Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[CH:15]=[C:14]([CH3:21])[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([Cl:20])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: Cc1cc(Cl)c(CO)c(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)c(C=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
DMSO (14.2 mL, 200 mmol) was added to a stirred solution of oxalyl chloride (8.7 mmol, 99 mmol) in dichloromethane (100 mL) at −70° C. After 15 min, alcohol (10) (6.40 g, 33.3 mmol) in dichloromethane (25 mL) was added, followed by triethylamine (56 mL). The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was washed with aqueous sodium bicarbonate (75 mL), dried (MgSO4), and concentrated under vacuum. The residue was purified by column chromatography (elution with 10% ethyl acetate in hexanes) to afford 5.00 g (78%) of (11) as a pale yellow oil which solidified on standing: LCMS (MH+, 190), Rf 0.48 (20% ethyl acetate in hexanes).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15](O)=O)=[O:7])(C)(C)C.[C:18]([N:26]=C=O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:29]1([NH2:36])[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[NH:35]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:36]=[C:15]1[C@@H:9]1[CH2:10][C:11](=[CH:13][Cl:14])[CH2:12][N:8]1[C:6]([NH:26][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7]
Reactant: Nc1ccccc1N
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: O=C(NC(=O)N1CC(=CCl)C[C@H]1c1nc2ccccc2[nH]1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and 1,2-benzenediamine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=381.4.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[N:27][N:26]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:27][N:26]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nnc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (300 mg, 0.94 mmol), 1,4-dichlorophthalazine (188 mg, 0.94 mmol) and N,N-diisopropylethylamine (410 μl, 2.36 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 18 hours. More 1,4-dichlorophthalazine (188 mg, 0.94 mmol) was added and the reaction stirred at room temperature for 36 hours, then heated at 55° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was washed with more aqueous sodium bicarbonate, brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 92:8:0.8 by volume) to provide the title compound (183 mg, 61%). LRMS APCI+ m/z 481 [M]+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>CO.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a solution of 4.29 gm (77 mmol) potassium hydroxide in 50 ml methanol were added 5.0 gm (26 mmol) 5-bromoindole and 7.84 gm (51 mmol) 4piperidone .HCl.H2O and the reaction mixture was stirred for 18 hours at reflux under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, diluted with 500 ml water and the mixture extracted well with dichloromethane. The combined organic extracts were washed with water followed by saturated aqueous sodium chloride and dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 6.23 gm (86.5%) of the title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[CH3:30][S-:31].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:28][C:20]1[CH:19]=[C:18]([CH:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][S:31][CH3:30])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (95.1 mg, 0.19 mmol) in acetone (1 mL) was cooled to 0° C. and then treated with sodium thiomethoxide (12.9 mg, 0.18 mmol). The reaction stirred at 0° C. for 1.5 h and then was treated with a second aliquot of sodium thiomethoxide (3.6 mg, 0.051 mmol). The reaction was stirred at 0° C. and then slowly warmed to 25° C. over 1.5 h. A third aliquot of sodium thiomethoxide (3–4 mg, 0.042–0.057 mmol) was added, and the reaction mixture was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS indicated the reaction had gone to completion. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 ethyl acetate/hexanes) afforded racemized 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (51.9 mg, 58%) as a white foam: mp 70–75° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1179.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][C@H:4]([OH:14])[CH2:3]1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:21])(=O)=O.O>C1COCC1>[CH3:21][O:14][C@H:4]1[CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][N:2]([CH3:1])[CH2:3]1
Reactant: CN1C[C@@H](O)C[C@@H](c2ccccc2)C1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1C[C@@H](c2ccccc2)CN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of cis-1-methyl-5-phenyl-3-piperidinol (2.03 g) in THF (20 ml) was treated with 60% sodium hydride dispersion in oil (480 mg) and heated 15 min. at reflux. The mixture was cooled to room temperature and treated with methyl tosylate (1.86 g) in THF (5 ml). The reaction mixture was stirred for 1 hour at ambient temperature, treated with water (5 ml) and the solvents removed under reduced pressure. The residue was partitioned between water (100 ml) and ether (100 ml). The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting oil was triturated with cyclohexane (10 ml) and the resulting crystals (300 mg; unchanged starting material) removed by filtration. The mother liquors were evaporated under reduced pressure and the resulting gum converted to the fumarate which was recrystallised from methanol/ethyl acetate to give the title compound as the sesquifumarate (500 mg) Mpt. 152°-4°
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:4]([C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[N+:14]=[N-:15]
Reactant: Nc1ccc(I)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(I)cc1F
Yield: 99 %

Procedure:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT overnight during which time solid precipitated out. 600 mL hexane was added and the mixture was vigorously stirred for a few hours. The solid was collected by filtration and washed with hexane to give 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) which was used directly without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([OH:23])[CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].COC(=O)[C@H](O)[C@H](C1C=CC=CC=1)NC(OCC1C=CC=CC=1)=O.CO[CH:51](OC)[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=1[O:60][CH3:61].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:23][CH:51]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=2[O:60][CH3:61])[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:5]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:24]
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Reactant: COC(=O)C(O)C(NC(=O)OCc1ccccc1)c1ccccc1
Agent: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1

Procedure:
N-Carbobenzyloxy-β-phenyl isoserine methyl ester (Preparation No. 19, 3C, 0.375 g, 1.14 mM) is dissolved in dry THF (10 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (4, 0.300 g, 1.42 mM) and pyridinium p-toluenesulfonate (10 mg) and the solution heated to distill off the THF and methanol. After ½ the THF is distilled off, THF (10 mL) is added and the reaction distilled to ½ volume again. The process is repeated three times. The reaction is then concentrated in vacuo and the residue chromatographed over 75 g silica gel packed and eluted in acetone-hexane (300 mL of 20-80 and 300 mL of 25-75). Fractions of 20 mL are collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9]CC)=O.[CH:16]1([C:19]2[NH:23][N:22]=[C:21]([NH2:24])[CH:20]=2)[CH2:18][CH2:17]1>Cl>[CH:16]1([C:19]2[CH:20]=[C:21]3[NH:24][C:7](=[O:9])[CH:6]=[C:5]([OH:13])[N:22]3[N:23]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: O=c1cc(O)n2nc(C3CC3)cc2[nH]1
Temperature: 25 °C

Procedure:
A sodium ethoxide solution (EtOH/EtONa, 0.5 N, 400 ml) containing diethyl malonate (50 mmol, 1 eq., 5.8 ml, 6.6 g) and 5-cyclopropyl-1H-pyrazol-3-amine (50 mmol, 1 eq., 6.16 g) is refluxed for 7 hours. After cooling to room temperature, an aqueous hydrochloric acid solution (5 N, 240 ml) is added until pH 5 is obtained. Volatiles are then removed under reduce pressure and the residue dried under vacuum to afford 2-cyclopropyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one x271. To this residue is successively added POCl3 (125 ml, 1.34 mol) and N,N-dimethylaniline (12.5 ml, 0.1 mol, 2 eq.) and the resulting mixture is refluxed during 3 hours. After cooling to room temperature, the reaction mixture is poured on ice and stirred during one hour at this temperature. The reaction mixture is extracted with dichloromethane, and the resulting organic phase is washed twice with water. The organic phase is dried over Na2SO4, filtered and evaporated under reduce pressure. The crude product is purified chromatography on silicagel (CH2Cl2/hexane: 40/60) to afford 5.85 g of 5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x272 as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:27]=[N:28][C:29]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[CH:36][N:37]3[CH3:42])[N:31]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:26]1[N:27]=[N:28][C:29]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[CH:36][N:37]3[CH3:42])[N:31]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nnc(Cl)nc1Nc1cccc2c1ccn2C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2c1ccn2C

Procedure:
Tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate (302 mg) and diisopropylethylamine (0.40 ml) were added successively to a solution of ethyl 3-chloro-5-(1-methyl-1H-indol-4-ylamino)-1,2,4-triazine-6-carboxylate (390 mg) obtained in the above-described Step 1 in THF (10 ml), and the reaction solution was allowed to react at 70° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 3-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-(1-methyl-1H-indol-4-ylamino)-1,2,4-triazine-6-carboxylate as a yellow solid.
Reaction SMILES: C[C:2]1[O:3][C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[S:35](C1C=CC=CC=1)(C1C=CC=CC=1)=[NH:36]>>[CH3:13][C:11]1[CH:2]=[N:36][S:35][C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N=S(c1ccccc1)c1ccccc1
Reactant: Cc1cc(=O)c2ccccc2o1
Product: Cc1cnsc1-c1ccccc1O

Procedure:
2-Methyl-4H-chromen-4-one was reacted with Lawesson's reagent, and the product was treated with 1,1′-sulfinimidoyldibenzene to provide 2-(4-methyl-1,2-thiazol-5-yl)phenol.
Reaction SMILES: [Si](OCC[N:11]1[C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][O:25][CH2:26][CH3:27])(C(C)(C)C)(C)C.ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:26]([O:25][CH2:24][C:12]1[NH:11][C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-:36])=[CH:15][C:14]=2[N:13]=1)[CH3:27]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2[nH]1
Reaction time: 2 h

Procedure:
1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.30 g, 5.96 mmol) was dissolved in 30 mL of CH2Cl2 and treated with meta-chloroperbenzoic acid (MCPBA) (1.80 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of 5% Na2CO3 solution and the layers were separated. The organic portion was then washed successively with H2O (20 mL) and brine (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.40 g of 1-2-{[tert-butyl(dimethyl)silyl]oxy)ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide as a purple syrup.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25].[CH3:26][CH2:27][CH2:28][C:29]1[C:34]([OH:35])=[C:33]([C:36]([CH3:38])=[O:37])[CH:32]=[CH:31][C:30]=1[OH:39]>>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([O:39][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:22]=[CH:21][C:9]3[CH2:10][CH2:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH3:14])[O:13][C:8]=3[C:7]=2[CH2:23][CH2:24][CH3:25])=[C:29]([CH2:28][CH2:27][CH3:26])[C:34]=1[OH:35])(=[O:37])[CH3:38]
Reactant: CCCc1c(OCCCBr)ccc2c1OC(C)(CCC(=O)OC)CC2
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)OC)CC3)ccc(C(C)=O)c1O

Procedure:
The title compound mp. 53°-55°, was prepared by the method of Example 6 using the product of Example 11 and 2,4-dihydroxy-3-propylacetophenone as starting materials. Structure assignment was confirmed by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(Cl)(Cl)Cl.CO>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(N)nc1

Procedure:
To a solution of 6-aminonicotinic acid (2.00 g, 14.48 mmol) dissolved in chloroform/MeOH (90 mL: 30 mL) was added (trimethylsilyl)diazomethane (2.0M in hexanes, 25 mL). After 15 minutes acetic acid (0.1 mL) was added and the solution was concentrated in vacuo to a residue. Trituration with EtOAc/Hex (2:1) provided methyl-6-aminonicotinate as a pale yellow solid after filtration. This material was used directly in the next step. To a solution of methyl-6-aminonicotinate (1.86 g, 12.22 mmol) dissolved in methylene chloride (90 mL) was added di-t-butyl dicarbonate (2.69 g, 12.34 mmol), 4-dimethylaminopyridine (0.15 g, 1.22 mmol) and triethylamine (2.00 mL, 14.66 mmol). After 14 h the reaction was diluted with EtOAc (400 mL) and washed with citric acid (1×50 mL, 10%), water (1×50 mL) and brine (1×50 mL) and was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40×150 mm column of SiO2, EtOAc/Hex gradient elution 1:6, 1:5, 1:3) to to give the title compound as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:9]2[CH2:27][NH:28][C@@H:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH3:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:48](=O)([O:54]C(C)(C)C)[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>ClCCl>[C:50]([O:49][C:48]([N:28]([CH2:27][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=2)=[O:15])[CH2:10]1)[C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: COC(=O)c1ccc(OC(=O)N2CCC(c3ccc(F)cc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccc(F)cc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 37 h
Yield: 47.8 %

Procedure:
To a solution of 888 mg of 4-(methoxycarbonyl)phenyl 4-(4-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidine-1-carboxylate in 9 mL of dichloromethane were added 0.7 mL of triethylamine and 868 mg of di-tert-butyl carbonate, followed by stirring at room temperature for 37 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 503 mg of 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as a pale yellow foamy substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH2:17][NH2:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH2:17][NH:18][C:45](=[O:46])[C:44]4[CH:48]=[CH:49][CH:50]=[C:42]([O:41][CH3:40])[CH:43]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)NCc2cc3c(-c4cccc(F)c4)n[nH]c3cc2OC)c1
Yield: 24.2 %

Procedure:
A total of 25.6 mg of C-{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-methylamine obtained in Production Example II-26 was dissolved in 1.9 ml of dimethylformamide, 15.3 mg of 1-hydroxybenzotriazole, 0.066 ml of diisopropylethylamine and 14.4 mg of 3-methoxybenzoic acid were added thereto, and 27.2 mg of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (i.e., WSC.HCl) was added thereto under ice-cooling and stirring. After stirring at room temperature for 5 hours, water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 0.5 N aqueous sodium hydroxide solution, 1 N hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (dichloromethane:methanol=10:1), to give 9.24 mg of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C:25]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)([OH:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: Cc1cc(Br)cnc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Br)cnc1C1(O)CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 2,5-dibromo-3-methylpyridine (3.88 g) in toluene (70 ml) was added dropwise a 1.6 M solution of n-butyllithium in n-hexane (10.6 ml) at −78° C., and stirred at the same temperature for 1 hour. Then, a solution of N-tert-butoxycarbonyl-hexahydroazepin-4-one (3.0 g) in toluene (16 ml) was added dropwise thereto, and stirred at the same temperature for 5 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (2.14 g) as a colorless clear oil.