Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([CH:24]=O)[C:21]([O-])=[O:22])[CH:15]=[N:16][C:17]=1[CH3:18]>CO>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]2[C:21](=[O:22])[NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[N:7][CH:24]=2)[CH:15]=[N:16][C:17]=1[CH3:18]
Reactant: Cc1cc(CC(C=O)C(=O)[O-])cnc1C
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C

Procedure:
Nitroguanidine (6.05 g) was added to a solution of sodium methoxide (prepared from 1.45 g sodium) in dry methanol (65 ml) and the mixture was boiled under reflux for 0.75 hours. 3-(5,6-Dimethyl-3-pyridyl)-2-formylpropionate (14.3 g) was added and the mixture was boiled under reflux for 40 hours and evaporated to dryness. Water (40 ml) was added to the residue and the mixture was extracted with chloroform (discarded). The aqueous phase was adjusted to pH 6 with hydrochloric acid and the solid which separated out was filtered off and recrystallised from dimethylformamide-ethanol to give 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone m.p. 212°-213°.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=[CH:4]1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[O:19])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCCn1ccnc1
Agent: Cl
Product: O=C(NCCCCn1ccnc1)c1ccco1

Procedure:
A portion of 1H-imidazole-1-butanamine dihydrochloride was then reacted with furoyl chloride as described in Example 1, giving the desired product, m.p. 88°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=1
Reactant: BrCC1CC1
Reactant: Cc1cc(Br)c[nH]c1=O
Product: Cc1cc(Br)cn(CC2CC2)c1=O

Procedure:
5-bromo-3-methyl-1H-pyridin-2-one was N-alkylated with bromomethylcyclopropane to give 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one. 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one (100 mg, 0.41 mmol), [2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid (217 mg, 0.5 mol), K3PO4 (263 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 41.3 umol) in dioxane (8 mL)/water (1 mL) were purged with N2 and heated at 70-80° C. for 12 h. Preparative HPLC gave the title compound (56.0 mg, 28.6% yield) as dull-red semisolid. 1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.61 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.10-7.15 (m, 1H), 6.92-7.00 (m, 2H), 6.82-6.89 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.71 (br. s., 1H), 3.93 (d, J=7.2 Hz, 3H), 3.12-3.21 (m, 2H), 2.24 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.22-1.33 (m, 1H), 0.57-0.67 (m, 2H), 0.36-0.43 (m, 2H). LCMS: 475.1 (M+1)+
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[CH2:8]([O:10][C:11]([C@H:13]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH3:9]>CCOCC>[ClH:7].[CH2:8]([O:10][C:11]([C@H:13]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 8 h

Procedure:
A mixture of 5 ml of 5N hydrogen chloride-ethyl acetate solution and 0.5 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 1 is allowed to stand at room temperature overnight. Twenty ml of ether and 100 ml of petroleum ether are added to the mixture to deposit colorless powder, which is collected by filtration to give 0.42 g of 3(R)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].CO>ClCCl>[C:24]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2cccc3ccccc23)co1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2cccc3ccccc23)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/salt bath) mixture of 2-amino-4-(naphth-1-yl)oxazole (1)(0.5 g) and triethylamine (0.8 ml) in anhydrous dichloromethane (5 ml) was added dropwise acetyl chloride (0.2 ml) over a minute. The resulting mixture was warmed to room temperature and left overnight. Further acetyl chloride (0.1 ml) was added and the mixture left for a further hour. Dichloromethane (40 ml) and few drops of methanol were added. The mixture was washed twice with brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (9) (0.35 g; m.p. 188-190° C.) was obtained following silica gel column chromatography of the residue in 2% methanol in chloroform.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1cnn2Cc1ccccc1
Reaction time: 2 h
Yield: 61.4 %

Procedure:
1-Benzyl-4-nitro-1H-indazole (672 mg, 2.65 mmol) was taken up in 26 mL of EtOH/water (4:1) and treated with NH4Cl (0.5 equivalents) and Fe powder (10 equivalents). The reaction was heated to reflux for 2 hours. The reaction was concentrated under reduced pressure, diluted with EtOAc:Et3N (4:1) and stirred for two hours. The reaction mixture was filtered over GF/F paper and concentrated to give a brown, viscous oil. This crude material was purified by column chromatography (30% EtOAc/hexanes) providing 363 mg (61%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][N:5]2[N:4]=1.[O:21]1CCCC1.OO.[OH-].[Na+].O>>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([OH:21])[CH:10]=[CH:11][N:5]2[N:4]=1
Reactant: C1CCOC1
Reactant: CSc1ncc2c(B3OC(C)(C)C(C)(C)O3)ccn2n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc2c(O)ccn2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazine (1.80 g, 6.18 mmol), Tetrahydrofuran (100 mL, 1000 mmol), and 50% aq. Hydrogen peroxide (1:1, Hydrogen peroxide:Water, 6.00 mL, 97.9 mmol) were added and stirred at room temperature for 2 hours. 19.10 M of Sodium hydroxide in Water (6.00 mL, 115 mmol) was added at 0° C. Vigorous gas evolution was observed for 15 minutes. The reaction was quenched with saturated sodium thiosulfate (100 mL). The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (0 to 100% EtOAc). The collected fractions afforded 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ol a yellow solid (1.00 g, 89%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[NH:17][C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)C.[OH-].[Na+]>C(O)C.O>[C:27]1([C:18]2[N:17]=[C:16]([S:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])[NH:20][C:19]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)CCCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 69.2 %

Procedure:
To a solution of 6.0 g (0.013 mole) 11-(4,5-diphenyl-1H-imidazole-2-ylthio)undecanoic acid ethyl ester in 150 ml ethanol was added, dropwise, a solution of 6.0 g sodium hydroxide in 150 ml water. The reaction mixture was stirred at reflux under nitrogen for 3 hours. The solvent was concentrated to half the volume and the remaining solution was extracted with diethyl ether. This organic layer was discarded. The aqueous layer was acidified to pH=1.0 using 1N hydrochloric acid and then extracted with diethyl ether. The organic layer was dried over magnesium sulfate and the solvent removed under vacuum. The resulting solid was recrystallized from methanol and triturated with diethyl ether to give 4.10 g (0.009 mole) of the title compound as a white solid, mp=193°-195° C. 1HNMR(DMSO-d6): δ12.6(s,1H), 7.6-7.1(m,10H), 3.6(t,2H,J=7Hz), 2.3(t,2H,J=7Hz), 1.8-1.1(m,17H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:43]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=1)[CH3:44])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH:43]([C:45]4[CH:54]=[CH:53][C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:46]=4)[CH3:44])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(OS(C)(=O)=O)c1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC(C)c3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-hydroxy-indol-2-yl]-2,2-dimethylpropanoate (EP 419,049, Example 1, Step C) (460 mg) in acetonitrile (5 mL) was added solid cesium carbonate (652 mg). To this mixture was added a solution of mesylate from Step B (326 mg) in acetonitrile (3 mL) and stirred at 70° C. for 1 hr. The reaction mixture was poured into 25% NH4OAc (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), and dried (MgSO4). The solution was evaporated to dryness and the residue was chromatographed on flash silica gel using ethyl acetate:hexane (1:4) as eluant to give the title compound identical to the one obtained from Method 1, Step A.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([OH:40])=O)=[C:32]2[S:41]([C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[CH:45]=1)(=[O:43])=[O:42].[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([N:56]1[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]1)=[O:40])=[C:32]2[S:41]([C:44]1[CH:45]=[C:46]([CH3:51])[CH:47]=[C:48]([CH3:50])[CH:49]=1)(=[O:42])=[O:43]
Reactant: Cc1cc(C)cc(S(=O)(=O)c2c(C(=O)O)[nH]c3ccc(Cl)cc23)c1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(S(=O)(=O)c2c(C(=O)N3CCN(C)CC3)[nH]c3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (1.22 g, 0.00275 g) was added to a solution of 5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indole-2-carboxylic acid (12) (1.00 g, 0.00275 mol), N-methylpiperazine (0.55 g, 0.0055 mol), triethylamine (0.55 g, 0.0055 mol) in anhydrous DMF (50 mL). Reaction was stirred at room temperature for 72 hours, then diluted with water and extracted with ethyl acetate. Organic extracts were washed with brine, dried and the solvent evaporated to give 1.20 g (98%) of pure title compound, mp 281-283° C. (from aqueous ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH:16]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:17]3[CH2:19][CH2:18]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].I[CH2:29][CH3:30]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH:16]([N:20]([CH2:29][CH3:30])[S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:17]3[CH2:19][CH2:18]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1)S(=O)(=O)CC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 40 mL scintillation vial was charged with ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-amide (0.075 g, 0.200 mmol) and DMF (3 mL). The reaction mixture was cooled to 0° C. and sodium hydride (0.012 g, 0.299 mmol) was added. The reaction was left to stir at room temperature for 20 min followed by the addition of iodoethane (0.050 g, 0.319 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with water (0.5 mL) and filtered. The filtrate was dissolved in DMF (3 mL) and purified using Xbridge C18 eluting with a 10 to 100% ACN-water to afford pure product ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethyl-amide as a white color solid. HRMS: (ESI) m/z 404.1190 [(M+H)+ Calcd for C20H22ClN3O2S 404.1199]. 1H NMR (400 MHz, MeOD) δ ppm 0.52-0.68 (m, 1H), 0.71-0.82 (m, 1H), 0.91-1.05 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.43 (t, J=7.5 Hz, 3H), 1.60-1.88 (m, 1H), 3.28 (q, J=7.3 Hz, 2H), 3.39-3.51 (m, 1H), 3.55-3.66 (m, 1H), 4.32 (d, J=10.6 Hz, 1H), 7.93 (dd, J=8.1, 1.8 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 8.87 (s, 1H), 9.04 (d, J=1.8 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:24])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([CH:22]=O)[N:21]=2)[CH2:7]1.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].N1CCCCC1.Cl>N1C=CC=CC=1.O>[C:31](/[CH:30]=[CH:22]/[C:20]1[N:21]=[C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:24])[S:18][CH:19]=1)([OH:33])=[O:32]
Reactant: O=Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
The resultant product (643 mg) of (70-2) was dissolved in pyridine (5 mL), malonic acid (291 mg) and piperidine (14 μL) were added, and the mixture was stirred at 100° C. for 3.5 hrs. The reaction mixture was poured into water, 1M hydrochloric acid was added to adjust to pH=4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (618 mg) as a white amorphous solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH2:21][CH2:22][CH3:23].[OH-].[Na+]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:21][CH2:22][CH3:23])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCCI
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCn1ncc2c(C(=O)O)cc(C3CC3)nc21

Procedure:
The title compound was prepared as in the same manner as described for intermediate 43 using ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol), sodium hydride (29.1 mg, 1.211 mmol), DMF (10 mL), 1-iodopropane (162 mg, 0.951 mmol), and NaOH (1 mL). The crude product was purified by silica gel chromatography (eluent: 0 to 10% MeOH:DCM) to afford the final product as a solid, 90 mg (42%). Regiochemical assignment supported by 2D HNMR. LCMS E-S (M+H)=246.0 1H NMR (400 MHz, DMSO-d6) δ ppm 13.83 (br s, 1H), 8.24 (s, 1H), 7.62 (s, 1H), 4.26 (t, 2H, J=7.2 Hz), 2.37-2.40 (m, 2H), 1.83-1.89 (m, 2H), 1.07-1.11 (m, 4H), 0.77 (t, 3H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.CN(C)C=O.[F:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][F:20])=[CH:31][CH:30]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(C)(C)CO)cc1
Reactant: FCCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)(C)COCc2ccc(OCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
Sodium hydride (0.9 g; 60% in oil) was added to 20 ml of toluene, and with heating, a solution of 2.5 g of 2-(4-methylphenyl)-2-methylpropyl alcohol in 10 ml of a mixture of 25% dimethylformamide and toluene was added dropwise over the course of 15 minutes. The mixture was stirred for 10 minutes, and then a solution of 2.9 g of 4-(2-fluoroethoxy)benzyl chloride in 10 ml of toluene was added dropwise over the course of 20 minutes. The mixture was further heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and then extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (100 g) column chromatography (developing solvent: a 2:1 mixture of toluene and n-hexane) to give 3.3 g of the desired 4-(2-fluoroethoxy)benzyl 2-(4-methylphenyl)-2-methylpropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([C:13]([OH:15])=O)[CH2:12][CH2:11]1.C(Cl)(=O)C(Cl)=O.[Br-].O[C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([C:13]2[O:15][C:24]3[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=3[CH:26]=2)[CH2:11][CH2:12]1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Br)c(C2(C(=O)O)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C2(c3cc4ccccc4o3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To the DCM solution (6 ml) of 1-(2-bromo-5-methoxy-phenyl)-cyclopropane carboxylic acid (0.3 g, 1.1 mmol), DMF (2 drops) and oxalyl chloride (0.23 ml, 2.5 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hrs. The residues obtained from the reaction solution after concentration under reduced pressure were dissolved in toluene (6 ml), added with (2-hydroxybenzyl)triphenylphosphonium bromide (0.605 g, 1.32 mmol) and TEA (0.46 ml, 3.3 mmol), and the resulting mixture was stirred and heated at 100° C. overnight. The residues obtained after concentration under reduced pressure were purified by silica gel column (hexane:DCM) to obtain the title compound (0.309 g, 81%).
Reaction SMILES: [Cl-].[NH4+].[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[N:18]=[C:17]([C:29]([F:32])([F:31])[F:30])[CH:16]=2)=[CH:11][CH:10]=1)(=[O:5])[CH3:4]>O.CCO.[Fe]>[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:29]([F:31])([F:30])[F:32])[CH:16]=2)=[CH:13][CH:14]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(N)cc2)cc1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a solution of ammonium chloride 58.8 mg in H2O 0.5 ml was added iron powder 368 mg and EtOH 2 ml. The reaction mixture was warmed in oil bath, and a solution of 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 460.7 mg in EtOH 3 ml was added. After being refluxed for 3 hours, the reaction mixture was cooled to ambient temperature and unsoluble matter was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in AcOEt, and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from IPE to give 2-{4-[1-(4-aminophenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 182.3 mg as a powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O1CCOCC1.O.CCCCC>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCCCC
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a room temperature solution of 1 g (6.8 mmol) of trans-2-amino-1-cyclohexylcarboxylic acid in 50 ml of dioxane: H2O (1:1) containing 1.7 ml (12.2 mmol) of triethylamine was added 1.54 g (7.46 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was stirred at 25° C. for 18 h. The resulting mixture was diluted with pentane to afford 1.119 g (51%) of the desired sulfonamide product as a white solid. 1H NMR(DMSO-d6): 7.7 ppm (dd, 2H, Ar), 7.4 ppm (d, 1H, NH), 7.0 ppm (dd, 2H, Ar), 3.8 ppm (s, 3H, OMe), 3.5 ppm (m, 1H, N—CH), 1.0-1.7 ppm (m, 9H, hydrocarbon).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:21]=1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(C)cc(C)n3)CC2)cc1
Yield: 45.3 %

Procedure:
A solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.7 g) obtained in Example 88(2), 2-chloro-4,6-dimethylpyrimidine (1.0 g) and potassium carbonate (3.0 g) in acetonitrile (50 ml) was refluxed under heating for 7 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil. The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) and crystallized from diisopropyl ether and recrystallized from ethyl acetate-hexane to give the title compound (1.1 g) as white crystals.