Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[C:7]3[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:6]=23)[CH2:3][CH2:2]1.Cl.[CH3:20][NH:21][O:22][CH3:23].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([N:21]([O:22][CH3:23])[CH3:20])=[O:13])=[CH:9][N:8]=[C:7]3[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:6]=23)[CH2:2][CH2:3]1
Reactant: CCn1ncc2c(NC3CC3)c(C(=O)O)cnc21
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CC3)c(C(=O)N(C)OC)cnc21
Reaction time: 1 h

Procedure:
4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (500 mg, 0.0020 mole) and N,O-dimethylhydroxylamine hydrochloride (298 mg, 0.0030 mole) were taken in dimethylformamide. At 0° C., hydroxybenzotriazole (550 mg, 0.0040 mole) and N-methylmorpholine (1.34 ml, 0.012 mole) were added and the reaction mixture was stirred for about 1 hour. 1-(3-dimethylaminopropyl) 3-ethyl carbodiimide hydrochloride (780 mg, 0.0040 mole) was added and the reaction mixture was stirred for about 14 hours. Water was added and extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oily compound. Yield: 500 mg. m/z: (M++1) 290.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])=[C:11]([F:23])[CH:10]=2)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C1COCC1.Cl.O>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=2)[C:9]2[CH:10]=[C:11]([F:23])[C:12]([C:16]([CH3:22])([CH3:21])[CH2:17][OH:18])=[C:13]([F:15])[CH:14]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)C(C)(C)c1c(F)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(F)c(C(C)(C)CO)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
To a solution of methyl 2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropanoate (2.17 g, 4.62 mmol) in THF (30 mL) was added 1M DIBAL-H/THF solution (13.87 mL, 13.87 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 hr. 1M DIBAL-H/THF solution (1.0 mL, 1.0 mmol) was added again thereto at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. To the reaction mixture were added 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane), and then silica gel column chromatography (NH, solvent gradient; 3→50% ethyl acetate/hexane) to give 2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropan-1-ol (1.310 g, 2.97 mmol, 64.2%) as a colorless oil.
Reaction SMILES: CSCCO.[H-].[Na+].[N+:8]([C:11](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)[C:12]([O:14]C)=[O:13])([O-:10])=[O:9]>O1CCCC1>[N+:8]([C:11](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)[C:12]([OH:14])=[O:13])([O-:10])=[O:9]
Reactant: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: CSCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 100 g of 2-(methylthio)ethanol in dry tetrahydrofuran was added slowly to a solution of 6.0 g of sodium hydride (57% in mineral oil) in dry tetrahydrofuran at 0°. The mixture was then allowed to warm to room temperature and 13.1 g of methyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate (1A), prepared as described in U.S. Pat. No. 3,962,234, was added, and the mixture was allowed to stand overnight at room temperature. The solvent then was evaporated under reduced pressure, the residue was poured into water and the mixture was extracted with ether. The separated aqueous phase was acidified with acetic acid, and the product was extracted with methylene chloride. The extract was dried (MgSO4), decolorized, and the solvent was evaporated under reduced pressure. The residue was washed with pentane, then crystallized from ether and recrystallized from isopropyl alcohol to give the 2-(methylthio)ethyl ester of nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetic acid (1B), as a pale yellow solid, m.p.: 72°-73°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[OH-].[NH4+:16]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]([C:7]([NH2:16])=[O:8])[C:5]=1[C:10]([O-:9])=[O:11])([O-:3])=[O:2].[NH4+:1]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cccc([N+](=O)[O-])c1C(=O)[O-]

Procedure:
100 g (518 mmol) of 3-nitrophthalic anhydride were introduced at RT and treated rapidly with 170 ml of concentrated ammonium hydroxide solution with stirring. The mixture was stirred at RT for 1 h. The precipitate was filtered off and dried in a desiccator. Yield: 95.6 g (88%).
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]12.CCN(CC)CC.[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])OCC1CN2C(CS(=O)(=O)CC2)CN1)([CH3:23])[CH3:22]>ClCCl>[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[O:8][CH2:7][C@H:5]1[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]2[CH2:1][NH:6]1)([CH3:23])[CH3:22]
Reactant: OC[C@H]1CN2CCNCC2CN1
Reactant: CC(C)(C)[Si](C)(C)OCC1CN2CCS(=O)(=O)CC2CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN2CCNCC2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting (3R)-octahydro-2H-pyrazino[1,2-a]pyrazin-3-ylmethanol (D89, 528 mg, 3.08 mmol) was dissolved in 20 mL of dichloromethane and treated with Et3N (1.29 mL, 9.25 mmol) and TDBMSCI (929.5 mg, 6.17 mmol). The reaction was stirred at room temperature overnight and then for additional 24 h. It was checked by UPLC/MS, which showed conversion to product: peak at 0.47 min, m/z=286 (M+1), 172 (M-TBDMS+1). The crude was purified by flash chromatography (silica, CH2Cl2: (0.5 M NH3 in MeOH) 98:2 to 85:15). The residue obtained evaporating the fractions containing the product was dissolved in dichloromethane:MeOH 90:10 and the insoluble material was filtered away. The solutin was evaporated to give 638 mg of the target product.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:5]([OH:7])=[O:6])C.[CH3:8][C:9]([NH:12][CH2:13][C@H:14]([OH:28])[CH2:15][O:16][C:17]1[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:19][S:20][N:21]=1)([CH3:11])[CH3:10].[OH2:29]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:11][C:9]([NH:12][CH2:13][C@H:14]([OH:28])[CH2:15][O:16][C:17]1[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:19][S:20][N:21]=1)([CH3:8])[CH3:10].[CH:3](/[C:5]([OH:7])=[O:6])=[CH:2]/[C:1]([OH:16])=[O:29]
Reactant: O
Reactant: CCC(C)C(=O)O
Agent: CC(=O)[O-]
Agent: CC(C)(C)NC[C@H](O)COc1nsnc1N1CCOCC1
Agent: [Zn+2]
Product: O=C(O)/C=C\C(=O)O

Procedure:
15 grams of Carbopol 974P is dispersed in 40 grams of heavy mineral oil USP and is added to 841.5 grams of water containing 2.5 grams of timolol meleate with vigorous stirring. 100 grams of water containing 1.0 gram of zinc acetate is added in a controlled fashion with homogenization to get a particle size distribution size below 5 micron.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11](Br)[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of p-nitrophenol (56.0 g. 0.4 mole) in acetone (400 ml.) was added n-butyl bromide (60.0 g., 0.44 mole) and potassium carbonate (anhydrous, 56.0 g., 0.4 mole). The mixture was heated on the steam bath for 48.0 hours. The acetone was removed from the reaction mixture in vacuo. Then, water (400 ml.) was added to the residue, which was extracted twice with benzene (200 ml. portions). The benzene layers were washed thrice with 10% sodium hydroxide solution (150 ml. portions). The washed layers of benzene were then dried over anhydrous potassium carbonate and the solvent was removed in vacuo. The product obtained after evaporation of the solvent was a crude yellow liquid (63.0 g. 79%). This was used in Part B without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: COCCCN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: COCCCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-methoxypropylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(3-methoxypropyl)terephthalamide. MS (Q1) 459 (M)+.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:3]=1.[Cl-].ClC=[N+](C)C.ClC1C(C(OCC)=O)=CN=C(C2C=CC=C([N+]([O-])=O)C=2)N=1.[NH2:49][NH2:50]>CCOCC.CCCCCC>[NH:49]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:3]=1)[NH2:50]
Reactant: NN
Reactant: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1O
Agent: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1Cl
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1NN
Yield: 33 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (5 g, 24 mmol) with 3-nitrobenzamidine (5 g, 25 mmol) to afford 86% of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (6 g, 21 mmol) with (chloromethylene)dimethylammonium chloride (4 g, 31 mmol) concentration of reaction mixture, followed by hexane and ether wash afford 45% of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.9 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 33% of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.8 g, 6 mmol) with citraconic anhydride in analogy to Example 21, to afford 80% (0.5 g) of the title compound; m.p. 118-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25].[Na+].[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[Br:22][CH2:23][C:24]([NH:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: Nc1ccoc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1ccoc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3-Amino-2-benzoylfuran (4.93 g, 0.025 mol) was dissolved in s dry methylene chloride (50 mL). The solution was cooled to 0° C. under nitrogen and triethylamine (3.8 mL, 0.0275 mol) was added followed by bromoacetyl bromide (2.4 mL, 0.0275 mol). The mixture was stirred at 0° C. for five hours. Next another 10% of triethylamine and bromoacetyl bromide were added and the reaction was left over night. Ehtyl acetate (200 mL) and saturated NaCl (75 mL) were added. The ethyl acetate layer was separated, washed with saturated NaCl solution, dried over sodium sulfate, filtered and concentrated in vacuo. A tan solid was obtained in theoretical yield (7.7 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:25]([CH3:27])[CH3:26])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: CSc1ccc2c(C(=O)C(F)(F)F)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-methylsulfanyl-1H-indol-3-yl)-ethanone (200 mg, 0.77 mmol) in N,N-dimethylformamide (2 mL) at 25° C. was treated with potassium carbonate (160 mg, 1.16 mmol). The reaction was stirred at 25° C. for 15 min and then was treated with 2-iodopropane (0.11 mL, 1.16 mmol). The reaction was stirred at 25° C. for 18 h and then was heated at 60° C. for 2 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(1-isopropyl-6-methylsulfanyl-1H-indol-3-yl)-ethanone (216 mg, 93%) as an off-white solid: mp 67-69° C.; (ES)+-HRMS m/e calcd for C14H14F3NOS (M+) 301.0748, found 301.0740.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of 4-fluorophenyl methyl sulfone (2.00 g), (R)-2-methylpiperazine (2.30 g) and K2CO3 (3.20 g) in anhydrous DMF (80 mL) was heated at 100° C. for 5 hours. The reaction mixture was filtered to remove salts and the solvent was evaporated under reduced pressure to give a yellow oil. Purification by flash chromatography (CHCl3/MeOH) gave 1.36 g (47%) of the title compound as a pale yellow solid. M+(ESI): 255.2. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 100%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[CH:15]=[CH:14][C:13]=1[CH2:22][OH:23].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[CH:15]=[CH:14][C:13]=1[CH:22]=[O:23]
Reactant: Cc1nc2c(Br)c(CO)ccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc2c(Br)c(C=O)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (1.13 mL, 0.016 mol) was added to oxalyl chloride (0.84 mL, 0.0099 mol) in methylene chloride (37.10 mL) at −78° C. After 10 minutes, (4-bromo-2-methyl-1,3-benzothiazol-5-yl)methanol (1.71 g, 0.00662 mol) in methylene chloride (74 mL) was added and the resultant mixture was stirred at −78° C. for 30 minutes. Triethylamine (4.62 mL, 0.0331 mol) was then added and the mixture was stirred for 5 h and the temperature allowed to gradually warm up to room temperature. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated to dryness. The resultant solid was used directly in next step (1.70 g, 100%). LCMS calculated for C9H7BrNOS(M+H)+: m/z=255.9; found: 255.9.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][CH:10]=N1.[N:13]1([CH2:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH-:27])=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>C(OCC)(=O)C>[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH:10]=[CH:11][CH:12]=[N:8]3)=[CH:28][CH:29]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: [NH-]CCCOc1ccc(Cn2cccn2)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cnn(CCCOc2ccc(Cn3cccn3)cc2)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (5 ml) and sodium hydride (60% oil dispersion) (62 mg) was added pyrazole (100 mg), and the mixture was stirred for 30 minutes. An anhydrous N,N-dimethylformamide solution (5 ml) of 3-[4-(1-pyrazolyl)methylphenoxy]propylamide (produced in Reference Production Example 1 described below) (434 mg) was then added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then diluted with ethyl acetate (50 ml), which was washed twice with saturated aqueous ammonium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was subjected to silica gel column chromatography, which afforded 340 mg of 1-{3-[4-(1-pyrazolyl)methylphenoxy]propyl}pyrazole (compound 31) in colorless oil. Yield, 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using (+)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (1.351 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (480 mg, 1.99 mmol, 1.5 eq.) to obtain a residue. The residue was chromatographed on silica gel (70 g) packed with ethyl acetate, loaded with ethyl acetate, and eluted with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane to give the title compound:
Reaction SMILES: [C:1]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21]C(=O)OCC2C=CC=CC=2)[CH:12]=[C:11]([CH3:32])[N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CCOC(C)=O.[Pd]>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:13]1[CH:12]=[C:11]([CH3:32])[N:10]=[C:9]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[N:14]=1
Reactant: Cc1cc(-c2ccncc2NC(=O)OCc2ccccc2)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccncc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 90 %

Procedure:
Method 26 was followed using benzyl 4-(2-(di-BOC-amino)-6-methylpyrimidin-4-yl)pyridin-3-ylcarbamate (1.0 equiv.), Pd/C (20% by weight) in EtOAc yielding 4-(3-aminopyridin-4-yl)-N,N-di-BOC-6-methylpyrimidin-2-amine in 90% yield. LCMS (m/z): 402.3 (MH+); LC Rt=3.0 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH2:23][CH3:24])[N:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:23]([N:22]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:19][CH:20]=[N:21]1)[CH3:24]
Reactant: CCn1nccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (927 mg, 6.5 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.70 g, 19.6 mmol) and 5-(bromomethyl)-1-ethyl-1H-pyrazole (8.5 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM/MeOH to afford 2-{[(1-ethyl-1H-pyrazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (265 mg, 16% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.32 (t, J=7.0 Hz, 3H), 2.21 (s, 3H), 4.15 (q, J=7.2 Hz, 2H), 4.50 (s, 2H), 6.04 (bs, 1H), 6.22 (d, J=1.7 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H).
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Cl:32][C:33]1[C:34]([N:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]3[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=3)[CH2:63][CH2:62]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:33]1[C:34]([N:61]2[CH2:62][CH2:63][N:64]([CH2:67][C:68]3[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=3)[CH2:65][CH2:66]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[CH:46][CH:47]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cnc2[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Yield: 48.4 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-chloro-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (10 mg, 0.0169 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (4 mg, 49%) as a pale yellow solid;
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH3:21])[CH:12]=2)[OH:10])=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][CH:7]=2)=[O:10])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH3:21]
Reactant: CCOc1cc(C(O)c2ccc(N(C)C)cc2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(NC)cc2)ccc1OC
Yield: 24.5 %

Procedure:
To a stirred solution of (4-dimethylamino-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (1.29 g, 4.3 mmol) in CH2Cl2 (30 mL) at room temperature was added activated MnO2 powder (2.1 g, 24 mmol) and kept adding 23 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (3-ethoxy-4-methoxy-phenyl)-(4-methylamino-phenyl)-methanone as an brown solid (0.30 g, 23% yield): 1H NMR (CDCl3) δ 1.48 (t, J=7 Hz, 3H, CH2CH3), 2.92 (d, J=3 Hz, 3H, NCH3), 3.95 (s, 3H, OCH3), 4.16 (q, J=7 Hz, 2H, CH2CH3), 4.27 (brs, 1H, NH), 6.57-6.62 (m, 2H, Ar), 6.88-6.91 (m, 1H, Ar), 7.33-7.39 (m, 2H, Ar), 7.72-7.76 (m, 2H, Ar). The product was used in the next step without further purification.