Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:21][C:22](O)=[O:23])[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)=[CH:6][CH:7]=1)#[N:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][NH2:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:26].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[C:1]([C:3]1[N:4]([CH2:21][C:22]([NH:38][CH2:37][CH2:36][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=2)=[O:23])[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:18])([CH3:19])[C:12]=3[CH:20]=2)=[CH:6][CH:7]=1)#[N:2]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)n3CC(=O)O)cc21
Reactant: CCOc1cc(CCN)ccc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CCNC(=O)Cn2c(C#N)ccc2-c2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1OC

Procedure:
A solution of [2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetic acid (0.6 g, 1.8 mmol), 3-ethoxy-4-methoxyphenylethylamine (0.36 g, 1.9 mmol), diiso-propylethylamine (0.26 g, 2 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.7 g, 1.8 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethylacetate. The ethylacetate solution was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethanol to afford the title compound, m.p. 160-162° C. (0.2 g, 22%): 1H-NMR (DMSO-d6) δ 1.3 (t, J=6.9 Hz, 3H), 1.59 (s, 6H), 2.61 (t, 2H, J=7 Hz), 3.29 (q, J=6.9 Hz, 2H), 3.71 (s, 3H), 3.97 (q, J=6.9 Hz, 2H), 4.6 (s, 2H), 6.32 (d, J=5.1 Hz, 1H), 6.65 (dd, J=7.6, 2.0 Hz, 1H), 6.77 (d, J=2.3, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.26 (m, 2H), 8.3 (t, J=6 Hz, 1H), 10.42 (s, 1H), MS (APCI (+)) m/z 503 (M+H)+
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:24])[CH2:5][C:6](=[O:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])#[N:2].CO.COB(CC)CC.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:3][CH:4]([OH:24])[CH2:5][CH:6]([OH:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])#[N:2]
Reactant: N#CC[C@@H](O)CC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: N#CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 10 h

Procedure:
Crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide, approximately 0.2 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (105 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (24 g, 0.63 mol) is added over 30 minutes. The reaction mixture is maintained at -78° C. for 5 hours, allowed to warm to room temperature, and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (40 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (400 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (500 mL). The ethyl acetate solution is concentrated by vacuum distillation to give [R-(R*,R*)])-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide as an oil which is used without further purification. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate(147 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.Cl.[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[C:33]([F:39])[CH:32]=1>ClCCl.CN(C)C=O>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([S:12][CH3:13])=[CH:11][C:3]=2[O:2][CH3:1])=[C:33]([F:39])[CH:32]=1
Reactant: COc1cc(SC)ccc1C(=O)O
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(SC)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methoxy-4-(methylthio)benzoic acid (5.0 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. and treated with oxalyl chloride (6.6 mL, 75.6 mmol). A drop of N,N-dimethylformamide was added and the reaction was heated to a gentle reflux for 2 h. After cooling to room temperature, the solution was concentrated in vacuo to remove the excess oxalyl chloride, diluted with dichloromethane (53 mL) and cooled to 0° C. The resulting solution was treated with N,N-diisopropylethylamine (11.6 mL, 67 mmol) and 4-bromo-2-fluorobenzylamine hydrochloride (9.7 g, 40.2 mmol). The resulting solution was stirred at room temperature overnight, concentrated in vacuo, diluted with ethyl acetate and successively washed with 2 N HCl and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Rf 0.43 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 8.63 (t, J=6 Hz, 1 H), 7.70 (d, J=8.1 Hz, 1 H), 7.50 (dd, J1=9.6 Hz, J2=2.1 Hz, 1 H), 7.38 (dd, J1=8.4 Hz, J2=2.0 Hz, 1 H), 7.28 (t, J=8.4 Hz, 1 H), 6.94 (br s, 1 H), 6.89 (dd, J1=5.7 Hz, J2=1.7 Hz, 1 H), 4.46 (d, J=6 Hz, 2 H), 3.91 (s, 3 H), 2.51 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[N:12]1([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][NH:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)NC(=O)NC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1NCc2ccc(N3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.7 %

Procedure:
To a solution of 16 (0.7 g, 2.11 mmol) in a mixture of CH2Cl2 (15 mL) and THF (5 mL) at 0° C. was added TFA (5 mL) and the mixture was stirred at room temperature for 6 h. The solvent was evaporated under vacuum to afford 0.66 g (96%) of compound 5 as a dark brown gum. IR (KBr) νmax. cm−1: 3261 (NH), 3032 (Ar—H), 1691 (C═O), 1613, 1513, 1415 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=3.18 (m, 4H, 2CH2); 3.42 (m, 4H, 2CH2); 4.23 (s, 2H, CH2); 6.66 (m, 2H, aromatic-H); 6.73 (m, 1H, aromatic-H); 8.80 (br. s, 1H, NH); 8.86 (br. s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) δ=46.35 (CH2), 46.73 (CH2), 48.63 (CH2), 114.19 (aromatic-C), 114.38 (aromatic-C), 116.49 (aromatic-C), 118.83 (aromatic-C), 131.87 (aromatic-C), 144.81 (aromatic-C), 154.72 (C═O). Calculated (%) for C14H16F3N4O2 (329.12); C: 48.56, H: 4.95, N: 16.18. found (%); C: 48.45, H: 5.05, N: 16.15.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl>[CH3:22][C:3]1[C:2]([NH:1][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])=[N:11][C:10]2[C:5]([N:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
To a stirred mixture of 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 79 mg, 0.269 mmol) and TEA (0.18 mL, 1.34 mmol) in DCM (3 mL) was added cyclopropane carbonyl chloride (0.037 mL, 0.404 mmol). After the addition, the mixture was stirred at RT 24 h, concentrated, and purified on a silica gel column (0-10% MeOH/DCM) to give the title compound (55 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.47 (1H, br. s.), 10.52 (1H, br. s.), 8.05 (1H, d, J=7.6 Hz), 7.64 (1H, d, J=8.0 Hz), 7.54 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=2.0 Hz), 6.93 (1H, br. s.), 3.43 (2H, td, J=6.7, 2.3 Hz), 2.89 (2H, t, J=6.8 Hz), 2.74 (3H, s), 2.21 (1H, br. s.), 0.95-1.04 (2H, m), 0.90 (2H, d, J=7.2 Hz). m/z (ESI, +ve) 362 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:34][CH2:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCC1CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCC2CCCCC2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), cyclohexanemethylamine (0.53 mL, 6.1 mmol) and MeOH (0.11 mL) is heated at 100° C. for 48 h. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-50:50) gives 0.23 g of the product 79. 1H NMR (CDCl3) δ 7.80-7.35 (m, 2H), 7.18 9s, 1H), 7.10-6.90 (m, 6H), 6.90-6.70 (m, 2H), 5.45-5.30 (m, 2H), 3.45-3.15 (m, 2H), 2.00-1.50 (m, 5H), 1.45-0.95 (m, 15H); MS: m/z 434 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+].O>CN(C)C=O>[C:18]([O:21][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:20])[CH3:19]
Reactant: BrCc1cccc2sc(-c3ccccc3)nc12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cccc2sc(-c3ccccc3)nc12

Procedure:
53 g (0.176 mol) of the compound from Example I and 20 g (0.2 mol) of potassium acetate were stirred at room temperature in 500 ml of dimethylformamide for 24 h, the solvent was stripped off in vacuo, water was added, and the product was filtered off with suction and dried. Yield: 46 g (92% of theory) M.p. 83°-84° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:27]([O:29][CH3:30])=[O:28])=[CH:37][CH:36]=2)[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
18.9 g (86.2 mmol) of benzyl 4-hydroxypiperidine-1-carboxylate, 25.4 g (86.2 mmol) of methyl (2S)-2-(t-butoxycarbonylamino)-3-(4-hydroxyphenyl)propionate and 27.1 g (103.4 mmol) of triphenylphosphine were dissolved in 500 ml of tetrahydrofuran. 37.5 g (86.2 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred for 15 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:7][P:8]([OH:10])[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12].ClC(OCC)=O>O1CCCC1>[CH:1]1([CH2:7][PH:8](=[O:10])[O:9][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: OP(O)CC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A tetrahydrofuran solution of 19.3 g of cyclohexylmethylphosphonous acid is cooled to 5°, at which temperature a suspension forms, and treated with 12.14 g of triethylamine. An exothermia ensues and the suspension is re-cooled to 5° before slow addition of 13.02 g ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran. An exothermic reaction occurs with gas evolution. The white suspension is stirred overnight at room temperature and subsequently filtered. The filtrate is concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic phase is removed, dried and concentrated in vacuo to give a yellow oil. Distillation in high vacuum affords ethyl (cyclohexylmethyl)phosphinate; b.p. 120°-130° (2×10-2 mbar); 1H-NMR (CDCl3): δ (ppm)=7.17 (1H, d, J=527 Hz, P--H), 4.13 (2H, m, CH2OP), 1.95-1.58 (7H, m, 3×CH2 +CH), 1.38-0.75 (9H, m, 3×CH2 +CH3).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#N.[CH2:14]([N:16](CC)CC)C.[NH2:21][C@H:22]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1>ClCCl>[CH2:39]([C@@H:22]([NH:21][C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][CH:3]=[C:8]([C:14]#[N:16])[CH:7]=1)[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30](=[O:31])[C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:26][CH2:25]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCN(CC)CC
Reactant: N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(/C=C/C(=O)O)cc1
Solvent: ClCCl
Product: N#Cc1cccc(/C=C/C(=O)N[C@H](Cc2ccccc2)CN2CCC(C(=O)c3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (E)-3-(4-cyano-phenyl)-acrylic acid (0.042 g, 0.242 mmol) in dichloromethane (1 ml) is added triethylamine (0.046 ml, 0.331 mmol) and (benzotriazo-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (0.126 g, 0.242 mmol). The reaction mixture is stirred at ambient temperature for 5 minutes and then a solution of [1-((R)-2-amino-3-phenyl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone (0.075, 0.220 mmol) in dichloromethane (1 ml) is added. Stirring is continued for a further 3 hours, then the reaction mixture is diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate solution and saturated brine. The dichloromethane is dried over magnesium sulphate and the solvent evaporated. The crude product is purified by flash silica chromatography (ethyl acetate:hexane, 5:1 elution) to afford (E)-N-{(R)-1-Benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-3-(3-cyano-phenyl)-acrylamide. [MH]+496.8.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([S:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH:5]([S:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:7]=1)[CH3:2]
Reactant: CCOCC(Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCC(Sc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
A solution of the ethyl ({4-[(2-(ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)thio]-2-methylphenyl}oxy)acetate (Enantiomer 1) (12 mg, 0.023 mmol) in THF (1 mL) and MeOH (1 mL) was treated with aqueous NaOH (2N, 1 mL) and the resulting mixture agitated at ambient temperature for 15 h. Aqueous HCl (2N, 1 mL) was then added and the organic solvents removed under vacuum using a Genevac. The residue was the then made up to 2 mL by the addition of water and then extracted using DCM (3×3 mL) in an hydrophobic frit. The residue was reduced and then purified further by mass directed autoprep HPLC to afford the title compound as an oil (7 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([NH:55][CH2:54][C:51]3[CH:50]=[N:49][C:48]([CH3:47])=[N:53][CH:52]=3)=[O:23])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:3]1
Reactant: Cc1ncc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylic acid (350 mg, 1.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (430 mg, 2.2 mmol), 1-hydroxybenzotriazole hydrate (170 mg, 1.1 mmol), CH2Cl2 (50 mL) were added (2-methylpyrimidin-5-yl)methanamine (210 mg, 1.7 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.2 mmol). The mixture was stirred at room temperature for 4 h, and then washed with water and aq. Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 20-60% MeCN/water[10 mM Et2NH]) to yield a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21](SC)[CH:20]=2)=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1)=[O:8].O[O:28][S:29]([O-:31])=O.[K+].[CH:33](O)(C)C>O1CCCC1.O>[NH3:4].[F:1][C:2]1[CH:3]=[N:4][C:5]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([S:29]([CH3:33])(=[O:31])=[O:28])[CH:24]=2)=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1)=[O:8]
Reactant: O=S([O-])OO
Reactant: CC(C)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)c1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)c1
Product: N

Procedure:
A solution of 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (70 mg, 0.18 mmol) in tetrahydrofuran (1 ml) was added to a solution of oxone™ (229 mg, 0.37 mmol) in water (1 ml) and isopropylalcohol (4 ml) under nitrogen at room temperature and the reaction was stirred for 3 h. The reaction mixture was passed through a chemelute cartridge, washing with tetrahydrofuran, and the eluent was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2 changing to 96:4:0.4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(3-methylsulfonyl-phenoxy)-nicotinamide (50 mg) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:7]2=[N:6][C:5]=1[CH3:14])#[N:2].C(N([CH2:20][CH3:21])CC)C>CO>[C:1]([CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][C@H:11]3[C:20]4[C:21](=[CH:1][CH:3]=[CH:4][CH:5]=4)[CH2:7][C@@H:12]3[OH:13])[C:7]2=[N:6][C:5]=1[CH3:14])#[N:2]
Reactant: CCN(CC)CC
Reactant: Cc1nc2c(O)cccn2c1CC#N
Solvent: CO
Product: Cc1nc2c(O[C@H]3c4ccccc4C[C@@H]3O)cccn2c1CC#N
Yield: 18.8 %

Procedure:
750 mg 3-cyanomethyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine are reacted, analogously to the method described in Example 21, with 210 mg (-)-1R,2S-indenoxide and 400 mg triethylamine in aqueous methanol (60 ml methanol+15 ml water) at room temperature. After 3 days the solution is evaporated and the residue taken up in 50 ml water. The precipitate is filtered off and purified by chromatography over silica gel (mobile phase: ethyl acetate/methanol=10:1). After evaporation the residue is precipitated from methylene chloride/cyclohexane. 120 mg of the title compound is isolated. [α]D22 =+113° (c=1, chloroform).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.[C:11]([O:14]CC=C)(=[O:13])[CH3:12].C1(C=CC(O)=CC=1)O>>[C:11]([O:14][CH2:1][CH:5]1[CH2:4][CH:8]2[CH2:7][CH:6]1[CH:10]=[CH:9]2)(=[O:13])[CH3:12]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CCOC(C)=O
Agent: Oc1ccc(O)cc1
Product: CC(=O)OCC1CC2C=CC1C2
Temperature: 180 °C
Reaction time: 9 h

Procedure:
Dicyclopentadiene 1094 g (manufactured by Wako Pure Chemical Industries, Ltd.), 1772 g of allyl acetate (manufactured by Wako Pure Chemical Industries, Ltd.), 1 g of hydroquinone (manufactured by Wako Pure Chemical Industries, Ltd.) were placed into an autoclave, and a space was replaced by nitrogen. The mixture was stirred at an internal temperature of 180° C. in a sealed system for 9 hours (rotating speed=300 rpm). The reaction mixture was filtered, and volatile components were evaporated. The residue was subjected to precision distillation (length of column=120 cm, filler=Propak, reflux ratio=10/1, pressure=10 mmHg, trap temperature=89° C.), thereby obtaining colorless and transparent NBCH2OCOCH3. The peak purity thereof was measured by gas chromatography, and the NBCH2OCOCH3 has the purity of 99.9% and endo/exo ratio of 83/17.