Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([NH2:15])=O)[NH:8][C:9]2=O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([C:13]#[N:15])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Product: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Yield: 81.8 %

Procedure:
A solution of 7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (550 mg, 2.46 mmol) in POCl3(10 mL) was heated to reflux for 6 hours. The solvent was subsequently removed in vacuo and the crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EA=30:1) to give the title compound (450 mg, 81.8%). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.80 (dd, J=1.6 Hz and 8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:27]([O:29][C:30](=O)[C:20]=2[CH:19]=1)=[O:28]>>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[N:1]1[C:27](=[O:28])[C:21]2[C:20](=[CH:19][CH:18]=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=2)[C:30]1=[O:29]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1N
Product: Cc1ccc(-c2nc3ccccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methylphenyl)benzoxazole (250 mg, 1.1 mmol) and 1,2,4-benzenetricarboxylic anhydride (214 mg, 1.1 mmol) the title compound was obtained. 375 mg (84%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.33(d, 2H), 8.23(dd, 1H), 8.12(d, 1H), 7.79(m, 2H), 7.68(d, 1H), 7.44(m, 2H). MS 397 m/z (M−H)−.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1>COC(C)(C)C>[CH:1]1([NH:7][C:8]([NH:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCC1
Reactant: CN1CCN(CCCN)CC1
Solvent: COC(C)(C)C
Product: CN1CCN(CCCNC(=S)NC2CCCCC2)CC1
Reaction time: 18 h
Yield: 82.7 %

Procedure:
Cyclohexyl isothiocyanate (1.51 g, 10.7 mmole) in 5 mL t-butyl methyl ether was added to a solution of 1.68 g (10.7 mmole) 3-(4-methyl-1-piperazinyl)propylamine (Lancaster Synthesis, Windham N. H.) in t-butyl methyl ether (10 mL). After 18 hr at room temp., filtration gave 2.64 g (83%) 1-cyclohexyl-3-[(4-methyl-1-piperazinyl)propyl]thiourea, melting pt. 109–111° C. A solution of 2.388 g (8 mmole) of this thiourea in 12 mL ethanol containing 2.1 mL (25.2 mmole) conc. HCl was added to a warm solution of 2.755 g (16 mmole) 2-methyl-1,4-naphthoquinone in 20 mL warm ethanol with stirring. After 3 days, 1.925 g crude solid was filtered out. Of this, 1.0 g was recrystallized from 20 mL 95% methanol+80 mL acetone to give 0.927 g (40%) of the title compound, melting pt. 242–244° C.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cccs1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Agent: [Cl-]
Product: Fc1c(OCCNCc2cccs2)ccc2ccccc12
Yield: 82 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and thiophen-2-carbaldehyde in 82% yield as a white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:17])=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 98.7 %

Procedure:
Using 4-chloroaniline (1.42 g, 11.0 mmol) and 4-nitrobenzoic acid (1.76 g, 10.4 mmol), the procedure of Reference Example 16 was repeated to obtain 2.84 g (98.5%) of the title compound in the form of yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([NH:17][NH2:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([CH:24]=[C:25]2[CH2:34][CH2:33][C:32]3[CH:31]=[C:30]([C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28][C:27]=3[C:26]2=O)[CH2:23][CH2:22][CH2:21][CH2:20]1>Cl.C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([N:17]2[CH:24]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:25]3[C:26]([C:27]4[CH:28]=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:32]=4[CH2:33][CH2:34]3)=[N:18]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NN)cc1OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(OCc3ccccc3)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 64 h
Yield: 96 %

Procedure:
A mixture of 2-(benzyloxy)-4-hydrazinylbenzonitrile; Preparation 13 (358 mg, 1.5 mmol), Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (284 mg, 1.0 mmol), ethanol (7 mL), and 1 drop of concentrated hydrogen chloride was stirred under argon at 80° C. for 64 hours. The mixture was cooled to room temperature, concentrated and purified by normal phase flash column chromatography on a 40 g silica gel column (20-80% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate (yellow foam, 485 mg, 0.96 mmol, 96% yield). The title compound was largely present as (±)-(3RS,3aSR)-methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.51 (m, 7H), 1.56-1.68 (m, 1H), 1.82 (ddd, J=25.85, 12.96, 3.89 Hz, 1H), 1.95-2.08 (m, 1H), 2.15-2.31 (m, 1H), 2.82-2.95 (m, 1H), 3.11 (d, J=16.38 Hz, 1H), 3.53-3.63 (m, 1H), 3.87 (s, 3H), 4.91 (dd, J=9.53, 5.50 Hz, 1H), 5.31 (q, J=12.35 Hz, 2H), 6.85 (d, J=8.32 Hz, 1H), 6.96 (s, 1H), 7.35 (t, J=7.25 Hz, 1H), 7.39-7.57 (m, 5H), 7.80-7.92 (m, 2H), 8.10 (d, J=8.32 Hz, 1H). ES-MS m/z 506 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (6S)-5′-bromo-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (3.00 g, 7.73 mmol) in THF (30 mL) at 0° C. was added triethylamine (1.29 mL, 9.28 mmol). The resulting mixture was stirred for 10 min, then 2-(trimethylsilyl)ethoxymethyl chloride (1.64 mL, 9.27 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 4 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=520.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:20].CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][Br:20])=[CH:4][CH:3]=1
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
50.1 g (0.202 mol) of 3,3-bis(4-fluorophenyl)propanol were dissolved in 150 ml of toluene, and a solution of 21.8 g (0.081 mol) of PBr3 in 50 ml of toluene was added dropwise. The mixture was stirred at room temperature for 30 minutes and at 60° C. for 90 minutes and, for hydrolysis, was poured onto 400 ml of ice, 200 ml of ether were added, the organic phase was separated off, washed with NaHCO3 solution and NaCl solution, dried and concentrated and the residue was distilled in vacuo for purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC[C:21]([O-:23])=[O:22].[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:21]([OH:23])=[O:22])[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCC(=O)[O-]
Reactant: Fc1cccc(Cn2ccc3cc(F)cnc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(F)cnc2n1Cc1cccc(F)c1
Yield: 90.2 %

Procedure:
A mixture of 6.9 g (20.58 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate (WO07/010,138) and 1.89 g (33.7 mmol) of potassium hydroxide in a mixture of 80 mL of ethanol and 10 mL of water is heated under reflux for 1.5 h. After this time, the reaction mixture is concentrated at reduced pressure, and is then taken up in 200 mL of water. The solution is acidified with additions of concentrated hydrochloric acid, and then extracted three times with 50 mL of dichloromethane. The organic phases are combined, dried over sodium sulfate and then concentrated at reduced pressure. The resultant product is triturated in 5 mL of dichloromethane. A precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 5.35 g of the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH3:24])[N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1CN(c2ccc(=O)n(C)n2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Methyl(3S,4R)-4-(4-chlorophenyl)-1-(6-oxo-1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate obtained in Step A of Preparation 22 was dissolved in DMF (5 ml). Cs2CO3 (1.11 g, 3.41 mmol) was added, and methyl iodide (0.71 mL, 11.40 mmol) was added dropwise. The reaction mixture was stirred at 20-30° C. for 2 hours and concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.55 g, 70%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])(=[O:4])=[O:3].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:20]([N+:17]([O-:19])=[O:18])[CH3:21])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1C(F)(F)F
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1)[N+](=O)[O-]

Procedure:
A stirred mixture of 4-methanesulfonyl-3-trifluoromethyl-benzaldehyde (Example 5001a) (12 g, 47 mmol), nitroethane (27.5 ml, 380 mol) and ammonium acetate (1.22 g, 16 mmol) is heated at reflux under argon for 18 hours. The mixture is concentrated to give an oil which is dissolved in dichloromethane (200 ml) and washed with water (3×200 ml), followed by brine (200 ml). The organic extract is dried (MgSO4), filtered and the solvent removed to give the product as red oil. This is used immediately in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[NH2:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.N1C=CC=CC=1>[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=2[N:14]=1)[CH3:16]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1c(N)cc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(N)c2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a mixture of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine (1.3 g), 2-ethylsulfanylbenzoic acid (1.3 g), and pyridine (12 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (86 mg) were added at room temperature. The mixture was stirred at room temperature for 5 hours, then heated to 110° C., and stirred with heating for 8 hours. After the reaction mixture was allowed to cool to room temperature, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 339 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-6-trifluoromethyl-3H-benzimidazole-4-ylamine (hereinafter, Present Compound 336).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1)=[O:17]
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(Cl)cc1)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
1-(Bromomethyl)-4-chlorobenzene (592 mg, 2.88 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and potassium carbonate (478 mg, 3.46 mmol) in acetone (40 ml) under nitrogen at 20° C. The reaction mixture was stirred at 55° C. for 18 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (30×3 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 320 mg.
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].O>CN(C=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:8][O:9][CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)(C)OC[C@H](CO)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1COC[C@@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of compound 14b (562 mg, 2.0 mmol) in DMF (10 mL) at 0° C. was added NaH (200 mg, 5.0 mmol). The reaction was stirred for 30 min and to it was added methyl 2-(bromomethyl)benzoate (366 mg, 1.6 mmol). The reaction mixture was stirred for 3 h, poured into H2O and extracted with EA (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 14c (275 mg, 40% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[S:21])[C@H:12]([CH2:13]O)[C@@H:11]([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:9][O:10][C@H:11]([C:15]([F:16])([F:17])[F:18])[C@H:12]1[CH2:13][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:19]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
N-(((3S,4R,5S)-3-(2-Fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (31.1 g) was dissolved in pyridine (150 mL), and the mixture cooled to −20° C. Trifluoromethanesulfonic anhydride (14.0 mL) was added dropwise over 30 min and the reaction was allowed to warm to 0° C. After stirring for 2 h, the reaction was quenched by the addition of ammonium chloride (sat., aq., 400 mL) and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (2% to 30% EtOAc/hex) to obtain the title compound (18.50 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (dd, J=13.9, 3.5 Hz, 1H), 3.25 (d, J=13.6 Hz, 1H), 3.61 (br. s., 1H), 4.00-4.10 (m, 1H), 4.66 (d, J=8.8 Hz, 1H), 4.78-4.87 (m, 1H), 7.12-7.60 (m, 6H), 7.68-7.73 (m, 1H), 7.99-8.16 (br. s., 2H), 8.62-8.66 (m, 1H)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].[CH:23](N(CC)C(C)C)([CH3:25])[CH3:24].C(Br)C=C>C(Cl)Cl>[CH2:25]([N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[C:3]2=[O:22])=[CH:8][CH:9]=1)(=[O:14])=[O:15])[CH:23]=[CH2:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.6 %

Procedure:
Synthesized according to General Procedure 23. To a stirring suspension of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 0.59 mmol) in CH2Cl2 (0.50 mL), under N2, at 0° C., was added N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) followed by allylbromide (51 uL, 0.59 mmol). The mixture was stirred at ambient temperature for 19 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (220 mg, 0.57 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H), 2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[SH:11].Cl[CH2:17][C:18]([OH:20])=[O:19].[OH-].[K+].Cl>CN(C)C=O.O>[C:18]([CH2:17][S:11][C:7]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:14]=[C:13]([F:15])[CH:12]=2)[CH:10]=[CH:9][N:8]=1)([OH:20])=[O:19]
Reactant: O=C(O)CCl
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CSc1nccn1Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
1-(3,5-Difluorobenzyl)-2-mercaptoimidazole (2.26 g, 0.010 mole) and chloroacetic acid (0.95 g, 0.010 mole) were dissolved in a mixture of dimethylformamide (10 ml) and water (0.5 ml), and potassium hydroxide (1.12 g, 0.020 mole) in water (10 ml) was added dropwise with stirring at ambient temperature over 30 minutes. Stirring at ambient temperature was continued for five hours. The solution was then diluted with water (10 ml) and acidified with concentrated hydrochloric acid. A trace of precipitate formed. The mixture was filtered and the pH of the filtrate was adjusted to 5.5 with concentrated ammonium hydroxide and the mixture was extracted with three portions of methylene chloride. Concentration of the combined extracts gave a clear, heavy oil which was triturated with boiling ether. A white crystalline solid formed which was filtered and recrystallized from ethyl acetate hexane to give 1.18 g (42% yield) of 2-(carboxymethylthio)-1-(3,5-difluorobenzyl)imidazole, mp 101°-103° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)#[N:19].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:28][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]#[N:19])[CH:21]=1)[CH3:27])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Reactant: CC(N)c1cccc(C#N)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A mixture of 5.65 g of 3-chloro-2(R)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester, 2.92 g of N-[1-(3-cyanophenyl)ethyl]amine, 2.60 g of Hunig base and 10 ml of ethanol is heated under reflux for 5 days, then cooled to room temperature and concentrated by evaporation. Chromatography of the residue on silica gel gives 3-{N-[1 -(3cyanophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester in the form of an oil; [α}20D =+8.6 0.8 (c=1.225 in trichloromethane).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[C:14]1([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[C:14]1([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:12][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: N#CCC(=O)Nc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)c2ncccc12)C(=O)Nc1ccccc1
Yield: 75 %

Procedure:
A solution of 8-hydroxy-5-quinolinecarboxaldehyde (1.732 g, 0.010 mol), N-phenyl cyanoacetamide (1.602 g, 0.010 mol) and piperidine (0.255 g, 0.003 mol) in absolute ethanol (50 ml) was heated for 3 h at reflux. The reaction mixture was chilled to about 10°-15° C., the precipitate filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Almost pure title compound was obtained in about 75% yield (2.365 g).