Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([C:8](=[O:10])[NH2:9])[N:7]=1.[N:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.CN1CCCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[C:8]([C:6]1[N:7]=[C:2]([C:47]2[CH:48]=[CH:49][N:44]=[CH:45][CH:46]=2)[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(-c5ccncc5)nc4C(N)=O)cc3)CC2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Under an argon atmosphere, to a mixture of tert-butyl (3R)-3-{[3-bromo-5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (300 mg), pyridin-4-ylboronic acid (196 mg), and N-methylpyrrolidone (6 mL) were added tetrakistriphenylphosphine palladium (0) (79 mg) and a 2 M aqueous sodium carbonate solution (797 μL), followed by stirring at 100° C. for 4 hours. After leaving to be cooled, ethyl acetate and water were added thereto, followed by stirring, and then the insoluble matter was separated by filtration. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-150:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-3-(pyridin-4-yl)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (222 mg) as a yellow solid.
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[C:20]2[S:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O1CCCC1.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[S:19]1[C:20]2[C:12]([O:11][C@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][NH:24][CH3:23])=[CH:13][CH:14]=[CH:15][C:16]=2[CH:17]=[C:18]1[C:21]#[N:22]
Reactant: CN
Reactant: N#Cc1cc2cccc(O[C@@H](CCI)c3ccccc3)c2s1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CNCC[C@H](Oc1cccc2cc(C#N)sc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 7-{[(1S)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (222 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added 40% aqueous methylamine (0.83 mL) and the solution was stirred at room temperature for 16 hours. The solvent removed in vacuo and the residue purified by flash chromatography with a gradient of 0–15% methanol in dichloromethane. To a solution of free base (155 mg, 0.48 mmol) in methanol (1 mL) and added a warm solution of fumaric acid (40 mg, 0.48 mmol) in methanol (1 mL). The solvent removed in vacuo, and the solid residue triturated with diethyl ether (5 mL), then dried in a vacuum oven at 40° C. for 1 h to give the title compound (0.20 g, 85%); δH (300 MHz, DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 7.05–6.98 (1H, m, ArH), 6.43 (2H, s, CHCO2H), 5.85–5.75 (1H, m, CHO), 3.05–2.90 (2H, m, 1-CH2), 2.52 (3H, s, NHCH3) and 2.46–2.07 (2H, m, 2-CH2).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)(=[O:3])[CH3:2].[CH3:20][CH:21]([C:25]([NH:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:22](O)=[O:23]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:22](=[O:23])[CH:21]([CH3:20])[C:25]([NH:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[O:26])[C:8](=[O:12])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CC(=O)N1C[C@H](N)C(=O)N(C(C)C)c2ccccc21
Product: CC(=O)N1C[C@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(C(C)C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-isopropyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e=493 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:17])[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:19]([O:21][C:22]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:23]=1[C:24](=N)OCC)[CH3:20].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:17][C:24]([C:23]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:22]=3[O:21][CH2:19][CH3:20])=[N:16][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Reactant: NC(CC1CCCC1)C(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Yield: 62.7 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-cyclopentyl-propane-1,2-diamine (170 mg, 0.672 mmol) and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride (210 mg, 0.806 mmol) in ethanol (10 mL) was added triethylamine (82 μL, 0.806 mmol). The reaction mixture was heated at gentle reflux for 6 h. The solvent was removed and the residue was partitioned between water and methylene chloride. The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with ethyl acetate then 5–10% methanol in ethyl acetate to give 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (174 mg, 63%, 4.5:1.0 ratio of cis:trans) as a white foam. HR-MS (ES, m/z) observed 413.1993, calculated for C24H30N2O2Cl [(M+H)+] 413.1991.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[C:1]([O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Reactant: COc1cc(CO)ccc1O
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 100.5 %

Procedure:
Decanoic acid (25.0 g, 145 mmol), vanillyl alcohol (21.7 g, 141 mmol), and Novozym 435 (723 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 48 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, hexane (100 ml) was added to the reaction mixture, and the mixture was stirred for 1 hour. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were removed by filtration. Hexane (100 ml) and 10% aqueous citric acid solution (200 ml) was added to the filtrate to allow partitioning. The aqueous layer was further extracted with hexane (150 ml), and the combined hexane layer was washed with 10% aqueous citric acid solution (100 ml), water (100 ml) and saturated brine (100 ml). The hexane layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the mixture (43.7 g) of vanillyl decanoate and decanoic acid. As a result of the analysis, the yield of vanillyl decanoate was 97.0% and the purity was 98.6 area % by HPLC. The mixture contained 3.94 wt % of decanoic acid relative to vanillyl decanoate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH2:39]([O:41][C:42]([C:44]1[C:45](=[O:61])[C:46]([C:58](O)=[O:59])=[CH:47][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[CH:49]=1)=[O:43])[CH3:40]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:58]([C:46]1[C:45](=[O:61])[C:44]([C:42]([O:41][CH2:39][CH3:40])=[O:43])=[CH:49][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[CH:47]=1)=[O:59])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)O)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)N(CC)CC)c1=O
Reaction time: 5 h

Procedure:
Diethylamine (130 μl) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (528 mg) were added to a solution of the compound obtained in Step 2 (270 mg) in dichloromethane (3.0 ml) at room temperature, and the mixture was stirred for five hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 160 mg of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([NH2:75])[CH:70]=1)[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])[CH:70]=1)[CH3:66]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-aminobenzoic acid ethyl ester (Aldrich, 43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 10% EtOAc/methylene chloride) to give a white solid. 55 mg.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][N+:9]2=[CH:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]>CO.[Ni]>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[CH2:19]([NH+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]
Reactant: CCN(CC)CC
Reactant: O=S(=O)([O-])CCC=[N+]1CC=Cc2ccc(O)cc21
Agent: [Ni]
Solvent: CO
Product: CC[NH+](CC)CC
Product: O=S(=O)([O-])CCCN1CCCc2ccc(O)cc21
Reaction time: 0.07 h

Procedure:
To a suspension of 2.67 g (10 mmole) of 3-(7-hydroxyquinolinio-1-yl)propanesulfonate in 500 ml of methanol, 1.5 g of triethylamine was added and stirred 3-5 min until clear solution was prepared. To this solution 0.5 g Ni Raney was added and mixture hydrogenated at room temperature for 3 hours. The reaction mixture was suction filtered through diatomaceous earth and the filtrate evaporated under reduced pressure. The resulting crystallized yellow compound washed with diethyl ether and filtered off. Yield 3.7 g (99%).
Reaction SMILES: I[CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+].CN(C=O)C>>[N:19]([CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CC(I)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N=[N+]=[N-])C(=O)Nc2cc([N+](=O)[O-])ccc21

Procedure:
3-Iodo-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (5.367 g, 0.015 mol), Sodium azide (6.49 g, 0.1 mol), and DMF (100 mL, 2 mol) were stirred at rt for 2 h. The reaction mixture was diluted with H20 and the resulting beige ppt was filtered.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH3:34])=[O:32])=[C:5]([CH3:35])[CH:4]=1)#[N:2].[CH2:36](N)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH2:34][CH3:36])=[O:32])=[C:5]([CH3:35])[CH:4]=1)#[N:2]
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C
Reactant: CCN
Product: CCNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-methylphenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (example 73), replacing methylamine with ethylamine as reagent. Yield: 45 mg; ESI mass spectrum [M+H]+=497; Retention time HPLC: 0.77 min (X012_S01).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25](Cl)=[O:26].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25]([C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25]([C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCCO1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CCCCO1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CCCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 22 %
Yield: 11 %

Procedure:
To a stirred solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.31 g, 52.56 mmol) in anhydrous THF (150 mL) is added n-butyllithium (2.5 M in hexanes, 21.05 mL, 52.56 mmol) over 25 min at −78° C. Then a solution of tetrahydro-pyran-2-carbonyl chloride (7.1 g, 47.78 mmol) in anhydrous THF (12 mL) is added dropwise. The reaction is stirred at −70° C. for 0.5 h, then allowed to warm to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (20 mL) is added and the reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME) to afford 3.81 g of (4S)-4-benzyl-3-{[(2S)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (78%, yield: 22%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.46-1.72 (4 H, m), 1.81-1.90 (2 H, m), 2.71 (1 H, dd, J=13.43, 9.77 Hz), 3.30 (1 H, dd, J=13.43, 3.05 Hz), 3.54 (1 H, td, J=11.52, 2.14 Hz), 4.06-4.19 (3 H, m), 4.60 (1 H, m, J=9.88, 6.75, 3.28, 3.28 Hz), 4.97 (1 H, dd, J=10.60, 1.91 Hz), 7.12-7.30 (5 H, m)) and 1.65 g of (4S)-4-benzyl-3-{[(2R)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (93%, yield: 11%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.80 (4 H, m), 1.90-2.06 (2 H, m), 2.83 (1 H, dd, J=13.58, 9.16 Hz), 3.24 (1 H, dd, J=13.50, 3.28 Hz), 3.53-3.61 (1 H, m), 4.11-4.17 (1 H, m), 4.19-4.24 (1 H, m), 4.25-4.31 (1 H, m), 4.71-4.78 (1 H, m), 4.96 (1 H, dd, J=10.60, 2.06 Hz), 7.16-7.37 (5 H, m))
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>C1COCC1.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: CN(C)CCCCCCO
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCCCCN(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
6-Dimethylamino-1-hexanol (8.80 g, 60.6 mmol) was dissolved in 2/1 mixture of THF/DMF (150 mL) and the solution was cooled in an ice/water bath. Sodium hydride (3.25 g, 80.8 mmol, 60% in oil) was added. After 40 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added and the solution was allowed to warm to room temperature over 1 h. After 3 h, the reaction was quenched by the addition of 1M NaHSO4. Tetrahydrofuran was removed in vacuo, and the solution was washed with EtOAc. The aqueous phase was basified with 3M NaOH and extracted with ether. The combined ether phases were dried over K2CO3, filtered, and the product was crystallized by the addition of 4M HCl/dioxane to give O-(2-methoxybenzyl)-6-dimethylaminohexanol (10.4 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Yield: 73.6 %

Procedure:
1-[5-(3-Bromo-4-fluorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.139 mmol, 43.6 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (51.8 mg, yield 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.CCOC(C)=O.[CH3:39][N:40](C=O)C>O.CCCCCC.[C-]#N.[Zn+2].[C-]#N>[C:39]([C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1)#[N:40]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1cc(C#N)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A stirring solution of N-(6-chloro-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.21 mmol, example 12), tetrakis-triphenylphosphine palladium(0) (24 mg, 0.020 mmol, CAS RN 14221-01-3) and zinc cyanide (31 mg, 0.26 mmol, CAS RN 557-21-1) in DMF (1.5 mL) was heated to 100° C. for 30 min, 120° C. for 30 min and 150° C. for 30 min by microwave irradiation. After cooling, the reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed three times with water and once with brine and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave crude product. The title compound was isolated by flash chromatography (25% EtOAc in n-hexane) as a viscous oil (7.5 mg, 8%). MS (ESI): m/z=463.9 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl>[C:24]([O:23][C:22]([N:12]1[CH2:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 110.3 %

Procedure:
4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (Lancaster, 1.00 g, 4.35 mmol), triethylamine (0.92 g, 9.13 mmol), and di-tert-butyl carbonate (Aldrich, 1.04 g, 4.78 mmol) were combined in dichloromethane (100 mL) and stirred at room temperature for 14 hours. The mixture was washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL), saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated in vacuo to give 4-(4-chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.41 g, 100%) of as a viscous yellow oil, which was used without further purification. 4-(4-Chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (334 mg, 1.14 mmoL) was dissolved in acetone/water (1:1, 10 mL), and N-methylmorpholine-N-oxide (Aldrich, 462 mg, 3.42 mmoL) and a catalytic amount of osmium tetroxide (Aldrich) were added. The mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium sulfite (2 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated in vacuo to give cis-[rac]-4-(4-chlorophenyl)-3,4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (364 mg, 1.11 mmol, 97%) as a yellow oil.