Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:3].Cl.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][CH3:30])[CH2:24][CH2:23]1.Cl>O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:29]([CH2:28][C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH2:23][CH2:24]2)[CH3:30])=[CH:6][CH:7]=1
Reactant: CNC[C@H]1CC[C@H](CCCCCBr)CC1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
0.515 ml Diisopropyl-aethylamine, 0.674 g (3.00 mmol) 4-trifluoromethylphenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] and 0.828 mg potassium carbonate (dissolved in the minimal amount of water) were added to a suspension of 0.625 g (2.00 mmol) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-amine hydrochloride in 20.0 ml of tetrahydrofuran kept at −10° C. The reaction mixture was then intensively stirred for 1 hour at −10° C. and for 3 hour at room temperature. 0.200 g 4-trifluoromethylphenyl chloroformate were added and stirring at room temperature continued for additional 2 hours. The reaction mixture was subsequently acidified with dilute hydrogen chloride solution. It was then evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 1:1 v/v mixture of hexane and dichloromethane as the eluent giving 0.90 g (96.9%) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 464 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:13].[C:14](N)(=S)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.O>C(O)CO>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:13][C:3]=2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: NC(=S)c1ccccc1
Reactant: COc1cc(C(=O)O)cc(S)c1N
Agent: Cl
Solvent: OCCO
Solvent: O
Product: COc1cc(C(=O)O)cc2sc(-c3ccccc3)nc12
Temperature: 60 °C
Reaction time: 7 h
Yield: 32.6 %

Procedure:
4-Amino-3-mercapto-5-methoxybenzoic acid (600 mg) and thiobenzamide (450 mg) were suspended in ethylene glycol (10 ml). Conc. hydrochloric acid (1.0 ml) was added thereto, and the mixture was stirred for 7 hours at 60° C. The reaction mixture was cooled to room temperature, then cold water was added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (280 mg, Y.:32%) as white crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: BrCC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(Sc2c(NCC3CC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.8 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid, 20 ml of water, 15 ml of ethanol and 2 ml of 4 N aqueous lithium hydroxide, 2.2 g of cyclopropylmethyl bromide are added while stirring and the pH of the mixture adjusted with lithium hydroxide to 7.0 during 24 hours. Thereupon,it is filtered, the filtrate diluted with water, washed with diethyl ether and acidified with concentrated hydrochloric acid. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-cyclopropylmethylamino-5-sulfamoylbenzoic acid melting at 200°-204°.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=O)(C)(C)C.[ClH:23]>>[ClH:23].[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:20])[N:11]1[CH2:21][CH2:22][NH:8][CH2:9][CH:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Agent: Cl
Product: O=C1c2c(O)cccc2C2CNCCN12
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one (24 mg, 0.08 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 5 min, the solution was concentrated, diluted with water, and lypholized to give the desired product as an off-white solid (8 mg, 42%). MS (ESI) 205.2 (M−Cl).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: Cc1cccc(N)c1F
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 83.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and 2-fluoro-3-methylaniline (0.085 g, 0.68 mmol), the title compound (0.2 g, 85%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:27]=[N:28][C:29]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][CH:31]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc(-c5ccccc5)nn4)cc3CC[C@@H]12
Yield: 48.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 3-chloro-6-phenyl-pyridazine (88 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 77 mg (49%) of the title compound as an amorphous solid. mp 199°-200°. FDMS: m/e=415. α[D]589 =+67.26 (c=0.63, chloroform).
Reaction SMILES: COC1C=CC(C[N:8]([C:16]2[S:17][C:18]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)=[C:19]([Cl:21])[N:20]=2)C(=O)OC(C)(C)C)=CC=1>CC(O)=O>[Cl:21][C:19]1[N:20]=[C:16]([NH2:8])[S:17][C:18]=1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(Cl)c(-c3ccc4cnccc4c3)s2)cc1
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(-c2ccc3cnccc3c2)s1
Temperature: 120 °C
Yield: 85.7 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 4-methoxybenzyl(4-chloro-5-(isoquinolin-6-yl)thiazol-2-yl)carbamate(1.5 g, 3.12 mmol) and AcOH. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc.,) at 120° C. for 5 minutes. Excess AcOH was removed under high vacuum. The residue was dissolved in DCM and washed with saturated NaHCO3 (50 mL) and saturated sodium chloride. This intermediate was synthesized in the same manner as described previously and water dried over Na2SO4, filtered and concentrated in vacuo to provide 4-chloro-5-(isoquinolin-6-yl)thiazol-2-amine (0.7 g, 81% yield), m/z (%): 263.2 (100%, M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[N:12]([O-])=O.[Na+]>CC(O)=O>[N+:1]([C:4]1[C:5]2[N:11]=[N:12][NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]nnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
To a mixture of 3-nitrobenzene-1,2-diamine (15.0 g) in AcOH (100 mL) was added NaNO2 (7.0 g). The reaction mixture was stirred for 15 min at RT, then heated at 60° C. for about 2 h, over which time the reaction mixture turned red. The mixture was cooled to RT, diluted with ice water, and the resulting precipitate filtered off and washed with ice water, then dried under vacuum to yield 4-nitro-1H-benzotriazole (13.45 g, 83.6% yield) as a light brown solid. The product was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH:2]=[CH2:3].[O-]CC.[Na+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.C(O)(=O)C>C(O)C>[O:20]=[C:21]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])=[N:8][CH:28]=[C:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: C=CCOc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
2-Allyloxybenzamidine hydrochloride1 (19.07 g., 0.0896 mole) was added to a cooled (ice-water), stirred solution of sodium ethoxide (12.25 g., 0.18 mole) in ethanol (100 ml.). To this cooled, stirred mixture was added a solution of diethyl ethoxymethylenemalonate (19.4 g., 0.0896 mole) in ethanol (15 ml.). The mixture was heated under reflux for 2.5 hours and then allowed to stand at room temperature for 18 hours. The mixture was poured into ice-water containing acetic acid. The solid was collected and recrystallized from cyclohexane to give the title compound (24.0 g., 89%), m.p. 118°-120°. Recrystallization from cyclohexane gave product with m.p. 118.5°-120.5°.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:28]4[C:19](=[CH:20][C:21]5[O:26][CH2:25][CH2:24][O:23][C:22]=5[CH:27]=4)[O:18][CH2:17]3)[C:9]2=[O:29])[CH2:4][O:3]1>C(O)(=O)C.O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:28]3[C:19](=[CH:20][C:21]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:27]=3)[O:18][CH2:17]2)[C:9]1=[O:29]
Reactant: CC1(C)OC[C@H](CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)O1
Solvent: O
Solvent: CC(=O)O
Product: O=C1N(C[C@H](O)CO)c2ccccc2C12COc1cc3c(cc12)OCCO3
Yield: 99.2 %

Procedure:
A solution of 1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.66 g, 1.61 mmol) in glacial acetic acid (10 mL) and water (5 mL) was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was recrystallized from ethyl acetate to afford 1′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.59 g, 99%): mp 179-181° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 7.30-7.25 (m, 1H), 7.13-7.07 (m, 2H), 7.01-6.95 (m, 1H), 6.46 (s, 1H), 6.21-6.19 (m, 1H), 5.02-4.94 (m, 1H), 4.71-4.57 (m, 3H), 4.14-4.06 (m, 4H), 3.81-3.54 (m, 3H), 3.39-3.32 (m, 2H); MS (ES+) m/z 369.9 (M+1).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[N:11]1[S:12][N:13]=[C:14]2[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12>C([O-])(O)=O.[Na+].C(OCC)C.O>[N:11]1[S:12][N:13]=[C:14]2[C:19]([S:20]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and benzo-2,1,3-thiadiazole-4-sulfonyl chloride (2.35 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (2.55 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.34 (d, J=8.8 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 6.37 (s, 1H), 5.24 (s, 1H), 2.19 (s, 1H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[C:10]([Cl:31])[CH:9]=1>N1C=CC=CC=1>[Cl:31][C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:30]=[CH:29][C:11]=1[O:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:14]=1[O:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Oc1ccc(N)cc1Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2cc(F)ccc2OCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethane sulphonyl chloride (0.05 ml) was added to a solution of the product from step (iv) (0.19 g) in pyridine (10 ml) and stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue dissolved in DCM (10 ml) and trifluoroacetic acid (10 ml).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:13]1([CH2:12][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Reaction time: 4 h

Procedure:
A solution of 6-hydroxyindan-1-one (1.60 g, 10.8 mmol (M. Phialas, P. G. Sammes, P. D. Kennewell, R. Westwood, J. Chem. Soc. Perkin Trans. 1: 687 (1984)), benzyl alcohol (1.23 mL, 11.9 mmol), triphenylphosphine (4.25 g, 16.2 mmol) under a N2 atmosphere in THF (100.0 mL) was treated with diethyl azodicarboxylate (2.55 mL, 16.2 mmol). The mixture was allowed to stir for 4 h then quenched with H2O. The mixture was then extracted with hexane (3×50 mL), the organic layers combined, dried with Na2SO4, and the solvent removed in vacuo. The residue was then submitted to column chromatography (SiO2 260-400 mesh, 4:1 hexanes: ethyl acetate) to provide the title compound (1.852 g, m.p. 99°-101° C.) as a solid. 'H NMR (400 MHz, CDCl3) δ 7.445-7.305 (m, 6H), 7.272-7.247 (m, 2H), 5.084 (s, 2H), 3.079 (m, 2H), 2.723-2.694 (m, 2H) .
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH:20]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:26](=[O:27])[CH2:25][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CC1CCCC1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(CC1CCCC1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-cyclopentylacetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.88-8.04 (m, 2H), 7.73-7.75 (m, 1H), 7.59-7.69 (m, 4H), 2.33 (d, J=7.4 Hz, 2H), 2.16-2.28 (m, 1H), 1.75-1.87 (m, 2H), 1.59-1.69 (m, 2H), 1.49-1.58 (m, 2H), 1.19-1.31 (m, 2H); MS (ESI−) M/Z 380 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.I[CH2:26][C:27]([F:30])([F:29])[F:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CI
Reactant: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ncn1CC(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-2A-1b: 1.20 g, 3.36 mmol), 2-iodo-1,1,1-trifluoroethane (705 mg, 3.36 mmol) and Cs2CO3 (2.19 g, 6.72 mmol) in DMF (20 ml) was heated at 100° C. for 17 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified via a Shimadzu HPLC system using a Waters XTERRA C18 50×50 mm column and a mixture of two solvent systems (0.1% NH4OH/CH3CN and H2O/0.1% NH4OH) to give the title compound 2A-1 (300 mg, 20%) as an amorphous solid: +ES MS (M+1) 439.1; 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.54–7.30 (m, 8H), 4.7 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=1>>[F:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[CH:13]([NH:12][C:7]1[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[N:25]=4)[CH:3]=3)[N:8]=1)[CH2:14][CH2:15]2
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: Fc1ccc2c(c1)CCC2Nc1ccc2cc(Br)ccc2n1
Product: Fc1ccc2c(c1)CCC2Nc1ccc2cc(Nc3cccc(C(F)(F)F)n3)ccc2n1

Procedure:
The title compound, yellow foam, MS: m/e=439.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(5-fluoro-indan-1-yl)-amine (see example 102, step A) and commercially available 2-amino-6-trifluoromethyl-pyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][N:19]([CH3:22])[CH:20]=O>C(OCC)(=O)C>[CH3:8][C@H:6]1[CH2:20][N:19]([C:22]2[CH:9]=[CH:10][CH:11]=[CH:5][N:4]=2)[CH2:18][CH2:3][N:7]1[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 3 h
Yield: 46 %

Procedure:
The product of Example 25B (0.24 g, 1.33 mmol) in N,N-dimethylformamide (10 mL) was treated with 2-chloromethyl-1H-benzimidazole (0.21 g, 1.27 mmol) and cesium carbonate (0.41 mmol, 1.27 mmol) at 23° C. with stirring for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (1–3% methanol/dichloromethane gradient) to afford 178 mg (46% yield) of the title compound as a light yellow solid. mp 149–151° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5; C, 70.33; H, 6.89; N, 22.78. Found: C, 70.21; H, 6.77; N, 22.62.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:14][N:15]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](O)c1nnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of (S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (30.0 mg, 0.151 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.8 mg, 0.302 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potassium carbonate (62.6 mg, 0.453 mmol) and 4:1 dioxane:water (5 mL) was heated to 85° C. for 1 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel and extracted with DCM. The organic layer was dry-loaded onto silica gel, and the material was purified via column chromatography, eluting with 10% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z 245.08 (100) [MH+]. HPLC: tR=2.00 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Sn](C)(C)C>CN(C)C=O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH3:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 120 °C

Procedure:
A solution of Intermediate 1 (228 mg) obtained in Example 1, Step A and tetramethyltin (0.69 ml, Tokyo Kasei Kogyo) in N,N-dimethylformamide (4 ml) is added with tetrakis(triphenylphosphine)palladium(0) (29 mg, Kanto Chemicals), and the mixture is stirred at 120° C. with heating for 12 hours. The reaction mixture is cooled to room temperature, then added with saturated brine (5 ml), and extracted 3 times with ethyl acetate (5 ml for each time). The combined organic layer is washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and then the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (176 mg (predictive yield)).