Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:29][OH:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]>C(Cl)Cl.O1CCOCC1.O=[Mn]=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:29]=[O:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CO)nc3Cl)c2F)c1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C=O)nc3Cl)c2F)c1
Reaction time: 66 h
Yield: 30 %

Procedure:
MnO2 (2.5 g, 29 mmol) was added to a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxamide (428 mg, 0.91 mmol) in DCM (30 mL) and 1,4-dioxane (5.0 mL). The mixture was stirred for 66 h and then the MnO2 was filtered off by through a pad of celite. Resin with 10% MeCN in DCM and the filtrates were concentrated, dried in vacuo to give the crude product (128 m, 30%) which was used for the next step without purification.
Reaction SMILES: C([O:8][C@H:9]([CH3:42])[C@H:10]([O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH:39]3[CH2:41][CH2:40]3)(=[N:32][C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:31])=[CH:26][CH:25]=2)[N:14]=1)[CH3:11])C1C=CC=CC=1>C(O)C.[Pd]>[CH:39]1([S:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:15]3[N:14]=[C:13]([O:12][C@H:10]([CH3:11])[C@H:9]([OH:8])[CH3:42])[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=3)=[CH:29][CH:28]=2)(=[N:32][C:33](=[O:38])[C:34]([F:36])([F:35])[F:37])=[O:31])[CH2:41][CH2:40]1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Yield: 79 %

Procedure:
A solution of (RS)—S-(4-{[4-{[(1R,2R)-2-(benzyloxy)-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximide in ethanol was admixed with palladium on carbon (10%) and hydrogenated under atmospheric pressure at room temperature. The mixture was filtered and concentrated by evaporation (yield: 79%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][CH:8]([F:57])[C:9]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][N:51]=2)=[CH:46][CH:45]=1)([OH:43])[CH2:10][C:11]1[N:12]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=[C:14]([CH2:16][C:17]([CH3:23])([CH3:22])[CH:18]([OH:21])CO)[N:15]=1>O1CCCC1.O>[F:57][CH:8]([F:7])[C:9]([C:44]1[CH:45]=[CH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][N:51]=2)=[CH:48][CH:49]=1)([OH:43])[CH2:10][C:11]1[N:12]([C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][C:17]([CH3:23])([CH3:22])[CH:18]=[O:21])[N:15]=1
Reactant: CC(C)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1)C(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Temperature: 25 °C

Procedure:
Sodium periodate was added to a solution of 4-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-3,3-dimethylbutane-1,2-diol (300 mg, 0.43 mmol) in tetrahydrofuran/water (2:1) (10 mL) at 0° C. After stirring at ambient temperature until complete (by LCMS), the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 3-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-2,2-dimethylpropanal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:18][CH2:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:18][CH2:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:7]2=[N:8][CH:9]=1
Reactant: CCOC(=O)N1CCC(C2c3ncccc3CCc3cc([N+](=O)[O-])cnc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCC(C2c3ncccc3CCc3cc(N)cnc32)CC1
Yield: 89.2 %

Procedure:
Ethyl 4-(3-nitro-6,11-dihydro-5H-cyclohepta[2,1-b:4,5- b′]dipyridin-11-yl)-1-piperidinecarboxylate ( 0.14gm, 0.367 mmol) was dissolved in 15 ml of ethanol. Palladium/carbon (10%, 20 mg) was added and the reaction mixture hydrogenated at 50 psi of hydrogen for 2 hours. The palladium was filtered and the ethanol evaporated to give 0.12 gm of the title product. FABMS (M+1)=367
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 57.9 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (8.92 g) and 1-benzylpiperazine (6.30 g) were condensed in the same manner as in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methyl butylcarbamate to yield 8.06 g of tert-butyl (s)-1-(4-benzylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 58%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:17]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([OH:31])[CH:25]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:23])[CH2:18]1)[CH3:16]>>[CH2:15]([C:17]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:25]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:23])[CH2:18]1)[CH3:16]
Reactant: CCC1(c2cc(O)cc(F)c2)CCOC(C)C1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CCC1(c2cc(F)cc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOC(C)C1
Yield: 52 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with (2RS,4RS)-4-ethyl-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyran to give (2RS,4RS)-4-ethyl-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-2-methyltetrahydropyran in 52% yield, m.p. 99° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:35][CH:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:40])([CH3:39])[CH2:32]3)[N:27]=[C:26]([CH3:41])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:35][CH:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:39])([CH3:40])[CH2:32]3)[N:27]=[C:26]([CH3:41])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CC(N(C)C)C(C)(C)C2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC(N(C)C)C(C)(C)C2)n1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.0775 g, 0.136 mmol) in MeOH (5 mL) was added 10% Pd/C (50% water, 23 mg). The mixture was hydrogenated under balloon pressure for 1 h, and then filtered. The solution was concentrated in vacuo, and the residue was crystallized from EtOAc-hexanes to afford [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (0.0566 g, 87% yield, mixture of diastereomers) as an off-white solid. LCMS: (M+H)+: 480.1.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[N:14]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[OH:3][CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[N:14]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:32][CH:33]=1)[S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH3:2]
Reactant: CC(=O)c1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)ncc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)ncc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 4-({(4-acetylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoic acid (20.0 mg, 0.036 mmol) prepared in Example 112 in ethanol (1 mL) was added sodium borohydride (10.0 mg, 0.264 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 1 mol/L hydrochloric acid. The reaction solution was concentrated under reduced pressure, and then diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 4-({[4-(1-hydroxyethyl)isoquinolin-3-yl][4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid (17.1 mg, 87%) as a white powder.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:29])[CH3:28])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[OH:8][C@@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 4-((4S,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (232.2 mg) in THF (6 mL) was added tetrabutylammonium fluoride-THF solution (2.0 mL, 1 mol/L), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3), and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 38.9 mg, 22.9%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(C(=O)c2csc(N3CC(O)C3)n2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (422 mg, 1.49 mmol) (obtained as described in Reference Example 30(2)) in methylene chloride (21 ml) were added methanesulfonyl chloride (0.14 ml, 1.79 mmol) and triethylamine (0.25 ml, 1.79 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:methanol (3:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (537 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 59 %

Procedure:
As described for example 116e, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (107 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropylamine, to the title compound (72 mg, 59%) which was obtained as a white solid. MS: m/e=410.1 [M+H]−.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)COc1ccc(-n2ncc(C(=O)O)c2N)cc1C#N
Yield: 43.7 %

Procedure:
To a solution (10 ml) of ethyl 5-amino-1-(3-cyano-4-isobutoxyphenyl)-pyrazole-4-carboxylate (1 g) in ethanol was added 5 N aqueous sodium hydroxide solution (1 ml) with string, and the mixture was refluxed under heating for 2 hours. After the completion of the reaction, the reaction mixture was poured into water, and the mixture was neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of dioxane and water to give 0.4 g of 5-amino-1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylic acid, melting point 204° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:3]([C:7]([NH2:9])=[O:8])=[CH:4][S:5][CH:6]=1.C([Sn]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])(CCCC)CCCC)CCC>>[CH3:26][Si:25]([C:24]#[C:23][C:2]1[C:3]([C:7]([NH2:9])=[O:8])=[CH:4][S:5][CH:6]=1)([CH3:28])[CH3:27]
Reactant: NC(=O)c1cscc1Br
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C[Si](C)(C)C#Cc1cscc1C(N)=O
Yield: 27.7 %

Procedure:
The product from step B (1 g), tributylstannyl(trimethylsilyl)acetylene (2.16 g) and palladium(tetrakis)triphenylphoshine (0.28 g) were placed into degassed toluene (20 ml) and the mixture was heated under reflux for 16 hours under an atmosphere of nitrogen. After cooling, the solvent was removed and the residue was chromatographed on silica gel (hexane:ethylacetate 3:1). After three consecutive crystallisations from hexane, 0.3 g of 4-(trimethylsilyl)ethinyl-3-thiophene formamide was obtained (m.p. 90-94° C.).
Reaction SMILES: N1C=CN=C1[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7].[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1.O.Cl>CN(C)C=O>[NH:26]1[C:25]([NH:24][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:22][C:15]4[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=4[CH2:13][C:12]=3[CH:23]=2)=[O:7])=[N:29][N:28]=[N:27]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2)c1ncc[nH]1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
Suspend 7-(imidazolylcarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (0.6 g.) in dry dimethylformamide (20 ml.). With stirring, add 5-aminotetrazole (0.61 g.) and warm the mixture to 65°-75° C. and keep at that temperature for about 3/4 hour. Allow the mixture to cool, pour into water and acidify with hydrochloric acid. Filter and wash with isopropanol and ether to yield 7-(5-tetrazolylaminocarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.CON(C)[C:17]([C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[N:24][N:25]([CH3:26])[C:21]=2[CH:20]=1)=[O:18]>O1CCCC1>[CH3:26][N:25]1[C:21]2[CH:20]=[C:19]([C:17](=[O:18])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=3)[CH:28]=[CH:27][C:22]=2[N:23]=[N:24]1
Reactant: CON(C)C(=O)c1ccc2nnn(C)c2c1
Reactant: Cc1cccc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3nnn(C)c3c2)n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of 2,6-dimethylpyridine (292 μl, 2.5 mmol) in 10 ml anhydrous tetrahydrofuran was cooled to −30° C. A 2.5M solution of n-butyllithium in hexanes (1.0 ml, 2.5 mmol) was slowly added dropwise. Once the addition was complete, the reaction was stirred at −30° C. for 1 hour. In a separate flask, a solution of 3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (500 mg, 2.27 mmol) in 3 ml anhydrous tetrahydrofuran was cooled to −30° C. The cold anion solution was slowly added dropwise to the cold amide solution. Once the addition was complete, the reaction was allowed to slowly warm to room temperature over several hours and stirred overnight. The reaction was quenched with water and the solvent removed by rotary evaporation. The residue was dissolved in saturated aqueous ammonium chloride and extracted three times with chloroform. The combined organics were washed once with water and then once with brine. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. Crude material was purified on Biotage Flash 40S silica gel column using hexanes/ethyl acetate gradient system (80:20 to 40:60, respectively) as eluent to afford 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone (320 mg, 53%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=2[CH:16]=1)(=[O:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH2:14][C:13]([C:11]1[O:12][C:8]2[C:7]([CH3:17])=[C:6]([CH3:18])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:16][C:9]=2[CH:10]=1)=[O:15]
Reactant: CC(=O)Oc1cc2cc(C(C)=O)oc2c(C)c1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
1-(5-Acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (83 mg) (prepared from 1-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone from Example 14 with acetanhydride and pyridine), was dissolved in chloroform (10 mL). Bromine (50 mg) was added and the solution was stirred at 70° C. for 10 min. When the color of bromine disapeared, the mixture was evaporated to dryness. The residue was purified by silica gel column eluting with 30% EtOAc in hexane to give 85 mg of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone as a white solid. 1H NMR (CDCl3, 300 MHz) δ: 7.58 (s, 1H), 7.26 (s, 1H), 4.43(s, 2H), 2.51, 2.37, 2.21(3 s, 9H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 182.55, 170.13, 153.71, 150.74, 146.81, 131.21, 124.51, 122.92, 115.15, 113.28, 30.69, 21.27, 13.54, 12.80 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1([CH3:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C:15]([CH3:25])([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1(C)Cc2ccccc2CN1
Product: CC1(C)Cc2ccccc2CN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=4[CH3:24])=[N:13][NH:12][C:11](=[O:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:31]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=4[CH3:24])=[N:13][NH:12][C:11](=[O:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1)(=[O:33])[CH3:32]
Reactant: Cc1c(-c2n[nH]c(=O)c3[nH]c4cc(Br)ccc4c23)cccc1[N+](=O)[O-]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 109 %

Procedure:
A mixture of 7-bromo-1-(2-methyl-3-nitrophenyl)-3H-pyridazino [4,5-b]indol-4(5H)-one (2.00 g, 5.01 mmol), tributyl(1-ethoxyvinyl)stannane (4.06 mL, 12.02 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.422 g, 0.601 mmol), and triethylamine (0.908 mL, 6.51 mmol) in 1,4-Dioxane (100 mL) was heated at 95° C. for 24 hr. Upon cooling to room temperature, the mixture was filtered through CELITE®. The filtrate was concentrated under vacuum to dryness. To the residue was added THF (100 mL) and 1 N HCl solution (100 mL), and the mixture was stirred at 60° C. for 1.5 hr. It was concentrated under vacuum to a volume of 100 mL, neutralized with 1 N NaOH solution to pH 4-5, and extracted with ethyl acetate (3×150 mL). The combined, cloudy organic solution was concentrated under vacuum to dryness. To the residue was added hexane (100 mL), and the mixture was stirred at room temperature for 1 hr. The clear solution was decanted and the residue was repeated with this operation for two more times. The solid material was collected by suction filtration to give a crude product (1.98 g, 5.46 mmol, >100% yield) as a beige solid.