Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([F:21])([F:33])[F:34])(=[O:31])=[O:30])[CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2C(F)(F)F)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-(trifluoromethyl)benzenesulfonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a colorless solid. MS (ESI+) for C19H19F3N2O3S m/z 413 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:37][C@@H:38]([CH2:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)[C:39](O)=[O:40])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[CH2:16][CH2:15][N:14]([C:39](=[O:40])[C@@H:38]([NH2:37])[CH2:42][C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)[CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)C1(Cc2ccc(-c3ccccc3)cc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide (3.98 mmol; 1.7 g) in DMF (20 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (4.63 mmol; 1.26 g), N,N-diisopropyl-N-ethylamine (13.9 mmol; 2.46 mL) and HBTU (6.02 mmol; 2.28 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting solution was stirred for 7 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:5]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][C:2]([C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc(-c2ccccc2)cc1
Yield: 41 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 4-biphenylcarbonyl chloride for benzoyl chloride, the title compound was obtained as a white solid in 41% yield: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=7.2 Hz, 2H), 7.39-7.69 (m, 7H), 4.12 (q, J=6.9 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.30(t, J=7.5 Hz, 2H), 1.76 (m, 2H), 1.65 (m, 2H), 1.40 (m, 4H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[H-].[Na+]>N1C=CC=CC=1>[CH2:10]([O:22][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 29.4 g (0.157 mole) of dodecanol and 500 ml of pyridine is flushed with nitrogen and stirred at room temperature after which 7.55 g (0.314 mole) of sodium hydride is added. The mixture is heated to 100° C. for 20 hours, then refluxed 1 hour after which 2.0 g of cuprous chloride is added. The mixture is refluxed with stirring under nitrogen for 20 hours, then poured into an ice-water-hydrochloric acid mixture with stirring and filtered. The resulting oily precipitate is extracted into ether, washed with 5% hydrochloric acid solution, water and salt water, dried over sodium sulfate, filtered, and evaporated on a steam bath replacing the ether with hexane. The solid obtained is recrystallized from methanol to give 5-dodecyloxy-2-furoic acid, M.P. 122°-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[C:8]([F:15])=[C:7]2[F:16])[CH3:2].[CH2:17]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26](O)[C:27]#[CH:28])[CH2:22][CH2:21]1)[CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11]([CH:10]=[C:9]([O:14][CH:17]([CH:20]3[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]3)[C:18]#[CH:19])[C:8]([F:15])=[C:7]2[F:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1ccc2cc(O)c(F)c(F)c2c1
Reactant: C#CC(O)C1CCC(CCC)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#CC(Oc1cc2ccc(OCC)cc2c(F)c1F)C1CCC(CCC)CC1
Reaction time: 18 h

Procedure:
10.5 g (46.8 mmol) of 6-ethoxy-3,4-difluoronaphthalen-2-ol are initially introduced in 100 ml of THF together with 10.0 g (55.5 mmol) of 1-(4-propylcyclohexyl)prop-2-yn-1-ol and 15.0 g (57.2 mmol) of triphenylphosphine, and 11.5 ml (59.1 mmol) of DIAD are added over the course of 20 min with ice-cooling. After 18 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1). The further purification is carried out by recrystallisation from n-heptane, giving 7-ethoxy-1,2-difluoro-3-[1-(4-propylcyclohexyl)prop-2-ynyloxy]naphthalene as a yellowish solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(OCC)(=O)C>[NH2:24][CH2:23][CH2:22][NH:25][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Reactant: NCCN
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cccc(Cl)c3)nc(NCCN)nc21
Temperature: 150 °C

Procedure:
200 mg (0.58 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-isopropyl-9H-purine are dissolved in 6 ml (90 mmol) of ethylenediamine and the mixture is heated under reflux for 3 hours (oil bath temperature of 150° C.). After cooling to room temperature, the reaction mixture is taken up in 250 ml of ethyl acetate and extracted with 150 ml of water. The aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and dried under an HV. 2-(2-Amino-ethylamino)-6-(3-chloro-phenyl-amino)-9-isopropyl-9H-purine is obtained; Rf=0.27 (methylene chloride:methanol:concentrated ammonium hydroxide solution=900:100:1); EI-MS: (M+H)+=346; m.p. 55–56° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[CH:20]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH:20]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CCC(Cl)c1c(F)cccc1Cl
Reactant: N#Cc1ccc(OCc2ccsc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
2-Hydroxy-4-(3-thienylmethoxy)benzonitrile (0.5 g) is added portionwise to a stirred suspension of sodium hydride (90 mg, 60% dispersion in mineral oil) in dry DMF (100 mL). After stirring at ambient temperature for 30 minutes, ethyl (RS)-4-chloro-4-(2-chloro-6-fluorophenyl)butanoate (0.62 g) is added in one portion and the reaction stirred for 48 hours at 90° C. The reaction mixture is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-(2-chloro-6-fluorophenyl)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)butanoate (360 mg) as an orange oil.
Reaction SMILES: [NH2:1]C1C(N[C@H]2C[C@@H](CO)C=C2)=NC=NC=1Cl.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[C@H:27]1[CH2:31][C@@H:30]([CH2:32][OH:33])[CH:29]=[CH:28]1.Cl>C(OC(OCC)OCC)C>[NH2:1][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[C@H:27]1[CH2:31][C@@H:30]([CH2:32][OH:33])[CH:29]=[CH:28]1
Reactant: Nc1c(Cl)ncnc1N[C@@H]1C=C[C@H](CO)C1
Reactant: OC[C@H]1C=C[C@@H](n2cnc3c(Cl)ncnc32)C1
Agent: Cl
Solvent: CCOC(OCC)OCC
Product: Nc1ncnc2c1ncn2[C@@H]1C=C[C@H](CO)C1

Procedure:
(1R,4S)-4-(6-Chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (1R,4S)-4-[(5-Amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (from part d of this example, 9.63 g, 40.0 mmol), triethylorthoformate (150 mL), and concentrated hydrochloric acid (14 mL) were stirred for 3 hours. Volatiles were evaporated and the residual solid was partitioned between chloroform (300 mL) and saturated aqueous sodium carbonate (100 mL). The aqueous layer was extracted with chloroform (2×100 mL). The combined chloroform layers were dried (sodium sulfate). Volatiles were evaporated under reduced pressure and the residual yellow glass was chromatographed on silica gel. Elution with ethyl acetate gave title compound as white needles from ethyl acetate (7.45 g, 74%), m.p. 121-124° C.; 1H-NMR (DMSO-d6) δ: 8.81 (s, 1H), 8.64 (s, 1H), 6.24 and 6.21 (two m, 2H), 5.75 (m, 1H), 4.75 (t, J=5.4 Hz, 1H), 3.34 (m, 2H), 2.95 (m, 1H), 2.75 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.N(OCCC(C)C)=O.[ClH:44]>C(#N)C.[Cu](Cl)Cl>[Cl:44][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[S:27][CH:28]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
15.00 g (28.84 mmol) of 2-amino-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 1A) were initially charged in 200 ml of acetonitrile, and 6.76 g (57.69 mmol) of isopentyl nitrite and 7.76 g (57.69 mmol) of copper(II) chloride were added. The mixture was stirred at 70° C. for 6 h. After cooling to RT, 750 ml of 1N hydrochloric acid were added and the mixture was stirred for 30 min. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After removal of the solvent, the crude product was purified by column chromatography on silica gel (mobile phase: toluene/ethyl acetate 4:1). This gave 10.8 g (69% of theory, purity 90%) of the desired target compound. For further purification, the product may, if appropriate, be triturated with diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:16][NH2:17]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][NH2:17])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CSc1nncc(-c2ccc(F)cc2)n1
Reactant: NN
Solvent: C1CCOC1
Solvent: CO
Product: NNc1nncc(-c2ccc(F)cc2)n1

Procedure:
To a solution of 11.9 g. of 5-(p-fluorophenyl)-3-(methylthio)-1,2,4-triazine in 50 ml. of 1:1 methanol-tetrahydrofuran is added 2.1 ml. of 95% hydrazine. The mixture is refluxed for 12 hours and then cooled. The solid which forms is collected by filtration and washed with hexane, giving 5-(p-fluorophenyl)-3-hydrazino-1,2,4-triazine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.[H-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20].Cl>O1CCCC1>[C:14]([CH:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[C:18]([O:19][CH3:20])=[O:21])#[N:15]
Reactant: COc1ccc2cccc(CC#N)c2c1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1cccc2ccc(OC)cc12

Procedure:
(7-Methoxy-naphth-1-yl)acetonitrile (20 g) is dissolved in 150 ml of anhydrous tetrahydrofuran. Sodium hydride (202.8 mmol) is added at ambient temperature, and the mixture is refluxed for 30 minutes. Dimethyl carbonate (12 ml) is added with caution, and the reaction mixture is refluxed for 30 minutes. The mixture is poured into ice-cold water, and the aqueous phase is acidified with 21 ml of 37% hydrochloric acid solution and then extracted twice with 100 ml of ether. The organic phase is washed with water, dried, decolored and evaporated. The oil obtained is precipitated from ether, and the precipitate formed is filtered off under suction and then recrystallized to yield the title product in the form of a white solid.
Reaction SMILES: ClCCl.[CH2:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][C@@H:20](O)[C@H:19]([O:23][CH2:24][O:25][CH3:26])[CH2:18]2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(S(F)(F)[F:33])CC)C>O>[CH2:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][C@H:20]([F:33])[C@H:19]([O:23][CH2:24][O:25][CH3:26])[CH2:18]2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Solvent: O
Solvent: ClCCl
Product: COCO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@@H]1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 ml of a dichloromethane solution of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridine was added dropwise into a solution of 10 ml of dichloromethane containing 278 μl of diethylaminosulfur trifluoride at −78° C. over 10 minutes. After stirring at room temperature for one hour, it was heated under stirring at 40° C. for one hour. After cooling as it was, the reaction solution was poured into water. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (2:1), to give 56.7 mg of 2-benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]pyridine (1H-NMR (CDCl3) δ=3.38 (3H, s), 3.65-3.82 (4H, m), 3.97 (2H, s), 4.41-4.43 (1H, m), 4.69-4.75 (2H, m), 5.18 (1H, br.d, J=49 Hz), 6.18 (1H, d, J=8 Hz), 6.38 (1H, d, J=7 Hz), 7.01-7.36 (6H, m)) and 294 mg of a crude refined product of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine. This crude purified product was purified by a thin layer chromatography (developed three timed using hexane/ethyl acetate (5/1) and three times using hexane/ethyl acetate (4/1)), to give 47.8 g of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine (1H-NMR (CDCl3) δ=3.48 (3H, s), 3.54-3.73 (4H, m), 3.97 (2H, s), 4.00-4.04 (1H, m), 4.41-4.46 (1H, m), 5.41 (2H, d, J=56 Hz), 6.15 (1H, d, J=8 Hz), 6.37 (1H, d, J=7 Hz), 7.17-7.35 (6H, m)).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(O)(=O)C.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
4-Fluoro-3-nitro-benzaldehyde (3.39 g, 0.0200 mol) was dissolved in methylene chloride (100 mL) and acetic acid (3.50 mL, 0.0616 mol) and the mixture was cooled to −10° C. Piperidine (2.4 mL, 0.024 mol) was then added to the cooled mixture over 10 minutes. Sodium triacetoxyborohydride (17.0 g, 0.0802 mol) was added in one portion. After stirring at 0° C. for 18 hours, the reaction was poured into a mixture of 1N aqueous HCl and ice. The organic phase was removed, and the aqueous layer was made basic by the addition of NaOH pellets. The aqueous layer was extracted twice with methylene chloride, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in methylene chloride and purified by silica gel chromatography (ethyl acetate/hexanes as eluent) followed by further purification by preparative HPLC to yield 2.69 g of 1-(4-fluoro-3-nitro-benzyl)-piperidine as a TFA salt.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:9])[CH3:8].[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:7]([CH3:9])[CH3:8])\[CH3:24])[CH3:19]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: CC(C)Oc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1OC(C)C
Temperature: 23 °C
Yield: 64.2 %

Procedure:
Potassium t-butoxide (7.36 g, 0.066 mol) was added to a stirred solution of 2-isopropoxy-phenol (5.00 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 4.86 g, 0.033 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (5.60 g, 65%) as a yellow oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=O)[CH2:12][CH:13]=O)=[CH:7][CH:6]=1.OO>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][N:3]=[N:2][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(C(=O)C(CC=O)c2ccc(Cl)cc2)cc1
Agent: OO
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nnccc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Hydrazine hydrate (0.8 mP, 16.5 mmol) was added to a solution of 3-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-4-oxo-butyraldehyde (4.5 g, 12.8 mmol) in ethanol (100 ml), followed by stirring at room temperature for 1 hour. Hydrogen peroxide solution 31% (6 ml) was added to the reaction mixture, and the resulting mixture was stirred at 60° C. for 18 hours. The mixture was concentrated under reduced pressure and the residue was separated and purified by chromatography on a silica gel column [silica gel 70 g, chloroform/methanol (50/1)], whereby the title compound was obtained as a pale yellow amorphous solid (2.60 g, 58.8%).
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([CH3:26])=[CH2:25]>C(O)C>[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1)([CH3:26])=[CH2:25]
Reactant: C=C(C)c1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccncc3)cc2n1
Solvent: CCO
Product: C=C(C)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccncc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
There was dissolved, in ethanol (2 mL), (7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.4 mg, 0.0976 mM), then 3-isopropenyl-benzaldehyde (14.3 mg, 0.0976 mM) was added to the solution and the mixture was stirred at room temperature overnight. The reaction liquid was filtered and then the resulting solid was washed with diethyl ether to thus give the title compound (26.6 mg, yield: 62%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.[ClH:29].O1CCOCC1>C(O)(C)C>[ClH:29].[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2[nH]ncc12
Yield: 100 %

Procedure:
Under nitrogen, the 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (60 mg, 0.156 mmol) obtained in Example 725 was dissolved in isopropyl alcohol (2 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (2 ml), and the resulting mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2, 100/4). Then, a 4N-hydrochloric acid/1,4-dioxane solution was added thereto and the solvent was distilled off under reduced pressure to obtain 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole monohydrochloride (55 mg, yield 100%) as a hygroscopic light-yellow solid.