Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)#[N:2]>C(O)C.CC(C)=O.[C].[Pd]>[C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of Compound 10 (0.55 g, 1.5 mmol) obtained in Example 10 in ethanol (5.5 mL) and acetone (8.0 m) was added 10% palladium-carbon (containing 50% of water) (0.11 g), and the mixture was subjected to a hydrogenation reaction at room temperature and ordinary pressure for 3 hours. After removal of the catalyst, the solvent was evaporated in vacuo from the filtrate to give Compound 20 (0.54 g, 100%) as a mixture of isomers in a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH:8]C=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].[CH2:20](OCC)C>>[CH3:20][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH2:6][CH2:7][NH2:8]
Reactant: CCOCC
Reactant: O=CNCCc1ccsc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1sccc1CCN
Reaction time: 0.5 h

Procedure:
A solution of 3-thienylethyl formamide (62.0 g) in dry diethylether (100 ml) was added dropwise over 1 hour to a stirred suspension of lithium aluminium hydride (19.0 g) in diethylether (500 ml) at room temperature under nitrogen. After 2 hours at reflux temperature the mixture was allowed to cool and the following were added, water (19 ml), 2M sodium hydroxide (38 ml) and water (57 ml). After vigorous stirring for 0.5 hours the suspension was filtered and the filtrate evaporated. The liquid residue (58 g) was dissolved in ethanol (60 ml) and ethanolic hydrogen chloride (~5M, 90 ml) added. After cooling the white crystals of methyl thiophene-3-ethylamine hydrochloride (m.p. 149°) were filtered. The hydrochloride salt was converted to the free base by extraction between dichloromethane and aqueous ammonia, followed by distillation to give methyl thiophene-3-ethylamine (b.p. 78° at 2 mmHg) as a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][NH:10][CH3:11]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:10]([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Brc1cccc(Br)n1
Solvent: CCO
Product: CN(C)c1cccc(Br)n1

Procedure:
Heat a stirred mixture of 2,6-dibromopyridine (15; g, 63; mmol) and dimethylamine (40% aqueous solution, 21.4; mL, 190; mmol, 3; equiv) in ethanol (75; mL) for 3; days at 70° C. Evaporate the yellow solution to a reduced volume and dilute with ethyl acetate (100; mL). Wash with water (40; mL), brine (40; mL) and dry over sodium sulfate. Decant the liquid and evaporate to give pale yellow oil (13.8; g). Distill using a Kügelrohr apparatus to give the title product as a colorless liquid (12.4; g, b.p.=100-140° C. at 0.1 mbar). MS (m/z): 201, 203; (M+1).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1.[BH4-].[Na+]>CO>[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH2:16][NH:2][CH3:1])=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylamine (7.5 ml, 15.00 mmol) was added to a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 3 g, 12.70 mmol) in MeOH (60 ml) and the reaction mixture was stirred at room temperature for approximately 3 h. NaBH4 (690 mg, 18.24 mmol) was added portonwise and stirring was continued at room temperature for 40 min. Solvents were concentrated and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM and the organic layers were washed with water. The combined organic layers were dried using Na2SO4, filtered and evaporated to yield the title compound as an orange oil. (UPLC-MS 3) tR 0.35 min; ESI-MS 252.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.29 (s, 1H), 5.30 (s, 1H), 4.91 (br s, 1H), 3.73 (s, 2H), 3.36-3.47 (m, 8H), 2.73 (t, 2H), 2.47 (s, 3H), 2.21 (br s, 1H), 1.95-1.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn].[O:29]1CCO[CH2:31][CH2:30]1>>[CH2:1]([O:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([C:30](=[O:29])[CH3:31])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(C(=O)OCc2ccccc2)c1
Reactant: C1COCCO1
Agent: [Sn]
Product: CC(=O)c1ccc(C(=O)OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In dioxane was placed 4-bromo-1,3-benzenedicarboxylate dibenzyl ester (1.78 g, 4.2 mmol), tri-n-butyl(1-ethoxyvinyl), tin (1.70 g, 4.7 mmol), and bis-triphenylphosphine palladium (II) dichloride (175 mg, 0.25 mmol). The mixture was warmed to 100° C. and stirred for 24 hours. The dark solution was evaporated at reduced pressure to give an oil. The oil was purified by MPLC (90 g silica gel, 3:1 [hexane:ethyl acetate]). This gave 0.91 g of the ethoxyvinyl intermediate. This was then placed into a solution of acetic acid (25 mL) and water (5%) and stirred for 1 hour. The mixture was evaporated in vacuo to give an oil which was purified by MPLC (90 g silica gel, 8:2 [hexane:ethyl acetate]). This gave 699 mg (43%) of a white solid. MS: M+1=389.2.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15]C1>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:19][C:13]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC1(Br)CCCCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)/C(=N\OC1(C)CCCC1)C(C)=O
Yield: 50.1 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (5.86 g, 36.8 mmol), 1-bromo-1-methylcyclohexane (6.01 g 36.8 mmol), and silver trifluoromethanesulphonate (9.45 g, 36.8 mmol) were reacted together by a similar method to that described in Example 9a to give the title compound (4.45 g, 50%); νmax (film) 2970, 1745, 1690, 1590, 1370, 1320, 1230, 1070, and 990 cm-1 ; δH (60 MHz, CDCl3), 1.31 (3H, t, J 7 Hz), 1.48 (3H, s), 1.1-2.2 (8H, m), 2.35 (3H, s), and 4.30 (2H, q, J 7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][C:9](=[O:11])[C:8]3[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2c(c1)OCCO2

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,3-dihydrobenzo[1,4]dioxin-6-ylamine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([SH:18])[C:15]([CH3:19])=[N:14]1.[H-].[Na+].Br[C:23]1[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]([C:30]#[N:31])=[C:26]([C:28]#[N:29])[N:27]=1.O>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([S:18][C:23]2[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]([C:30]#[N:31])=[C:26]([C:28]#[N:29])[N:27]=2)[C:15]([CH3:19])=[N:14]1
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(C#N)c1C#N
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Sc1nc(C#N)c(C#N)n1COCC[Si](C)(C)C

Procedure:
Crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-thiol, prepared as in EP No. 350 237, (10 g) in tetrahydrofuran (50 ml) was added to a stirred suspension of sodium hydride (80%, dispersion in oil, 1.0 g) in tetrahydrofuran (50 ml) at 0°. Then a solution of 2-bromo-4,5-dicyano-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (10 g) in tetrahydrofuran (100 ml) was added, dropwise, with stirring at 0°-5°. The mixture was stirred at room temperature for 20 hours and then was poured into water and extracted with ethyl acetate. Conventional work-up and purification by column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[4,5-dicyano-1-(2-trimethylsilylethoxymethyl]-1H-imidazol-2-ylthio]-5-methyl-2H-1,2,3-triazole, as a pale yellow oil, nD 24°=1.526 (compound 9a).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:60])[CH2:58][NH2:59])[CH2:53][CH2:52]1)=[O:50])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:60])[CH2:58][NH:59][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH:9]=2)=[O:14])[CH2:53][CH2:52]1)=[O:50])[CH3:47]
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)CNC(=O)c2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 2-phenyl-1,3-thiazole-4-carboxylic acid (5.1 mg) and DIPEA (3 eq) in DMF (0.4 mL) was added TBTU (1.2 eq) in DMF (0.2 mL). Then, a solution of 4-(2-amino-acetyl)-piperazine-1-carboxylic acid ethyl ester (5.4 mg, prepared as described in WO2006114774) in DMF (0.2 mL) was added. After stirring overnight at RT, the reaction mixture was directly purified by preparative HPLC (IV) to give 4.9 mg of the desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>C1CCCCC1>[O:15]([C:22]1[CH:23]=[C:24]([NH:25][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][C:2]([F:14])([F:13])[F:1])[CH:6]=2)[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: FC(F)(F)COc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
The 3-(2,2,2-trifluoroethoxy)benzaldehyde (0.360 g, 1.76 mmol) product from EX-659A and 3-phenoxyaniline (0.326 g, 1.76 mmol) were combined in 50 mL of cyclohexane with 3 Å molecular sieves (1 g) and stirred overnight at 80° C. The mixture was cooled, filtered, and evaporated, then dissolved in 50 mL of methanol and cooled to 0° C. Solid sodium borohydride (0.030 g, 0.79 mmol) was added in portions, and the mixture was stirred overnight. The reaction was quenched with 5% aq. NaHCO3 and extracted with ether (3×). The combined ether layers were washed with water and brine, dried over MgSO4, filtered, and evaporated to give 0.50 g (76%) of the desired N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine product as an amber oil, >95% pure by normal phase HPLC analysis. MS m/z=373 [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([O:10]C)[CH:3]=1.[Br:12]Br.[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl.C(Cl)(Cl)(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([OH:8])[C:4](=[CH:3][C:2]=1[CH3:1])[OH:10]
Reactant: BrBr
Reactant: COc1ccc(C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O)c(O)cc1Br

Procedure:
To a solution of homoveratrole (136.4 g, 1.1 mol) in chloroform (1.2 L) and dichloromethane (300 mL) was slowly added a solution of bromine (66 mL, 1.28 mol, 1.2 eq.) in carbon tetrachloride (250 mL). After 5 hours the reaction mixture was neutralized to pH7 with an aqueous solution of sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was dried over sodium sulfate, filtered, and the volatiles were removed in vacuo, affording the title compound as a light brown solid, m.p.: 92-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[NH:18]([C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[C:19]([NH2:21])=[NH:20].[OH-].[Na+]>CO.O>[N:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[NH:23][C:22]=1[N:18]=[C:19]1[NH:21][C:9]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:21][C:19](=[N:18][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[NH:20][C:8]2([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:20]1
Reactant: O=C(C(=O)c1cccc(Cl)c1)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccc2)NC(=Nc2nc4ccccc4[nH]2)N3)c1

Procedure:
Following the procedure of Example 1, 1-(3-chlorophenyl)-2-phenylethanedione (0.25 g, 1.0 mmol) and 2-guanidinobenzimidazole (0.215 g, 1.2 mmol) in methanol (12 mL) was treated with a solution of sodium hydroxide (48 mg, 1.2 mmol) in 1.2 mL of water. The title compound was isolated as pale yellow crystals (130 mg, 39% yield). MS (ESI) m/z 559 [M+H]+.
Reaction SMILES: [H-].[Na+].CO.[CH3:5][O:6][C:7]1[C:8]2[O:22][CH2:21][O:20][C:9]=2[CH:10]=[C:11]([CH2:13][CH:14]2[CH2:19][O:18][C:16](=[O:17])[CH2:15]2)[CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH:28]=O.Cl>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[C:8]2[O:22][CH2:21][O:20][C:9]=2[CH:10]=[C:11]([CH2:13][CH:14]2[CH2:19][O:18][C:16](=[O:17])/[C:15]/2=[CH:28]/[C:27]2[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=2)[CH:12]=1
Reactant: COc1cc(CC2COC(=O)C2)cc2c1OCO2
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2/C(=O)OCC2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
Sodium hydride (60%, 0.43 g, 10.8 mmol) and methanol (0.016 ml, 0.4 mmol) were added to 20 ml of toluene under an argon stream. The solution was added further with (RS)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]butanolide [1.0 g, 4 mmol, G. E. Schneiders and R. Stevenson, J. Chem. Soc. Perkin I, 999, (1982)] and 3,4,5-trimethoxybenzaldehyde (1.24 g, 6.3 mol), followed by stirring at room temperature for 24 hours. The reaction mixture was added with 2N-HCl. The solution was dissolved in ethyl acetate, from which the water layer was removed. The organic layer was washed with saturated NaCl and then, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus obtained was purified by column chromatography (silica gel: "MERCK #9385", 50 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 732 mg of the title compound were obtained as a colorless solid (yield: 43%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (77 mg, 63%). MS (ISP) 489.3 [(M+H)+]; mp 231-233° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.FC(F)(F)C1C=C([C:19]23[CH2:28][CH:23]([O:24][C:25]2([CH3:27])[CH3:26])[N:22]([CH3:29])[CH2:21][CH2:20]3)C=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:19]1([C:25]([CH3:27])([CH3:26])[OH:24])[CH2:28][CH2:23][N:22]([CH3:29])[CH2:21][CH2:20]1
Reactant: COc1ccc(OC)cc1
Reactant: CN1CCC2(c3cccc(C(F)(F)F)c3)CC1OC2(C)C
Solvent: CC(C)=O
Product: COc1ccc(OC)c(C2(C(C)(C)O)CCN(C)CC2)c1

Procedure:
4-(2',5'-Dimethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from 1,4-dimethoxybenzene by the procedure described in Example 3 except that acetone was used in place of cyclopentanone in the synthesis of III; m.p. 139°-140°; NMR (in CDCl3): τ 3.0-3.3 (m, 3H); 6.2 (2s, 6H); 6.6-8.5 (m+s, 12H) and 8.9 (broad, 6H). Anal. Calcd. for C17H27NO3 : C, 69.59; H, 9.29; N, 4.77. Found: C, 69.66; H, 9.09; N, 4.66.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[Br:19][C:20]1[CH:31]=[CH:30][C:23]2[S:24][C:25](B(O)O)=[CH:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:19][C:20]1[CH:31]=[CH:30][C:23]2[S:24][C:25]([C:2]3[CH:3]=[N:4][N:5]4[CH:10]=[C:9]([C:11]5[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=5)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=34)=[CH:26][C:22]=2[CH:21]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Reactant: OB(O)c1cc2cc(Br)ccc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(-c3cc4cc(Br)ccc4s3)c12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (25.0 mg, 0.071 mmol), 5-bromobenzeno[B]thiophene-2-boronic acid (19.0 mg, 0.074 mmol), tetrakis(triphenylphosphine)palladium (0) (8.2 mg, 7.1 μmol), and sodium carbonate (15.0 mg, 0.141 mmol) were suspended in Dioxane (900 μl)/Water (100 μl). The mixture was sparged with argon for 10 minutes, heated to 90° C. and stirred overnight. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford a tan solid that contained unidentified impurities. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to afford 3-(5-bromo-1-benzothien-2-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H); 8.33 (s, 1H); 8.27 (s, 1H); 8.06 (s, 1H); 8.03 (d, 1H); 7.88 (d, 1H); 7.64 (s, 1H); 7.41 (dd, 1H); 7.03 (s, 1H); 4.05 (s, 3H); 3.88 (s, 3H). LRMS (ESI) calculated for C20H1679BrN4OS [M+H]+, 439.0; found 438.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccc(Cl)cc2[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1[N+](=O)[O-]

Procedure:
A suspension of 7-chloro-4-hydroxycarbostyril (0.5g.) in glacial acetic acid (4 ml.) was nitrated with concentrated nitric acid (0.7ml.) at 100° C and worked up in the usual manner to give the title compound, m.p. (aqueous ethanol) 166° - 167° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26]>>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([N:7]1[CH2:8][CH:4]2[CH:5]([CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3]2)[CH2:6]1)=[O:26]
Reactant: Cc1ccoc1C(=O)O
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: Cc1ccoc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. For C20H20N4O2, 348.16; m/z found 349.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([NH:26][C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][N:28]=2)[CH2:14][C@H:13]1[CH2:39][CH3:40])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:48][C:49]1[CH:50]=[C:51]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[C:52]#[N:53].Cl>COC(C)(C)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:48][C:49]2[CH:56]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:54]=[C:51]([C:52]#[N:53])[CH:50]=2)[C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][N:28]=2)[CH2:14][C@H:13]1[CH2:39][CH3:40])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound obtained in Example 21 (2) above (177 mg) was dissolved in tert-butyl methyl ether (3 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Thereto were added tetrabutylammonium iodide (46 mg), potassium tert-butoxide (105 mg) and 3-Bromomethyl-5-trifluoromethyl-benzonitrile (124 mg), and the mixture was stirred for 2 hours. 1N HCl and ethyl acetate were added to the reaction mixture and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (NH-silica gel; hexane:ethyl acetate=4:1→3:2) to give the titled compound (39 mg). MS (m/z): 749 [M+H]+.