Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[CH2:24][C:5]([C:4]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=1[O:2][CH3:1])=[O:7]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OC)c1OC

Procedure:
Methyl 2,3,4-trimethoxybenzoate from preparation 1 (2.7 g, 10 mmol) and 3,5-dichloro-4-methylpyridine (prepared according to literature procedures) was dissolved in dry THF (40 mL). The reaction was cooled on ice and treated dropwise (during 5 minutes) with 1M lithium bis(trimethylsilyl)amide (12 mL, 12 mmol). After 1.5 hours at 0° C. the reaction was quenched with NH4Cl (sat, 100 mL). The organic products were extracted with EtOAc (2×100 mL), and the combined organic phases washed with NaCl (sat, 100 mL). The organic phase was dried over Na2SO4, evaporated in vacuo and purified by flash chromatography using a gradient of EtOAc in heptane as eluent. 2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3,4-trimethoxy-phenyl)-ethanone was obtained as a white solid. 1H NMR (CDCl3) δ=8.43 (2H, s), 7.55 (1H, d), 6.69 (1H, d), 4.61 (2H, s), 4.02 (3H, s), 3.87 (3H, s), 3.84 (3H, s). Yield 2.3 g (65%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[NH:26][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g, 4.40 mmol) in methanol (15 mL) were added (trans)-2-phenylcyclopropanamine (0.762 g, 5.72 mmol) and acetic acid (0.252 mL, 4.40 mmol), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (0.415 g, 6.60 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL) and the mixture was concentrated to remove methanol. The resulting aqueous layer was extracted with DCM (3×). The DCM extract was washed with 10% HOAc aqueous solution, dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 720 mg of product as pale yellow oil. MS: (M+H)+=345.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.75 (m, 18H), 1.86-1.95 (m, 1H), 2.35 (dt, J=7.01, 3.69 Hz, 1H), 2.60-2.86 (m, 4H), 4.08 (br. s., 2H), 6.91-7.38 (m, 5H).
Reaction SMILES: [Br:1]Br.[F:3][CH2:4][C:5]([CH2:10][F:11])([CH3:9])[C:6](=[O:8])[CH3:7]>C(Cl)Cl>[F:3][CH2:4][C:5]([CH2:10][F:11])([CH3:9])[C:6](=[O:8])[CH2:7][Br:1]
Reactant: CC(=O)C(C)(CF)CF
Reactant: BrBr
Solvent: ClCCl
Product: CC(CF)(CF)C(=O)CBr

Procedure:
51 ml (1 mol) of bromine were added dropwise to 136 g (1 mol) of 3,3-bisfluoromethylbutane-2-one in 700 ml of methylene chloride such that decoloration was continuous. The solvent was then distilled off under a water pump vacuum. An almost quantitative yield of crude 3,3-bisfluoromethyl-1-bromo-butan-2-one was obtained as an oil, which could be further reacted directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.O=[C:13]([CH3:25])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][N:10]=[C:13]([CH3:25])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(C)=NCC(O)c2cccc(Cl)c2)cc1

Procedure:
2-(3-Chlorophenyl)-2-hydroxyethylamine (24.4 g, 0.142 mol) and methyl 4-(2-oxopropyl)benzoate (26 g, 0.135 mol) were combined and refluxed in 500 ml toluene for 3 hours, collecting formed H2O with a Dean-Stark trap. The reaction mixture was cooled and stripped of solvent to yield intermediate methyl 4-[2-(2-(3-chlorophenyl)-2-hydroxyethylimino)propyl]benzoate.
Reaction SMILES: F.F.F.C(N(CC)CC)C.[C:11]([O:14][C@H:15]1[C@@H:19]([NH:20][C:21]([CH2:23][C:24]2[C:36]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:22])[C@H:18]([CH2:37][O:38][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:17][C@@H:16]1[N:56]1[CH:64]=[N:63][C:62]2[C:57]1=[N:58][CH:59]=[N:60][C:61]=2[Cl:65])(=[O:13])[CH3:12]>O1CCCC1>[C:11]([O:14][C@H:15]1[C@@H:19]([NH:20][C:21]([CH2:23][C:24]2[C:36]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:22])[C@H:18]([CH2:37][OH:38])[O:17][C@@H:16]1[N:56]1[CH:64]=[N:63][C:62]2[C:57]1=[N:58][CH:59]=[N:60][C:61]=2[Cl:65])(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@H]1[C@@H](NC(=O)Cc2cccc3c2Cc2ccccc2-3)[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@@H]1n1cnc2c(Cl)ncnc21
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@@H](NC(=O)Cc2cccc3c2Cc2ccccc2-3)[C@H](CO)O[C@@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine trihydrofluoride (1.6 mL, 9.82 mmol) was added to a stirring solution of 7 (1.54 g, 1.95 mmol) in anhydrous tetrahydrofuran (20 mL) at rt, and the resulting solution was stirred at rt for 24 h, then tlc-grade silica gel was added and volatiles were removed under reduced pressure. The residue was loaded on a tlc-grade silica gel column packed with dichloromethane and eluted with a gradient of dichloromethane to 1:19 methanol/dichloromethane to give 8 as a white solid, containing minor impurities (1.00 g, 93%). A small sample was purified by preparative silica gel tlc (1:19 methanol/dichloromethane) to give pure 8 as a white solid. Rf 0.16 (1:19 methanol/dichloromethane); mp 196-197° C.; [α]D22 +35.78 (c 0.34, CHCl3); UV (MeOH) λmax 264.0, 299.5, 288.5; 1H NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.42 (s, 1H), 7.79-7.75 (m, 2H), 7.59-7.57 (m, 2H), 7.44-7.38 (m, 2H), 7.35-7.29 (m, 2H), 6.22 (d, J=2.2 Hz, 1H), 5.54-5.52 (m, 1H), 5.20 (d, J=8.0 Hz, 1H), 4.87-4.82 (m, 1H), 4.60-4.49 (m, 2H), 4.29-4.19 (m, 3H), 4.00 (d, J=12.0 Hz, 1H), 3.76 (d, J=12.0 Hz, 1H), 2.11 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.5, 156.1, 151.8, 151.3, 150.5, 144.5, 143.4, 141.2, 132.2, 127.7, 126.9, 124.6, 119.9, 88.7, 84.3, 75.5, 66.7, 61.1, 50.5, 47.0, 20.5; Mass ([M+H]+) 550, ([M+Na]+) 572. Anal. Calcd for C27H24ClN5O6: C, 58.97; H, 4.40; N, 12.73. Found: C, 59.05; H, 4.62; N, 12.33.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8].C(OCC)(=O)C>CN(C)C=O>[C:1]([S:3][CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)Br)nc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)SC(C)=O)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Potassium thioacetate (0.54 g, 48 mmol) was added to 7-(1-bromoethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.57 g, 40 mmol) dissolved in dimethylformamide (16 ml), followed by stirring at room temperature for 2 hours. The reaction solution was mixed with ethyl acetate, washed with water and with brine, and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7-(1-acetylthioethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.13 g, 73%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[C:14]=2[N:13]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:12]1=[O:15])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2c([N+](=O)[O-])cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCn1c(=O)n(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (26.7 mg of a 60% dispersion in mineral oil, 0.66 mmol) was added to a solution of tert-butyl (4-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (96 mg, 0.327 mmol) in DMF (5 mL). After 10 min, methyl 4-bromobutyrate (178 mg, 0.98 mmol) was added and the reaction was stirred at room temperature for 18 h. The mixture was quenched with H2O and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=394 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C=NCc1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NCc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 54 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, benzyl isocyanate (0.32 g, 2.41 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 96:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(benzylamino)carboxamide (0.42 g, 54%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.69 (m, 3H), 7.34-7.19 (m, 5H), 6.67 (t, J=5.8 Hz, 1H), 6.60 (t; J=5.9 Hz, 1H) 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H) 4.67 (d, J=5.9 Hz, 2H), 4.23 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.07-2.03 (m, 1H); 13C NMR (DMSO-d6) δ 175.63, 172.75, 167.56, 167.03, 158.05, 141.01, 140.70, 134.61, 133.31, 131.52, 128.19, 126.98, 126.55, 121.66, 48.83, 42.99, 30.93, 21.98; Anal. Calcd. For C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.78; H, 4.53; N, 13.18.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-:26].[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:26])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)nc(Cl)c21
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)[nH]c(=O)c21
Yield: 87.4 %

Procedure:
To a solution of 2,6-dichloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-purine (0.12 g, 0.31 mmol) in dioxane (5 ml) was added aqueous solution of sodium carbonate (0.012 g, 1.24 mmol, in 4 ml water). Reaction mixture was refluxed overnight. Reaction mixture was concentrated and water was added in it and it was extracted with ethyl acetate. Ethyl acetate layer was washed with brine and water, dried over sodium sulphate, filtered and concentrated. Residue obtained was washed with ether to obtained 2-chloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 87%) as white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][CH:25]([CH2:28][C:29]([NH2:39])=[O:30])[CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
Compound 259 (0.077 g, 0.16 mmol) was suspended in DMF (1.5 mL) and 1,1′-carbonyldiimidazole (0.028 g, 0.17 mmol) was added. The reaction was stirred at 70° C. After 1 h, the suspension was cooled to 0° C. and ammonia gas was sparged therein. The tube was sealed and warmed to 70° C. After 1 h, the reaction was diluted in water (30 mL) and filtered. Purification by reversed phase HPLC (10-90% acetonitrile in water with 0.1% TFA) provided compound 260 (0.025 g, 26% yield) as a TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 1.25-1.39 (m, 2 H) 1.70-1.84 (m, 4 H) 1.89 (dt, J=7.27, 3.58 Hz, 1 H) 2.05 (d, J=7.09 Hz, 4 H) 2.14 (br. s., 2 H) 2.27 (d, J=8.31 Hz, 2 H) 2.80 (t, J=10.88 Hz, 2 H) 3.70 (d, J=12.23 Hz, 2 H) 5.52 (quin, J=9.05 Hz, 1 H) 6.80 (br. s., 1 H) 7.31 (br. s., 1 H) 7.74 (br. s., 1 H) 7.98 (br. s., 1 H) 8.05 (br. s., 1 H) 8.13 (d, J=3.91 Hz, 1 H) 8.21-8.28 (m, 1 H) 9.51 (s, 1 H) 11.36 (br. s., 1 H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:17](OC)(OC)OC>>[CH3:15][C:9]1([N:8]2[C:7]3=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]3[N:1]=[CH:17]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(OC)OC
Reactant: CC1(Nc2nc(O)ccc2N)CCCCC1
Product: CC1(n2cnc3ccc(O)nc32)CCCCC1

Procedure:
From 5-amino-6-(1-methylcyclohexylamino)pyridin-2-ol and trimethyl orthoformate, prepared in a similar manner as the one described in Example 1.127, Step D, the title compound was obtained. LCMS m/z=232.20 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ ppm 1.54-1.67 (m, 4H), 1.68-1.76 (m, 2H), 1.83 (s, 3H), 2.22-2.30 (m, 2H), 2.59-2.68 (m, 2H), 6.94 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 9.17 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li].[NH:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][OH:27]>>[OH:27][CH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: OC[C@H]1CCCN1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@@H]1CO

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ from 4′-trifluoromethyl-biphenyl-4-carboxylic acid, lithium salt using (R)-2-pyrrolidine methanol as the amine. MS (ES+) 350.2
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.O.NN>C(O)C>[CH3:1][O:2][CH2:3][C:4]1([NH2:13])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1
Reactant: COCC1(N2C(=O)c3ccccc3C2=O)Cc2ccccc2C1
Agent: NN
Solvent: CCO
Solvent: O
Product: COCC1(N)Cc2ccccc2C1

Procedure:
A mixture of 2-(2-methoxymethylindan-2-yl)-isoindole-1,3-dione (0.30 g, 0.976 mmol) and hydrazine hydrate (47 μl, 0.976 mmol) in 95% ethanol (15 ml) is heated to reflux for 45 hours. Further hydrazine hydrate (9.4 μl, 0.976 mmol) is added and the reaction refluxed for an additional 16 hours, followed by addition of a final portion of hydrazine hydrate (9.4 μl, 0.976 mmol) and a further 16 hours reflux. After cooling, the resultant suspension is filtered and the filter cake washed with ethanol. The combined filtrate and washings are evaporated and triturated with ether to afford 2-methoxymethylindan-2-ylamine, MH+178.
Reaction SMILES: [ClH:1].Cl.Cl.[N:4]1([C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:19][N:18]3CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)[CH:8]=[CH:7][N:6]=[CH:5]1>[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[ClH:1].[N:4]1([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:19][NH:18]3)=[O:14])=[CH:36][CH:37]=2)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=C(NCC1CN(c2ccccc2)CCN1Cc1ccccc1)c1ccc(-n2ccnc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: O=C(NCC1CN(c2ccccc2)CCN1)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Example 1, react 4-(1H-imidazol-1-yl)-N-[[4-phenyl-1-(phenylmethyl)piperazin-2-yl]methyl]benzamide trihydrochloride (12.3 g, 22 mmol) with H2 over Pd(OH)2 (1.5 g) catalyst to give the title compound.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@H:17]2[CH2:21][C:20](=[O:22])[C@H:19]([OH:23])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@@H:19]1[CH2:18][C@@H:17]([C@@:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8](=[O:10])[O:9][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:6]2)[CH2:21][C:20]1=[O:22])(=[O:26])[CH3:25]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@H]2CC(=O)[C@H](O)C2)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C[C@@H]([C@]2(c3ccccc3)O[C@@H](C(C)(C)C)OC2=O)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 32 mg of (2R,5R)-2-(t-butyl)-5-((1R,3R)-3-hydroxy-4-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 1 ml of pyridine, 0.5 ml of acetic anhydride was added, followed by 1 hour's stirring at room temperature. The reaction liquid was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/acetone=20/1) to provide 27 mg of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnccc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Pyridin-4-yl-carbamic acid tert-butyl ester (1.74 g, 8.95 mmol) (prepared as described in Venuti et al, J. Med. Chem. 1988, 31(11), 2136-45) dissolved in THF (150 mL) was cooled to −78° C. and a solution of 1.7M tert-butyllithium in hexanes (11.6 mL, 19.70 mmol) was added dropwise. After the addition, the stirring was continued for 1 h to −78° C. and the solution was then allowed to warm to −20° C. and stirred for an additional 3 h. The reaction was cooled again to −78° C. and tributyltin chloride (2.91 mL, 10.74 mmol) was added dropwise and the reaction was allowed to reach room temperature overnight. A saturated ammonium chloride solution was added and the product extracted with dichloromethane. The combined organics were dried over magnesium sulfate, the solvent was evaporated and residue purified by flash chromatography eluting with 20% ethyl acetate in hexanes to yield 2.12 g of (3-tributylstannyl-pyridin-4-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(N(CC)CC)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrite (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])(=O)=O.[O:28]=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[N-:30]1.[K+].O>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][N:30]1[C:31](=[O:38])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]1=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.1 %

Procedure:
To a solution of (E)-6-(2-(tert-butoxycarbonylamino)phenylamino)-6-oxohex-4-enyl methanesulfonate (1) (200 mg, 0.5 mmol) in DMF was added potassium 1,3-dioxoisoindolin-2-ide (111 mg, 0.6 mmol), the mixture was stirred at RT for 12 hours. The mixture was poured into 100 mL water, then extracted with MTBE (25 mL×2), and the organic layers were washed with water (25 mL×3) and brine (3×20 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-tert-butyl 2-(6-(1,3-dioxoisoindolin-2-yl)hex-2-enamido)phenylcarbamate (3) (135 mg, yield 60%) as a yellow oil after purification by column chromatography on silica gel (eluent: PE:EA=1:1). LC-MC found 450 (M+H)+.