Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>C(#N)C.CO>[CH2:1]([O:8][C:9]([C@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Solvent: CO
Product: CC(C)C[C@@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of D-Leucine benzylester (6.3 mmol) in acetonitrile (9 mL) and MeOH (3 mL) was added 1,3-propane sultone (691 mg, 5.7 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with aconitrile (2×20 mL). The solid was dissolved in 20% water/EtOH (75 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and dried in vacuo, affording the title compound (960 mg, 49%). 1H NMR (D2O, 500 MHz) δ ppm 7.52 (m, 5H), 5.41 (d, 1H, J=12.2 Hz), 5.35 (d, 1H, J=12.2 Hz), 4.16 (m, 1H), 3.22 (m, 2H), 2.97 (t, 2H, J=6.8 Hz), 2.16 (m, 2H), 1.88 (m, 1H), 1.79 (m, 1H), 1.76 (m, 1H), 0.94 (d, 6H, J=3.9 Hz). 13C (DMSO, 125 MHz) δ ppm 169.60, 135.62, 129.24, 129.21, 129.11, 68.08, 58.09, 49.87, 46.48, 24.77, 23.50, 22.50, 22.04. [α]D=−2.1° (c=0.00095 in water), ES-MS 344 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:12])[NH:10][NH:11][C:4]=2[CH:3]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:12])[NH:10][N:11]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2[nH][nH]c(=O)c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (3.1 g, 16.85 mmol) and trityl chloride (4.93 g, 17.69 mmol) in DMF (50 mL) was charged with sodium hydride (60% in mineral oil, 1.011 g, 25.3 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with Et2O (×3). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/DCM) to provide 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one. MS ESI calc'd. for C26H20ClN3O [M+1]+ 426. found 426.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.O=P(Cl)(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[C:5]([Cl:19])=[N:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)c2cc3ccccc3cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1ncc(Br)c2cc3ccccc3cc12
Temperature: 55 °C
Reaction time: 2 h

Procedure:
4-Bromo-benzo[g]isoquinoline 2-oxide (7-4) (380 mg, 1.39 mmol, 1 eq) was taken up in a ¼ v/v mixture of POCl3 and chloroform (20 ml) and the resulting solution was stirred at 55° C. for 2 hrs. The reaction mixture was then carefully poured into sat. aq. sodium bicarbonate, extracted with ethyl acetate, dried, and concentrated to give the crude desired chloride 7-5. LRMS m/z: found 294.0, 292.0, calcd. (M+H) 294.0, 292.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH2:37]Cl)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH2:16]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17]#[C:18][CH3:19]>C1COCC1.O.C(OCC)(=O)C>[CH2:16]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17]#[C:18][CH3:19]
Reactant: CC(C)C(N)C(=O)O
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of 0.500 g (4.255 mmol) D,L-valine in 40 mL of THF/water (1:1) was added 5.0 mL of triethylamine followed by 1.144 g (4.681 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride and the reaction was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate and the organic layer was washed with water and 5% HCl solution, dried over MgSO4, filtered and concentrated in vacuo. The solid residue was washed with ether/hexanes (1:1) to provide 0.383 g (28%) of the sulfonamide as a white solid. Electrospray Mass Spec 323.9 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([C:14]([O-:16])=[O:15])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([C:14]([OH:16])=[O:15])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1nnn(Cc2ccccc2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nnn(Cc2ccccc2)c1O
Yield: 88.9 %

Procedure:
Stir a 90° C. solution of 1-benzyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylate (1.46 g; 1.0 equiv; 5.90 mmoles) and sodium hydroxide (1N; 10.00 mL; 1.7 equiv; 10.00 mmoles) for 9 hours. Add 1N hydrochloric acid until the pH is 2, then filter the reaction and dry the filter cake to afford 1-benzyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (1.15 g; 89%): MS (m/z): 220(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 91.9 %

Procedure:
Into a reactor were introduced 2.80 g (11.3 mmol) of the 1,1-bis(4-fluorophenyl)propanol, 60 mL of toluene, and 14 mg of p-toluenesulfonic acid monohydrate under a nitrogen atmosphere. Azeotropic dehydration was conducted for 1 hour with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2.39 g (92%) of the target compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)/[C:11](=[C:26]3/[C:27]([CH3:39])=[N:28][N:29](C(OC(C)(C)C)=O)[C:30]/3=[O:31])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[CH3:39][C:27]1=[N:28][NH:29][C:30](=[O:31])/[C:26]/1=[C:11]1\[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:3][CH:4]=3)=[CH:10]\1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CS(=O)(=O)Cl
Reactant: CC1=NN(C(=O)OC(C)(C)C)C(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1C(=O)OC(C)(C)C
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NS(C)(=O)=O)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-tert-butyl 4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1 (2H)-carboxylate and methanesulfonyl chloride according to the procedure described in Example 21. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 3.09 (s, 3H) 6.69 (s, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.63 (t, J=7.58 Hz, 1H) 7.72 (d, J=8.59 Hz, 2H) 7.83-7.94 (m, 2H) 8.13 (d, J=8.34 Hz, 1H) 10.40 (s, 1H); ESI-MS: m/z calc'd for C20H18N4O3S2 426.08. found 427.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:5](=[O:6])[CH2:4][C@H:3]1[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[H][H]>CO.[Pd]>[CH3:1][N:2]1[C:5](=[O:6])[CH2:4][C@H:3]1[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: CN1C(=O)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C[C@H]1C(=O)O
Yield: 97.4 %

Procedure:
In 10 ml of methanol was dissolved 450 mg of compound (11) and 45 mg of 10% Pd-C was added to the solution followed by catalytic hydrogenation at ambient temperature under an atmospheric pressure of hydrogen. The catalyst was filtered off and the solvent was removed by distillation under reduced pressure to obtain 258 mg of (S)-1-methyl-4-oxo-2-azetidinecarboxylic acid (12).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:12](CC2C=CC(OC)=CC=2)[C:11]1=[O:31])(C)(C)C.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O.CCOC(C)=O>[CH:16]1([CH:13]2[NH:12][C:11](=[O:31])[CH:10]([CH2:9][CH2:8][CH2:7][OH:6])[O:15][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(CN2C(=O)C(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1NC(C2CCCCC2)COC1CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (400 mg, 0.84 mmol, 1.0 equiv) in CH3CN (0.3 mL) and water (0.3 mL) was added CAN (922 mg, 1.68 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour then second portion of CAN (900 mg) was added. After stirred at room temperature for 1 hour, the reaction mixture was diluted with EtOAc and the phases were separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 50% to 100% EtOAc to give 5-cyclohexyl-2-(3-hydroxy-propyl)-morpholin-3-one 134 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Nc1cccc(F)c1)c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Nc1cccc(F)c1)c1cccc(F)c1
Yield: 99 %

Procedure:
To a solution of ethyl 2-(3-fluorophenyl)-2-(3-fluorophenylamino)-acetate (2.00 g, 6.81 mmol) in THF/H2O (1:1 mixture, 10 mL), is added LiOH (816 mg, 34.0 mmol) and the mixture is reacted for 2 hours at RT (LC-MS monitoring: complete conversion). 1N HCl (15 mL) is added and the desired compound is extracted with EtOAc. The resulting crude is purified by flash chromatography (Hexane/EtOAc=1/1) in order to obtain 1.79 g of I11 as a pale yellow solid (99% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:33][S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])(=[O:31])=[O:32])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O-:3])=[O:2]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the carboxylic acid (Example 33) (0.5 g), 2-methylbenzene sulphonamide (0.28 g), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.37 g) and 4-dimethylaminopyridine (0.05 g) in dichloromethane (6 ml) was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-2% ethyl acetate in dichloromethane, gave a yellow oil which, on crystallisation from methanol, afforded N-[1-(3-nitrobenzyl)indolin-5-ylcarbonyl]-2-methylbenzene sulphonamide, m.p. 159°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]#[C:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH:9]=1)[NH2:8]>CN(C=O)C.[Cu]I>[CH:12]([C:11]1[NH:8][C:7]2[C:6]([CH:10]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)([CH3:14])[CH3:13]
Reactant: COc1ccc(C#CC(C)C)c(N)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C)[nH]c2c1
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-methoxy-2-(3-methylbut-1-ynyl)aniline (Compound 135, 1.8 g, 9.5 mmol) in DMF (20 ml) was added CuI (101 mg, 0.53 mmol). The reaction was stirred at 160° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a brownish red solid.
Reaction SMILES: [CH2:1]([CH:3]([C:19]([OH:21])=[O:20])[N:4]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5]P(O)=O)[CH3:2].[P:22]([Cl:25])(Cl)[Cl:23]>C1C=CC=CC=1>[CH2:1]([CH:3]([C:19]([OH:21])=[O:20])[N:4]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5][P:22]([Cl:25])[Cl:23])[CH3:2]
Reactant: CCC(C(=O)O)N(C[PH](=O)O)C(=O)OCc1ccccc1
Reactant: ClP(Cl)Cl
Solvent: c1ccccc1
Product: CCC(C(=O)O)N(CP(Cl)Cl)C(=O)OCc1ccccc1

Procedure:
Ethyl-N-(benzyloxycarbonyl)-N-(hydroxyphosphinylmethyl)glycine was dissolved in benzene and added dropwise to a stirred solution of phosphorus trichloride to yield ethyl-N-(benzyloxycarbonyl)-N-[bis(chloro)phosphinomethyl]glycine. After stirring for 5-10 minutes, the solution was filtered and concentrated in vacuo to yield the phosphine dichloride (21.8 g, 0.0619 mole) which was dissolved in tetrahydrofuran. To the tetrahydrofuran solution was added isopropanol (3.71 g, 0.0619 mole) and triethylamine (6.255 g., 0.0619 mole) dissolved in 50 ml. of tetrahydrofuran. After stirring for one hour, thiophenol (6.86 g., 0.0619 mole) and triethylamine (6.255 g., 0.0619 mole) dissolved in 50 ml. of tetrahydrofuran was added. The reaction mixture was then stirred for two hours and sulfur (1.98 g., 0.0619 mole) was added and stirring continued overnight. The reaction mixture was then filtered, concentrated to dryness and dissolved in diethyl ether. The diethyl ether solution was then washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate and dried over magnesium sulfate. The ethereal solution was then filtered and concentrated in vacuo to yield a residue. The residue was dissolved in methanol and centrifuged to remove unreacted sulfur; the supernatant liquid was decanted and concentrated to dryness. This residue was chromatographed on silica gel employing diethyl ether as a solvent to yield ethyl-N-(benzyloxycarbonyl)-N-[(phenylthio, isopropoxy)phosphinothioylmethyl]glycine (23 g.) as an oil having a refractive index of ND25 =1.5755 and having the following analysis.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[OH:4].[N-:14]=[N+:15]=[N-:16].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.O>[NH2:1][C@@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N:14]=[N+:15]=[N-:16])=[CH:7][CH:6]=1)[OH:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N[C@@H](CF)[C@H](O)c1ccc(I)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](N)CF)cc1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To the stirred solution of (1R,2R)-2-Amino-3-fluoro-1-(4-iodo-phenyl)-propan-1-ol (1 g, 3.38 mmol) in dimethylsulfoxide:water (9:1, 10 mL) is added NaN3 (0.26 g, 3.99 mmol), Na-ascorbate (0.1 g, 0.50 mmol), CuSO4.5H2O (0.17 g, 0.68 mmol), L-proline (78 mg, 0.67 mmol), K2CO3 (93 mg 0.67 mmol) and resulting reaction mixture heated to 60° C. for 5 hours. Diluted with cold water and extracted with ethylacetate and washed with excess of water and brine. Organic layer dried over sodium sulphate and solvent is evaporated in vacuo to get the crude title compound (0.6 g, crude), used as such in next step. LC-MS (m/z): [M+H]=211.2.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([CH3:19])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[C:12]([CH3:19])[CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Reaction time: 3 h

Procedure:
4-iodoaniline (3.3 g, 15.0 mmol), (4-chloro-2-methylphenyl)boronic acid (3.3 g, 19.5 mmol), Pd(dppf)Cl2 (1.22 g, 1.5 mmol), and K2CO3 (4.1 g, 30 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL) and heated to 90° C. After 3 h the resulting mixture was diluted EtOAc and water and the layers were separated. The organic layer was dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].C([N-]C(C)C)(C)C.[Li+]>CN(C)C=O.C(#N)C.O1CCCC1>[C:11]1([NH:10][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: c1ccc(Nc2ccccc2)cc1
Temperature: -78 °C

Procedure:
In Scheme 1, Step A, a 2-(arylamino)-benzoic acid or diphenylamine (3) is prepared from the coupling of a suitable benzoic acid (1) and a suitable aniline (2) in the presence of a strong base, for example, lithium 1,1,1,3,3,3-hexamethyldisilazane (LiHMDS) or lithium diisopropylamide, in a polar aprotic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide. For example, the aniline (2) and the benzoic acid (1) are dissolved in a suitable organic solvent and cooled to about −78° C. under nitrogen. The suspension is treated with an excess of a suitable base, such as LiHMDS, and allowed to warm to room temperature. The reaction is typically complete within about 2 hours to about 5 days. The resulting benzoic acid (3) can be isolated by removing the solvent, for example by evaporation under reduced pressure or by filtering the precipitated solid through Celite® and washing with a suitable solvent. The benzoic acid (3) can be further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(C(N)C2CCCCC2)CCCCC1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO>[C:1]([OH:12])(=[O:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/C(=O)O
Reactant: [H][H]
Agent: NC(C1CCCCC1)C1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: CC(C)=CCCC(C)CC(=O)O
Yield: 99.9 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.34 g (2 mmoles) of geranic acid, 20 ml of methanol, and 0.39 g (2 mmoles) of dicyclohexylmethylamine. Then, 5.6 mg (0.007 mmole) of Ru((+)-BINAP)(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (+)-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 12 hours at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 25° C. Thereafter, the solvent was distilled off to provide 0.34 g of citronellic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH:6]2C.C([OH:16])C>[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:16])[CH2:6]2
Reactant: CCO
Reactant: COc1ccc2c(c1)C(C)C(=S)N2
Agent: [Ni]
Product: COc1ccc2c(c1)CC(=O)N2
Yield: 71 %

Procedure:
Desulfurization of 1.5 g (7.17 mmol) of 5-methoxy-3-methylthio-2-oxindole dissolved in 100 ml of absolute ethanol with W-2 Raney-Ni gave in 71% yield 5-methoxy-2-oxindole, mp. 148.5°-150.5° (lit. mp. 152°-154°).*
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]1([C@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4]/[C:3]/1=[N:17]\[C@@H:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC1CCCCC1=O
Solvent: Cc1ccccc1
Product: CC1CCCC/C1=N\[C@H](C)c1ccccc1
Yield: 83.2 %

Procedure:
A stirred solution of 2-methylcyclohexanone (5 g, 44.64 mmol) and (R)-1-phenylethanamine (5.4 g, 44.64 mmol) in toluene (50 mL) was maintained at 140-145° C. for 24 h. The solvent was removed under reduced pressure to afford 8 g (84%) of a diastereomeric mixture of (1R,E)-N-(2-methylcyclohexylidene)-1-phenylethanamine (I-8a) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19](=[O:28])[C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19](=[O:28])[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)cc(C(=O)c2nccn2CC(CCO)c2ccc(Cl)c(Cl)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)c2nccn2CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)c1
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
3-(3,4-Dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]butan-1-ol (0.63 g) (see Preparation 47) and triethylamine (0.20 g) were dissolved in dichloromethane (12 ml), cooled in an ice-bath and methanesulphonyl chloride (0.19 g) added. The mixture was stirred for 30 minutes, dichloromethane (35 ml) added and the solution washed sequentially with water (2×30 ml) and brine (30 ml). The organic phase was dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was dissolved in acetonitrile and the solvent removed under reduced pressure to give 1-methanesulphonyloxy-3-(3,4-dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]-butane (0.72 g) as an oil.