL) containing DIEA (22 μL) and DMAP (catalitic amount). The resulting mixture was then heated at 90° C. under N2 for 1 d. After cooling, the mixture was diluted with EtOAc, washed sequentially with 1N HCl, satd. NaHCO3 and water, dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel) using CH2Cl2/MeOH (15:1) as an eluent to give N-[2-chloro-4-(3-methylthioureido)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (22.7 mg). ESMS: m/z 512 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CN(C)C=O.O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CSc1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.6 %

Procedure:
To a suspension of 2-methoxybenzenethiol (10 g, 71.4 mmol) and potassium carbonate (20 g, 143 mmol) in dry N,N-dimethylformamide (100 mL) was added dropwise over 20 mins a solution of bromoacetaldehyde diethyl acetal (10.3 mL, 71.4 mmol) in dry N,N-dimethylformamide (50 mL). The resulting suspension was allowed to stir at room temperature for 45 mins before being diluted with water (500 mL) and extracted with hexane (200 mL). The organic phase was further extracted with brine (4×100 mL), with the resulting organic phase being dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (18.6 g) which was ca 95% pure. This material was further purified by flash chromatography eluting silica gel with hexane:ether [10:1] to give a colourless oil (18 g, 98%). δH (300 MHz, CDCl3) 7.34 (1H, d, Ar), 7.2 (1H, m, Ar), 6.92–6.80 (2H, m, Ar), 4.62 (1H, t, J=7 Hz, CH(OEt)2), 3.85 (3H, s, OCH3), 3.70–3.42 (4H, m, OCH2CH3), 3.10 (2H, d, J=7 Hz, SCH2), 1.12 (6H, t, J=7 Hz, OCH2CH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[OH:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:37]([CH:34]3[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][OH:27])[CH2:32][CH2:33]3)=[O:38])[CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:25][CH:26]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)CO)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 41.4 %

Procedure:
To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (200 mg) obtained in Example 137a, 1-(hydroxyacetyl)piperidine-4-carboxylic acid (129 mg) and triethylamine (127 μL) in acetonitrile (5 mL) were added WSC.HCl (176 mg) and HOBt (140 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), potassium carbonate (317 mg) was added, and the mixture was stirred at room temperature for 3 hr. The solution was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 15→100% ethyl acetate/hexane) to give 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-{[1-(hydroxyacetyl)piperidin-4-yl]carbonyl}piperidin-4-yl]-N-methylbenzamide (108 mg, 41%) as a white powder.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C-:18]#[N:19].[K+]>C(#N)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:18]#[N:19])=[CH:3][CH:4]=2)[N:9]=1
Reactant: [C-]#N
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCCC2)c2ccc(C#N)cc2n1
Yield: 75.2 %

Procedure:
A suspension of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline (1.50 g, 4.43 mmol), potassium cyanide (578 mg, 8.87 mmol), tetrakis(triphenylphosphine)palladium(0) (256 mg, 0.22 mmol), and copper iodide (85 mg, 0.44 mmol) in acetonitrile (10 mL) was refluxed for 90 min. After cooling the mixture was diluted with ethyl acetate, filtered, and the filtrate was washed with brine, dried (Na2SO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (791 mg, 75%). Light brown solid, ISP-MS: m/e=238.3 ([M+H]+).
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:19][CH:20]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:22]
Reactant: N#Cc1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(5,6,7,8-Tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzonitrile (may be prepared as described in Description 11) (assumed 0.148 mmol) was dissolved in dichloromethane (2 ml) and acetic acid (2 drops). Acetone (16 μl, 0.22 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added and the mixture stirred at room temperature for 2 hours. Further aliquots of acetone (32 μl, 0.44 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added and stirring continued for a further 70 hours. Methanol was added and the solution poured onto a 2 g SCX column which was eluted with methanol then 2M ammonia in methanol. The basic fractions were evaporated and the residue purified by flash chromatography eluting with 0-5% 2M ammonia in methanol/dichloromethane to afford the title compound (E34).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]1([O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[C:11]1([O:21][CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: c1ccc2c(OCC3CCCN3)cccc2c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: c1ccc2c(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)cccc2c1

Procedure:
1.6 235 mg of 6-chloropurine, 400 mg of 2(-naphthalen-1-yloxymethyl)pyrrolidine and 0.8 ml of triethylamine are dissolved in 30 ml of 1-butanol and irradiated in the microwave at 120° C. for 6 h. After removal of the solvent in vacuo, the residue is taken up in 10 ml of methanol, the crystals which precipitate in the process are filtered off with suction and washed with methanol, giving 340 mg of colourless crystals 6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine (“A1”); Rt.: 1.806 min; [M+H]+346; m.p. 207-208°;
Reaction SMILES: CO[C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[CH2:22]([Al+]CC(C)C)[CH:23](C)C.[CH:31]([Mg]Br)=[CH2:32]>C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:3]([OH:20])[CH:22]=[CH2:23])=[O:7])([CH3:10])([CH3:11])[CH3:12].[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:3]([OH:20])[CH:31]=[CH2:32])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: C=C[Mg]Br
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Product: C=C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9 %
Yield: 54 %

Procedure:
A solution of 10.25 g (36.7 mmol) Of N-(t-butyloxycarbonyl)phenylalanine methyl ester in 60 ml of toluene was cooled to -78° C. under inert atmosphere and treated dropwise over a period of 45 min with 35 ml (52.5 mmol) of diisobutylaluminum hydride in toluene. The resulting solution was stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesium bromide, and allowed to warm to 0° C. for 16 h. The solution was subsequently quenched cautiously with methanol, treated with aqueous Rochelle salts, stirred for a few min, and filtered. The residue was digested several times with ethyl acetate and filtered; and the combined filtrates were washed with saturated brine, dried over MgSo4, and concentrated. Silica gel chromatography using 20% ethyl acetate in hexane gave 5.46 g (54%) of the desired compound (m.p. 98°-100° C., Rf 0.19, 3:1 hexane:ethyl acetate) along with 0.92 g (9%) of (3R,4S)-4-(t-butyloxycarbonylamino)-3-hydroxy-5-phenyl-1-pentene. 1H NMR (CDCl3) δ 1.39 (s, 9 H), 2.27 (br, 1 H), 2.90 (AA', 2 H), 3.80 (m, 1 H), 4.11 (m, 1 H), 4.79 (m, 1 H), 5.19 (dt, J=11, 1.5 Hz, 1 H), 5.28 (dt, J=18, 1.5 Hz, 1 H), 5.90 (ddd, J=18, 11, 6 Hz, 1 H), 7.15-7.35 (m, 5 H). Mass spectrum: (M+H)+ =2.76.