Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[N:18]([CH3:23])[C:17]3[CH2:24][CH:25]4[NH:29][CH:28]([C:16]=3[C:15]=2[C:14]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[C:20]([CH3:22])[C:19]3[N:18]([CH3:23])[C:17]4[CH2:24][CH:25]5[NH:29][CH:28]([C:16]=4[C:15]=3[C:14]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])c1cccc(Cl)c1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2cccc(Cl)c2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Yield: 39 %

Procedure:
Intermediate 1 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-chlorophenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (136 mg, 39%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.83 (dt, J=7.5, 1.5 Hz, 1H), 7.43-7.49 (m, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.33 (s, 1H), 5.22 (br s, 1H), 4.71 (br s, 1H), 3.85 (s, 3H), 3.35 (br s, 1H), 2.76 (s, 3H), 2.45 (d, J=15.9 Hz, 1H), 2.12-2.38 (m, 2H), 1.86-1.97 (m, 1H), 1.52-1.66 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: B(Br)(Br)Br.[C:5]1([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:28](#N)[CH3:29].C([O-])([O-])=[O:32].[Na+].[Na+]>C(Cl)Cl>[C:28]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:18][CH2:19]1)(=[O:32])[CH3:29]
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1N1CCN(CCNc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCNc2ccccc2C(C)=O)CC1
Temperature: 25 °C

Procedure:
A solution of 1 M boron tribromide in CH2Cl2 (2.37 mL) was dropped into another solution containing 0.74 g of 1-(N-phenyl-2-aminoethyl)-4-(2-methoxyphenyl)piperazine in 10 ml, of CH2Cl2 stirred at −3° C. in nitrogen atmosphere. Subsequently, 0.25 mL of acetonitrile at room temperature was added and the mixture was stirred for 1h at room temperature and for 8 h until precipitation. After cooling at room temperature, the mixture was treated with a 10% aqueous solution of Na2CO3 and the organic phase that separated was dried on anhydrous Na2SO4 and evaporated to dryness. The crude was purified via flash chromatography (CH2Cl2-MeOH 98:2) and the residue crystallized from EtOH giving 0.33 g (39%) of the title compound. Melting point: 92-94° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[Si]([O:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1)(C(C)(C)C)(C)C.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[C:26]2[CH:37]=[CH:38][C:23]([OH:22])=[CH:24][CH:25]=2)=[CH:36][CH:35]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (952 mg), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (2.90 g) and 1N-aqueous sodium hydroxide solution (4.6 ml) in methanol (20 ml) was stirred at room temperature for 4 hours. This reaction mixture was concentrated and extracted with chloroform and the extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=19:1). The resulting 2-[4-(4-t-butyldimethylsilyloxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone was dissolved in tetrahydrofuran (15 ml). To this solution was added 1M tetrabutylammonium fluoride/tetrahydrofuran (3.8 ml), and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and the resulting precipitate was collected by filtration, rinsed with water, and dried to provide the title compound as colorless solid (1.332 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)[CH2:17][CH3:18].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([O:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[CH:10][CH:11]=2)=[O:26])[CH2:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: Oc1ccc(-c2ccc(F)c(F)c2)cc1
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Temperature: 60 °C

Procedure:
3,4-Difluoro-4'-hydroxybiphenyl (2.0 g, 10 mmols) was dissolved in dried pyridine (5 cc), followed by adding to the solution, a solution obtained by dissolving trans-4-propylcyclohexanecarboxylic acid chloride (2 g, 11 mmols) in dry toluene (10 cc), heating the mixture at 60° C. for 3 hours with stirring, then adding the resulting material to water (100 cc), then washing the separated toluene layer with 6N hydrochloric acid, 2N aqueous solution of NaOH and further with water, distilling off toluene from the toluene layer, and recrystallizing the residual crystals from ethyl acetate (10 cc) to obtain the objective 3,4-difluoro-4'-biphenylyl trans-4-propylcyclohexanecarboxylate (2.5 g, 70%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>C1COCC1.CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:2]=1
Reactant: Nc1cccnn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Nc1cccnn1)Oc1ccccc1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a suspension of pyridazin-3-amine (5 g, 50 mmol) in THF (50 mL) and CH3CN (70 mL) was added pyridine (5.10 mL, 63.1 mmol) followed by phenyl chloroformate (6.95 mL, 55.2 mmol) slowly. The reaction was stirred overnight. The reaction was filtered to remove the precipitate. The filtrate was concentrated and then taken up in CH2Cl2 which was washed with water. The organic layer was dried using SPE phase separators and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH/CH2Cl2). An undesired side product eluted first followed by the title compound which was concentrated to give a white solid (7.5 g, 70% yield). MS (APCI 10 V) AP+1 216.12; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20-7.24 (m, 2H) 7.25-7.28 (m, 1H) 7.39-7.44 (m, 2H) 7.64-7.69 (m, 1H) 8.05 (dd, 1H) 8.94 (dd, 1H) 11.34 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:28]([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)(=[O:30])[CH3:29]>C(Cl)Cl.C1COCC1>[Cl:1][CH2:2][C:3]([N:34]1[CH2:35][CH2:36][CH:32]([NH:31][C:28](=[O:30])[CH3:29])[CH2:33]1)=[O:5]
Reactant: CC(=O)NC1CCNC1
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)CCl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of chloroacetic acid (0.715 g, 7.56 mmol, 1 eq.) in DCM (15 mL) and THF (12 mL) at r.t. was added EDC.HCl (1.89 g, 9.83 mmol, 1.3 eq.) and HOBt (1.33 g, 9.83 mmol, 1.3 eq.). The reaction mixture was stirred at r.t. for 30 min and then 3-acetamidopyrrolidine (1.26 g, 9.83 mmol, 1.3 eq.) was added. After stirring two days at r.t., the reaction mixture was diluted with water, HCl 1M, and DCM. The aqueous phase was extracted with DCM five times. The combined organic layers were washed with a saturated NaHCO3 solution, with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude oil was used as such in the next step.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:42]([Cl:44])[Cl:43]>C(O)(=O)C>[NH3:1].[CH2:42]([Cl:44])[Cl:43].[C:20]1([NH:19][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N
Product: c1ccc(NCc2ccc(OCCCN3CCCCC3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (277 mg), aniline (108 mg), and acetic acid (0.07 mL) in DCM (5 mL) was treated with sodium triacetoxyborohydride (340 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (10 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (256 mg). 1H NMR (400 MHz, CDCl3): 7.27 (m, 2H), 7.18 (m, 2H), 6.88 (m, 2H), 6.72 (m, 2H), 6.64 (m, 2H), 4.24 (s, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.94 (br, 1H), 2.48 (m, 2H), 2.41 (br, 4H), 1.98 (m, 2H), 1.64–1.57 (m, 4H), 1.48–1.41 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.C([Li])CCC.[C:33](=[O:35])=[O:34].Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=[C:2]([C:33]([OH:35])=[O:34])[CH:7]=1
Reactant: O=C=O
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-[methyl(phenylmethyl)amino]-6-[3-(trifluoromethyl)phenoxy] pyridine (6.38 g, 0.0146 mol) was dissolved in about 300 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [10 ml (ca. 1.63 M in hexane solution), 0.0146×1.1 mol] and then stirred for about 10 minutes. After the interior of the reactor was replaced with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 30 ml of a 1 N aqueous hydrochloric acid solution, distributed in ethyl acetate-water, and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.I[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:18]=[C:15]([NH:14][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[CH:5]=1)[C:2]([F:19])([F:20])[F:1])/[CH:16]=[CH:17]/[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:31]([F:32])([F:34])[F:33])[CH:23]=1
Reactant: C=CC(=O)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: O=C(O)c1ccc(I)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(C(=O)O)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Under argon, first 3.34 g (7.90 mmol) of N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-acrylamide from Example 2. Stage 1, and then 2.49 g (7.90 mmol) of 4-iodo-2-(trifluoromethyl)benzoic acid (commercially available, CAS Registry Number: 954815-11-3), 0.206 g (7.90 mmol) of triphenylphosphine, 88.4 mg (0.39 nmol) of palladium(II) acetate and 13.5 g (133 mmol) of triethylamine were initially charged in 67 ml of N,N-dimethylformamide, and the reaction mixture was stirred at 100° C., for 5 hours. After addition of water, the solution was extracted with ethyl acetate, and then the organic phase was washed three times with saturated sodium chloride solution and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [OH-:1].[Na+].[NH:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=O)[C:4]1=[O:5].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH2:15][CH3:16]>C(O)C>[C:18]1([C:14]2[C:15]([CH3:16])=[C:6]([C:4]([OH:1])=[O:5])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [OH-]
Reactant: CCC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O

Procedure:
Ten milliliters (2N) of a sodium hydroxide aqueous solution was added dropwise to an ethanol (20 ml) suspension containing 1.47 g of isatin and 2.68 g of propiophenone at room temperature, and the reaction mixture was then heat-refluxed for 26 hours. The resulting reaction mixture was allowed to cool, and then concentrated under reduced pressure. Ice water was added to the residue, and the mixture was extracted with ethyl ether. The aqueous layer was acidified with dilute hydrochloric acid. The precipitate was collected by filtration, and dried to form 1.47 g of the above-mentioned compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:17]=[C:16]([CH:18]=O)[S:15][C:14]=2[CH3:20])=[CH:9][N:8]=1)=[O:5].CC1C=CC(S([CH2:36][N:37]=[CH2:38])(=O)=O)=CC=1.[CH3:39][NH2:40]>CO>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:17]=[C:16]([C:18]3[N:40]([CH3:39])[CH:36]=[N:37][CH:38]=3)[S:15][C:14]=2[CH3:20])=[CH:9][N:8]=1)=[O:5]
Reactant: Cc1sc(C=O)cc1-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Reactant: CN
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: Cc1sc(-c2cncn2C)cc1-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 110 °C

Procedure:
To a solution of 2,6-difluoro-N-(5-(5-formyl-2-methylthiophen-3-yl)pyrazin-2-yl)benzamide (A, 1.8 mmol) and p-tosylmethyl isocyanide (2 mmol) in methanol (18 mL) was added of a solution of methylamine (4 mmol, 2N in methanol). The mixture was heated in the microwave reactor at 110° C. for 2 h. Removal of solvent and purification of residue by flash chromatography gave 2,6-difluoro-N-(5-(2-methyl-5-(1-methyl-1H-imidazol-5-yl)thiophen-3-yl)pyrazin-2-yl)benzamide (B, 0.24 g) as yellowish solids. 1H-NMR (CD3OD) □9.50 (s, 1H), 8.69 (s, 1H), 7.70 (s, 1H), 7.5 (m, 2H), 7.1 (m, 3H), 3.71 (s, 3H), 2.72 (s, 3H)ppm; ESMS calcd for C20H15F2N5OS: 411.1. Found: 412.1 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:9]1=[N:10][NH:11][C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[C:8]1[CH2:7]2.C(NC(C)C)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>C1COCC1>[CH:37]([O:36][C:34]([N:10]1[C:9]2[C:21]3[C:6]([CH2:7][C:8]=2[C:12]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11]1)=[CH:5][C:4]([O:3][CH3:2])=[C:23]([O:24][CH3:25])[CH:22]=3)=[O:35])([CH3:39])[CH3:38]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine HCl (Compound 14) (0.50 g, 0.0014 mole), THF (10 mL), and Diisopropyl amine (0.512 mL, 0.00295 mole) was stirred until the solid completely dissolved. Isopropyl chloroformate (1.5 mL, 0.0015 mole) was added slowly at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo from the resulting organics. Attempt to separate resulting isomers with reverse-phase chromatography was not successful. Placed isomer containing fractions in refrigerator. Much of major isomer crystallized. Filtered white crystals of title compound from solution (Compound 436). MS m/z 412 (M+H)+;
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:24][C:25]1[CH:30]=[C:29](/[C:31](/[C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[C:40]([O:46][CH3:47])[N:39]=2)=[CH:32]\[CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:28]=[CH:27][C:26]=1[S:48][CH2:49][CH2:50][CH2:51][OH:52]>C(Cl)(Cl)Cl.O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:52][CH2:51][CH2:50][CH2:49][S:48][C:26]2[CH:27]=[CH:28][C:29](/[C:31](/[C:38]3[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[C:40]([O:46][CH3:47])[N:39]=3)=[CH:32]\[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:30][C:25]=2[Cl:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCO)c(Cl)c2)nc1OC
Agent: CN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCOS(=O)(=O)c3ccc(C)cc3)c(Cl)c2)nc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Triethylamine (87 μL), trimethylamine hydrochloride (20 mg) and 4-methylbenzenesulfonyl chloride (60 mg) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol (95 mg) in chloroform (2 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (120 mg) as a yellow amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:28]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1)=[O:13])=O)([O-:3])=[O:2].[NH2:29]/[C:30](/[CH3:36])=[CH:31]\[C:32]([O:34][CH3:35])=[O:33].[CH2:37](O)[CH3:38]>>[CH3:37][C:38]1[NH:29][C:30]([CH3:36])=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:28]=2)[C:11]=1[C:12]([O:14][CH2:15][CH2:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1)=[O:13]
Reactant: COC(=O)/C=C(/C)N
Reactant: CCO
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)CC(=O)OCCNC(=O)c1cccnc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCNC(=O)c2cccnc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 70 %

Procedure:
25 g (0.07 moles) of 2-(N-nicotinoylamino)ethyl 2-(3-nitrobenzylidene)acetylacetate and 7.51 g (0.07 moles) of methyl 3-aminocrotonate are heated uner reflux in 70 ml of ethanol for 45 minute. The solution is the cooled to room temperature to obtain 2-(N-nicotinoylamino)ethyl 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as yellow crystals melting--after recrystallisation in ethanol--at 207°-209° C. The yield is 70% of the theoretical yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O[CH2:40][C:41]1[CH:42]=[C:43]([N:47]([CH2:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=1>C1COCC1.CCOC(C)=O>[O:38]([CH2:40][C:41]1[CH:42]=[C:43]([N:47]([CH2:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[S:48]([CH2:51][CH3:52])(=[O:49])=[O:50])[CH:44]=[CH:45][CH:46]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CO)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(COc2ccccc2)c1
Reaction time: 72 h

Procedure:
To a solution of triphenylphosphine (0.141 g, 0.539 mmol) in 3.5 mL THF was added diethylazodicarboxylate (0.165 g, 0.539 mmol). After 5 min phenol (0.061 g, 0.646 mmol) was added as a solution in 2 mL THF. After 5 min N-(3-(hydroxymethyl)phenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (0.165 g, 0.539 mmol) was added as a solution in 2 mL THF and the reaction was stirred for 3 days. The mixture was diluted with EtOAc, washed with 1 N NaOH and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with 4:1 to 2:1 DCM/EtOAc to give the title compounds as a clear oil. 1H NMR: 8.48 (d,J=1.5 Hz, 1H), 8.36 (s,1H), 7.64 (d,J=7.8 Hz, 1H), 7.36-7.23 (m,5H), 7.19 (m,2H), 6.95 (t,J=7.8 Hz, 1H), 6.91 (d,J=7.8 Hz, 1H), 5.01 (s,2H), 4.84 (s,2H), 3.03 (q,J=7.6 Hz, 2H), 1.39 (t,J=7.6 Hz, 3H). MS calcd. 382.1; MS (M+1) 383.1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H]>CCCCCC.CN(C=O)C>[CH2:12]([O:19][C:5]1[C:4]([Br:3])=[CH:9][C:8]([Cl:10])=[CH:7][N:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: Clc1cnc(Cl)c(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Clc1cnc(OCc2ccccc2)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In a microwave tube NaH (60% in paraffin. 56 mg. 1.4 mmol) was washed with hexane and 3-bromo-2,5-dichloro-pyridine (245 mg. 1.08 mmol) in dry DMF (2 mL) were added. To this suspension BnOH (123 μL. 1.23 mmol) in dry DMF (1 mL) was dropped carefully. The reaction mixture was stirred 15 min until the formation of hydrogen has ceased. The tube was sealed and stirred at 100° C. in a microwave reactor for 30 min. After removal of the solvent in vacuo the residue was partioned between water (10 mL) and DCM (10 mL) and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine dried over Na2SO4 filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. GC-MS (m/z): 297 [M+].
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#N.[C:13](=O)(O)[O-:14].[Na+].C[OH:19]>Cl.O>[NH2:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]([O:14][CH3:13])=[O:19])=[N:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: O=C([O-])O
Reactant: CO
Reactant: N#Cc1ccc(S(N)(=O)=O)cn1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(S(N)(=O)=O)cn1
Temperature: 50 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
6-Cyanopyridine-3-sulfonamide (10 g, 0.0545 mol) is dissolved in dry HCl in methanol (400 ml) at 25-26° C. under nitrogen atmosphere. Reaction mixture is heated to 50° C. and stirred for 15 h at 50° C. The reaction mixture is concentrated under vacuum and the residue obtained is diluted with water (100 ml) and basified with solid sodium bicarbonate to pH 6-7. The reaction mixture is stirred for 15 minutes and filtered. The resulting solid obtained is washed with water (50 ml) and dried under vacuum to afford the title compound (9 g, 76%) as light yellow solid. 1H NMR (DMSO-d6) δ 9.08 (d, J=3 Hz, 1H), 8.38 (dd, J=9 and 3 Hz, 1H), 8.26 (d, J=9 Hz, 1H), 7.79 (m, 2H), 3.93 (s, 3H). HPLC (max plot) 94%; Rt 3.45 min; LC/MS: (ES+) 216.9.