Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1)(=[O:4])=[O:3]>[OH-].[OH-].[Pd+2].CO.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(N)cn1
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A suspension of 241 mg (0.34 mmol) of 20% of Pearlman's catalyst on carbon and 693 mg (3.43 mmol) of the 2-methanesulfonyl-5-nitropyridine in 15 mL of MeOH and 3 mL of ethyl acetate was stirred under an atmosphere of hydrogen for 3 hours. The solution was filtered and concentrated. The crude mixture was further purified by filtration through a silica column with ethyl acetate to afford 510 mg (86%) of 6-methanesulfonylpyridin-3-ylamine.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:17](Br)(=[O:19])[CH3:18]>C(Cl)Cl>[C:4]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Br
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
Lithium hydroxide monohydrate (600 mg, 25.0 mmol) was added to a solution of the amine 3 (1.44 g, 8.53 mmol) dissolved in CH2Cl2 (125 mL) at 0° C. A solution of acetyl bromide (1.97 mL, 25.6 mmol) in CH2Cl2 (10 mL), was added dropwise over 5 minutes at 0° C. to the reaction mixture which was then allowed to warm to ambient temperature and stirred for 2 hours. The reaction crude was filtered, concentrated under reduced pressure, and purified by flash chromatography over silica, eluting with a gradient of 100% CH2Cl2 to 10% MeOH/90% CH2Cl2, yielding product 4 as white solid (1.11 g, 61.5%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:9](=[O:18])[C:8]=2[CH:19]=1.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[N:24]([CH3:29])[C:23](=[O:30])[CH:22]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:12][CH2:13][N:14]([C:21]4[N:26]([CH3:27])[C:25](=[O:28])[N:24]([CH3:29])[C:23](=[O:30])[CH:22]=4)[CH2:15][CH2:16]3)[CH2:10][C:9](=[O:18])[C:8]=2[CH:19]=1
Reactant: COc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)C(=O)CC1(CCN(c3cc(=O)n(C)c(=O)n3C)CC1)O2
Yield: 61 %

Procedure:
A solution of 3,4-dihydro-6-methoxyspiro-[(2H)-1-benzopyran-2,4'-piperidin]-4-one hydrochloride (0.568 g, 2 mmol), 6-chloro-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione (0.349 g, 2 mmol) and sodium bicarbonate (0.42 g, 5 mmol) in acetonitrile was heated at reflux for 42 hours. After cooling, the reaction mixture was concentrated in vacuo to dryness. The residue was partitioned between chloroform and water. The chloroform solution was washed twice with water and once with saturated brine solution and then dried over sodium sulfate and concentrated to dryness in vacuo. The solid residue was recrystallized from methanol/ethanol to give the title compound (0.47 g, 61% yield) mp 202°-203° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.[F-].[K+]>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[OH:10]
Reactant: COc1cc(O)c([N+](=O)[O-])c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(O)c(N)c(Cl)c1
Yield: 73 %

Procedure:
A solution of 3-chloro-5-methoxy-2-nitrophenol [1] (450 mg) and tin(II) chloride dihydrate (2 g, 4 eq.) in ethyl acetate (30 mL) was heated under reflux for 4 h. The mixture was cooled, diluted with ethyl acetate and aqueous potassium fluoride. The mixture was filtered through celite. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent afforded the title compound (280 mg) as a pale solid. NMR (DMSO-d6): 9.74 (m, 1H), 6.33 (d, 1H, J=2.4 Hz), 6.30 (d, 1H, J=2.4 Hz), 4.19 (m, 2H), 3.60 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 3-nitro-4-pyridinol (20 g, 143 mmol) in toluene (300 mL) was added phosphorous oxychloride (65.7 g, 429 mmol) at 0° C. The resulting mixture was warmed to room temperature, then heated to reflux (110° C.) for 16 hours. After cooling to rt, the solvent was removed in vacuo and the residue was poured on ice, then basified with K2CO3 to pH≈10. The mixture was extracted with ethyl acetate and the organic phase was washed twice with water, followed by once with brine before concentrating to a brown oil which solidified on standing (22.5 g, 99%). MS (ES+) m/e 159 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]1>CC(C)=O>[NH2:11][C:6]1[N:5]=[C:4]([S:12][CH3:13])[N:3]=[C:2]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CSc1nc(N)c([N+](=O)[O-])c(Cl)n1
Reactant: O=S1CCNCC1
Solvent: CC(C)=O
Product: CSc1nc(N)c([N+](=O)[O-])c(N2CCS(=O)CC2)n1
Yield: 78.2 %

Procedure:
3.08 gm (0.014 mol) of 4-chloro-6-amino-2-methylthio-5-nitro-pyrimidine were dissolved in 50 ml of acetone, and a solution of 3.2 gm (0.027 mol) of thiomorpholine-1-oxide in 20 ml of acetone was added dropwise at room temperature, while stirring. After stirring the mixture for 1.5 hours more, ice was added to the reaction mixture, and the yellow precipitate formed thereby was suction-filtered off and recrystallized from ethanol. Yield: 78.2% of theory; m.p. 239°-242°C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:21][C@@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(O)CCC>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[N:3]=[CH:4][N:5]=1
Reactant: OCCc1c(Cl)ncnc1Cl
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Temperature: 130 °C
Yield: 98.2 %

Procedure:
2-(4,6-dichloropyrimidin-5-yl)ethanol (1.90 g, 9.84 mmol) was dissolved in 1-butanol (97 mL) and N,N-Diisopropylethylamine (3.43 mL, 19.7 mmol) and (S)-1-Aminoindane (1.26 mL, 9.84 mmol) were added. The solution was heated at 130° C. for 3 days. Solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 100% ethyl acetate in methylene chloride to afford the title compound (2.80 g, 98%). LC/MS: Rt=1.63 min, ES+ 290 (AA standard).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH:28][C:29](=[O:47])[N:30]([CH3:46])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([N:30]([CH3:46])[C:29]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:47])[CH:36]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCCCC)c1
Temperature: 92.5 °C
Yield: 84.4 %

Procedure:
In a manner similar to that of Example 34a, 3 mg (0.013 mmol) of palladium acetate and then 9 mg (0.026 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 505 mg (1.3 mmol) of ethyl (E)-3-(3-butoxy-4-iodophenyl)-2-methylacrylate prepared as described in Example 19h, 494 mg (1.7 mmol) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]urea and 1.3 mL of aqueous 2 M potassium phosphate solution in 6.5 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 2 hours. The reaction medium is hydrolyzed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated off and the brown oil obtained (1.3 g) is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 558 mg (84%) of ethyl (E)-3-[2-butoxy-3′-(3-heptyl-1-methyl-ureido)biphenyl-4-yl]-2-methylacrylate are obtained.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=O)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.[BH4-].[Na+].[ClH:29]>CO.[OH-].[Na+].CO>[ClH:29].[ClH:29].[ClH:29].[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][CH2:11][C:8]2[N:7]=[CH:6][C:5]3[O:4][CH2:3][CH2:2][O:1][C:10]=3[CH:9]=2)[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CCC(NCc3cc4c(cn3)OCCO4)CC2)cc1
Reaction time: 2 h

Procedure:
A solution of 3.0 g of 2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-carbaldehyde and 3.4 g of 4-amino-1-benzylpiperidine in 30 mL of methanol was stirred for 50 minutes at room temperature, and a solution of 0.34 g of sodium borohydride in 30 mL of 0.01 mol/L sodium hydroxide/methanol was added dropwise thereto under ice cooling. The mixture was further stirred for 2 hours under ice cooling, 6 mL of concentrated hydrochloric acid was added dropwise thereto at 10° C. or lower and stirred for 1 hour 30 minutes. The solid product was obtained by filtration to give 6.8 g of 1-benzyl-N-(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)piperidin-4-amine trihydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:12]([Br:13])=[CH:11][C:10]([C:14]([F:26])([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[Br:27])=[O:5].[F-:35].[K+]>CS(C)=O>[Br:27][C:8]1[CH:9]=[C:10]([C:14]([F:26])([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:12]([Br:13])[C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:28]=[CH:29][CH:30]=[C:31]([N+:32]([O-:34])=[O:33])[C:2]=1[F:35]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1F
Temperature: 145 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To 108 ml of DMSO were added 5.44 g (8.34 mmol) of 2-chloro-N-(2,6-dibromo-4-(perfluorobutan-2-yl)phenyl)-3-nitrobenzamide and 4.90 g (84.3 mmol) of potassium fluoride (spray-dried product), followed by stirring at 145° C. for 2 hours. The reaction solution was poured into ice-water to precipitate the crystal, and the obtained crystals were filtered and washed with hexane. The obtained crystals were purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=5:1) to prepare 2.42 g (yield 46%) of a target compound.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[C:6](/[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Br:37])\[CH2:7][NH:8][CH:9]([C:17](=[O:29])[NH:18][C:19]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[N:20]=1)[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)C>O1CCCC1>[Br:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:6]1[CH2:7][N:8]([CH:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:17]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C:25]([OH:28])([CH3:26])[CH3:27])[N:20]=2)=[O:29])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)/C=C(\CNC(CC1CCOCC1)C(=O)Nc1ccn(CC(C)(C)O)n1)Oc1ccccc1Br
Solvent: C1CCOC1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)N2CC(Oc3ccccc3Br)=CC2=O)n1
Yield: 34.7 %

Procedure:
A solution of (E)-3-(2-bromo-phenoxy)-4-{1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-4-yl)-ethylamino}-but-2-enoic acid ethyl ester (250 mg) in tetrahydrofuran (8 mL) was placed in an Emrys Optimizer microwave tube and microwaved at 160° C. for 3 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 4 g, 30% to 100% ethyl acetate/hexanes) which afforded 2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (80 mg, 35%) as a light yellow solid: HR-ES-MS (m/z) calculated for C25H31BrN4O5 [M+H]+ 547.1551, observed 547.1551. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.11-1.48 (m, 3H), 1.53-1.73 (m, 3H), 1.73-1.89 (m, 1H), 3.11-3.31 (m, 2H), 3.72-3.87 (m, 2H), 3.89 (s, 2H), 4.24 (d, J=18.4 Hz, 1H), 4.62 (d, J=18.4 Hz, 1H), 4.66-4.72 (m, 1H), 4.79 (s, 1H), 4.93 (dd, J=10.6, 4.8 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 7.22-7.34 (m, 1H), 7.48-7.53 (m, 2H), 7.54 (d, J=2.1 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 10.81 (br. s., 1H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][S:8][C:9]1[C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1>O1CCOCC1>[C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:16]2[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH3:7])[C:14]=3[N:15]=2)[CH2:26][CH2:27]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: CSc1ncnc2c(N3CCSCC3)nc(N3CCNCC3)nc12
Solvent: C1COCCO1
Product: CSc1ncnc2c(N3CCSCC3)nc(N3CCN(C(=O)CC(C)=O)CC3)nc12
Reaction time: 0.5 h

Procedure:
1.6 gm (0.02 mol) of diketene were slowly poured, while stirring, into a solution of 3.6 gm (0.01 mol) of 8-methylthio-2-piperazino-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 177°-179° C.) in 50 ml of dioxane. After stirring for 30 minutes more, the solvent was evaporated in vacuo, and the residue was taken up in about 100 ml of water. The precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C=O)cn2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(CO)cn2)cc1
Yield: 66.9 %

Procedure:
To a solution of 4-tert-butyl-N-[6-{2-(5-formylpyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide (143 mg) in tetrahydrofuran-isopropanol (4 ml-4 ml) is added sodium borohydride (13 mg) under ice-cooling, and the mixture is reacted for two hours. The mixture is treated with aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=200:1~50:1), and crystallized from diethyl ether to give 4-tert-butyl-N-[6-{2-(5-hydroxymethylpyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide (96 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]([O-])([O-])OC>>[CH3:11][O:10]/[C:3](/[CH2:2][Cl:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COC([O-])[O-]
Product: CCOC(=O)/C=C(/CCl)OC
Reaction time: 8 h
Yield: 83 %

Procedure:
Two grams of amberlyst 15 ion exchange resin was added to a solution of 8.23 g (0.05 mol) of ethyl 4-chloroacetoacetate in 25 mL of methyl orthoformate. The solution was stirred overnight, the resin was filtered, and excess ortho ester was removed in vacuo. The residue was then heated slowly over 1 h to 190° C., after which it was allowed to cool and then short path distilled to yield 7.37 g (83%) of ethyl 3-methoxy-4-chlorocrotonate as a colorless liquid: bp 145°-148° C. (40 mm); VPC (6 ft 5% SF 96 on 60-80 mesh chromosorb G; 160° C.; 60 cm3 /min He flow) tR =1.9 min; NMR (CDCl3) 1.10 (t, 3H, J=7 Hz, COOCCH3), 3.73(s, 3H, OCH3), 4.20 (q, COOCH2C, J=7 Hz, COOCH2C), 4.67 (s, 2H, ClCH2), 5.17 (s, 1H, CH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ncc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pt].[H][H]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CC2CCCCCN2)cc1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(CC2CCCCCN2)cc1

Procedure:
Hydrogenate 12 g of the title compound of Example 16 in 300 ml of ethyl alcohol with platinum/hydrogen. After the absorption of hydrogen has ceased, filter off the catalyst and concentrate the filtrate to obtain 10.5 g (100% of theory) of the title compound as a dark brown viscous oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C1C=CC2N(O)N=NC=2C=1.[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[OH:36])(=[O:26])[CH3:25].C(Cl)CCl>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:13][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([C:24](=[O:26])[CH3:25])=[C:28]([OH:36])[CH:29]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:5]
Reactant: CC(=O)c1ccc(C(=O)O)cc1O
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (968 mg, 4.66 mmol), HOBT (105 mg, 0.78 mmol) and 4-acetyl-3-hydroxy-benzoic acid (700 mg, 3.89 mmol) were dissolved in DMF (5 ml). EDIA (3.01 g, 23.3 mmol) and EDC were added and the mixture was stirred at room temperature for 72 h. Then the mixture was partitioned between EA and saturated sodium chloride solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1.[C:34]([O:38][C:39]([NH:41][C@@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:43](O)=[O:44])=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([I:25])=[CH:27][C:28]=1[NH:33][C:43](=[O:44])[C@@H:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])[C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: Nc1ccc(I)cc1N
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cc(I)ccc1N)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.7 %

Procedure:
HATU (16.25 g, 42.7 mmol) was added to a stirred solution of 4-iodobenzene-1,2-diamine (10 g, 42.7 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (9.88 g, 42.7 mmol) and DIPEA (14.93 mL, 85 mmol) in DMF (120 mL) at 0° C. and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water and EtOAc. The organic layer was washed with water, 10% NaHCO3 solution, brine, dried over Na2SO4 and concentrated to yield (S)-tert-butyl (1-((2-amino-5-iodophenyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (20 g). LC/MS (Condition B-10): Rt=1.94 min. LC/MS: Anal. Calcd. for [M+H]+ C17H27IN3O3: 448.10; found 448.2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1cccnc1Br
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-3-methylpyridine. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[O:16][C:17](=O)[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CC1C=CC(C)=CC=1>[CH2:1]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:17](=[O:16])[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: CCCCCCOc1ccc(N)cc1
Solvent: Cc1ccc(C)cc1
Product: CCCCCCOc1ccc(NC(=O)CC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
4-Hexyloxyaniline (1, 1.00 g, 5.17 mmol) and methyl-4,4-dimethyl-3-oxopentanoate (1.65 mL, 10.3 mmol) were suspended in 5 mL p-xylene and heated to reflux for 17 hours. The reaction was cooled to room temperature and purified by flash chromatography on silica gel eluting with 10% acetone, hexane to yield a brown solid. Recrystallization from hexane provided 1.35 g (82%) of a white solid. mp 70-72° C.; Analysis calculated for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C, 71.72; H, 9.42; N, 4.30.