Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:17][N:18]1[C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]([CH3:26])=[N:19]1>O1CCCC1.O>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:23]([C:22]2[N:18]([CH3:17])[N:19]=[C:20]([CH3:26])[CH:21]=2)=[O:24])[CH:3]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(O)cc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(O)ccc2C)n(C)n1
Yield: 63.3 %

Procedure:
To a solution of 3-amino-4-methylphenol (3.71 g, 30.1 mmol) and triethylamine (4.38 mL, 31.6 mmol) in tetrahydrofuran (30 mL) was added dropwise with stirring under ice-cooling a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (5.02 g, 31.6 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (4.67 g, 63%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[Na+]>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:19][CH:20]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C1CSC(=O)N1
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 155 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1.5 g (4.7 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate, 0.68 g (5.8 mmole) 2,4-thiazolidinedione and 0.96 g (11.8 mmole) sodium acetate were mixed and heated under vacuum to 155° C. The reaction mixture melted and was removed from the heat after 15 minutes. Water/acetone (2:1) was added and the mixture was stirred for 1 h. Filtration gave 1.67 g (yield 83%) of 5-(4-[2-(4-methanesulfonyloxyphenyl)-ethoxy]benzylidene)thiazolidine-2,4-dione as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32](O)=[O:33])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32](=[O:33])[NH:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:13]([Cl:19])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (800 mg), (R) —N-Boc-2-pyrrolidinecarboxylic acid (608 mg) and HBTU (1.46 g) in dry DMF (30 ml) containing N-methylmorpholine (1.26 ml) was stirred at room temp for 18 h. Silica gel (5 g) was then added and the mixture evaporated. The residue was purified by chromatography. Elution with 12:1 petrol:ethyl acetate gave a viscous brown gum (987 mg)
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][O:9]1.CO.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>[Fe].O>[F:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][O:9]1
Reactant: O=[N+]([O-])c1ccc(NCCCC2CCCO2)c(F)c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Nc1ccc(NCCCC2CCCO2)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 2-fluoro-4-nitro-N-(3-(tetrahydrofuran-2-yl)propyl)aniline (480 mg, 1.79 mmol), MeOH (40 mL), water (20 mL), iron powder (504 mg, 9.03 mmol) and NH4Cl (193 mg, 3.61 mmol) was stirred at 60° C. overnight. The mixture was then cooled to rt and saturated NaHCO3 aqueous solution was added. The resulting mixture was filtered and the filtrate was extracted with DCM (30 mL×4). The combined organic layers were washed with brine (40 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as red liquid (260 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)[N:3]=1.[C-:19]#[N:20].[K+].C([Sn](Cl)(CCCC)CCCC)CCC>C(#N)C.CCCCCCC.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[N:9]=[C:8]([C:4]3[N:3]=[C:2]([C:19]#[N:20])[CH:7]=[CH:6][CH:5]=3)[O:12][N:11]=2)[CH:14]=1
Reactant: Brc1cccc(-c2nc(-c3cccnc3)no2)n1
Reactant: [C-]#N
Agent: [Fe+2]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC#N
Product: N#Cc1cccc(-c2nc(-c3cccnc3)no2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-6-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)-pyridine (250 mg, 0.83 mmol) and 80 mg of potassium cyanide (1.24 mmol) in 15 ml of acetonitrile was degassed three times (vacuum/nitrogene), added a solution of 24 μl Tributyltin chloride (1 μmol) in heptane, 2.3 mg of bis-(diphenylphosphino)ferrocene (4.1 μmol) and 4 mg of bispalladium tris(dibenzylidene acetone) (4.1 μmol) were added. The suspension was degassed three times and stirred at ambident temperature for 30 minutes. The mixture was degassed again and heated at 80° C. for 17 hours. The reaction mixture concentrated, residue was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulphate, concentrated, and purified by column chromatography over silica gel using 20% ethyl acetate in petroleum ether, Yield 80 mg. Mp 201-203° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(=O)CC>[Cl:23][CH2:22][CH2:21][CH2:20][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(O)cc1)C1CC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCCl)cc1)C1CC1
Temperature: 25 °C
Yield: 90 %

Procedure:
The product from Example 151A (10 g, 61.7 mmol), K2CO3 (12.7 g, 91.9 mmol), and 1-bromo-3-chloropropane (10.74 g, 68.2 mmol) in 2-butanone (100 mL) was refluxed for 24 hours, cooled to ambient temperature, filtered, and concentrated. The filtrate was heated at 40° C. under reduced pressure for 3 hours to provide the title compound (13.256 g, 90% yield) of sufficient purity for subsequent use without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4]1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>S(=O)(=O)(O)O.C(OCC)C>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: COC(=O)c1ccc2c(c1)CCC(CO)C2
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)CCC(COC1CCCCO1)C2
Reaction time: 1 h
Yield: 99.3 %

Procedure:
10.0 g of methyl 6-hydroxymethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was added to 3.82 g of 2,3-dihydropyrane. After further adding 5 drops of concentrated sulfuric acid, the resulting mixture was stirred for 1 hour. To this were further added 1.00 g of 2,3-dihydropyrane and 3 drops of concentrated sulfuric acid, followed by stirring for 5 hours. The resulting reaction mixture was mixed with 100 ml of diethyl ether, and the mixture was washed with saturated sodium bicarbonate aqueous solution, water and saturated sodium chloride aqueous solution in that order, followed by drying. By distilling off the solvent, 13.72 g of methyl 6-[(2-tetrahydropyranyl)oxymethyl]-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was obtained in the form of yellow oil.
Reaction SMILES: Cl.[Sn].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=[O:21])[CH:16]=3)[C:11]2=O)=[CH:7][CH:6]=1.[C:26](O)(=O)C>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([O:22][CH3:26])=[O:21])[CH:16]=3)[CH2:11]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CN2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Reactant: CC(=O)O
Agent: Cl
Agent: [Sn]
Product: COC(=O)c1ccc2c(c1)C(=O)N(Cc1ccc(OC)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Concentrated hydrochloric acid (30 ml) and a tin powder (3.2 g) were added to a suspension of 2-(4-methoxybenzyl)-1,3-dioxoisoindoline-5-carboxylic acid (3.13 g) in acetic acid (30 ml), followed by stirring at room temperature for 12 hours, and a tin powder (1.2 g) was further added thereto, followed by stirring at room temperature for one day. An insoluble substance was filtered with celite, water was added to the filtrate, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was made into a DMF (50 ml) solution, potassium carbonate (7.0 g) and iodomethane (6.3 ml) were added thereto, followed by stirring at room temperature for 4.5 days. The reaction solution was concentrated and ethyl acetate was added to the residue, followed by washing with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain methyl 2-(4-methoxybenzyl)-3-oxoisoindoline-5-carboxylate (910 mg) as a colorless solid.
Reaction SMILES: [C:1]12([C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][C:4]([C:9]([O:11][CH3:12])=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[K+]>CO.O>[CH3:12][O:11][C:9]([C:4]12[CH2:7][CH2:8][C:1]([C:13]([OH:15])=[O:14])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:10]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Yield: 56 %

Procedure:
A solution of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (58.0 g, 0.25 mol) in methanol (600 mL) was heated to reflux and then a solution of potassium hydroxide (9.8 g, 0.175 mol) in methanol (100 mL) and water (12 mL) was added over 30 min. The reaction mixture was refluxed for 24 h and concentrated. The residue was diluted with water and extracted with ethyl acetate (200 mL×2) to recover some starting material (22.0 g). The resulting aqueous layer was acidified to pH=3 by addition of hydrochloric acid and extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the titled product (30.0 g, 0.14 mol, yield 55%). 1H NMR (400 MHz, CDCl3) δ ppm 3.65 (s, 3H), 1.81 (s. 12H); MS (ESI) m/z=211.3 [M+H]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=1.[NH2:18][NH2:19]>O1CCOCC1>[NH:18]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=1)[NH2:19]
Reactant: OCCCc1cc(Cl)cc(N2CCOCC2)n1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1cc(CCCO)nc(N2CCOCC2)c1
Yield: 87.6 %

Procedure:
3-(4-Chloro-6-morpholin-4-yl-pyrid-2-yl)-propan-1-ol (19.4 mmol) is dissolved in dioxane (30 mL). To the reaction mixture is added anhydrous hydrazine (10 mL, 300 mmol). The reaction is then heated at reflux for five hours. The solvent is removed under reduced pressure, and the crude solid is dissolved in a mixture of dichloromethane (800 mL) and 10% potassium carbonate (40 mL). The organic layer is isolated, dried with sodium sulfate, and evaporated to yield crude 3-(4-hydrazino-6-morpholin-4-yl-pyrid-2-yl)-propan-1-ol (4.3 g., 17 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)Nc2ccc(F)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and 4-fluoroaniline: MS (APCI) m/z 392 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[S:4][N:3]=1.[P:9](Cl)([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[S:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:11][P:9]([O:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[S:4][N:3]=1)([O:14][CH2:15][CH3:16])=[S:10])[CH3:13]
Reactant: CSc1nc(O)ns1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nsc(SC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.6 g of the product of Step A, 9.5 g of diethyl chlorothiophosphate and 7 g of potassium carbonate in 50 ml of acetone was stirred overnight at room temperature and the mixture was then filtered. The filtrate was concentrated by evaporation under reduced pressure and was chromatographed over silica. Elution with a 9-1 benzene-ethylacetate mixture yielded 3-(diethoxythiophosphoryloxy)-5-methylthio-1,2,4-thiadiazole with a refractive index of nD20 = 1.5534 and Rf=0.4.
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9]2[NH:10][C@H:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.ClCCl>[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9]2[N:13]([C:35](=[O:37])[CH3:36])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(SCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
To a solution of 2-[(4-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydrochloride (197) (0.50 g, 1.25 mmol), triethylamine (0.384 mL, 2.75 mmol), 4-dimethylaminopyridine (20 mg) in dichloromethane (20 mL) is added acetic anhydride (0.130 mL, 1.38 mmol), and the mixture is stirred at rt for 3 h. Additional acetic anhydride (0.100 mL, 1.06 mmol) is added, and the mixture is stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water, brine, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is recrystallized from heptane: dichloromethane (95:5) to give 0.37 g of the product 549. 1H NMR (CDCl3) δ 7.60-7.40 (m, 2H), 7.10-6.90 (m, 8H), 6.90-6.75 (m, 2H), 6.75-6.65 (m, 2H), 5.65 (d, 1H), 5.43 (d, 1H), 4.33 (q, 2H), 1.91 (s, 3H). MS: m/z 405 (M++1).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:26][CH2:27][CH:28]=[O:29])=[CH:21][CH:20]=1>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH2:26][S:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([F:30])([F:17])[F:31])=[CH:20][CH:21]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
3.77 Grams of methyl acetoacetate were dissolved in 5 ml of water, and 4.5 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.31 g of sodium acetate and 0.54 g of benzyltriethylammonium chloride were added thereto and then 14.7 g of a toluene solution containing 39.8% of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at 45°-50° C. for 6 hours and then at room temperature for 12 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave crude 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone in a yield of 80.9%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc2cnn(C3CCCCO3)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
To a solution of 6-(bromomethyl)-1-(2-tetrahydropyranyl)indazole (4.0 g, 14 mmol) (100) in DMF (30 mL) was added sodium azide (6 g, 92 mmol) in one portion. The suspension was heated at 90° C. for 30 minutes and a yellow solution was formed. After cooling down to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ether (2×150 mL). Combined organic layers were washed with brine then dried (MgSO4). Evaporation of solvent gave an yellow oil which was purified by column chromatography to yield title compound (2.91 g, 83%). TLC Rf 0.31 (70:30 of hexane-ethyl acetate); MS (electrospray) 258 (M+1); 1H NMR (CDCl3) δ1.75 (m, 3H), 2.10 (m, 2H), 2.55 (m, 1H), 3.72 (m, 1H), 4.01 (m, 1H), 4.48 (s, 2H), 5.73 (dd, 1H, J=8.2, 2.8 Hz), 7.12 (dd, 1H, J=8.2, 0.8 Hz), 7.55 (s, 1H), 7.71 (d, 1H, J=8.2 Hz), 8.02 (s, 1H).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C[O:22]C1C=CC(CO)=CC=1>[Cl-].[NH4+].C(OCC)(=O)C>[NH2:15][C:12]1[N:11]=[C:10]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3](=[O:22])[NH:8][CH:7]=2)=[CH:14][N:13]=1
Reactant: COc1ccc(CO)cc1
Reactant: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reaction time: 1.5 h

Procedure:
After sodium (455 mg, 19.8 mmol) was dissolved in 4-methoxybenzyl alcohol (15 ml) at 90° C. under an atmosphere of nitrogen gas, 5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (1.80 g, 6.60 mmol) was added thereto and the mixture was stirred as it was. After 1.5 hours, the reaction mixture was cooled as it was and then diluted with an aqueous saturated ammonium chloride solution and ethyl acetate. The resulting organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated. Trifluoroacetic acid (40 ml) was added to the residue, followed by stirring at 65° C. After 18 hours, the reaction mixture was cooled as it was and diluted with dichloromethane, water and 5N hydrochloride. The resulting aqueous layer was washed with ethyl acetate and adjusted to pH 6 with 5N sodium hydroxide. The resulting crystals were collected by filtration and washed with water, to give crude crystals of the title compound. The resulting crude crystals were suspended in ethyl acetate, collected by filtration and washed with ethyl acetate, to give the title compound (820 mg, 49%) as a colorless solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:10][C@@H:11]([CH3:25])[C:12]([N:14]1[C@H:19]([C:20](=[O:22])[NH2:21])[CH:18]2[CH2:23][CH2:24][CH:15]1[CH2:16][CH2:17]2)=[O:13])[CH2:7][CH2:8][CH3:9])=[O:5])C.Cl>[OH-].[Na+]>[C:4]([C@@H:6]([NH:10][C@@H:11]([CH3:25])[C:12]([N:14]1[C@H:19]([C:20](=[O:22])[NH2:21])[CH:18]2[CH2:23][CH2:24][CH:15]1[CH2:16][CH2:17]2)=[O:13])[CH2:7][CH2:8][CH3:9])([OH:5])=[O:3]
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1C2CCC(CC2)[C@H]1C(N)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2CCC(CC2)[C@H]1C(N)=O)C(=O)O
Reaction time: 24 h
Yield: 94 %

Procedure:
4.25 mmol (1.5 g) of the compound obtained in Example 1 are dissolved in 50 cm3 of 0.1N sodium hydroxide. The solution is left for 24 hours at room temperature, neutralized by adding 1N hydrochloric acid and then evaporated to dryness. The residue is taken up with 50 cm3 of isopropanol, filtered and evaporated, then taken up in 40 cm3 of water. The expected product is obtained after lyophilization.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]([Mg]Br)=[CH2:44].Cl>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][N:27]=[C:19]2[N:18]1[C@H:28]1[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH:43]=[CH2:44])[CH2:32][CH2:33]1
Reactant: C=C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)CO[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.50 g) was dissolved in tetrahydrofuran (5 mL), vinylmagnesium bromide (2.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 46%).