Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)=[N+]=[N-].[C:13](O)(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].C1(N=C=NC2CCCCC2)CCCCC1>[Pd].C(OCC)(=O)C>[C:13]([NH:1][CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17]
Reactant: [N-]=[N+]=NCC1CN2C(=O)CC2O1
Reactant: C=CCCC(=O)O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C=CCCC(=O)NCC1CN2C(=O)CC2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
600 mg of (3RS,5RS)-3-Azidomethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one was hydrogenated with 1.0 g of 10% Palladium on activated carbon in Ethyl acetate at 50 psi for 1 hr. After removal of catalyst by filtration, 360 mg (3.6 mmol) of 4-Pentenoic acid and 300 mg (1.8 mmol) of 1,3-Dicyclohexyl carbodiimide were added under ice-cooling. The reaction mixture was then stirred at room temperature for 2 hrs. Resulted solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash silicagel column using Hexane-Ethyl acetate (1:1) as eluent and the title compound was obtained as oil.
Reaction SMILES: OS(O)(=O)=O.[OH:6][C:7]1[CH:22]=[CH:21][C:10]2[NH:11][C:12]([CH2:17][C:18]([OH:20])=[O:19])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[CH3:23][CH2:24]O>>[CH2:23]([O:19][C:18](=[O:20])[CH2:17][C:12]1[NH:11][C:10]2[CH:21]=[CH:22][C:7]([OH:6])=[CH:8][C:9]=2[S:14](=[O:16])(=[O:15])[N:13]=1)[CH3:24]
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Temperature: 80 °C

Procedure:
EtOH (15 mL) and 150 μL of H2SO4 (conc.) were added into the compound 10c (5.03 mmol) and the mixture was heated to 80° C. for 45 minutes with stirring. The solvent was partially evaporated to half of the original volume under reduced pressure. EtOAc (30 mL) was added and the resulted mixture was washed with H2O (15 mL×3) via extraction. The aqueous layer was back extracted with EtOAc once (60 mL) and the combined organic layer was dried over anhydrous MgSO4, filtered, concentrated to give the desired product (4b) (1.11 g) as a gray solid. This crude material was directly used in next step without further purification. LC-MS: (ESI+) m/e=285.10 [M+1]+ (exact ms: 284.05).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>CN(C)C=O>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:14]4[N:18]=[C:17]([CH2:19][O:20][C:21]5[CH:34]=[CH:33][C:24]([CH2:25][CH:26]6[S:30][C:29](=[O:31])[NH:28][C:27]6=[O:32])=[CH:23][CH:22]=5)[N:16]([CH3:35])[C:15]=4[CH:36]=3)=[CH:4][CH:3]=2)=[O:46])=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(NC(=O)Nc4ccc(Cl)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a mixture of 5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) and N,N-dimethylformamide (10 ml) was added 4-chlorophenyl isocyanate (0.15 g) and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added diethyl ether. The precipitate was isolated by filtration and recrystallized from a mixture of tetrahydrofuran and ethyl acetate to afford the title compound (0.37 g, mp 157-162° C.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH2:26]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: COB(OC)OC
Solvent: CC#N
Solvent: O
Product: COc1c(N2C=CN=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.86 g of anhydrous piperazine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.46 g of the objective compound.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:17]=[C:16]3[O:18]C[O:20][C:15]3=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccccc2)oc2cc3c(cc12)OCO3
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)oc2cc(O)c(O)cc12
Temperature: -25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A solution of 2-benzyl-3-methyl-5,6-methylenedioxybenzofuran (226 mg, 0.85 mmole) in methylene chloride (10 mL) was cooled at -65° C. and a 1M solution of boron tribromide in methylene chloride (0.85 mL) was added dropwise. The mixture was allowed to warm up to -25° C. and was kept in that range for 1 hour. Methanol (5 mL) was then added and the mixture was evaporated in vacuo. The residue was chromatographed on silica gel and eluted with 25% ethylacetate in hexane to yield 128 mg of 2-benzyl-3-methyl-5,6-dihydroxybenzofuran, mp. 95.5°-98° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[C:17]([Zn+])([CH3:20])([CH3:19])[CH3:18].C1COCC1>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:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: CC(C)(C)[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccc(C(C)(C)C)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 50 mg (0.043 mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M t-butylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 5% to 50% EtOAc/Hexanes) gave 2-tert-butyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001109555). LC-MS calculated for C15H16N2S 256, observed m/e 257.0 (M+H)+. 1H-NMR (500MHz, CDCl3) δ 8.74 (s, 1H), 7.76 (d, 1H), 7.45 (s, 1H), 7.12 (d, 1H), 2.77 (s, 3H), 2.12 (m, 1H), 0.97 (d, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12](N(CC)CC)C.CI>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(CC)CC
Solvent: CI
Solvent: C1CCOC1
Product: CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-amino-ethyl)-carbamic acid-tert-butyl ester (5 g) and triethylamine (6.5 ml) in tetrahydrofuran (1000 ml) at 0° C. was added methyliodide (1.94 ml) dropwise over a period of 1 hour. The mixture was allowed to warm to ambient temperature and stirred for 72 hours before removal of solvents by evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and solvent removed by evaporation to give the title compound (3.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.COC(C)(C)C.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.[Cu]I>[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COc1nn(C)c(=O)n1Cc1cc(C#CC[Si](C)(C)C)ccc1C
Temperature: 80 °C
Reaction time: 9 h
Yield: 34 %

Procedure:
A mixture of 624 mg (2.0 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention), 700 mg (6.3 mmol) of 3-(trimethylsilyl)-1-propyne, 63 mg (0.095 mmol) of PdCl2(PPh3)2, 32 mg (0.17 mmol) of copper (I) iodide, 104 mg (0.40 mmol) of triphenylphosphine and 1.0 g of triethylamine in 6 ml of acetonitrile was stirred at 80° C. under an atmosphere of nitrogen for 9 hours. After cooling to room temperature, the reaction mixture was diluted with tert-butyl methyl ether, washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with hexane:ethyl acetate=2:1) to obtain 0.30 g (0.68 mmol) of 4-{5-(3-trimethylsilyl-1-propynyl)-2-methylbenzyl}-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 527 of the present invention).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])ccc(OCC2CC2)c1Cl
Temperature: 100 °C
Yield: 93.4 %

Procedure:
2-Chloro-3-methyl-4-nitrophenol (2.71 g) was reacted with bromomethylcyclopropane (3.89 g) in dry DMF (30 ml) in the presence of potassium carbonate (3.99 g), heating the mixture at 100° C. overnight. The DMF was evaporated in vacuo, and the residue was partitioned between 2M HCl and ethyl acetate. The organic extracts were combined and dried (MgSO4) and evaporated to give 2-chloro-3-cyclopropylmethyloxy-6-nitro toluene (3.26 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:18])=[CH:14][C:15]=2[CH3:17])[C:10]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:18][S:36]([C:30]3[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])=[CH:14][C:15]=2[CH3:17])[C:10]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(Cc3ccccc3)c12
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2c(F)cccc2F)cc2c(C3CCN(C)CC3)cn(Cc3ccccc3)c12
Yield: 44.5 %

Procedure:
By a method similar to Example 56, using 1-benzyl-7-methyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indole (1.81 mmol, 0.604 g) in THF (4.5 mL), sodium hydride (2.17 mmol, 0.087 g, 60% dispersion in mineral oil), and 2,6-diflurobenzenesulfonyl chloride (1.99 mmol, 0.422 g) afforded 0.411 g (45%) of the title compound: mp=158° C.; mass spectrum (ion spray): m/z=511 (M+1); 1H NMR (DMSOd6): 7.96-7.86 (m, 1H), 7.41 (dd, J=5.73, 3.48 Hz, 2H), 7.31-7.19 (m, 4H), 6.94 (d, J=2.20 Hz, 1H), 6.82 (d, J=6.59 Hz, 2H), 6.62 (d, J=1.87 Hz, 1H), 5.55 (s, 2H), 2.81-2.77 (m, 2H), 2.56-2.42 (m, 1H), 2.36 (s, 3H), 2.20 (s, 3H), 1.96 (m, 2H), 1.72-1.67 (m, 2H), 1.53 (m, 2H); Calculated for C28H28F2N2O3S-0.3H2O: C, 65.17; H, 5.59; N, 5.43. Found: C, 65.27; H, 5.47; N, 5.49.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[CH2:7])CCC.O.[Br:35]N1C(=O)CCC1=O>O1CCCC1>[Br:35][CH2:5][C:6]([C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7]
Reactant: C=C(OCCCC)c1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2c(c(C(=O)CBr)cn2COCC[Si](C)(C)C)c1=O
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To 8.80 g (17.8 mmol) of 3-(1-butoxyvinyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(a) were added 21.1 ml of water and 341 ml of tetrahydrofuran, and 100 ml of tetrahydrofuran solution containing 4.70 g (26.4 mmol) of N-bromosuccinimide was added dropwise to the mixture under cooling in ice-bath. After the dropwise addition, the mixture was stirred at the same temperature 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 6.64 g of the title compound as a white solid. (Yield: 72%)
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[CH3:26][NH2:27].[BH4-].[Na+].[ClH:30].C(=O)([O-])O.[Na+]>CO>[ClH:30].[F:1][C:2]1[C:3]([CH2:22][NH:27][CH3:26])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1F
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1F
Reaction time: 0.5 h
Yield: 9 %

Procedure:
4-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (10 mg) was dissolved in methanol (5 mL), 40% methylamine methanol solution (236 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (12 mg) was added at room temperature, and the 5 mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 1 mg, 9%).
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.B(Br)(Br)Br>ClCCl.O>[OH:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 5-methoxy-4-nitroindole (110 mg, 0.57 mmol) in dichloromethane (12 ml) was cooled to −30° C. under an atmosphere of nitrogen. Boron tribromide (0.74 ml of a 1M solution in dichloromethane, 0.74 mmol) was added dropwise then the mixture warmed to ambient temperature and stirred for 1 hour. The mixture was cooled to 5° C., diluted with dichloromethane (5 ml), and water (10 ml). After stirring for 5 minutes the insoluble material was filtered off and the dichloromethane layer separated, dried (MgSO4), and evaporated to give a dark oil which was and purified by silica column chromatography eluting with dichloromethane to give 5-hydroxy-4-nitroindole (68 mg, 67%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].[CH3:8][N:9]1[CH:13]=[C:12]([CH:14]=O)[C:11]([C:16]2[O:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[N:10]1.C(O)(=O)C.O>C(O)C>[CH2:6]([O:5][C:1]([NH:2][N:3]=[CH:14][C:12]1[C:11]([C:16]2[O:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[N:10][N:9]([CH3:8])[CH:13]=1)=[O:4])[CH3:7]
Reactant: Cn1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1cn(C)nc1-c1ccc([N+](=O)[O-])o1
Yield: 97 %

Procedure:
Add a solution of 19.5 g of ethyl carbazate in 250 ml of ethanol dropwise to 35 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde and 1 ml of glacial acetic acid in 400 ml of ethanol. Stir the resulting reaction mixture for 80 minutes at from 35° to 40° C, and add 650 ml of water dropwise to the thus-obtained suspension at room temperature. Cool in an ice bath and separate the produced precipitate by vacuum filtration. Wash the residue with ethanol/water (1:1) and with water to obtain a 97% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 217.5° to 219° C (with decomposition)].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:14][CH3:15])[C:5]=2[N:6]=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[S:3][C:4]3[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:14][CH3:15])[C:5]=3[N:6]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)O)c2sc(N)nc12
Product: COc1ccc(C(=O)O)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole-7-carboxylic acid methyll ester and 4-fluoro-benzoyl chloride the title compound was obtained as a white solid (91% yield), MS: m/e=361.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[N:3]=1
Reactant: Clc1n[nH]c2ccccc12
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cn1nc(Cl)c2ccccc21)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Chloro-1H-indazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3); 7.64-7.70 (m, 1H), 7.38-7.48 (m, 2H), 7.18-7.26 (m, 2H), 6.94-7.0 (m, 2H), 6.82-6.88 (dd, 2H), 5.2 (s, 2H), 3.72-3.82 (m, 4H), 3.02-3.08 (m, 4H). 13C NMR (400 MHz, CDCl3): 165, 158.2, 142.8, 134.8, 128.8, 128.4, 122, 121.6, 118.8, 118.6, 115.4, 115.2, 110.6, 110.0, 51.8, 50.6, 50.2, 45.2, 42.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:18][CH2:19][CH3:20])=[C:8]2[C:14]([CH3:15])=[N:13][N:12]([CH2:16][CH3:17])[C:9]2=[N:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:19]([O:18][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:16][CH3:17])[N:13]=[C:14]([CH3:15])[C:8]=12)[CH3:20]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2CC)c1OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOc1c(CO)cnc2c1c(C)nn2CC
Yield: 82 %

Procedure:
By treating the 4-ethoxy-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (prepared by combining the procedures of Examples 2b and 3a, m.p. 93°-94°) with lithium aluminium hydride as in Example 3b, 4-ethoxy-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-methanol is obtained. Yield 82%, m.p. 85°-86°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])(C)C)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.N1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[OH-].[Na+].ClC(OCC1C=CC=CC=1)=O>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:23]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Reactant: C1CCNCC1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 188 mg (0.56 mmol) of 4-(3-(4-fluorophenyl)-3-oxo-propyl)-1-(t-butoxycarbonyl) piperidine (from EXAMPLE 189, Step A) in 5 mL of CH2Cl2 at 0° C. was treated with 3 mL of TFA and the resulting mixture was stirred cold for 30 min. The solution was concentrated. A solution of the crude piperidine in 5 mL THF/5 mL of 1.0 N NaOH at 0° C. was treated with 0.09 mL (0.63 mmol) of benzyl chloroformate and the resulting mixture was stirred cold for 30 min. The reaction mixture was partitioned between 50 mL of ether and 10 mL of H2O and the layers were separated. The organic layer was washed with 10 mL of sat'd NaCl, dried and concentrated. Flash chromatography on 10 g of silica gel using 2:1 v/v hexanes/ether as the eluant afforded 196 mg (95%) of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.10-1.20 (m, 21), 1.43-1.53 (m, 1H), 1.60-1.71 (4H), 2.72-2.82 (m, 2H), 2.97 (t, J=7.5, 21), 4.154.21 (m, 2H), 5.12 (s, 2H), 7.11-7.15 (m, 2H), 7.26-7.36 (5H), 7.96-8.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:20][C:21]2[CH:22]=[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]5[CH2:38][CH2:39]5)=[O:36])[N:33]=4)[CH:30]=3)[CH:40]=[CH:41][C:42]=2[CH3:43])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1nn(C)cc1Cl
Yield: 71.7 %

Procedure:
In the same manner as in Example 55 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (83.0 mg, 0.519 mmol), tetrahydrofuran (5 mL), thionyl chloride (89.0 μL, 1.02 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.464 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (155 mg, 72%) was obtained as a white solid.