Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl>[N+](CC)([O-])=O>[C:5]([C:20]1[CH:19]=[CH:18][C:16]2[C:17]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]=2[CH:21]=1)(=[O:7])[CH3:6]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)oc1ccccc12
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of aluminum chloride (40 g, 300 mmole) in nitroethane (220 mL) under dry nitrogen was added acetyl chloride (9.5 g, 120 mmole) at 0°-5° C. The solution was stirred for 15 min, then dibenzofuran (16.8 g, 100 mmole) was added slowly and the reaction turned deep yellow-green. After 45 min at 0°, the yellow-green suspension was added to a mixture of ice and 3N HCl. The mixture was extracted with ether (2×300 mL) and extracts were dried (Na2SO4), filtered and concentrated. The crude ketone, a light amber oil, was judged to be sufficiently pure by thin layer chromatography (TLC) to use
Reaction SMILES: [CH2:1]([C:5]1[CH2:6][C:7]2[C:12]([C:13]=1OC)=[CH:11][C:10]1[O:16][CH2:17][O:18][C:9]=1[CH:8]=2)[CH2:2][CH2:3][CH3:4].P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH2:6][C:7]2[C:12]([C:13]=1[Br:20])=[CH:11][C:10]1[O:16][CH2:17][O:18][C:9]=1[CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: BrP(Br)Br
Reactant: CCCCC1=C(OC)c2cc3c(cc2C1)OCO3
Solvent: ClC(Cl)Cl
Product: CCCCC1=C(Br)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
Dissolved in 100 ml of chloroform was 9.3 g of 2-n-butyl-3-methoxy-5,6-methylenedioxyindene, followed by a dropwise addition of 15.4 g of phosphorus tribromide over 1 hour under ice cooling. After stirring the resultant mixture for further 4 hours, the reaction mixture was stirred for additional 4 hours at room temperature. The reaction mixture was washed with water, a 5% aqueous solution of sodium hydroxide and water successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 20:1 mixture of n-hexane and ether) to give 7.6 g of 2-n-butyl-3-bromo-5,6-methylenedioxyindene having a melting point of 63.0°-64.0° C. as crystals (yield: 68%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].O>CO>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([OH:13])([CH2:14][O:33][CH3:32])[C:15]([F:17])([F:16])[F:18]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Yield: 42.9 %

Procedure:
2.14 g (4.64 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 are stirred with 2.57 g (7.9 mmol) Caesium carbonate in 37 ml methanol. After 3 days water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (methanol in dichloromethan 0 to 5%) yields 0.98 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:19]([F:31])=[CH:18][N:17]=1>>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([F:31])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=4[CH:14]=3)[N:21]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gave (±)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.13 (bs, 1H), 9.70 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 8.04 (d, 1H, J=2.4 Hz), 7.68 (m, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.37 (bs, 1H), 7.19 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 5.35 (dd, 1H, J=6.6 Hz), 3.69 (s, 3H), 3.53 (dd, 1H, J=10.5 and 11.1 Hz), 3.21 (dd, 1H, J=6.0 Hz); LCMS: purity: 100%; MS (m/e): 450 (MH+).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)C.I([O-])(=O)(=O)=[O:26].[Na+]>CC(C)=O.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][CH:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1)(=[O:26])[CH3:1]
Reactant: C=C(C)c1cc(-c2coc(CCC(=O)OC)n2)cc(C(F)(F)F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)CCc1nc(-c2cc(C(C)=O)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a stirred solution of methyl 3-(4-(3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 49, 0.175 g, 0.516 mmol), and osmium tetroxide solution (0.21 g, 4 wt % in water, 0.033 mmol) in acetone (10.0 mL) and water (3.0 mL) was added sodium periodate (0.331 g, 1.55 mmol) at room temperature and the mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-acetyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.128 g, 73%) as a white solid: ESI MS m/z 342 [M+H]+.
Reaction SMILES: CON(C)C(C1SC=NC=1)=O.[CH3:12][N:13]([CH3:26])[C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[CH:16][CH:15]=1.[CH3:27][N:28]1[C:32](C(C2SC=NC=2)=O)=[CH:31][N:30]=[CH:29]1>>[CH3:26][N:13]([CH3:12])[C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:32]2[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: Cn1cncc1C(=O)c1cncs1
Reactant: CON(C)C(=O)c1ccc(N(C)C)cc1
Agent: CON(C)C(=O)c1cncs1
Product: CN(C)c1ccc(C(=O)c2cncn2C)cc1

Procedure:
The title compound was prepared by substituting N-methoxy-N-methylthiazole-5-carboxamide (Intermediate 11: step a) with 4-(dimethylamino)-N-methoxy-N-methylbenzamide then following the procedure described for the preparation of (1-methyl-1H-imidazol-5-yl)(thiazol-5-yl)methanone (Intermediate 13).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([O:27][CH3:28])[CH:5]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([O:27][CH3:28])[CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Reaction time: 48 h
Yield: 35.7 %

Procedure:
A solution of 3-methoxy-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (875 mg, 2.25 mmol) in ethyl acetate was treated with 10% palladium on activated carbon (83 mg). The reaction was stirred under a balloon of hydrogen gas for 6 h. At this time, the reaction was filtered through a pad of Celite®, rinsed with ethyl acetate and concentrated in vacuo. LCMS indicated incomplete conversion to the desired product. Due to solubility issues, the residue was dissolved in acetone (200 mL) at 25° C. and was treated with 10% palladium on activated carbon (83 mg). The reaction was stirred under a balloon of hydrogen gas for 2 d. At this time, the reaction was filtered through a pad of Celite®, rinsed extensively with acetone and concentrated in vacuo. LCMS still indicated incomplete conversion to the desired product. The residue was dissolved in methylene chloride (150 mL) at 25° C. and was treated with 10% palladium on activated carbon (83 mg). The reaction was stirred under a balloon of hydrogen gas for 4 d. At this time, the reaction was filtered through a pad of Celite®, rinsed with methylene chloride (2×50 mL) and concentrated in vacuo. Flash chromatography (40 g silica column, 10-25% ethyl acetate/hexanes) afforded 3-methoxy-4-[3-oxo-3-(2-phenylamino-pyridin-3-yl)-propyl]-benzoic acid methyl ester (313.4 mg, 35.6%) as a yellow solid.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[N:10]=[CH:9][N:8](COC(=O)C(C)(C)C)[C:7]2=O>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[N:10]=[CH:9][N:8]=[CH:7]2
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnn1
Agent: N
Solvent: CO
Product: COc1cc2cncnc2cc1OCCn1ccnn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
5.1M Ammonia in methanol (30 ml) was added to a solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,3-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.4 g, 3.5 mmol) in a solution of methanol (30 ml). After stirring overnight at ambient temperature, the volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (946 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[S:7])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]>[OH-].[Na+].CCO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[S:7][C:14]3[CH:13]=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: Cc1ccc(NC(=S)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)sc2c1
Temperature: 90 °C

Procedure:
To 2M aqueous solution K3Fe(CN)6 (4 mL, 8 mmol) (pre-heated to 90° C.) is added dropwise to a suspension of 4-chloro-N-p-tolyl-3-trifluoromethyl-thiobenzamide (660 mg, 2 mmol) in 2M NaOH (9 ml) and EtOH (3 ml). The mixture is heated at 90° C. overnight. The mixture is cooled to room temperature and extracted with EtOAc (50 ml×2). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The mixture is purified by ISCO system (EtOAc/Hexanes: 20 minutes run 0 to 100% of EtOAc). 2-(4-Chloro-3-trifluoromethyl-phenyl)-6-methylbenzothiazole is isolated (170 mg, 26%), as well as 380 mg of the starting material.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:31])[CH:3]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[OH:36][C:34]([C:33]([F:38])([F:37])[F:32])=[O:35].[CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)cn3COCC[Si](C)(C)C)nc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)c[nH]3)nc2n1
Reaction time: 16 h

Procedure:
To a solution of 5,7-Dimethyl-2-{2-[4-thiophen-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-ethyl}-imidazo[1,2-a]pyrimidine (360 mg, 0.79 mmol) in DCM (4.5 mL) was added trifluoroacetic acid (4.5 mL). The reaction was shaken under an atmosphere of argon for 16 hours. The volatiles were removed in vacuo to yield the title compound as the TFA salt. LC-MS: m/z=324.5 (MH+), tR=0.33 minutes, method A.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:15]>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: CI
Reactant: Cc1ccc2[nH]ccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ccn2C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 4-bromo-5-methylindole (3.55 g, 16.9 mmol) (21) in 10 ml of anhydrous DMF is added to a suspension of sodium hydride (1.01 g, 60% in mineral oil, 25.3 mmol, 1.5 eq.) in 10 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, and then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C. Iodomethane (2.40 g, 18.6 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, and then is warmed to 50° C. and stirred for an additional 2 hours. The reaction mixture is poured into 100 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine dried over anhydrous sodium sulfate. The solvent is evaporated and the product (22) is taken to dryness under high vacuum to give 3.75 g of pure compound. 1H NMR (400 MHz, CDCl3) δ 7.17 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.05 (1H, 4, J=3.2 Hz), 650 (1H, dd, J=0.4, 2.8 Hz), 3.77 (3H, 3), 2.51 (3H, s); MS (+VE) m/z 224 (M+).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]1([C:15]2[CH:24]=[C:23]([OH:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:9]1([C:15]2[CH:24]=[C:23]([O:25][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Oc1cc(-c2ccccc2)nc2ccccc12
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1cc(-c2ccccc2)nc2ccccc12

Procedure:
Ethyl 2-bromopropionate (4.3 cc) is added dropwise to a stirred suspension of 2-phenyl-4-quinolinol (6.63 g) and potassium carbonate (8.3 g) in methyl ethyl ketone (200 cc). The mixture is heated for three hours under reflux. The mixture is brought back to room temperature (approximately 20° C.), the insoluble material drained and the solvents removed under reduced pressure. The residue is taken up with 40°-70° petroleum ether (100 cc) and drained. Ethyl 2-[(2-phenyl-4-quinolyl)oxy]propionate (9.2 g), m.p. 80° C., is thereby isolated.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].CC(C)(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C.P(=O)(O)(O)O.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:4][C:2]([NH:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)Nc1cccnc1N1CCNCC1
Reaction time: 1 h

Procedure:
Isobutylene (10 ml) is condensed into a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 200 mg) in methylene chloride (10 ml) at -70°. Phosphoric acid (85%, 50 μl) is added and the mixture stirred for 60 minutes. Boron trifluoride etherate (200 μl) is added dropwise and the resulting suspension is stirred 8 hours at reflux and overnight at 20°-25° allowing the isobutylene to evaporate. The suspension is diluted with water and ammonium hydroxide is added until basic to pH paper and then extracted with methylene chloride (3×). The combined extracts are dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to a liquid which is flash chromatographed (silica gel, 230-400 mesh), eluting with methanol/chloroform (3/20). The appropriate fractions are pooled and concentrated to give an oil. The NMR, CMR, IR, and MS (m/e) M+234 support the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[N:14]=[C:15]([C:17]4[C:18]([CH3:26])=[N:19][N:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=45)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([C:17]4[C:18]([CH3:26])=[N:19][N:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=45)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In a 500 mL round bottomed flask was placed 4-(4-chlorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4,5,6,7-tetrahydro-1,3-benzothiazol-4-ol prepared above. The material was suspended in 1,2-dichloroethane (50 mL) and the suspension was stirred for 60 min at 90° C. To the hot solution were added triethylsilane (2 mL, 10 mmol) and trifluoroacetic acid (3 mL, 40 mmol). The mixture Was stirred for 2 days at the same temperature. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and then washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography, eluting with 30% to 100% EtOAc/hexane to yield the title compound (622 mg; 91.8%) as a yellow crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ ppm 8.66 (dt, 1H), 7.95 (dt, 1H), 7.33-7.37 (m, 3H), 7.16 (d, 2H), 6.96 (td, 1H), 4.27 (t, 1H), 2.84-2.93 (m, 2H), 2.56 (s, 3H), 2.15-2.21 (m, 1H), 1.77-1.88 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41](Br)=[CH:42][CH:43]=1)(=[O:38])=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:42][CH:43]=1)(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and [2-(5-bromo-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.51) (193 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as a yellow solid (89 mg, 32%). MS (ISN) 558.0 [(M−H)−]; mp 196° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])=[CH:2]1.[NH2:17][OH:18].Cl>C(N(CC)CC)C>[OH:18][NH:17][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:7]
Reactant: O=C(O)CCCCCCC(=O)c1ccoc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccoc1)NO
Yield: 33 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50j for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 33% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 8.09 (br s, 1H), 7.46 (m, 1H), 6.75 (m, 1H), 2.76 (t, J=7.5 Hz, 2H), 2.10 (t, J=7.5 Hz, 2H), 1.60-1.72 (m, 4H), 1.36 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 23.90, 24.99, 28.45(2), 32.48, 39.98, 108.19, 127.37, 144.15, 147.43, 171.08, 196.21.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].Cl.[CH3:42][NH2:43]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:13])[NH:43][CH3:42])=[CH:15][CH:16]=1)[CH:17]1[CH2:18][CH2:19][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:21][CH2:22]1)#[N:2]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Yield: 71.2 %

Procedure:
Using general procedure E, 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 131) (30 mg, 0.056 mmol) and methylamine hydrochloride (19 mg, 0.28 mmol) afforded COMPOUND 132 as a white solid (22 mg, 72%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.3 Hz), 1.15-1.26 (m, 1H), 1.52-1.75 (m, 4H), 2.15-2.37 (m, 2H), 2.31 (s, 6H), 2.59 (t, 1H, J=11.1 Hz), 2.76-2.88 (m, 3H), 2.96 (d, 3H, J=4.2 Hz), 3.20-3.33 (m, 1H), 3.67-3.74 (m, 1H), 3.85-3.89 (m, 1H), 3.89 (s, 2H), 5.91 (br s, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.2 Hz), 7.04-7.09 (m, 1H), 7.41-7.46 (m, 3H), 7.54-7.57 (m, 3H), 8.25 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.54, 27.07, 29.47, 30.73, 31.40, 40.13, 43.97, 48.36, 52.39, 56.37, 60.80, 112.55, 113.05, 119.20, 123.36, 127.70, 128.80, 128.86, 129.76, 130.13, 131.07, 134.52, 139.01, 141.73, 150.81, 168.13, 170.24. ES-MS m/z 552 (M+H). Anal. Calcd. for C34H41N5O2.0.9H2O: C, 71.90; H, 7.60; N, 12.33. Found. C, 71.72; H, 7.71; N, 12.72.
Reaction SMILES: [OH-].[K+].[CH:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[I-].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CS(C)=O>[N:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:7]1[CH:8]=[CH:3][CH:4]=[CH:5][N:6]=1)[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CN(c1ccccn1)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl 2-(di(pyridine-2-yl)amino)acetate was prepared with modification to Kirin et al., 2007, J. Inorg. Chem., 3686-3694, the entire contents of which are incorporated herein by reference. Potassium hydroxide (3.0 g, 53.6 mmol, 4.6 equiv) was added to a solution of 2,2′-dipyridylamine (2.0 g, 11.7 mmol) in 40 ml DMSO and stirred at room temperature for 16 hours (h). Potassium iodide (200 mg, 1.2 mmol, 0.1 equiv) and tert-butyl bromoacetate (4 ml, 2.3 equiv) were added to the mixture, and the reaction was stirred for 2 h at room temperature. The reaction mixture was extracted with diethyl ether (3×50 ml). The organic fractions were combined and dried over magnesium sulfate, and the solvent was removed by rotary evaporation. The crude product was isolated by flash chromatography (SiO2, hexane/ethyl acetate=8:2) to give a yellow oil. DPA was obtained (Yield: 2.92 g (88%)), and confirmed by 1H NMR (CDCl3, 300 MHz): δ 8.33 (ddd, J=5.0, 1.9, 0.9 Hz; 2H), 7.53 (m, 2H), 7.23 (m, 2H), 6.88 (ddd, J=7.2, 5.0, 0.9 Hz; 2H), 4.84 (s, 2H), 1.42 (s, 9H). ESI-MS (cation): 286 m/z (M+H+) obsd, 286 m/z calcd.