Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>COCCOC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccc(Cl)cc1
Yield: 59.4 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (45 mg, 0.12 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-chloro-phenylboronic acid (27 mg, 0.17 mmol) and Pd[PPh3]4 (13 mg, 0.012 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (30 mg, 61%). LC-MS m/e 421.26 (M+H+)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc(C(F)(F)F)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 61 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 3-trifluoromethylbenzenesulfonyl chloride under the conditions used in example 2 giving 61% of the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[CH3:27][NH2:28].O>C(O)C>[CH3:27][NH:28][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:2]
Reactant: COC(=O)C1CC(=O)N(c2ccc(/C=C/c3ccc(OC)cc3)cc2)C1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=O)C1CC(=O)N(c2ccc(/C=C/c3ccc(OC)cc3)cc2)C1

Procedure:
A solution of 400 mg (1.1 mmol) of (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 1.4 ml of a solution of methylamine in ethanol (33%) is heated at 90° C. for 18 h in a sealed vial. For the working-up, the cooled solution is treated with water to precipitate the product. The solid material is collected on a filter funnel, washed with water, finally, with heptane. After crystallization of the crude amide from a mixture of N,N-dimethylformamide and methanol, 98 mg (25% of theory) of (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide are obtained as a light brown solid; MS: m/e=351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)=[C:5]([N+:19]([O-])=O)[CH:4]=1.[H][H]>C(O)C.[Pd]>[NH2:19][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=1
Reactant: [H][H]
Reactant: COc1ccc(Nc2ccc([N+](=O)[O-])nc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Nc2ccc(N)nc2)c(N)c1

Procedure:
To a solution of (4-Methoxy-2-nitro-phenyl)-(6-nitro-pyridin-3-yl)-amine (1.5 g, 1.55 mmol) in ethanol (50 ml) was added Pd/C (0.05 g) under N2. The mixture was shaken under a positive pressure of hydrogen at 5° C. for 4 h. After removal of the catalyst by filtration, the filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The crude product, N5-(2-Amino-4-methoxy-phenyl)-pyridine-2,5-diamine, thus obtained was used directly for the next step.
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[N:7]=1>C(O)(=O)C.[Fe]>[CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
Dissolve methyl-(1-methyl-piperidin-4-yl)-(5-nitro-benzooxazol-2-yl)-amine (0.583 g, 2.01 mmol), in acetic acid (8 mL), and add iron (1.12 g, 20.1 mmol) to the solution. Stir the mixture at 40° C. for 3 h. Filter the reaction mixture through Celite® and wash with water/MeOH. Concentrate the reaction mixture in vacuo. Subject the residue to silica gel flash column chromatography, eluting with 10% 2N NH3 in MeOH/CH2Cl2, to yield the desired product (0.474 g, 91%). MS (ES+) 261.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl-].[Cl-].[Cl-].[Al+3].[C:17](Cl)(=[O:19])[CH3:18].Cl.[OH-].[Na+]>O.ClCCl>[OH:12][C:9]1[C:10]([C:17](=[O:19])[CH3:18])=[CH:11][C:2]([CH3:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Cc1ccc(O)c2ncccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(C)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 5-methylquinolin-8-ol (5.91 g, 37.1 mmol, from ChemBridge), aluminum trichloride (20.00 g, 150.0 mmol), and acetyl chloride (12.1 mL, 170 mmol) was stirred at 0° C. for 4 hours, then heated at 130° C. for 12 hours, cooled, and decomposed with water (39 mL) (caution! with external ice-cooling if necessary) and conc. HCl (13 mL). The precipitate was filtered, and dried under reduced pressure. The solid obtained was then dissolved in 50 mL of water. To the solution was added 100 mL of dichloromethane. The mixture was cooled with an ice bath and the pH adjusted to 4 with slow addition of 20% NaOH. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, brine and dried over sodium sulfate. The suspension was filtered through a plug of cotton and concentrated to dryness. The residue was used directly in the next step (5.8 g, 78%). LCMS calculated for C12H12NO2 (M+H)+: m/z=202.1; Found: 202.0.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>[Cl-].C[N+](C)(C)C>[Cl:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: Clc1nc2cc(I)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
Heat a solution of 5-iodo-1,3-dihydro-benzimidazol-2-one (6.50 g, 25.0 mmol; Feitelson et al. (1952) J. Chem. Soc. 2389) and tetramethylammonium chloride (1.37 g, 12.5 mmol) to 100° C. in POCl3 (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-iodo-1H-benzimidazole as a gray solid.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[N:4]=[CH:3]1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:10]1[C:5]2[N:4]=[CH:3][NH:2][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C(O)c1cccc2[nH]cnc12
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid hydrochloride (2.0 g, 10.1 mmol), N,O-dimethylhydroxylamine hydrochloride (1.47 g, 15.1 mmol) and ethyldiisopropylamine (7.02 mL, 40.3 mmol) in DMF (10 mL) at room temperature was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (3.90 g, 10.3 mmol) in a single portion. The mixture was stirred at room temperature overnight then concentrated in vacuo. Purification by SiO2 chromatography followed by trituration with EtOAc provided 1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide (945 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[NH:27])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: N#Cc1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1
Product: N#Cc1ccc(NC(=N)Nc2ncccc2OCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
To a stirring suspension of N-(3-benzyloxy-2-pyridyl)-N'-(4-cyanophenyl)thiourea (2 g, 0.0055 mol) in ammonia-saturated methanol (40 ml) was added yellow mercuric oxide (3 g, 0.014 mol). Stirring was continued for 20 h, then the mixture filtered through celite, and the solid washed several times with chloroform. The filtrate was evaporated to a white solid, which was triturated with ether. Yield 1.12 g (59%), m.p. 173°-175 ° C.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[CH:22]=O)/[N:7]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:31]1([CH2:22][C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[C:11](/[N:10]=[C:8]2\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\2[CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)=[O:24])[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2CN2CCC2)s1
Reaction time: 2 h
Yield: 79 %

Procedure:
In a 20 mL vial, to a solution of Example 375C (52 mg, 0.118 mmol) in dichloromethane (2 mL) was added azetidine (20.22 mg, 0.354 mmol), followed by addition of acetic acid (7.09 mg, 0.118 mmol) and sodium triacetoxyborohydride (37.5 mg, 0.177 mmol) and the mixture was stirred for 2 hr. The reaction was quenched with saturated NaHCO3 and extracted with dichloromethane (3×5 mL). The organics were combined, dried, filtered, concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, gradient elution over 25 min with solvents A:B (100:0 to 10:90); solvent A=CH2Cl2; solvent B=7M NH3/MeOH (1):CH2Cl2 (9)) to afford the title compound in 79% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 1.61-1.76 (m, 1H) 1.79-1.91 (m, 2H) 1.91-2.06 (m, 3H) 3.18 (t, J=6.94 Hz, 4H) 3.60-3.71 (m, 1H) 3.74-3.85 (m, 1H) 4.06 (s, 2H) 4.23-4.36 (m, 3H) 7.32 (s, 1H) 7.74-7.78 (m, 2H) 8.21-8.25 (m, 1H); MS (DCI/NH3) m/z 482 (M+H)+. Anal. calcd C25H32F3N3O2S.0.3 C6H6: C, 62.02; H, 6.56; N, 8.10. Found: C, 61.94; H, 6.43; N, 8.38.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:37]=[CH:36][C:28]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.CCOC(C)=O.O>[CH:14]([N:12]1[CH:13]=[C:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:28]([CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:36][CH:37]=3)[CH:3]=2)[N:10]=[N:11]1)([CH3:16])[CH3:15]
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)n1cc(-c2cc(-c3ccc(CN4CCOCC4)cc3)cnc2N)nn1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (500 mg, 1.77 mmol) and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine (537 mg, 1.77 mmol) in ethylene glycol dimethyl ether (6.0 mL)/water (4.0 mL) was added Cs2CO3 (1.15 g, 3.54 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(dppf)Cl2.DCM (72.2 mg, 0.08 mmol) was added and allowed to stir at 140° C. for 6 h in microwave. After 6 h, the reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude product. The crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5-95% MeOH in DCM to afford the title compound as a brown solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C@@H:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C@@H:16]4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]1(O)CCCC1>>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:27][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c(OC2CCCC2)c1
Reactant: OC1CCCC1
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OC2CCCCC2)c1

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole and substituting cyclohexanol for cyclopentanol while making non-critical variations the title compound was obtained as 278 mg (32%) of a white foam: 1H NMR (400 MHz, CDCl3) δ 7.84 (br s, 1 H), 7.35-7.26 (m, 3 H), 7.15-7.11 (m, 1 H), 7.04-7.01 (m, 2 H), 6.95 (d, J=7.2 Hz, 1 H), 4.08-4.06 (m, 1 H), 3.09-3.07 (m, 2 H), 2.97-2.96 (m, 2 H), 2.85-2.83 (m, 2 H), 2.47-2.37 (m, 2 H), 1.90 (m, 2 H) 1.71 (m, 2 H), 1.51 (m, 2 H), 1.41 (m, 2 H), 1.15 (m, 3 H); HRMS (FAB) calcd for C24H28N2O+H1: 361.2280 found 361.2270.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][N:13]=1.Cl>O1CCCC1.Cl[Ni]Cl>[F:2][C:3]1[CH:4]=[C:5]([C:12]2[N:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:16][N:17]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCCCc1cnc(Cl)nc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCc1cnc(-c2cc(F)cc(F)c2)nc1
Yield: 15.4 %

Procedure:
Grignard reagent was prepared from dried magnesium and 49.0 g (254 mmol) of 3,5-difluorobromobenzene in 200 ml of tetrahydrofuran (THF), 1 g of NiCl2 (dppp) was added thereto, 36.0 g (195 mmol) of the 2-chloro-5-pentylpyrimidine described above was added dropwise thereto, and the product was heated to reflux for 2 hours. The reaction solution was cooled down, and added into 200 ml of 1N-hydrochloric acid. The product was extracted with ether, and the extract was washed with saturated aqueous solution of sodium bicarbonate and water in turn, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=1/1) to obtain 8.0 g (30 mmol) of 2-(3,5-difluorophenyl)-5-pentylpyrimidine. Yield of this product was 15%.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:17]1[C:25]2[CH:24]=[CH:23][C:22]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[C:21]([OH:33])[C:20]=2[CH:19]=[N:18]1.O>CN(C)C=O>[CH2:1]([O:33][C:21]1[C:22]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[N:18][N:17]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH2:2][CH3:3]
Reactant: Oc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Reaction time: 2 h
Yield: 107.5 %

Procedure:
Under a nitrogen atmosphere, n-propyl iodide (257 μl, 2.64 mmol) and cesium carbonate (860 mg, 2.64 mmol) were added to a solution of 1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-ol (700 mg, 2.20 mmol) in N,N-dimethylformamide (7 ml) at room temperature. After 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (852.6 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[O:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCOc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2cccc(OCC[C@@H]3CCCCN3)c2)cc1
Yield: 89 %

Procedure:
A solution of the product (0.250 g, 0.629 mmol) from step 1 in 4N HCl in dioxane (1.57 mL) was stirred at ambient temperature for about 1 h and then concentrated in vacuo. The residue was triturated with ether and dried in a 55° C. vacuum oven to afford the desired product as a white solid (0.187 g, 89%): 1HNMR (400 MHz, DMSO-d6): δ 8.98 (br s, 2H), 7.40 (m, 2H), 7.28 (t, 1H, J=8.4 Hz), 7.15 (tt, 1H, J1=7.6 Hz, J2=1.2 Hz), 7.02 (m, 2H), 6.73 (ddd, 1H, J1=8.4 Hz, J2=2.4 Hz, J3=0.8 Hz), 6.57 (m, 2H), 4.09 (m, 2H), 3.21 (m, 2H), 2.85 (td, 1H, J1=12 Hz, J2=2.8 Hz), 2.13 (m, 1H), 1.93 (m, 2H), 1.59 (m, 5H). MS; m/z 298 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH2:8][Cl:13])=[CH:6][N:7]=1
Reactant: Cc1cc(CO)cnc1Cl
Reactant: O=S(Cl)Cl
Product: Cc1cc(CCl)cnc1Cl

Procedure:
The preparation is carried out analogously to Example 6A from 1.00 g (6.35 mmol) (6-chloro-5-methylpyridin-3-yl)methanol and 5 ml thionyl chloride. 1.26 g of the title compound, which is reacted without further purification, are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](=[O:73])[NH:14][C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[C:18]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]3[C:53](=[O:54])[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]3=[O:55])=[C:17]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][N:62]3[C:70](=[O:71])[C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:63]3=[O:72])[CH:16]=2)=[CH:11][C:10]([CH:74]=[CH:75][C:76]([O:78][CH2:79][CH3:80])=[O:77])=[C:9]1[C:81]#[C:82][C:83]([OH:96])([C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[C:12]([C:13](=[O:73])[NH:14][C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:28](=[O:37])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]3=[O:36])[C:18]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]3[C:46](=[O:55])[C:47]4[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]3=[O:54])=[C:17]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][N:62]3[C:70](=[O:71])[C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:63]3=[O:72])[CH:16]=2)=[CH:11][C:10]([CH2:74][CH2:75][C:76]([O:78][CH2:79][CH3:80])=[O:77])=[C:9]1[C:81]#[C:82][C:83]([OH:96])([C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)[C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1cc(C(=O)Nc2cc(CCCCCCN3C(=O)c4ccccc4C3=O)c(OCCCCCCN3C(=O)c4ccccc4C3=O)c(CCCCCCN3C(=O)c4ccccc4C3=O)c2)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)Nc2cc(CCCCCCN3C(=O)c4ccccc4C3=O)c(OCCCCCCN3C(=O)c4ccccc4C3=O)c(CCCCCCN3C(=O)c4ccccc4C3=O)c2)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.7 %

Procedure:
To a stirred solution of 9 (0.07 g, 0.06 mmol) in EtOAc (20 mL) was added 10% dry Pd—C (0.007 g). The resulting mixture was stirred at room temperature for 48 hours under a H2 balloon. Pd—C was filtered off and the filtrate was concentrated to give 10 as colorless oil (0.06 g, 74%). The crude product was subjected to the next reaction without further purification. 1H NMR of the crude product is as follows. 1H NMR (400 MHz, CDCl3) δ 7.78-7.80 (m, 4H), 7.63-7.68 (m, 5H), 7.21-7.28 (m, 6H), 7.12-7.20 (m, 8H), 6.76-6.77 (d, J=7.2 Hz, 1H), 6.59 (s, 1H), 5.52 (s, 2H), 4.03-4.09 (m, 2H), 3.62-3.69 (m, 8H), 2.60-2.62 (m, 2H), 2.42-2.53 (m, 8H), 2.19-2.22 (m 2H), 1.42-1.72 (m, 14H), 1.35-1.40 (m, 10H), and 1.24 (m, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24]OS(C)(=O)=O)[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24][N:1]=[N+:2]=[N-:3])[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Temperature: 90 °C
Yield: 45 %

Procedure:
Sodium azide (1.10 g, 16.90 mmol) was added to the mixture of methanesulfonic acid 1-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-ylmethyl ester and methanesulfonic acid 3-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-3H-[1,2,3]triazol-5-ylmethyl ester, obtained in Example 9, in DMF (10 mL) and heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The solution was washed with water (100 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Removal of volatiles and purification of the residual material by silica gel column chromatography (eluent, 1:9–3:7 ethyl acetate/hexane) yielded compounds 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-4-ylmethyl azide (13A) (800 mg, 45%) followed by 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-5-ylmethyl azide (13B) (850 mg, 50%).