Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[NH:30][C:29]([C@@H:31]2[CH2:36][C@@H:35]3[C@@H:33]([CH2:34]3)[NH:32]2)=[N:28][CH:27]=1.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C.CO.O>[I:25][C:26]1[NH:30][C:29]([C@@H:31]2[CH2:36][C@@H:35]3[C@@H:33]([CH2:34]3)[N:32]2[C:43](=[O:44])[C@@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[CH:46]([CH3:48])[CH3:47])=[N:28][CH:27]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: Ic1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
HATU (464 mg, 1.22 mmol) was added to a solution of (1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (280 mg, 1.02 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (214 mg, 1.22 mmol) and DIEA (1.8 mL, 10 mmol) in DMF (3 mL). The reaction mixture was stirred 2 h at room temperature and then diluted with MeOH (5 mL) and water (5 mL). The volatiles were removed under vacuum and the residue was purified with flash chromatography (sample was dry loaded on silica gel and eluted with 0-100 ethyl acetate/hexanes) to afford methyl(S)-1-((1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (500 mg, 0.925 mmol, 91% yield) as yellowish oil. LC-MS retention time 0.850 min; m/z 432.97 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.09 (s, 1H), 5.09 (dd, J=8.9, 4.6 Hz, 1H), 4.47-4.60 (m, 1H), 3.67 (s, 3H), 3.59-3.62 (m, 1H), 2.39-2.49 (m, 1H), 2.29-2.39 (m, 1H), 2.12 (dq, J=13.6, 6.8 Hz, 1H), 1.95-2.06 (m, 1H), 1.11 (dt, J=8.6, 5.5 Hz, 1H), 0.94-1.02 (m, 3H), 0.91 (d, J=6.7 Hz, 3H), 0.76 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(O[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.CC[O-].[Na+]>>[CH2:15]([O:14][C:12](=[O:13])[C:11]([CH:4]1[CH2:5][CH2:6][CH:2]([CH3:1])[C:3]1=[O:7])=[O:17])[CH3:16]
Reactant: CC1CCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C1CCC(C)C1=O
Temperature: 25 °C
Yield: 27.9 %

Procedure:
2-methylcyclopentanone (1.0058 g, 10.2 mmol) and diethyloxalate (1.38 mL, 10.2 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 3.4 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 4. The crude material was purified with 98:2 to 96:4 Hexanes: EtOAc to obtain 0.5635 g (27.7%) of 4. 1H (CDCl3, 400 MHz): δ 4.29 (2H, q, J=7.1 Hz), 2.96 (1H, ddd, J=17.6, 8.1, 1.5 Hz), 2.69 (1H, ddd, J=17.6, 9.5, 8.1 Hz), 2.57-2.47 (1H, m), 2.24 (1H, dtd, J=12.5, 8.3, 2.4 Hz), 1.49 (1H, dtd, J=12.5, 10.3, 8.4 Hz), 1.34 (3H, t, J=7.1 Hz), 1.13 (3H, d, J=7.0 Hz) ppm. 13C (CDCl3, 100 MHz): δ 164.09, 153.19, 117.67, 62.92, 44.76, 30.60, 30.36, 26.55, 14.63, 14.37 ppm.
Reaction SMILES: [F:1][C:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][CH:5]([CH2:9][CH:10]([OH:32])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=[O:7].[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].N1C=CN=C1>CN(C)C=O>[C:38]([Si:35]([CH3:37])([CH3:36])[O:32][CH:10]([CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH:5]([CH2:4][CH2:3][C:2]([F:1])([CH3:34])[CH3:33])[C:6]([OH:8])=[O:7])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reaction time: 96 h
Yield: 38.6 %

Procedure:
To a solution of 2-(3-fluoro-3-methyl-butyl)-4-hydroxy-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoic acid (1.63 g, 3.49 mmol) in dimethylformamide (10 mL) was added t-butyldimethylsilyl choride (3.2 g, 20.9 mmol) and imidazole (2.9 g, 41.9 mmol). The reaction was stirred for 4 days then quenched with methanol and stirred another 0.5 hours. The solution was diluted with ether and water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (784 mg, 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)([O-])=O>CO.[Pd]>[CH3:15][S:14][C:10]1[N:9]=[C:8]([O:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:18]([NH2:19])=[CH:17][CH:16]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CO
Product: CSc1nccc(Oc2ccc(N)c(N)c2)n1
Reaction time: 2 h

Procedure:
4-(3,4-Dinitro-phenoxy)-2-methylsulfanyl-pyrimidine (Step A, 1.0 g, 3.2 mmol, 1.0 eq.) was dissolved in MeOH (10 mL) and the atmosphere was replaced by argon. A catalytic amount of 10% Pd/C was added and the argon was replaced by a H2 atmosphere. The mixture was hydrogenated for 2 h at RT at 60 psi using a Parr hydrogenation apparatus. More Pd/C was added and the mixture was hydrogenated for another 4 h at 60 psi. The Pd/C was removed by filtration. The crude aniline was purified using column chromatography (0-100% EtOAc in hexanes) to give 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-benzene-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:39][CH3:40])[CH:35]=3)[CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:39][CH3:40])[CH:35]=3)[CH:30]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:27][CH:28]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC)ccc2c1
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (4.0 mg, 0.0072 mmol) in ethanol (1 mL) was added LiOH (2.0 N in water, 0.1 mL, 0.2 mmol), then the mixture was stirred for one hour The mixture was diluted with DCM, then acidified with 2.0 N HCl (aq). The layers were separated, then the organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to obtain the title compound as a white solid. 1H NMR (600 MHz, CD3OD): δ 7.53-7.48 (m, 6H); 7.42 (d, J=8.5 Hz, 1H); 7.33-7.28 (m, 5H); 6.98-6.94 (m, 2H); 5.47 (s, 1H); 4.32 (d, J=11.7 Hz, 1H); 3.79 (s, 3H); 3.51-3.47 (m, 2H); 2.50 (s, 2H); 1.56 (t, J=7.6 Hz, 2H); 1.04 (d, J=9.5 Hz, 2H); 0.73 (t, J=7.3 Hz, 3H); LC3 2.61 min. [M+H]+ 531.
Reaction SMILES: C(OC(N1CCC2C(=CC=C(C(=O)C[Br:20])C=2)C1)=O)(C)(C)C.[OH:22][CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1)[CH3:24]>>[Br:20][CH2:32][C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH:23]([OH:22])[CH3:24])=[CH:26][CH:27]=1)=[O:33]
Reactant: CC(=O)c1ccc(C(C)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)CBr)ccc2C1
Product: CC(O)c1ccc(C(=O)CBr)cc1

Procedure:
2-Bromo-1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone is prepared following preparation 29c from 600 mg (3.65 mmol) 1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:40]=1[CH2:41][CH2:42]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:42][CH2:41][C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH2:34])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: Nc1cnccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cnccc1CCOc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 4-nitronaphthol (0.95 g, 5.00 mmol), PPh3 (1.97 g, 7.50 mmol) and 2-(3-aminopyridin-4-yl)ethanol (16) (1.04 g, 7.50 mmol) in THF (20 mL) was added dropwise DIAD (590 μl, 3.75 mmol) at −15° C. The mixture was stirred for 1 hr at RT and the volatiles removed in vacuo. The residues was absorbed on silica (20 g) and purified by column chromatography (80 g) gradient elution with 50-100% EtOAc/iso-hexane and final elution with 5% MeOH/EtOAc to give 4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-3-amine a yellow solid (17) (1.36 g, 88%): m/z 310 (M+H)+ (ES+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
0.4 g (11 mmol) of 60% NaH is introduced into a flask containing 25 ml of anhydrous DMF under an argon atmosphere. A solution of 1.38 g (10 mmol) of 4-nitrophenol in 5 ml of anhydrous DMF is added dropwise, under agitation at 23° C. After 30 minutes a solution of 1.77 g (10 mmol) of 2-(chloromethyl)-quinoline in 5 ml of anhydrous DMF is added dropwise and agitation is continued for 15 hours while heating the mixture at 90° C. At the end of the reaction, the mixture is poured onto ice and an abundant precipitate forms. The suspension is filtered, rinsed twice with 25 ml of water followed by 20 ml of ethyl ether. A white solid is thus obtained with a yield of 75%. Melting point: 154-155° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)[CH2:4][OH:5].[C:14]([N:18]=[C:19]=[S:20])([CH3:17])([CH3:16])[CH3:15]>C(O)C.C(N(CC)CC)C.O.ClCCl>[C:14]([NH:18][C:19]([NH:2][CH:3]([CH2:6][N:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)[CH2:4][OH:5])=[S:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CN1CCN(CC(N)CO)CC1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN1CCN(CC(CO)NC(=S)NC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 42 h

Procedure:
To a solution of 1 g of 2-amino-3-(4-methyl-piperazin1-yl)-1-propanol hydrochloride in 20 mL of absolute ethanol and 1.43 mL of triethylamine, about 0.78 mL of tert-butylisothiocyanate are added. The reaction mixture is stirred under inert atmosphere at a temperature of about 20° C. for 42 hours then is heated at a temperature of about 50° C. for 1 hour 30 min. After cooling at a temperature of about 20° C., the reaction medium is evaporated under reduced pressure (2 kPa) at a temperature of about 30° C. The residue thus obtained is taken up in 10 mL of water and 40 mL of dichloromethane. The aqueous phase is extracted with 2 times 30 mL of dichloromethane. The organic phases are collected, washed with 15 mL of water, dried over magnesium sulfate, filtered, then concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. About 0.42 g of N-(tert-butyl)-N′-[2-hydroxy-1-(4-methyl-piperazin-1-ylmethyl)ethyl]thiourea are obtained in the form of a white paste. [Infrared spectrum between lamella of KBr 3279; 3075; 2939; 2806; 1533; 1459; 1359; 1295; 1204; 1010 and 821 cm−1].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([NH:17]C(OC(C)(C)C)=O)[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O)[CH3:2]>Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:5]1[CH2:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH:17]1)=[O:25])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (90 mL) was added to (R)-2-t-butoxycarbonylamino-5-(4-fluorophenyl)-5-oxovaleric acid ethyl ester (6.33 g), and the resultant was stirred at room temperature for 2 hours. The solvent was removed under a vacuum, and ethanol (50 mL) and 10% palladium on carbon (6 g, 50% water content) was added, and under a hydrogen atmosphere, stirring was continued for 20 hours at room temperature. The catalyst was filtered off on celite, and the solvent was removed under vacuum. The resultant was diluted in ethyl acetate and washed with sodium bicarbonate aqueous solution and brine, in sequence. The solvent was removed under vacuum, and the resultant was purified with silica gel column chromatography (heptane/ethyl acetate), and the title compound (3.11 g) was obtained. The physical property values are as follows.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Fc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1cccc2c1CCN2
Temperature: 12 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a stirred solution of 4-fluoro-1H-indole (950 mg, 7.03 mmol) in Acetic Acid (20 mL) at 12° C. under nitrogen was added sodium cyanoborohydride (1458 mg, 23.20 mmol) portionwise. The reaction was stirred at 12° C. for 2 hours, and at room temperature overnight. The reaction was worked up by pouring into sodium hydroxide (10 N). The aqueous was extracted with diethyl ether (3×100 mL), and the combined organics dried over sodium sulfate. LCMS analysis at this point indicated presence of product and some acylated product, along with some acylated starting material. The crude was dissolved in THF (10 mL) and treated with NaOH (6 N, 2 mL), then stirred at r.t. for 2 h. The reaction was stirred overnight, but no change in LCMS was observed, so the organic layer was removed, and the aqueous extracted with diethyl ether (2×10 mL), the combined organics were dried over sodium sulfate. The dried solution was filtered and concentrated, and the residue was purified by flash chromatography (0-25% EtOAc in hexanes, 24-g silica gel column) to afford 4-fluoro-2,3-dihydro-1H-indole (510 mg, 3.72 mmol, 52.9% yield) as a colorless oil. LC-MS (ES) m/z=138 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.94 (t, J=8.59 Hz, 2H), 3.48 (t, J=8.59 Hz, 2H), 5.79 (br. s., 1H), 6.23-6.35 (m, 2H), 6.87-6.99 (m, 1H).
Reaction SMILES: FC1C(O)=C(F)C(F)=C(F)C=1F.[C:13]([O:17][C:18]([C@H:20]([C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([NH:33][NH2:34])=[O:32])[CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:39]([N:46]=[C:47]=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:13]([O:17][C:18]([C@H:20]([C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([NH:33][NH:34][C:47](=[O:48])[NH:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:32])[CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)NCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.09 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide pentafluorophenol salt in 5 ml of pyridine was treated with 0.25 ml of benzyl isocyanate under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed in sequence with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated to give a yellow oil. This was dissolved in ethyl acetate and washed twice with 0.5% aqueous sodium hydroxide and then with saturated aqueous sodium chloride. The organic layer was again dried over anhydrous magnesium sulphate and evaporated to give 0.946 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-(benzyl)carbamoyl-4-methylvalerohydrazide in the form of a pale yellow foam.
Reaction SMILES: S(O[CH2:12][C:13]1[N:17]([C:18]2[S:19][C:20]([CH2:32][CH3:33])=[CH:21][C:22]=2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]([CH3:34])=[N:15][N:14]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44]>C(O)C>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:12][C:13]2[N:17]([C:18]3[S:19][C:20]([CH2:32][CH3:33])=[CH:21][C:22]=3[C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:16]([CH3:34])=[N:15][N:14]=2)[CH2:38][CH2:37]1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2COS(=O)(=O)c2ccc(C)cc2)s1
Reactant: CN1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN2CCN(C)CC2)s1
Yield: 49.8 %

Procedure:
To a suspension of 7 g of 3-tosyloxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 100 ml of ethanol is added 2 g of N-methyl-piperazine, and the mixture is refluxed for 5 hours. Aftr the completion of the reaction, the solvent is distilled off and water is added to the residue. The residue is made alkaline with potassium carbonate and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue obtained is allowed to react with 2.2 g of oxalic acid in ethanol. The crude crystals formed are recrystallized from aqueous ethanol to give 3.8 g of 3-(4-methyl-1-piperazinylmethyl)-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole dioxalate 1/2 hydrate as colorless crystals melting at 164° - 165°C (decomposition).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:26])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[I:26][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][C:10]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OCCc1ccc2oc(-c3ccccc3)cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
2-(2-Phenyl-benzofuran-5-yl)ethanol (11.18 g; 46.9 mmol) was dissolved in DCM (170 ml) and N-iodinesuccinimide (NIS; 11.31 g; 50.27 mmol) and triphenylphosphine (15.39 g; 52.67 mmol) was added under stirring. After keeping the reaction mixture at RT over night the reaction was extracted two times with 6% aqueous NaHCO3 solution and the organic layer was dried over Na2SO4. After filtering and removal of the solvent pure title compound was obtained after crystallization from methanol/DCM/cyclo-hexane. The mother liquor was collected and purified on silica gel (cyclohexane/ethylacetate 95/5 as mobile phase).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][CH:22]([CH3:23])[CH3:24])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)NC2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A solution of 4-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-benzoic acid (100 mg, 0.285 mmol), 4-amino-1-methanesulfonyl piperidine (66 mg, 0.370 mmol) and DIPEA (146 μL, 0.855 mmol) in DMF (2 mL) was treated with HATU (162 mg, 0.428 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-50% EtOAc in DCM) and triturating with Et2O gave the title compound (124 mg, 85%). 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=7.6 Hz, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.20 (t, J=8.7 Hz, 2H), 7.11 (dd, J=8.8, 5.0 Hz, 2H), 3.93-3.95 (m, 1H), 3.58 (d, J=11.8 Hz, 2H), 2.88 (s, 5H), 1.93 (s, 1H), 1.90 (s, 2H), 1.58-1.61 (m, 2H), 1.42-1.44 (m, 1H), 0.85 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 511.8 [M+1]+.
Reaction SMILES: ClC1C=C(C(F)(F)F)C=C(Cl)C=1N.Cl[C:15]1[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19](Cl)[C:20]=1[Cl:21].[F-].[Li+].N>CN1CCCC1=O>[Cl:21][C:20]1[CH:15]=[CH:16][C:17]([C:23]([F:24])([F:25])[F:26])=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Agent: N
Agent: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [F-]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(Cl)cc1

Procedure:
WO00/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the presence of N-methylpyrrolidone at 250° C. to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.