Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][NH:12][C@@:11]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH:30]3[CH3:35])=[O:28])(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=3)=[O:40])[C@H:11]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=4)=[O:40])[CH2:31][CH:30]3[CH3:35])=[O:28])[CH2:10]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(CS[C@@H]2CN[C@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(C(=O)N3CCNCC3C)C2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3C)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 154.3 %

Procedure:
0.51 g of 4-dimethylaminopyridine was added dropwise at room temperature to a solution of 1.83 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(2-methylpiperazin-1-ylcarbonyl)-2-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (ii) above] in 25 ml of dry acetonitrile, and then a solution of 0.90 g of 4-nitrobenzyl chloroformate in 15 ml of dry acetonitrile was added dropwise to the resulting mixture, whilst ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, after which it was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 7:3 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 2.28 g of the title compound, as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (182 mg). The resulting 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (184 mg) is dissolved in ethanol (5 ml), and thereto is added 1N-aqueous sodium hydroxide solution (305 μl), and concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (184 mg). MS (m/z): 598 [M+H]+
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:22]([Cl:40])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:40][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([F:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: Fc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(N2CCc3cc(F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (140 mg, 1.25 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (150 mg, 0.8 mmol) and N-(4-Bromo-2-chloro-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide (200 mg, 0.5 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature; concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].N[C:29]1C(C(OC)=O)=C2C(C3(C)CC3CO2)=CC=1.BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3([CH3:29])[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21C
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 41, starting from methyl (1aRS,7bSR)-5-amino-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 50) and 2-bromo-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[CH2:13]([NH:15][C:16]1[C:21]([CH:22]=O)=[CH:20][N:19]=[C:18]([S:24][CH3:25])[N:17]=1)[CH3:14]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N:12]=[CH:22][C:21]1[C:16]([NH:15][CH2:13][CH3:14])=[N:17][C:18]([S:24][CH3:25])=[N:19][CH:20]=1
Reactant: COc1cc(N)c(Cl)c(OC)c1
Reactant: CCNc1nc(SC)ncc1C=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCNc1nc(SC)ncc1C=Nc1cc(OC)cc(OC)c1Cl
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Into a solution of 3.78 g (20.2 mmol) of 2-chloro-3,5-dimethoxy-phenylamine in 110 mL of toluene was added 3.97 g (20.15 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. The reaction vessel was equipped with a Dean-Stark trap, and the reaction was warmed to reflux. After 3 hours, two drops of concentrated sulfuric acid were added to the reaction. The reaction was refluxed overnight then concentrated in vacuo to give 7.36 g (93%) of the title compound, which was used as is in the following example:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH2:20]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCNCCCN
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 58.8 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (240 g, 1.26 mole) in pyridine (600 ml) at 0° C. was added a solution of 1,5,9-triazanonane (50.0 g, 0.381 mole) in pyridine (100 ml) under a dry nitrogen atmosphere, maintaining the temperature ≤60° C. The addition required 15 minutes. The solvent was removed in vacuo and the resulting yellow oil was dissolved in ethyl acetate (1 l) and H2O (500 ml). The ethyl acetate layer was separated, washed with 0.1N HCl, H2O and saturated NaCl solution and dried (MgSO4). The solution was decolorized with silica gel and the solvent was removed in vacuo to give 133 g (59% yield) of the crude product as a glassy solid: 1H NMR (CDCl3) δ 1.71 (quint, J=6.6 Hz, 4 H), 2.42 (s, 6 H), 2.43 (s, 3 H), 2.96 (quart, J=6.4 Hz, 4 H), 3.11 (t, J=6.8 Hz, 4 H), 5.12 (t, J=6.6 Hz, 2 H), 7.30 (m, 6 H), 7.63 (m, 2 H), 7.73 (m, 4 H).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:10][O:9][N:8]=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH2:6][C:7]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:10][O:9][N:8]=1)=[N+:27]=[N-:28]
Reactant: CS(=O)(=O)OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
4-[4-(3-Chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-ylmethyl methanesulfonate (400 mg, 1.02 mmol) was dissolved in anhydrous DMF (10 mL) followed by addition of sodium azide (133 mg, 2.04 mmol). Reaction was stirred for 3 hrs. Consumption of starting material was monitored by TLC and HPLC. The reaction mixture was added to a mixture of (400 μL) bromine/water and stirred for 10 min. DCM was added and the layers were separated. The combined organics were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (225 mg, 65%). MF=C11H5ClFN7O3; LCMS calculated for C11H6ClFN7O3(M+H)+: m/z=338.020.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14](Cl)=[O:15])([CH2:11]2)[C@@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:33]=[C:34]([C@@H:42]([NH:44][CH3:45])[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(=O)(O)[O-].[Na+]>[F:30][C:31]([F:46])([F:47])[C:32]1[CH:33]=[C:34]([C@@H:42]([N:44]([CH3:45])[C:14]([C@@:10]23[CH2:11][CH:12]2[CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:9]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH3:43])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: CN[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To racemic Intermediate 40, one enantiomer being (1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (0.17 g, 0.56 mmol) in MC (5 mL) was added triethylamine (0.24 mL, 1.7 mmol) and (S)-1-(3,5-bis(trifluoromethyl)phenyl)-N-methylethanamine 0.15 g, 0.56 mmol) in MC (1 mL). The reaction was stirred at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and the phases separated. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. This material was flash chromatographed on silica using a gradient of 5 to 10% EtOAc/Hexanes to afford the title compound (0.06 g, 19% yield).
Reaction SMILES: C([N:4]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:5][C:6]([O:8]CC)=[O:7])(=O)C.O[Li].O>CO.O>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN(C(C)=O)S(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1ccc(S(=O)(=O)NCC(=O)O)cc1
Reaction time: 120 h
Yield: 69.1 %

Procedure:
To a stirred solution of N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester (Step 1) (0.24 g, 0.54 mmol) in methanol was added LiOH.H2O (0.06 g, 1.36 mmol) in water. After 5 days the reaction was complete and the solvents were removed in vacuo. The resulting semi-solid was partitioned between ethyl acetate and 1N KHSO4 solution. The ethyl acetate phase was dried over MgSO4, filtered and concentrated in vacuo yielding N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine (0.139 g, 69%) as a white powder: mp 242-248° C. 1H NMR (CDCl3/300 MHz with DMSO-d6) 7.76 (d, 2H, J=8.5 Hz), 7.33-7.22 (m, 5H), 7.19 (d, 2H, J=8.5 Hz), 6.35 (t, 1H, J=5.4 Hz), 3.63 (d, 2H, J=5.4 Hz), 2.39 (s, 3H). FABLRMS m/z 373 (M+H). FABHRMS m/z 372.0786 (M+, Calc'd 372.0780). Anal. Calc'd for C18H16N2O5S: C, 58.06; H, 4.33; N, 7.52. Found C, 58.09; H, 4.44; N, 7.45.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH2:15]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of isatin (4.41 g, 30 mmol) in DMF (60 mL) at 0° C. was added 60% NaH (1.50 g, 37.5 mmol) portionwise. After addition, the resulting mixture was stirred for 15 min at 0° C. and 1-bromo-3-methylbutane (4.7 mL, 37.5 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 1 h at 0° C. followed by 6 h at rt. The reaction was cooled to 0° C., quenched with sat. NH4Cl, ice, H2O, extracted with EtOAc (200 mL×2), dried over Na2SO4 and concentrated to give crude 1-isopentylisatin as a dark orange red liquid which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H, partially overlapping with the peak at 7.12 ppm), 7.12 (t, J=7.6 Hz, 1H, partially overlapping with the peak at 7.15 ppm), 3.66 (t, J=7.6 Hz, 2H), 1.67-1.57 (m, 1H), 1.48 (q, J=7.2 Hz, 1H), 0.92 (d, J=6.4 Hz, 6H); MS ESI 217.9 [M+H]+, calcd for [C13H15NO2+H]+ 218.1.
Reaction SMILES: C1O[C:9]2C=CC(N)=[CH:4][C:3]=2O1.C(OC)(=O)C(C)=O.[CH3:18][O:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>C(O)C(C)C>[CH2:18]([O:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[CH:3]([CH3:4])[CH3:9]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](C)Nc1ccc2c(c1)OCO2
Agent: COC(=O)C(C)=O
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2c(c1)OCO2

Procedure:
Following reductive amination General Procedure AA above and using 3,4-methylenedioxyaniline (Aldrich) and methyl pyruvate (Aldrich), N-(3,4-methylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above and using iso-butanol to provide the title compound as an oil. The reaction was monitored by silica gel tlc (Rf=0.61 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 64 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 64% of theory, C28H31N7O3 (513.6); EKA mass spectrum: (M+H)+=514.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14]C(OC(C)(C)C)=O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]O>>[CH3:22][O:13][C:11](=[O:12])[C@H:10]([NH2:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CO
Product: COC(=O)[C@H](N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A solution of (2R)-3-benzyloxy-2-(N-(t-butoxycarbonyl)amino)propanoic acid (23 g, 78 mmol, [α]D −4.4° (c=2, H2O )) in methanol (250 mL) was cooled to 0° C. and HCl (g) bubbled into the solution until saturated. The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo to afford 17 g (100% yield) of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester, a compound of formula (M), as a white solid; NMR (DMSO-d6) 8.7 (br s, 3), 7.4-7.3 (m, 5), 4.5 (q, 2), 4.4 (br s, 1), 3.8 (s, 2), 3.7 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.O.[C-:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
A solution of 5.2 g (32 mmol) of 2-chloro-5-chloromethylpyridine dissolved in 40 mL of ethanol was treated with 20 mL of water and 2.4 g (37 mmol) of potassium cyanide. The mixture was stirred and heated at 50° C. for 20 hours. The dark mixture was then partitioned between dichloromethane and water and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 4.54 g (92%) of Preparatory Compound E, (6-chloro-3-pyridinyl)acetonitrile, as a dark brown liquid: 1H NMR (CDCl3) δ 8.38 (d, J=3.0 Hz, 1H), 7.71 (dd, J=3.0 and 7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 3.80 (s, 2H) ppm. GCMS: (EI) m/z 152 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9].[S:34](N)([NH2:37])(=[O:36])=[O:35]>C(OC(=O)C)(C)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:10]([CH3:11])[C:8](=[O:9])[C:7]2[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:5]([S:4][CH2:3][CH2:2][NH:1][S:34](=[O:36])(=[O:35])[NH2:37])[CH:6]=2)=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: NS(N)(=O)=O
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN)cc(C(F)(F)F)c1
Solvent: CC(=O)OC(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(N)(=O)=O)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-(2-aminoethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.1 g, 209 μmol, example 237) in isopropylacetate (2 mL) was added sulfamide (80.2 mg, 834 μmol) and the mixture was heated at reflux for 23 hours while the solvent was vaporized. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (0.067 g; 57%). MS (ESI): m/z=559.11 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([N:23]3[CH2:24][CH2:25][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]3)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
172 mg (0.69 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylideneacetic acid, 144 mg (0.78 mmol) of t-butyl 1-piperazinecarboxylate, 148 mg (0.77 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5 N aqueous sodium hydroxide solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.ClCl.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]=[CH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccc(Br)cc1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)C=CCc1ccc(Br)cc1
Reaction time: 16 h

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl(4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2 Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.