Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.C(O)(=O)C.[ClH:25]>O>[ClH:25].[CH3:20][C:4]([NH2:3])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A mixture of 0.50 gram of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine, 10.7 ml. of glacial acetic acid, 6.7 ml. of water, and 1.07 ml. of concentrated hydrochloric acid is stirred and refluxed for 2.5 hours. The solution is evaporated to dryness and α,α-dimethyl-4-(phenylethynyl)-benzylamine hydrochloride is obtained as a light tan solid. The product is recrystallized from an isopropyl alcohol-methanol-ether mixture to give pure α,α-dimethyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 275°-278° (decomp.).
Reaction SMILES: O.[C:2]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:3].[H][H]>[Ir].CO>[C:7]1([C@@H:5]([OH:6])[CH2:4][C:2]#[N:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: N#CCC(=O)c1ccccc1
Agent: [Ir]
Solvent: O
Solvent: CO
Product: N#CC[C@H](O)c1ccccc1
Temperature: 70 °C

Procedure:
A mixed solvent (volume ratio=1:1, 5 mL) of water and methanol and the iridium aqua complex shown in the following Table 1 (0.5 mol % relative to 2-cyanoacetophenone) were mixed, and 2-cyanoacetophenone (1 mmol) and the hydrogen-donor compound shown in the following Table 1 (5 mmol) were added to the obtained solution at room temperature. The obtained mixture was stirred at 70° C. After confirming the disappearance of 2-cyanoacetophenone by thin layer chromatography, the reaction was quenched with brine (20 mL). The reaction mixture was subjected to extraction treatment (three times) with ethyl acetate (20 mL), and the obtained organic layers were combined. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=20:1) to give (S)-3-phenyl-3-hydroxypropionitrile. The conversion and optical purity are shown in Table 1.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1[N:33]=[C:32]([NH:34][CH:35]([C:42]([O:44][CH3:45])=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31]([C:46]#[N:47])=[CH:30][N:29]=1.C1COC2C=CC(N)=CC=2O1>>[C:46]([C:31]1[C:32]([NH:34][CH:35]([C:42]([O:44][CH3:45])=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:28]([NH:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[N:29][CH:30]=1)#[N:47]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: COC(=O)C(Nc1nc(Cl)ncc1C#N)c1ccccc1
Agent: Nc1ccc2c(c1)OCCO2
Product: COC(=O)C(Nc1nc(Nc2ccc3c(c2)OCCO3)ncc1C#N)c1ccccc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-cyano-N4-(methoxycarbonylbenzyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield 5-cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.23 (s, 1H), 7.41-7.32 (m, 5H), 7.01 (d, 1H, J=3.0 Hz), 6.86-6.71 (m, 3H), 6.54 (bs, 1H), 5.48 (d, 1H, J=6.3 Hz), 4.31 (bs, 4H), 3.68 (s, 3H); LCMS: ret. time: 25.53 min.; purity: 97%; MS (m/e): 418 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10]CC)=O)[N:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][CH3:27].Cl.O>C(O)CO>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:6]([C:8](=[O:10])[NH:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH2:26][CH3:27])[N:7]=1
Reactant: CCOC(=O)c1nc(NC)sc1-c1ccncc1
Reactant: CCN1CCCC1CN
Agent: Cl
Solvent: O
Solvent: OCCO
Product: CCN1CCCC1CNC(=O)c1nc(NC)sc1-c1ccncc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 43.5 %

Procedure:
A mixture of ethyl 2-methylamino-5-(4-pyridyl)-4-thiazolecarboxylate (2.63 g), 2-aminomethyl-1-ethylpyrrolidine (2.6 g) in a mixture of ethyleneglycol (10 ml) and conc. HCl (0.5 ml) was stirred at 80° C. for 6 hours. The reaction mixture was poured into water and the resultant solution was extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on alumina eluting with a mixture of diisopropylether and ethylacetate (1:1) and the fractions containing the desired compound were combined and evaporated in vacuo to give 2-methylamino-5-(4-pyridyl)-4-[(1-ethyl-2-pyrrolidinyl)methylcarbamoyl]thiazole (1.5 g). mp 76°-8° C.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: Cc1cccc(CN)c1C
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2cccc(C)c2C)c(=O)c1=O

Procedure:
Tetrahydrofuran (15 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol), 2,3-dimethylbenzylamine hydrochloride (0.858 g, 5 mmol, prepared according to the procedure of R. Fuller et al., J. Med. Chem., 16 (2), 101 (1973)) and triethylamine (0.506 g, 5 mmol) were refluxed 22.5 hours and then processed in a manner similar to that of Example 4, Step 3, to provide 1.337 g of crude product. Recrystallization (twice) of this material from methanol afforded 0.777 g of the title compound as a white solid: mp 196°-198° C. MS (m/z) 300 (M+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:26][C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:32](I)[CH3:33]>>[CH2:32]([N:29]1[CH:28]=[C:27]([CH2:26][N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])[CH:31]=[N:30]1)[CH3:33]
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Reactant: CCI
Product: CCn1cc(CN(C(=O)C2CCOc3c2cccc3[N+](=O)[O-])c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxamide (2.9 g) and ethyl iodide (1.1 mL) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (2.9 g) was obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:18][N:19]3[CH2:23][CH2:22][N:21]=[CH:20]3)[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Br>CO.C(O)(=O)C>[N:19]1([NH:18][C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]3[C:11]=2[CH2:10][CH2:9][NH:8]3)[CH2:23][CH2:22][N:21]=[CH:20]1
Reactant: Cc1ccc(NN2C=NCC2)c2c1N(C(=O)OC(C)(C)C)CC2
Agent: Br
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(NN2C=NCC2)c2c1NCC2
Yield: 97.4 %

Procedure:
1-t-Butoxycarbonyl-2,3-dihydro-4-(2-imidazolinylamino)-7-methylindole (0.384 g, 1.22 mmol) is dissolved in methanol (10 mL). To this solution is added 30% hydrogen bromide in acetic acid (2.5 mL). The solution is heated to reflux for 2.5 hours. The reaction mixture is concentrated by rotary evaporation and the resulting orange liquid taken up in chloroform. The chloroform solution is treated with 50% NaOH solution and extracted with three 25 mL portions of chloroform. The organic layers are collected and dried over anhydrous potassium carbonate. Filtration and removal of the solvent produces a brownish-orange solid which is purified via silica gel column chromatography using 10% methanol (ammonium hydroxide treated)/methylene chloride as the eluent to afford 0.257 g of 2,3-dihydro-4-(2-imidazolinylamino)-7-methylindole as a light-orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:47])([CH2:41][N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C@H:22]([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=2)[O:27][CH2:26]1)[CH3:23]>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:47])([CH2:41][N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C@H:22]([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[O:36])=[CH:39][CH:40]=2)[O:27][CH2:26]1)[CH3:23]
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: Cc1ccc(NC(=O)c2ccc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)cc2)cc1

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available p-toluidine (128 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (166 mg, yield 96%) as a pale yellow oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClC(Cl)C>[CH:1]1([NH:5][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6](=[O:8])[CH3:7])[CH2:14][CH2:13]3)=[CH:16][C:17]=2[F:23])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
To a solution of cyclobutanamine (1.26 mL, 14.7 mmol) and 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 14.7 mmol) in dichloroethane (50 mL) was added sodium triacetoxyborohydride (4.39 g, 20.6 mmol) followed by acetic acid (0.84 mL, 14.7 mmol) and the reaction was stirred at ambient temperature for 16 hours. 1 N aqueous NaOH was then added to basify the reaction and the product was extracted with Et2O (x3), washed with brine, dried with MgSO4, concentrated and dried in vacuo to give 1-[4-[4[(cyclobutylamino)methyl]-3-fluoro-phenyl]piperazin-1-yl]ethanone (4.76 g, 99% yield). The product was used without purification. LCMS (m/z) ES+ 306 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5].I[CH3:16]>O1CCCC1.O>[CH2:3]([O:6][N:7]([CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCON(C)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
Sodium hydride (NaH, 60% dispersion in mineral oil; 390 mg, 9.7 mmol, 1.1 equiv) was added to a stirred solution of tert-butyl 2-propenyloxycarbamate (2.0 g, 8.8 mmol, 1.0 equiv) in tetrahydrofuran (THF; 23 mL) at 0° C. The resulting bubbling white mixture was warmed to 23° C. and stirred for 15 minutes (min) Iodomethane (660 μL, 11 mmol, 1.2 equiv) was added and the resulting colorless solution was stirred at 23° C. for 18 h. The reaction mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford a yellow oil (1.6 g, 99%): 1H NMR (300 MHz, CDCl3) δ 5.98 (m, 1H), 5.37-5.24 (m, 2H), 4.33 (dt, J=6, 1 Hz, 2H), 3.10 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=O)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH3:10]
Reactant: CCOC(=O)CC(=O)c1cccc(C)n1
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([F:20])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[CH2:7])CCC.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][CH2:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([F:20])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: C=C(OCCCC)c1ccnc2c(F)cc(OC)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c2nccc(C(=O)CBr)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
9.0 g (32.7 mmol) of 4-(1-Butoxy-vinyl)-8-fluoro-6-methoxy-quinoline was dissolved in 200 mL of 3:1 THF/water. 6.4 g of N-bromosuccinimide was added and the contents stirred at rt for 3 hrs. Solvent was then removed by rotary-evaporation. The crude material was purified by flash chromatography on silica gel using 20% ethyl acetate/hexanes as the eluent to give 8.5 g (88%) of the desired product. 1H NMR (CDCl3, 400 MHz) 8.92 (d, 1H), 7.71 (m, 2H), 7.18 (d, 1H), 4.55 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[CH3:1][O:2][N:3]=[C:4]([C:9]([O:11][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH2:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: CON=C(C(C)=O)C(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=NOC)C(=O)OC
Reaction time: 1 h
Yield: 86.5 %

Procedure:
In 15 ml of acetonitrile was dissolved 795 mg of methyl 2-methoxyimino-3-oxobutyrate, followed by addition of 2.1 ml of triethylamine. Then, 1.9 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1 hour for silylation. The reaction mixture was concentrated under reduced pressure and the residue was suspended in 10 ml of carbon tetrachloride and the suspension was filtered in a nitrogen gas stream to remove insolubles. The filtrate was concentrated under reduced pressure to give 1.00 g of methyl 2-methoxyimino-3-trimethylsilyloxy-3-butenoate as oil. Yield 86.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[CH3:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[I-].[K+].C(=O)([O-])[O-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:4][N+:3]=1[O-:10]
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (222 mg, 1.25 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) in tetrahydrofuran (2 mL) were added a solution of 4-methylpiperidine (247 mg, 2.49 mmol) in tetrahydrofuran (1.5 mL), a catalytic amount of potassium iodide, and MP-Carbonate (2.55 mmol/g, 1.47 g, 3.74 mmol). The mixture was gently stirred at room temperature for one week. The mixture was filtered (20 μm polyethylene filter), and the beads were washed with several portions of methylene chloride. The filtrate was washed with NaHCO3 (aq. sat.), dried (Na2SO4), and the solvent was evaporated to give a crude product which was purified by column chromatography using chloroform/ethanol, (95:5), as the eluent to give 168 mg (56% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=1 Hz, 1 H), 7.41 (d, J=8 Hz, 1 H), 7.20 (dd, J=8, 2 Hz, 1 H), 3.41 (s, 2 H), 2.80-2.75 (m, 2 H), 2.00 (dt, J=12, 2 Hz, 2 H), 1.63-1.58 (m, 2 H), 1.45-1.30 (m, 1 H), 1.22 (m, 2 H), 0.92 (d, J=6 Hz, 3 H); MS (ES) m/z 241 (M++1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[C:28]([NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate (Intermediate 73) (0.208 g, 0.77 mmol) and N-ethyldiisopropylamine (0.266 mL, 1.54 mmol) in THF (5 mL) was treated with acetic anhydride (0.102 mL, 1.08 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was partitioned between DCM and sodium bicarbonate solution. The organic layer was concentrated and the residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 40% ethyl acetate/DCM). The desired product, tert-butyl 2-acetamido-1-(4-chlorophenyl)ethylcarbamate (0.151 g, 62.7%), was thus isolated as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[N:28][CH:29]=1)#[N:23].N1CCC(C(O)=O)CC1>>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:12][N:11]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH2:35][CH2:34]2)=[O:37])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Agent: O=C(O)C1CCNCC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 141-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as an orange oil. MS m/e: 524.3 [M]+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:46]1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH3:46])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.3 g, 0.5 mmol), methyl iodide (0.04 g, 0.02 ml, 0.3 mmol), sodium hydride (0.04 g, 1.6 mmol) and 18-crown-6 (0.3 g, 1 mmol) in N,N-dimethylformamide (3 ml) was heated at 60° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 30% ethyl acetate/hexane. The title compound was isolated as a white crystalline solid (285 mg, 97%).
Reaction SMILES: [OH:1][C:2]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:31]([CH3:34])([CH3:33])[CH3:32].[H][H]>[Pd].C(O)(=O)C>[OH:1][C:2]1[C:3]([C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:25][C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)N2CCCN(C(=O)OCc3ccccc3)CC2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C(=O)N2CCCNCC2)cc(C(C)(C)C)c1O
Reaction time: 7 h

Procedure:
A mixture of 46.6 g (0.1 mol) of 1-(4-hydroxy-3,5-di-tert.-butylbenzoyl)-4-benzyloxycarbonylhomopiperazine (Example 1), 350 ml of glacial acetic acid and 2.3 g of palladium black is treated with hydrogen while stirring at 70°-80° C. for about 7 hours. The catalyst is then filtered off, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in methylene chloride, and the solution is extracted by shaking with dilute sodium hydroxide solution and separated off. The organic phase is washed several times with water and then dried over anhydrous sodium sulfate. The residue left after the solvent has been removed in vacuo is recrystallized from acetonitrile with the addition of active charcoal.