Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][S:19][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:28])=[C:8]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][S:19][C:9]=23)=[CH:17][CH:16]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c2snc(-c3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2ccc(F)cc2)c2snc(-c3ccccc3)c2c1O
Yield: 67.5 %

Procedure:
A mixture of 7-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (69 mg, 0.175 mmol), glycine (394 mg, 5.25 mmol), and NaOMe (8.75 mL, 4.37 mmol, 0.5 M solution in MeOH) was refluxed for 24 h. After the mixture was cooled to r. t. it was concentrated in vacuo. The residue was dissolved in water (25 mL) and washed with CH2Cl2 (2×15 mL). The aqueous solution was then acidified by addition of aqueous 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound as white solid (50 mg): MS (m/z) 424.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.N12CCCN=C1CCCCC2>C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2cncn2)cc1
Yield: 68 %

Procedure:
To a stirred solution of 1,2,4-triazole (0.803 g, 11.6 mmol) in THF (100 mL) at 0° C. was added 4-fluorobenzyl bromide (2.0 g, 10.6 mmol), then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol) and the mixture was slowly warmed to room temperature. The solution was concentrated in vacuo, then purified by column chromatography (SiO2, MeOH/EtOAc, 5:95) to yield a white solid in 68% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:53][CH2:54][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:56][CH2:57]5)[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 30.2 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.075 g, 0.15 mmol), 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.058 g, 0.15 mmol) and para-toluenesulfonic acid (0.070 g, 0.37 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-5-(3-{2-[(5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.038 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.33-9.43 (m, 1H), 8.47 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.08-8.14 (m, 1H), 7.76-7.84 (m, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.34-7.55 (m, 3H), 7.30 (d, J=8.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.97 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.57 (d, J=5.1 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.06-3.19 (m, 6H), 2.88 (s, 3H), 2.59-2.72 (m, 6H), 2.38-2.44 (m, 1H), 2.16 (s, 3H), 1.80-1.91 (m, 2H), 1.50-1.71 (m, 2H). MS (M+2H, ES+) 839.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21]C)=[CH:16][N:15]=2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:40]([NH2:42])=[O:41]>CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[C:40]([NH2:42])=[O:41])[C:17]([OH:21])=[CH:16][N:15]=2)=[N:6]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N
Reactant: NC(=O)c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
25 mg of 4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-5-ol (1-11-1, 0.075 mmol, 1. eq.) were dissolved in 1.5 ml of N,N-dimethylformamide. 51.52 mg of potassium carbonate (0.373 mmol, 5 eq.) and 23.35 mg of 4-chloropyridine-3-carboxamide (0.149 mmol, 2 eq.) were added. The reaction mixture was stirred at 100° C. bath temperature in a pressure pipe for 48 h ours. The reaction mixture was filtered off. The residue was purified by preparative HPLC to yield 2.07 mg (0.004 mmol, 5.6%) of the analytically pure target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]([O:24]CC)=O)=[CH:19][C:18]=3[CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH2:30])=O>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]([NH2:30])=[O:24])=[CH:19][C:18]=3[CH:27]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC=O
Reactant: CCOC(=O)c1cc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1

Procedure:
According to the '614 patent, the preparation of 5-(1-pipearzinyl)benzofuran-2-carboxamide is carried out in four steps starting from ethyl 5-aminobenzofuran-2-carboxylate. According to first step, ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is prepared by reacting ethyl 5-aminobenzofuran-2-carboxylate with N,N-bis(2-chloroethyl)amine in dichloromethane to produce a reaction mass, followed by customary work-up using a solvent system (isopropanol/water 95:5). According to second step, the ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is subjected to BOC protection by reacting with di-tert-butyl dicarbonate in tetrahydrofuran to produce ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate. In third step, the ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate is reacted with formamide in the presence of sodium alkoxide in N-methylpyrrolidone to produce 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide. In fourth step, the 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide is then deprotected with methanolic HCl to produce the 5-(1-pipearzinyl)benzofuran-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([OH:10])=[O:9].Cl.[CH3:12]O>CCOCC>[CH3:12][O:9][C:8]([C:3]1[N:4]=[C:5]([CH3:7])[S:6][C:2]=1[Br:1])=[O:10]
Reactant: Cc1nc(C(=O)O)c(Br)s1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1nc(C)sc1Br
Yield: 82 %

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid (prepared as described in example 119, steps A to B) (1.50 g, 6.75 mmol) in methanol (80.00 ml) was treated with a saturated solution of HCl in ether (3.00 ml). The reaction mixture was heated at reflux for 3 h, then the volatiles were removed. The residue was purified by flash chromatography (methylene chloride/methanol) yielding 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (1.30 g, 82%) as a white solid, MS (ISP): m/e=235.9, 237.9 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:18])[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:14]([O:13][C:11]([NH:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH:4]([OH:18])[CH2:3][NH:2][C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)NCC(O)C(CC(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of the resultant compound of Example 76 (1.0 mmol) and triethyl amine (2.0 mmol) in chloroform (10ml) cooled to 0° C. was added isovaleryl chloride (1.0 mmol) in CHCl3 (2ml). After 3h, the solution was washed sequentially with 10% citric acid, saturated NaHCO3, and brine. Drying and evaporating provided the desired compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH3:2].[F:13][C:14]([F:22])([F:21])[C:15]([F:20])([F:19])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:15]([F:20])([F:19])[C:14]([F:22])([F:21])[F:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOCOc1ccc(I)cc1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOCOc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 145 °C

Procedure:
A mixture of 7.5 g of crude product of 1-ethoxymethoxy-4-iodobenzene, 10.0 g of sodium pentafluoropropionate salt, 10.27 g of copper (I) iodide, 120 ml of DMF and 45 ml of toluene was stirred while heating at 140 to 150° C. for one hour to remove about 40 ml of toluene. The reaction mixture was heated to reflux at 160 to 170° C. for further five hours, and then cooled to room temperature and poured into ice water. To the reaction mixture, 200 ml of diethyl ether was added. The reaction mixture was filtered through Celite™. The filtrate was extracted with diethyl ether. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5.45 g of 1-ethoxymethoxy-4-pentafluoroethyl benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2.Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])[CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1Br
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(Cn2ccc3cc(Br)c([N+](=O)[O-])cc32)c(OC)c1
Yield: 65 %

Procedure:
5-Bromo-6-nitroindole was reacted with methyl 4-bromomethyl-3-methoxybenzoate using the procedure described in part (a) of Example 1 to give methyl 4-(5-bromo-6-nitroindol-1-ylmethyl)-3-methoxybenzoate (HH) in 65% yield and as a bright yellow solid; partial NMR: 3.89 (s,3H,OCH3), 3.94 (s,3H,OCH3), 5.35 (s,2H,NCH2), 6.53 (dd,1H,H3 -indole), 7.38 (d,1H,H2 -indole), 7.89 (s,1H,H4 -indole), 8.03 (br s,1H,H7 -indole).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH2:22].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[NH2:22][C:16]1[C:17]([NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:19]=[CH:20][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 883.8 %

Procedure:
A 50 mL 3-necked round bottom flask fitted with a thermometer and an overhead stirrer was charged with tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.1 mmol) and acetonitrile (25 mL, HPLC grade). The reaction mixture was stirred at room temperature for 10 minutes to ensure complete dissolution of all solid material. Pyridine-2,3-diamine (1.50 g, 13.7 mmol) was added, the slurry was stirred for an additional 30 minutes, and resulted in the formation of a dark brown solution. The reaction mixture was cooled to 5° C. and trifluoroacetic acid (2 mL) was added over a period of 20 minutes. During the course of the addition, fuming was observed, accompanied by a slight temperature rise to 10-15° C. The reaction mixture was stirred for an additional 30 minutes at 5-10° C., and sodium triacetoxyborohydride (4.37 g, 20.6 mmol) was added over a period of 20 minutes. The ice bath was removed and the reaction mixture was stirred for an additional 30 minutes. The flask was placed back in an ice bath and aqueous 4M sodium hydroxide was added to the reaction in small portions to adjust the reaction mixture to pH 8. The solution was stirred for an additional 30 minutes, cooled to 5° C., and diluted with ice cold water (80 mL), and resulted in the formation of a brown precipitate. The resulting slurry was stirred overnight at room temperature. The solids were collected by vacuum filtration, washed with cold water (3×5 mL) and dried to constant weight to give 35.4 g (88% yield) of tert-butyl 4-(2-aminopyridin-3-ylamino)piperidine-1-carboxylate. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, 1H), 6.64 (d, 1H), 6.17 (dd, 1H), 5.43 (broad s, 2H), 4.48 (d, 1H), 3.88 (d, 2H), 3.38 (broad s, 1H), 2.87 (broad s, 2.87), 1.87 (d, 2H), 1.38 (s, 9H), 1.19 (m, 2H). MS (EI) for C15H24N4O2: 293 (MH+)
Reaction SMILES: CS(O[CH2:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:25]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(C(CCOC2CCCCO2)Cn2ccnc2)cc1Cl
Yield: 32.3 %

Procedure:
1-Methanesulphonyloxy-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (10 g) (see Preparation 29), imidazole (2.07 g) and potassium carbonate (7.65 g) were dissolved in anhydrous acetonitrile (50 ml) and heated under reflux under a nitrogen atmosphere for 3 days. The organic solvent was then removed under reduced pressure and the resulting aqueous suspension partitioned between dichloromethane and water. The organic phase was separated, washed sequentially with water and brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The crude product was chromatographed on silica gel eluting with 95:5, by volume, dichloromethane:methanol to give 1-(imidazol-1-yl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (3 g) as an oil and as a mixture of diastereomers.
Reaction SMILES: Cl.[CH2:2]1[O:31][C:30]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:28]=[CH:27][C:21]5[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=5[CH:19]=4)[O:8][C:7]=3[CH:29]=2)[O:3]1.I[CH2:33][CH3:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:2]1[O:31][C:30]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][N:13]([CH2:33][CH3:34])[CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:28]=[CH:27][C:21]5[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=5[CH:19]=4)[O:8][C:7]=3[CH:29]=2)[O:3]1
Reactant: CCI
Reactant: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc5c(cc4O3)OCO5)cc2o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)C[C@H]1COc2cc3c(cc2O1)OCO3
Temperature: 60 °C
Yield: 43.8 %

Procedure:
(S)-7-[3-[[(2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.60 g, 1.3 mmole), iodoethane (0.16 ml, 2.0 mmole) and diisopropylethylamine (2.26 ml, 13.0 mmole) were combined in 50 ml of DMF and heated at 60° C. for 2 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was dissolved in dichloromethane and washed with an equal volume of aqueous saturated sodium bicarbonate. The aqueous portion was back-extracted with dichloromethane and the combined organic portions were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum, and the residue redissolved in methanol and acidified with 4N HCl/isopropanol to pH<3 in an ice bath. The mixture was diluted with isopropanol to precipitate a white solid, which was recrystallized from methanol to give 0.25 g of the title compound as the monohydrochloride, m.p. 209° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:14]1CCC[CH2:15]1.C([Li])CCC.CN(C)C=O>O>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:15]=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a mixture of 3-bromobiphenyl (0.50 mL, 3.0 mmol) and tetrahydrofuran (8 mL) was added n-butyl lithium (2.6 mL, 1.5 M n-hexane solution, 3.9 mmol) under nitrogen atmosphere at −78° C., which was stirred for 20 minutes at that temperature. N,N-dimethylformamide (0.35 mL, 4.5 mmol) was added to the reaction mixture at the same temperature, and the temperature was gradually raised to 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (430 mg, 79%).
Reaction SMILES: [CH2:1]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH2:1]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:14][CH:15]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CCCCCCNC(=O)c1ccc(Cl)nn1
Product: CCCCCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid hexylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (35% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.85, 7.72, 7.56, 7.34, 6.97, 4.00, 3.90-3.64, 3.48-3.28, 1.58, 1.29, 0.85. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.5, 134.3, 132.8, 129.5, 127.6, 127.2, 126.9, 125.4, 46.4, 44.6, 44.4, 41.3, 39.4, 31.5, 29.5, 26.6, 22.6, 14.0. MS (ES+) m/z (%) 464 (M+1).
Reaction SMILES: [C:1]1([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[H-].[Na+].C1(C)C=CC=CC=1>O>[Cl:22][CH2:21][CH2:20][CH2:19][O:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC(CCCc1ccccc1)c1ccccc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCCOC(CCCc1ccccc1)c1ccccc1

Procedure:
A mixture of 30 g of 1,4-diphenyl-1-butanol, 42 g of 1-bromo-3-chloropropane, 9.5 g of sodium hydride (65%) and 400 ml of toluene was heated under refluxing for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(3-chloropropoxy)-1,4-diphenylbutane.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([CH3:15])=[N:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].[H][H]>CO.[Pd]>[NH2:12][C:10]1[C:9]([CH3:15])=[N:8][N:7]([C:2]([CH3:1])([CH3:6])[C:3]([NH2:5])=[O:4])[CH:11]=1
Reactant: Cc1nn(C(C)(C)C(N)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C(C)(C)C(N)=O)cc1N
Yield: 93.8 %

Procedure:
To a solution of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (2.5 g, 11.7 mmol) in MeOH (50 mL) was added Pd/C (1 g), exchanged with nitrogen for three times then with hydrogen, and the reaction was stirred at hydrogen atmosphere (1 atm) for 1 h at ambient temperature. The solution was filtered and the filtrate was concentrated under reduced pressure to give crude 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (2.0 g, 93%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:28](Cl)(=[O:30])[CH3:29]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28](=[O:30])[CH3:29])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cc(C)cc(Cl)c2)cc1
Yield: 70 %

Procedure:
To a suspension of 4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.30 g, 0.72 mmol) in 1.5 mL of acetic acid was added 1.5 mL of acetyl chloride at room temperature. The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was concentrated under vacuum and the residue was treated with ether to give 0.23 g (70%) of N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a white solid: mp (DSC) 232-235° C. Anal. Calc'd. for C19H15ClF3N3O3S: C, 49.84; H, 3.30; N, 9.18; S, 7.00. Found: C, 49.72; H, 3.48; N, 8.81; S, 7.18.