Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[N:20]=[C:19]2[C:15](=[N:16][N:17]=[N:18]2)[C:14](=[O:21])[N:13]=1.[H][H]>C(OCCO)C.[Pt]=O>[OH2:2].[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12]2[N:20]=[C:19]3[C:15](=[N:16][N:17]=[N:18]3)[C:14](=[O:21])[N:13]=2)[CH:5]=1.[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12]2[N:20]=[C:19]3[C:15](=[N:16][N:17]=[N:18]3)[C:14](=[O:21])[N:13]=2)[CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NN=NC2=N1
Agent: O=[Pt]
Solvent: CCOCCO
Product: COc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Product: O
Yield: 17.3 %

Procedure:
A solution of 2-(2-methoxy-5-nitrophenyl)-8-azapurin-6-one (1.87 g.) (prepared as described in Example 2) in 2-ethoxyethanol (50 ml.) was shaken at room temperature with a platinum oxide catalyst (0.12 g.) under hydrogen (5 kg/cm2). After the uptake of hydrogen was complete, the filtered solution was concentrated to dryness and the brown residual solid was recrystallised from aqueous N,N-dimethylformamide. A portion of this material was further purified by dissolution in 2N ammonium hydroxide solution followed by acidification of the filtered solution with 2N acetic acid. The brown precipitate was filtered, washed well with water and dried to give 2-(5-amino-2-methoxyphenyl)-8-azapurin-6-one hemihydrate (0.2 g.) in the form of a brown solid, m.p. 204°-206° C. (with decomposition, sintering at about 175° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([Cl:12])[CH:3]=1.[F:13][C:14]1[C:23]2[O:22][CH2:21][C:20](=[O:24])[N:19]([CH3:25])[C:18]=2[CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:16]2[CH:15]=[C:14]([F:13])[C:23]3[O:22][CH2:21][C:20](=[O:24])[N:19]([CH3:25])[C:18]=3[CH:17]=2)=[O:11])=[C:4]([Cl:12])[CH:3]=1
Reactant: CN1C(=O)COc2c(F)cccc21
Reactant: O=C(O)Cc1ccc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CN1C(=O)COc2c(F)cc(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 1, step 1, (4-bromo-2-chloro-phenyl)-acetic acid was converted to the acid chloride and reacted with 8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one in the presence of AlCl3 to give the title compound as a light-brown solid. MS (m/e, ISP neg. ion)=411.9 [M−H+].
Reaction SMILES: C(Cl)([Cl:3])=O.[CH:5]1([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(#N)C>O1CCCC1>[ClH:3].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:11][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)Cl
Reactant: C1COCCN1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: Cl
Product: Clc1ccc(C(=NC2CCCCC2)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 9.6 gm. (0.096 mole) of phosgene in tetrahydrofuran is added in one portion 19.0 gm. (0.08 mole) of N-cyclohexyl-p-chlorobenzamide. After ten minutes the reaction mixture is allowed to warm to room temperature, stirred overnight, and the mixture concentrated to a solid in vacuo with a bath temperature of 30°. The crude residue is suspended in 250 ml. of acetonitrile, cooled to 0° and treated with a solution of 28.0 gm. (0.32 mole) of morpholine in 100 ml. of acetonitrile. After allowing the reaction mixture to warm to room temperature it is heated at reflux for two hours, concentrated in vacuo to an oil and suspended in ether. A precipitate is collected and shown to be starting material. The filtrate is concentrated in vacuo, the residue taken up in acetone and treated with excess dry HCl in ether. Ether is added to the cloud point and the mixture cooled to give 3.7 gm. (13.5%) m.p. 278°-279°.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 123.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-N,N-dimethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (17 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.Br[CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9])[CH:14]=[CH2:13]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (7.50 g, 48.7 mmol), 3-bromoprop-1-ene (6.48 g, 53.5 mmol), and potassium carbonate (13.5 g, 97.0 mmol) in DMF (75 mL) was vigorously stirred at rt for 24 h. The reaction mixture was diluted with water (100 mL) while stirring. The white precipitate was collected by vacuum filtration. The solid was rinsed with water (300 mL). The solid was dried under high vacuum to afford 1-(2-(allyloxy)-4-fluorophenyl)ethanone (7.92 g, 40.0 mmol, 82% yield) as a white solid. LCMS (M+Na)+=217.1. 1H NMR (500 MHz, chloroform-d) δ 7.82 (dd, J=8.7, 7.0 Hz, 1H), 6.71 (ddd, J=8.7, 7.6, 2.3 Hz, 1H), 6.66 (dd, J=10.8, 2.3 Hz, 1H), 6.08 (ddt, J=17.3, 10.6, 5.3 Hz, 1H), 5.55-5.41 (m, 1H), 5.41-5.29 (m, 1H), 4.63 (dt, J=5.4, 1.4 Hz, 2H), 2.62 (s, 3H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[NH2:16][NH2:17]>C(O)C.C(OCC)(=O)C>[N+:12]([C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:16][NH:17]2)=[CH:8][CH:9]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12

Procedure:
In two portions of equal size, a total of 2.00 g (10.0 mmol) of methyl 2-fluoro-4-nitrobenzoate and 2.51 g (50.2 mmol) of hydrazine monohydrate in 36 ml of ethanol were heated in a microwave reactor at 120° C. for 2 h. The combined reaction solutions were diluted with ethyl acetate and washed with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. Yield: 1.66 g (purity 95%, 88% of theory)
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][CH:10]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]3)[C:9]=2[CH:29]=1)[CH2:2][CH2:3][CH3:4].[C:30](Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O)(=O)/C=C\C(O)=O>C1C=CC=CC=1.C(Cl)(Cl)Cl.CC(C)=O.[OH-].[NH4+]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][CH:10]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:28][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:21][CH2:20]3)[C:9]=2[CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(CCCC)cc32)CC1

Procedure:
In accordance with the general procedure described in the foregoing Examples, 4.1 grams of 8-(n-butyl)-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 3.2 grams of caprylyl chloride (octanoyl chloride) in a mixture of 18 milliliters of benzene and 7 milliliters of chloroform. A solution of 2.3 grams of maleic acid in 25 milliliters of acetone was then added to the mixture and the resulting 8-(n-butyl)-10-[4-(3-oxtanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin di(hydrogen maleate) which had a melting point of 113°-115°C, after recrystallization from acetone, was recovered. Its elemental analysis corresponded to the empirical formula C41H56N2O10S. The free base was obtained in the form of a colorless very viscous oil which was very soluble in vegetable oils by dissolving the salt in a dilute aqueous ammonium hydroxide solution and extracting the solution with benzene.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[CH:33][C:32]2=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: O=c1cc(-c2ccccc2)[nH]c2ccc(Br)cc12
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 5 h
Yield: 62.2 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate 23 (14.0 g, 30.2 mmol) and 6-bromo-2-phenylquinolin-4(1H)-one (1, 9.5 g, 31.7 mmol) in N-methylpyrrolidine (100 mL) was added cesium carbonate (14.7 g, 45.2 mmol). The reaction mixture was heated to 45° C. and stirred for 5 h and cooled. The reaction mixture was poured onto EtOAc and water and the white solids were removed by filtration. The layers were separated and the organic was washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (gradient elution 5% to 45% EtOAc in hexanes) to give 1-tert-butyl 2-methyl (2S,4R)-4-[(6-bromo-2-phenylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 24 (9.9 g, 62% yield) as a pale yellow solid. LRMS (M+H)+ Calcd.: 527. found 527.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH:19]([F:21])[F:20])[C:14]=1[CH2:22][S:23][C:24]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][N:25]=1.[OH2:31]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH:19]([F:21])[F:20])[C:14]=1[CH2:22][S:23]([C:24]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][N:25]=1)(=[O:9])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: Cn1nc(C(F)F)c(CSC2=NOC(C)(C)C2)c1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(F)F)c(CS(=O)(=O)C2=NOC(C)(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.9 %

Procedure:
3.6 g of m-chloroperbenzoic acid (purity:, 70%, 14.5 mmoles) was added, with ice-cooling, to a solution of 1.8 g (5.8 mmoles) of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved 30 in 15 ml of chloroform. The mixture was stirred at room temperature for 22 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 1.7 g (yield: 85.9%) of 3-(5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 78 to 79° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[CH3:10].[C:11](=[O:13])=[O:12]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:10]
Reactant: O=C=O
Reactant: Cc1cc([Mg]Br)ccc1F
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 4-fluoro-3-methylphenylmagnesium bromide in THF (1.0 M, 250 mL, 250 mmol) was added in a stream over 5 min to a mixture of Dry Ice (10 g) in dry THF (250 mL), and the reaction was allowed to warm to RT and concentrated. The residue was partitioned between water (500 mL) and ether (250 mL), and the layers were separated. The aqueous layer was washed with ether (2×250 mL) and acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was cooled in an ice bath and filtered. The solid was washed with water and dried to afford the title compound (25.92 g, 67%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.90-8.02 (m, 2H), 7.09 (t, J=8.9 Hz, 1H), 2.34 (d, J=1.7 Hz, 3H); IR (chloroform) 3400-2300 (broad), 1694 cm-1 ; MS(ES) m/e 155 [M+H+ ; m/e 153 [M-H]-.
Reaction SMILES: [CH2:1]([C:4]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl.[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].O.ON1C2C=CC=C[C:47]=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:47][O:40][C:39](=[O:41])[CH2:38][CH2:37][NH:36][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([C:4]([CH2:5][CH:6]=[CH2:7])([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:1][CH:2]=[CH2:3])=[CH:27][CH:28]=1
Reactant: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cc1
Reactant: NCCC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Yield: 57.5 %

Procedure:
A solution of 4-[1-allyl-1-(4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoic acid (0.044 g, 0.094 mmol), beta-alanine, hydrochloride salt (0.0189 g, 0.135 mmol), and 1-hydroxybenzotriazole hydrate (0.0193 g, 0.143 mmol) in DMF (2.0 mL) is treated with N,N-diisopropylethylamine (0.0480 mL, 0.275 mmol), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0278 g, 0.145 mmol) and stirred overnight. The reaction mixture is diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts are washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 10% EtOAc to 75% EtOAc to provide 0.0298 g (58%) of the title compound as a clear film. MS (ES): 552.2 [M+H]−.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18]2)=[N:13]1)(=[O:5])=[O:4])[CH3:2].[Cl:25]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Cl:25][C:20]1[N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][C:16]([C:21]([F:23])([F:24])[F:22])=[CH:15]2
Reactant: CCS(=O)(=O)c1ccccc1-n1cc2ccc(C(F)(F)F)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccccc1-n1nc2cc(C(F)(F)F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.8 %

Procedure:
A mixture of 226 mg of 2-(2-ethylsulfonylphenyl)-6-trifluoromethyl-2H-indazole, 86 mg of N-chlorosuccinimide and 2 ml of DMF was stirred at room temperature for 10 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was washed with n-hexane to obtain 250 mg of 3-chloro-2-(2-ethylsulfonylphenyl)-6-trifluoromethyl-2H-indazole (hereinafter, referred to as Compound of Present Invention 3).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC.CCCCCCC>[CH2:23]([C:24]1[CH:23]=[C:23]([C:24]([CH:8]2[C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)([C:5]2[CH:17]=[CH:16][CH:15]=[CH:7][CH:6]=2)[C:25]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:26]=2)[CH2:26][CH:25]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCCCC1=CCC(C(c2ccccc2)(c2ccccc2)C2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 171.2 %

Procedure:
To 2,7-di-tert-butylfluorene (15 g, 54 mmol) dissolved in Et2O (100 mL) was added n-BuLi (5.8 mL of 10 M in hexanes, 58 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The anion solution was added to 2-butyl-6,6-diphenylpentafulvene (F-1) (16 g, 56 mmol) dissolved in Et2O (100 mL) at −78° C. in 5 minutes. The mixture was warmed to room temperature and stirred for 2 days. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with Et2O. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave a viscous oil. The oil was stirred in heptane to give a white solid. The solid was filtered, washed with heptane and dried under vacuum. A mixture of isomers for the desired product (18.7 g, 61.3% yield) was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:21][CH2:22][CH3:23])=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]=1[S:9][CH2:10][C:11]#[N:12])#[N:2].[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:8](=[N:7][C:6]([N:28]3[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]3)=[CH:5][C:4]=2[CH2:21][CH2:22][CH3:23])[S:9][C:10]=1[C:11]#[N:12]
Reactant: OC1CCNCC1
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC#N)c1C#N
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCc1cc(N2CCC(O)CC2)nc2sc(C#N)c(N)c12
Temperature: 100 °C
Yield: 89 %

Procedure:
Trifluoro-methanesulfonic acid 5-cyano-6-cyanomethylsulfanyl-4-propyl-pyridin-2-yl ester (1.10 g, 3.00 mmol) (see Example 1, Method B) and 4-hydroxypiperidine (310 mg, 3.00 mmol) was suspended in 2 mL of dioxane. Triethylamine (0.84 mL, 6.0 mmol) was added and the reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) at 100° C. for 2 h. This reaction mixture was poured into water and the resulting solid was collected by filtration and air dried to provide 3-amino-6-(4-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile (845 mg, 89%).
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23].P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:3]1[NH:4][C:5]([CH3:13])=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:2]=1
Reactant: COc1ccc(-c2nc(C)c(-c3cccnc3)n2O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(-c3cccnc3)c(C)[nH]2)c(OC)c1
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 1-hydroxy-2-(2,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (6.6 g) in N,N-dimethylformamide (130 ml) was added phosphorus trichloride (3.7 ml) under ice-cooling. The mixture was stirred for 2 hours at 5° to 10° C. The reaction mixture was poured into water, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (methanol 0% to 15%). The fractions were collected and evaporated to give 2-(2,4-dimethoxypheyl)-5-methyl-4-(3-pyridyl)imidazole (2.82 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH2:11]([N:13](CC)[CH2:14]C)[CH3:12].C(NC)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([N:13]([CH2:11][CH3:12])[CH3:14])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ncc(Br)cn1
Reactant: CCN(CC)CC
Agent: CCNC
Solvent: ClCCl
Product: CCN(C)C(=O)c1ncc(Br)cn1
Temperature: 25 °C

Procedure:
5-Bromo-pyrimidine-2-carbonyl chloride (1600 mg, 7.225 mmol) was dissolved in dichloromethane (25 ml) and triethylamine (4.03 ml, 28.9 mmol) was added followed by ethyl-methyl-amine (0.68 mL, 7.92 mmol). The reaction was stirred at room temperature under nitrogen for 16 ours, after which time, LCMS indicated completion. The mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml) followed by 10% citric acid (50 ml) and brine (50 ml). The organic layer was separated and dried over MgSO4, the residue was filtered and the solvent was removed in vacuo to afford the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2-carboxamide (SM-3): (1.4 g, 79.4%) as a brown oil.
Reaction SMILES: [OH:1][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:21]I.O>C1COCC1>[CH3:21][O:1][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(nc1C)C(O)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(nc1C)C(OC)CCCC2
Reaction time: 1 h
Yield: 58.4 %

Procedure:
In an atmosphere of argon, ethyl 9-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.04 g, 4.16 mmol) was dissolved in anhydrous THF (8.0 ml), and the solution was mixed with sodium hydride (182.3 mg, 4.56 mmol) at 0° C. This was stirred at the same temperature for 1 hour, mixed with methyl iodide (0.33 ml, 4.76 mmol) by its dropwise addition and then stirred at room temperature for 1.5 hours. The reaction solution was mixed with water and extracted with ethyl acetate, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (639.8 mg, 58.4%) as yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37]Cl.COCNC(C1C(N(COC)S(C2C=CC(Cl)=C(C(F)(F)F)C=2)(=O)=O)=CC(Cl)=CN=1)=O>C1COCC1>[CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:35][O:36][CH3:37])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(C)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: COCNC(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 223 mg (0.51 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 352 mg of potassium carbonate and 116 μL of methoxymethyl chloride in 1 mL THF using the procedure used to prepare Intermediate 12. Yield: 200 mg of a white solid. LC-MSD, m/z for C18H19ClF3N3O5S [M+H]+=482.0, 484.0; HPLC retention time: 2.5 minutes.