Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[C:5](=[O:16])[CH2:6][CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[OH:20]O>CCO.[OH-].[Na+]>[CH:17]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:16])[CH2:6][CH:7]([C:14](=[O:20])[NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N(C(=O)CC(C#N)c1ccccc1)C(C)C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(C(=O)CC(C(N)=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropyl-3-cyano-3-phenylpropanamide (21.1 g, 82 mmol) was dissolved in EtOH (130 mL) and 2 M NaOH (100 mL). Hydrogen peroxide (30%, 20.2 mL, 200 mmol) was added and the mixture was stirred at ambient temperature for two hours. The resulting precipitate was filtered, washed with water and dried, yielding the title compound as white crystals, 15.6 g (69%): 1H NMR (CDCl3) δ1.09 (d, 3H), 1.19 (d, 3H), 1.31 (m, 6H), 2.51 (dd, 1H), 3.30 (dd, 1H), 3.41 (m, 1H), 4.02 (m, 1H), 4.18 (dd, 1H), 5.7 (br, 1H), 6.4 (br, 1H), 7.21-7.42 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[CH:17]([O-])([O-])OC>N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:12][CH3:17])/[CH3:11])([O-:3])=[O:2]
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)Nc1cccc([N+](=O)[O-])c1
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CO/C(C)=C\C(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A mixture of 33 g of m-nitro-acetylacetanilide, 38.1 g of methyl orthoformate and 13 drops of 36° Be sulfuric acid was allowed to stand for 16 hours and after the addition of 40 drops of quinoline and 150 ml of toluene, the mixture was heated to 130° C. while distilling of the methanol formed as an azeotrope. The mixture was cooled and vacuum filtered and the recovered precipitate was crystallized from acetone to obtain 24 g of m-nitro-3-methoxy-crotonanilide melting at 187° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]3[C:21]4[CH:36]=[C:35]([Br:37])[CH:34]=[N:33][C:22]=4[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:19]=3[CH:18]=[N:17][C:16]=2[C:38]#[N:39])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:27]1([S:24]([N:23]2[C:19]3[CH:18]=[N:17][C:16]([C:38]#[N:39])=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20]=3[C:21]3[CH:36]=[C:35]([Br:37])[CH:34]=[N:33][C:22]2=3)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Yield: 83.4 %

Procedure:
To a solution of 4-(9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy)piperidine-1-carboxylic acid tert-butyl ester (12.6 g, 20.6 mmol) in dichloromethane (36 mL) was added TFA (36 mL). After 1 hour at ambient temperature the reaction mixture was concentrated in-vacuo and the residue partitioned between saturated aqueous sodium carbonate solution (800 mL) and dichloromethane (2 L). The organic phase was separated, dried (Na2SO4), filtered and evaporated in-vacuo to afford the title compound as an off-white solid (8.8 g, 84%) which was used without further purification. 1H NMR (300 MHz, DMSO-d6): 9.46 (s, 1H), 8.90 (d, J=2.3 Hz, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.78 (t, J=7.4 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 4.85-4.85 (m, 1H), 3.17 (s, 1H), 3.00 (dt, J=13.0, 4.1 Hz, 2H), 2.50-2.49 (m, 2H obscured by solvent peak), 2.15-1.97 (m, 2H), 1.75-1.75 (m, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1.S(=O)(=O)(O)O>>[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]=[C:14]1[NH:15][CH2:16][CH2:17][NH:18]1
Reactant: Cc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)c(N=C2NCCN2)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6.4 gm (0.0234 mol) of 2-(2-chloro-4-methyl-phenylimino)-imidazolidine nitrate were added slowly over a period of 15 minutes to 10 ml of concentrated sulfuric acid at 20° C., while slightly cooling and vigorously stirring. The viscous reaction mixture was allowed to stand at room temperature for two hours, whereupon ice was added thereto, and the precipitate formed thereby was filtered off, recrystallized from methanol and dried. Yield: 2 gm (33.5% of theory) of 2-(2-chloro-4-methyl-5-nitro-phenylimino)-imidazolidine, m.p. 198°-201° C.; Rf -value 0.7 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol and 5 parts ammonium hydroxide; carrier: silicagel G; visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2([CH:31]=O)[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:36]=[C:37]([CH2:45][NH2:46])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.C(=O)([O-])O.[Na+]>ClC(Cl)C>[C:15]1([C:21]2([CH2:31][NH:46][CH2:45][C:37]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:35]([C:34]([F:33])([F:47])[F:48])[CH:36]=3)[CH2:30][CH2:29][C:24]3([O:25][CH2:26][CH2:27][O:28]3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: FC(F)(F)c1cc(CNCC2(c3ccccc3)CCC3(CC2)OCCO3)cc(C(F)(F)F)c1
Yield: 47 %

Procedure:
Sodium triacetoxyborohydride (4.77 g, 22.5 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599). (1.1 g, 4.5 mmol) and 3,5-bis(trifluoromethyl)benzenemethanamine (1.1 g, 4.5 mmol) in dichloroethane (50 mL) and the mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25), to give the title compound as a yellow oil (1.0 g, 47%). m/z (ES+) 473 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([O:16]C)=O)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][C:14]([C:12]1[N:13]=[C:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[NH:9][C:10](=[O:19])[C:11]=1[OH:18])=[O:16]
Reactant: CN
Reactant: COC(=O)c1nc(CC2CCCCC2)[nH]c(=O)c1O
Solvent: CO
Product: CNC(=O)c1nc(CC2CCCCC2)[nH]c(=O)c1O
Temperature: 140 °C
Yield: 36.7 %

Procedure:
A mixture of methyl 2-(cyclohexylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (30 mg, 113 μmol), methylamine (2M in THF) (1.5 ml, 3.00 mmol) and MeOH (10 ml) was heated in a microwave oven at 140° C. for 40 min. The cooled reaction mixture was concentrated in vacuo. The residue was heated in a mixture of MeOH and Amberlyst until all the product had dissolved. The resin was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.011 g; 35% with 95% purity). LCMS: m/z=266 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14]C)=O>C(#N)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:10]=[CH:11][C:12](=[O:14])[NH:1]2)=[CH:4][CH:5]=1
Reactant: COC(=O)/C=C/c1ccc(OC)cc1N
Solvent: CC#N
Product: COc1ccc2ccc(=O)[nH]c2c1
Yield: 84.9 %

Procedure:
A solution of methyl(2E)-3-(2-amino-4-methoxyphenyl)acrylate (Intermediate 4, 500 mg, 2.4 mmol) in acetonitrile (600 mL) was deoxygenated under vacuum, purged with nitrogen and irradiated at 365 nm with a long wave UV lamp (B-100AP, Blak Ray) for 28 hours. The solvent was removed under reduced pressure and the product was precipitated from dichloromethane (20 mL) by the addition of hexanes (100 mL) to give 357 mg (76% yield) of the crude product as a colorless solid, 90% pure by 1H-NMR (together with 10% dimer), mp 190° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]2[O:16][CH2:18][CH2:19][CH2:20][N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCOc2c(Br)cccc21
Temperature: 75 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl (3-bromo-2-hydroxyphenyl)carbamate (D52) (3 g, 10.41 mmol) in acetone (30 mL) was added 1,3-dibromopropane (3.17 mL, 31.2 mmol), K2CO3 (11.51 g, 83 mmol) and the mixture stirred at 75° C. for 16 hours. The reaction was then cooled to RT, filtered, the filtrate was evaporated. The residue was then purified on silica eluting with a gradient of 0-10% ethyl acetate in cyclohexane to afford the title compound (2.2 g). LCMS (A): m/z (M+H)+328/330, C14H18BrNO3 requires 327/329 (acidic).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:15][S:16]([O:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1)(=[O:18])=[O:17]
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of cis 3-((benzyloxy)methyl)-1-cyclobutanol (2.50 g, 0.0130 mol) in pyridine (50 mL) was cooled to 0° C. Methanesulfonyl chloride (1.21 mL, 1.79 g, 0.0126 mol) was added dropwise, keeping the temperature below 2° C. The mixture was stirred for four hours, and then poured into ice water (100 mL) and extracted with ethyl ether (2×50 mL). The combined organic layers were washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give cis 3-[(benzyloxy)methyl]cyclobutyl methanesulfonate (2.73 g, 0.0101 mol) as a yellow oil.
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4])[NH2:2].[CH2:18]([O:25][N:26]1[C:32](=[O:33])[N:31]2[CH2:34][C@H:27]1[CH2:28][CH2:29][C@H:30]2[C:35](O)=[O:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:18]([O:25][N:26]1[C:32](=[O:33])[N:31]2[CH2:34][C@H:27]1[CH2:28][CH2:29][C@H:30]2[C:35]([NH:2][NH:1][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:4])=[O:36])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl [(1R,2R)-2-(hydrazinylcarbonyl)cyclopentyl]carbamate 285 (0.15 g, 0.54 mmol) in 20 mL of DCM were added compound 1 (0.2 g, 0.82 mmol), HOBt (0.11 g, 0.82 mmol), DMAP (0.2 g, 1.64 mmol) and EDCI (0.16 g, 0.82 mmol). The mixture was stirred at room temperature for 18 h and purified by column chromatography to afford compound 286 as a solid (0.22 g, 82%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:26])=[C:13]([CH:25]=1)[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH3:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:26][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:25][C:13]=1[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH3:16]
Reactant: C[C@@H](Nc1cc(O[Si](C)(C)C(C)(C)C)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Nc1cc(O)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
To a stirred solution of (R)-5-(t-butyldimethylsilyloxy)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)aniline (18.5 g, 43.0 mmol) in anhydrous tetrahydrofuran (THF) (100 mL) at 0° C. was added a solution of tetrabutylammonium fluoride (TBAF) (1 M solution in THF, 43.0 mL, 43.0 mmol). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature and stirred for an additional 4 h. The reaction mixture was diluted with deionized water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with deionized water, brine, dried (Na2SO4), filtered, and concentrated in vacuo to give (R)-4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenol as a brown solid (15.3 g). The solid compound was carried to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:22](=[O:40])(=[O:39])[NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C@H:28]4[CH2:38][C@H:29]4[CH2:30][O:31][C:32]=3[C:33]=2[C:34]([O:36][CH3:37])=[O:35])=[C:6]([CH:21]=1)[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.F[C:42](F)(F)[C:43](O)=O>C(Cl)Cl>[CH2:42]([C@H:7]([O:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6]1[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:22]([NH:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([C@H:28]3[CH2:38][C@H:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:40])=[O:39])[CH3:43]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](OC1CCNC1)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (S)-3-[(1aR,7bS)-5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyloxy]pyrrolidine-1-carboxylate (Intermediate 214, 0.284 g) in trifluoroacetic acid (4 mL) and DCM (4 mL) was left at room temperature for 30 minutes. The mixture was evaporated in vacuo and the residue was azeotroped with toluene. The residue was dissolved in DCM (4 mL) and acetaldehyde (0.044 g) was added followed by sodium triacetoxyborohydride (0.212 g). The mixture was stirred at room temperature for 1 hour. The resulting solution was diluted with DCM and 1M sodium hydroxide solution and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give methyl (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.221 g) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][CH:7]([C:12]([NH2:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].[OH-].[Na+]>O>[CH3:1][O:2][C:3]([NH:6][CH:7]([C:12]([NH2:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11])=[O:4]
Reactant: COC(=O)Cl
Reactant: CSCCC(N)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(CCSC)C(N)=O
Yield: 60.4 %

Procedure:
85 ml (1.11 moles) methylchloroformate were dripped into a solution of 150 g (1.02 moles) DL-methionine amide in 200 ml water at 5-10° C., during which the pH was maintained at 8-10 by the addition of sodium hydroxide solution. After 30 min of subsequent reaction, 60 ml water was added, whereupon crystals formed which were filtered off, washed with water and dissolved in 250 ml water. This solution was extracted twice and the crystallization mother liquor extracted once with 500 ml methylene chloride in each instance. After drying in a vacuum, 162 g yellowish, crystalline residue remained. It was dissolved in 200 ml hot ethanol. Then, 400 ml MTBE was added and after the appearance of the first colorless crystals another 200 ml MTBE. After cooling in an ice bath, filtering off, washing with 200 ml MTBE and drying, 127 g (60k) Nα-methoxycarbonyl-DL-methionine amide with a melting point of 93-94° C. was obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:27][C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:42]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
WSC (1.2 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,6-diisopropylaniline (1.97 g, 10 mmols) and 6-bromohexanoic acid (2.93 g, 15 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 2.15 g (61%) of 6-bromo-N-(2,6-diisopropylphenyl)hexanamide as colorless needle-like crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>CCCCCC.C(OCC)(=O)C>[OH:34][CH2:33][C:32]([NH:31][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29])([CH3:36])[CH3:35]
Reactant: CC(C)(N)CO
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC(C)(C)CO)C(c1ccc(C(C)C)cc1)CO2
Yield: 39 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 39%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC.C(O)(C)C>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: c1ccc(CO[C@@H]2CCC[C@H]2c2ccn[nH]2)cc1

Procedure:
The 5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1H-pyrazole prepared in Example 148b was optically resolved with CHIRALPAK AD-H (Daicel Corp.; hexane/isopropanol=9:1) to yield the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(Cl)(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
[7-(Methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (2.31 g, 10.65 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.15 g, 15.98 mmol) were stirred in a 1:1 mixture of chloroform and methanol (140 ml) for 1 h at rt under argon. This mixture was then treated with NaBH(OAc)3 (10.16 g, 47.93 mmol) and stirred for a further 45 mins. The solvents were then removed from the reaction and crude residues purified by column chromatography on silica gel using a 0-35% MeOH/DCM gradient, to give the desired product (2.0 g; 47%).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:31][C:27]1[CH:26]=[C:25]([CH2:24][CH:7]([OH:6])[CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][C:12](=[O:15])[N:11]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Following the procedure described for Example 5, Step B, 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl }-heptanenitrile (261.7 mg, 0.551 mmol) was deprotected with TBAF (1M in THF, 0.83 mL, 0.83 mmol). The addition was performed at 0° C. and the reaction mixture was stirred at room temperature for 24 h. Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 7-{2-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (141 mg). 1H NMR (CDCl3) δ7.32 (m, 1H), 6.98 (m, 3H), 3.86 (m, 1H), 3.64 (m, 2H), 2.99-2.80 (m, 2H), 2.71 (m, 1H), 2.38 (m, 4H), 2.16 (m, 1H), 1.74-1.29 (m, 14H); MS 361.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH:17]=[CH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>C(#N)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][CH2:18][N:23]([CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:19])[CH2:20][CH2:21][CH3:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: CC#N
Product: CCCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 19.4 %

Procedure:
A solution of 400 mg (1.5 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 63 ml (0.75 mmol) propylamine in 5 ml acetonitrile was stirred for 16 h at room temperature, then for 6 h at 45° C., and finally for 16 h at 80° C. Concentration in vacuo and flash chromatography (20% H2O in acetone) afforded 84 mg (19%) of the title compound as a pale yellow oil. MS m/e (%): 578 (M+H+, 100).