Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH:12]([C@H:25]1[O:30][CH2:29][C@@H:28]([NH:31][C:32](=O)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>C1COCC1>[CH:12]([C@H:25]1[O:30][CH2:29][C@@H:28]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:27][CH2:26]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cc1ccc(F)cc1)N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(CCN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
Into a suspension of NaBH4 (0.21 g, 3.33 mmol) in dry THF (20 ml) was added BF3.Et2O drop wise at 0° C. The mixture was stirred for 1.5 Hours at room temperature and cooled to 0° C. A solution of cis-N-(6-benzhydryl-tetrahydropyran-3-yl)-2-(4-fluorophenyl)-acetamide 17 (0.17 g, 0.42 mmol) in dry THF (10 ml) was added dropwise into the solution. The mixture was refluxed overnight and cooled to room temperature. Methanol was added to quench the reaction followed by removal of solvent in vacuo. To the residue was added 20 ml 10% HCl/MeOH and the mixture refluxed for 1 hour. The reaction mixture was cooled down to room temperature and solid NaHCO3 was added at 0° C. to pH 9. The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic phases were dried over anhydrous Na2SO4, and the solvent was removed in vacuo. Flash chromatography gave 16p Cis-(6-benzhydryl-tetrahydropyran-3-yl)-[2-(4-fluorophenyl)-ethyl]-amine (0.13 g, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13].[NH2:17][C:18]1[CH:19]=[C:20]([Cl:31])[C:21]2[S:25][C:24]([F:27])([F:26])[C:23]([F:29])([F:28])[C:22]=2[CH:30]=1.C(Cl)Cl>C1(C)C=CC=CC=1>[Cl:31][C:20]1[C:21]2[S:25][C:24]([F:26])([F:27])[C:23]([F:29])([F:28])[C:22]=2[CH:30]=[C:18]([NH:17][C:12]([NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[O:13])[CH:19]=1
Reactant: Nc1cc(Cl)c2c(c1)C(F)(F)C(F)(F)S2
Reactant: NC(=O)c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c2c(c1)C(F)(F)C(F)(F)S2
Yield: 51.7 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 0.58 g (0.0037 mole) 2-chlorobenzamide, 0.52 g (0.0051 mole) oxalyl chloride, 0.95 g (0.0037 mole) 5-amino-7-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzothiophene, and 5 ml of methylene chloride in 75 ml of toluene produced 0.84 g of N-[[(7-chloro-2,2,3,3-tetrafluorobenzothien-5-yl)amino]-carbonyl]-2-chlorobenzamide as a solid (mp 140°-142° C.), compound 9 of Table 1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=[CH:34][CH:35]=CC=2N=[N:29]1.C(N(CC)C(C)C)(C)C.Cl.NN1CCCC1>CN(C=O)C>[N:28]1([NH:29][C:20]([C:18]2[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=2)=[O:22])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)on1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NN1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN2CCCC2)on1
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (120 mg, 0.4 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (192 mg, 0.6 mmol), N,N-diisopropyl ethyl amine (340 μL, 2.0 mmol) and N-aminopyrrolidine HCl (64 mg, 0.52 mmol). The resulting reaction mixture was for 4 h at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=1:0 to 4:1) afforded the title compound (108 mg, 73%) as a colourless oil. MS: m/e=369.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13].[CH3:15][I:16].CO>CC(C)=O>[IH:16].[CH3:15][S:13][C:12](=[NH:14])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1[nH]cnc1CSCCNC(N)=S
Reactant: CI
Solvent: CC(C)=O
Solvent: CO
Product: CSC(=N)NCCSCc1nc[nH]c1C
Product: I
Reaction time: 18 h
Yield: 62.1 %

Procedure:
A mixture of N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (2.29 g) and methyl iodide (1.56 g) in acetone (45 ml) containing methanol (5 ml) was left at room temperature for 18 hours. Concentration followed by recrystallisation from isopropyl alcohol-petroleum ether (b.p. 60/80°) gave the little compound (2.3 g) m.p. 128°-131°.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([S:10]([C:13]2[C:14]([S:25][CH3:26])=[N:15][N:16]3[C:21]([OH:22])=[CH:20][C:19]([CH2:23]Cl)=[N:18][C:17]=23)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO.CN(C=O)C>[C:4]1([S:10]([C:13]2[C:14]([S:25][CH3:26])=[N:15][N:16]3[C:21]([OH:22])=[CH:20][C:19]([CH2:23][N:2]([CH3:3])[CH3:1])=[N:18][C:17]=23)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CSc1nn2c(O)cc(CCl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: CSc1nn2c(O)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
5 ml of a 33% solution of dimethylamine in EtOH were added to a solution of 1.4 g (3.7 mmol) of 3-benzenesulphonyl-5-chloromethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated, the residue was partitioned between 0.5N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 4:1) yielded 1.3 g (92%) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder, m.p.>220°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:18])[CH2:16][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)CCl)CC1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h

Procedure:
A solution of trans-[4-(2-chloro-acetylamino)-cyclohexyl]-carbamic acid tert-butyl ester (330 mg, 1.14 mmol) in DCM (12 mL) was added to a solution of methylpiperazine (0.1 mL, 0.95 mmol) in DCM (1 mL) at RT. The resulting mixture was allowed to stir overnight, then diluted with DCM, and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM and then EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to yield 199 mg of trans-{4-[2-(4-methyl-piperazin-1-yl)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:19]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of Example 4A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl chloride and 30.12 g (0.185 mol) of octanoyl chloride. The product crystallizes from toluene/n-hexane.
Reaction SMILES: [ClH:1].[CH2:2]([CH2:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:17]=O>C(O)C>[ClH:1].[CH2:2]([CH2:9][NH:10][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][C:11]1=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCCC1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CC1(NCCc2ccccc2)CCCC1=O

Procedure:
87.5 g (0.55 mole) of N-benzylmethylamine hydrochloride, 84 g (1.0 mole) of cyclopentanone, 45 g of paraformaldehyde (1.5 moles of formaldehyde) and 500 ml of ethanol are refluxed for one hour whilst stirring, during which solution occurs. After the solution has cooled, the solvent is distilled off under reduced pressure, the oily residue is dissolved in 100 ml of isopropanol and 500 ml of ethyl acetate are then added, whereupon the product crystallizes out after some time.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[Br:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(OCCCBr)cc1F
Temperature: 75 °C
Yield: 86.6 %

Procedure:
A mixture of 3,4-difluorophenol (2.60 g, 20.0 mmol), 1,3-dibromopropane (20.3 mL, 2001 mmol), and potassium carbonate (2.76 g, 20.0 mmol) in acetonitril (30 mL) was heated at 75° C. overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel. (Horizon™, flash system from Biotage™. Column: Flash 40+M, 40×150 mm. Eluent: 3% ethyl acetate in heptane. Concentration in vacuo afforded, 4.35 g of the title compound as a colourless oil with a purity of ca. 90%.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[CH:7]=1)[CH3:3].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:2]([O:4][C:5]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[C:19]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:20]=1)=[O:11])=[O:15])[CH3:3]
Reactant: CCOC(=O)CCc1ccccc1OC
Reactant: CCOC(=O)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OC
Yield: 104.6 %

Procedure:
Following the procedure of Example 1, 30.6 g of isophthalic acid monoethyl ester monochloride and 30 g of ethyl 2-methoxybenzene propanoate were treated with 57 g of aluminum chloride in dichloromethane to provide 53.6 g of the desired title product, as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]([OH:19])=[O:18])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: O=C=O
Reactant: Clc1ccc(Br)c2[nH]ccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cl)c2cc[nH]c12
Temperature: -78 °C
Yield: 67 %

Procedure:
560 mg (2.43 mmol) of 7-bromo-4-chloro-1H-indole were dissolved in 15 ml THF. The reaction mixture was cooled to −78° C. and 4.55 ml of a 1.6 M butyl lithium solution in hexane were added under nitrogen in such a way, that the temperature did not exceed a maximum of −70° C. The yellow solution was stirred at 0 to 5° C. after complete addition for 30 min. The reaction mixture was cooled to −78° C. and dry ice was added. The reaction mixture was warmed to rt, stirred for 15 min and poured onto 100 ml water. The aqueous layer was washed twice with diethyl ether, acidified with 1N aqueous HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The crude residue was stirred with hexane for 15 min, filtered and dried to yield 319 mg (67%) of 4-chloro-1H-indole-7-carboxylic acid as an off-white solid. MS (ISP) 194.1 (M−H)−.
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.ClCCl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:22](O)([CH3:25])([CH3:24])[CH3:23]>P(Br)(Br)Br.N1C=CC=CC=1>[Br:1][CH:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[C:10]([O:12][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:11]
Reactant: CC(C)(C)O
Reactant: BrBr
Reactant: O=C(O)Cc1cccnc1
Agent: BrP(Br)Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Br)c1cccnc1
Yield: 43.6 %

Procedure:
After 3.7 ml (71.8 mmols) of bromine and 0.1 ml (0.1 mmol) of phosphorus tribromide were added to 10 g (57.6 mmoles) of 3-pyridylacetic acid, the resulting mixture was stirred at 80° to 90° C. for an hour. At room temperature 150 ml of dichloromethane was added to the mixture and 13.0 g (62.4 mmols) of phosphorus pentachloride was further added thereto. The mixture was stirred for an hour. The solution was dropwise added at -60° to -70° C. to a mixture of 150 ml of dichloromethane, 27 ml of tert-butanol and 23 ml of pyridine. After the temperature was elevated to room temperature, the solution was washed, in sequence, with 1N hydrochloric acid aqueous solution and saturated sodium hydrogencarbonate aqueous solution. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting oil was subjected to silica gel column chromatography and the column was eluted with dichloromethane-methanol (10:1) to give 6.8 g (43.6%) of t-butyl 2-bromo-2-(3-pyridyl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20](C=O)[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C1COCC1>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[N:16]([CH3:34])[C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: C1COCCN1
Reactant: O=Cc1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(-c2n[nH]cc2NC(=O)c2c(F)cccc2F)nc2c(N3CCOCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of 2,6-difluoro-N-[3-(4-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (30 mg, 0.08 mmol) and morpholine (14 mg, 0.16 mmol) in CH2Cl2 (5 ml) and THF (2 ml) was added 3 Å molecular sieves (1 g) followed by sodium triacetoxyborohydride (50 mg, 0.24 mmol) and the mixture stirred at ambient temperature under a nitrogen atmosphere for 2 h. The reaction mixture was filtered through Celite, reduced in vacuo then purified by flash column chromatography [SiO2, EtOAc-hexane (1:1, 1:0), then CH2Cl2-MeOH (95:5)] affording 2,6-difluoro-N-[3-(4-morpholin-4-yl-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (13 mg) as a cream solid. (LC/MS: Rt 1.80, [M+H]+ 439).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:36]=[CH:35][C:30](/[CH:31]=[CH:32]/[CH:33]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:33](/[CH:32]=[CH:31]/[C:30]2[CH:35]=[CH:36][C:27]([C:26]([F:25])([F:37])[F:38])=[CH:28][CH:29]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C/C=C/c1ccc(C(F)(F)F)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-(trifluoromethyl)cinnamaldehyde as described in Reference example 32 to obtain the desired compound as a major product (yield: 62%). Physical data and spectral data coincided with those of the compound described in Example 2.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.O[CH:9]([C:15]1[C:27]([CH3:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:29])[CH:16]=1)[CH:10]([O:13][CH3:14])[O:11][CH3:12].C1(C)C=CC=CC=1>C(#N)C.N1C=CC=CC=1>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][C:15]1[C:27]([CH3:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:29])[CH:16]=1
Reactant: CCOC(=O)COc1cc(C)c(C(O)C(OC)OC)cc1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)COc1cc(C)c(CC(OC)OC)cc1C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a stirred suspension of sodium iodide (72 g) and chlorotrimethylsilane (52 g) in acetonitrile (180 g) was added dropwise a solution of ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (50 g) in acetonitrile (80 g) in an ice-salt bath. The mixture was stirred for 30 minutes, and then toluene (400 g) and pyridine (25 g) were added. The reaction mixture was washed with an aqueous solution of sodium thiosulfate, an aqueous solution of citric acid, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (43 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Yield: 37 %

Procedure:
A solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (170 mg, 0.37 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously at room temperature for 120 hours. The mixture was diluted with ethyl acetate and acidified to pH 2 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 61 mg (37%) of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.6-7.4 (m, 4H), 7.3 (t, 1H, J=8 Hz), 7.1-6.9 (m, 3H), 6.6 (d, 1H, J=8 Hz), and 5 7 (s, 2H). IR (CHCl3, cm−1) 3423, 3201 (br), 1630, 1600, 1579, 1564, 1445, 1330, 1261, and 775. MS (ES) m/e 441, 443.
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+:8].[Na+].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[OH-].[Na+].[Cl-]>O>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][S:1]([O-:4])(=[O:3])=[O:2].[Na+:8]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: ClCC1CO1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])CC(O)CCl
Yield: 50 %

Procedure:
The title alkylating agent was made by reacting sodium metabisulfite (104.5 g) with epichlorohydrin (101.8 g) in water (481 g). To this solution of alkylating agent at 50°-60° C. was added the product from Part A (157 g). This mixture was stirred and heated to 85°-90° C. Reaction was continued with the pH maintained in the range 8 to 9 by the incremental addition of 50% aqueous NaOH. Reaction was continued until the pH had stabilized and the ratio of ionic chloride to total chloride exceeded 0.99. Vacuum was applied to remove water until sufficient water had been removed to give a 50% solids product which was a clear, yellow liquid.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:22](OCC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>CO>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]2[N:19]=[C:24]([CH3:26])[CH:23]=[C:22]([OH:27])[N:16]2[N:15]=1)(=[O:12])=[O:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nc(S(=O)(=O)Nc2ccccc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CO
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Reaction time: 120 h

Procedure:
A solution of 1 ml of 12N hydrochloric acid in 250 ml of methanol was added to a mixture of 20.0 g (65.1 mmol) of N-(2-trifluoromethylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide and 9.2 ml (72.2 mmol) of ethyl acetoacetate and the mixture heated to reflux with stirring. After about 5 days, most but not all of the starting material was found to have reacted by thin layer chromatography. The solution was chilled and the precipitate that formed was collected by filtration, washed with cold methanol and dried to obtain 16.5 g (67.9 percent of theory) of the title compound as a white solid hemihydrate melting at 245°-7° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.Cl.ClC[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:6][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(CN2CCNCC2)c1
Yield: 86.7 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (930 mg), 3-chloromethyl-pyridine hydrochloride (902 mg) and cesium carbonate (3.6 g) were reacted in DMF (5 ml), followed by further treatment with TFA, to obtain 1-pyridin-3-ylmethyl-piperazine (767 mg, 87%) as a pale brown oil.