Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OO)(C)(C)C.[CH2:7]([OH:18])[C@@H:8](O)[C@H:9]1[O:14][C:12](=[O:13])[C:11](O)=[C:10]1O.N>O>[C:12]([O:14][CH2:9][CH:8]1[O:18][CH2:7]1)(=[O:13])[C:11]([CH3:10])=[CH2:1]
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Reactant: CC(C)(C)OO
Agent: N
Solvent: O
Product: C=C(C)C(=O)OCC1CO1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
The initiator solution consisted of 2.5 g of 70% t-butyl hydroperoxide dissolved in 25 g of water and the reducing agent solution consisted of 1.4 g of erythorbic acid, 0.5 g of aqua ammonia, and 25 g of water. The reactor contents were heated to 50° C. and 52.8 g of monomer mixture #1 was added to the reactor. Two ml of the initiator solution and 1 ml of the reducing agent solution were separately added to the reactor. Polymerization was started. The remaining monomer mixture #1 was added over a 60 minute period followed by a 30 minute addition of monomer mixture #2. The remaining initiator and reducing agent solutions were added over a 105 minute period. After completion of the additions, the polymer dispersion was held at 70° C. for 30 minutes. The polymer dispersion was checked by gas chromatographic analysis for residual unreacted monomer. The monomer content was less than 1000 ppm. The dispersion was cooled to room temperature and the physical properties determined.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:11]1[C:15]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[C:14]([CH3:31])[N:13]([CH2:32][C:33]([O:35][CH2:36]C)=[O:34])[C:12]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:38][C:12]1[N:13]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:14]([CH3:31])=[C:15]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)(=[O:25])=[O:24])[C:11]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(C)c(I)c(Sc2ccccc2S(=O)(=O)N2CCCC2)c1C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cn1c(C)c(Sc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c1C
Temperature: 100 °C
Yield: 23.1 %

Procedure:
To a solution of phenylboronic acid (26.9 mg, 0.221 mmol) in methanol (1.0 mL) and toluene (1.0 mL) was added ethyl 2-(3-iodo-2,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)phenylthio)-1H-pyrrol-1-yl)acetate (121 mg, 0.221 mmol), palladium tetrakistriphenylphosphine (12.8 mg, 0.0110 mmol) and sodium carbonate (0.090 mL, 0.18 mmol). The reaction mixture was heated at 100° C. for 2.5 hours, then heated at 60° C. for 16 hours, after which an additional 0.10 equiv. of both phenylboronic acid and palladium tetrakistriphenylphosphine were added. The reaction was then heated at 100° C. for one more hour, after which it was allowed to cool down to room temperature, poured over ice water (10 mL), extracted with ether (2×20 mL), and washed with water (1×30 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated. Purification by column chromatography on silica gel afforded methyl 2-(2,5-dimethyl-3-phenyl-4-(2-(pyrrolidin-1-ylsulfonyl)phenylthio)-1H-pyrrol-1-yl)acetate (0.0246 g, 0.0510 mmol, 23% yield) as a light brown residue. LCMS: ES+ [M+H]+=485.3
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:24])[CH:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:30].Cl>C1COCC1.O>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:30])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:24])[CH:11]=[CH2:12]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C=CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(CC(=O)c1ccc(Br)cc1)(Cc1cccc(C(F)(F)F)c1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Diallyl-2-(3-trifluoromethylbenzyl)malonate (1.03 g, 3.01 mmol) in anhyd THF (20 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 84 mg, 3.31 mmol) in anhyd THF (20 mL) at room temperature. The clear solution was stirred at room temperature for 30 min and then a solution of 2,4′-dibromoacetophenone (1.0 g, 3.61 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to 50° C. for 3 h (TLC control), cooled to room temperature and then water (10 mL) was added cautiously. The reaction mixture was acidified to pH 3 with 2 N hydrochloric acid and then extracted with ethyl acetate (3×30 mL). The combined extract was washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10% ethyl acetate in heptane) afforded the title compound as a colorless oil (1.23 g)
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Yield: 72.1 %

Procedure:
15.0 g of ethyl 4-[p-chloro-N-(biphenyl-2-yl)benzamido]-butyrate is dissolved in 100 ml of benzene and, after the addition thereto of a solution of 2.8 g of potassium hydroxide in 20 ml of ethanol, is then stirred at room temperature for 5 hours. The solvent is then distilled off in vacuo, and the obtained residue is dissolved in water. The resulting aqueous solution is acidified with dilute hydrochloric acid, and the precipitate, which separates out, is taken up in methylene chloride. The residue remaining, after drying and distilling off the methylene chloride, is recrystallized from an ethanol/water mixture (2:1) to obtain 10.1 g (72.1% of theory) of 4-[p-chloro-N-(biphenyl-2-yl)benzamido]butyric acid, MP 135° to 137°.
Reaction SMILES: [NH2:1][C:2](=[N:34]O)[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[C:21]([OH:23])(=[O:22])[CH3:20].[NH2:34][C:2](=[NH:1])[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:33])[C:13](=[O:14])[N:12]([CH2:15][C:16]([NH:18][C@H:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C(N)=NO)cc2)C1=O)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](NC(=O)CN1C(=O)N[C@@](C)(c2ccc(C(=N)N)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 168.1 %

Procedure:
11 kg (22.869 mol) of ethyl (S)-3-(2-((S)-4-(4-(amino-hydroximino-methyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenyl-propionate were dissolved in 70 l of glacial acetic acid and this solution was introduced into a 125 l autoclave. A suspension of 1.0 kg of palladium/charcoal (10%; 50% water) and 5 l of glacial acetic acid was added to the solution. The mixture was hydrogenated for 15 h at 50° C. and 10 bar hydrogen pressure. The catalyst was filtered off with suction through a pressure filter under nitrogen and washed with 5 l of glacial acetic acid. The filtrate was completely evaporated in vacuo on a rotary evaporator at a bath temperature of 60° C. The residue was dissolved in 30 l of acetone and the solution was added, over 30 min and at 20° C., to 200 l of methyl tert-butyl ether. The mixture was subsequently stirred at room temperature for 1 h and the precipitated product was centrifuged. The filter cake was subsequently washed with 10 l of methyl tert-butyl ether, removed from the centrifuge and dried in vacuo. 10.1 kg (85%) of product were obtained. FAB-MS: 466 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH3:17][C:11]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][CH3:1])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CSc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccccc1SC
Temperature: 105 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
2-Methylsulfanyl-phenol (2.00 g, 14.29 mmol), 2-bromo-2-methyl-propionic acid, ethyl ester (28 g, 142.8 mmol) and powdered K2CO3 (4.93 g, 35.7 mmol) were mixed (no solvent) and stirred at 105° C. for 8 hrs. After cooling, water and CHCl3 were added. The CHCl3 was separated, dried (MgSO4) and concentrated. Xylene was added and concentrated in vacuo (4 times) to remove the bromo ester. The resulting oil was chromatographed on silica, eluting with CH2Cl2 to obtain the title compound (2.30 g, 63% yield).
Reaction SMILES: [OH:1][C:2]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O.Cl(O)(=O)(=O)=O.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCc1c(C)cc(OC)c(OC)c1O

Procedure:
To a solution (15 ml) of 3 g of methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate in ethyl acetate are added 0.015 ml of 60% perchloric acid and 600 mg of 5% palladium-on-carbon, and catalytic reduction is carried out at a 70° C. using hydrogen gas at the pressure of 100 kg/cm2. The catalyst is filtered off and the filtrate is washed in sequence with ice water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure gives colorless crystals of methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoate. m.p. 71°-72.5° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:21]([O-])([N+]([O-])=O)=[O:22]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1OC[C@@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 64.9 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-xylopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.2 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-xylopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]Cl)[C:22]=1[CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO.C(OCC)(=O)C>[CH2:14]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:22]=1[CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 25.5 %

Procedure:
To a liquid prepared by dissolving with stirring 7.8 g (0.052 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 61.5 g (0.319 mol, 5.8 eq.) of a 28% sodium methoxide solution in 360 mL of methanol, a liquid prepared by dissolving the whole amount of 4-hexyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 30° C. Subsequently, the mixture was heated to reflux for 30 minutes and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 200 mL of ethyl acetate, and then the organic layer was washed with 80 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 15.2 g of an orange-colored oily matter. The product was recrystallized from ethyl acetate (5 vol.), to obtain 5.0 g of colorless crystals (HPLC: 99.1 Area %, yield 25.5%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[CH2:12][N:13]2[C:17](=[O:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[S:14]2(=[O:24])=[O:23])[CH:6]=1>CN(C=O)C>[CH3:4][C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH2:12][NH:13][S:14]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]([O:2][CH3:1])=[O:18])(=[O:24])=[O:23])=[O:25])[CH:6]=1
Reactant: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1S(=O)(=O)NCC(=O)Nc1cc(C)on1
Yield: 74.4 %

Procedure:
To 60 ml DMF is added 13.5 grams (0.25 mole) of sodium methoxide. To this slurry at 15°C. is added a solution of 20 grams (0.062 mole) of 2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide dissolved in 70 ml DMF. The reaction mixture is stirred at 25°-30°C. for a half hour whereupon it is acidified and extracted with chloroform. These extracts are washed with sodium bicarbonate and water, dried (na2SO4) and concentrated to an oil which is triturated with petroleum ether to give 16.3 grams (75%) of methyl 2-{[({[(5-methyl-3-isoxazolyl)amino]carbonyl}methyl)amino]sulfonyl}benzoate, mp 153°-156°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](Cl)=[O:25]>C1COCC1>[F:21][C:22]([F:28])([F:27])[CH2:23][C:24]([NH:7][C:6]1[S:5][C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Cc1nc(-c2cccnc2)sc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2)sc1NC(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
286 mg (1.49 mmol) of 4-methyl-2-(pyridin-3-yl)-1,3-thiazole-5-amine were dissolved in THF, 0.52 ml of triethylamine was added, and 263 mg of trifluoropropionyl chloride were added while cooling with an ice bath. The mixture was stirred at room temperature overnight and then concentrated. Ethyl acetate, saturated sodium chloride solution and aqueous phosphate buffer pH=7 were added to the residue, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography (silica gel, cyclohexane, acetone).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][F:30])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][Mg]Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:39])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][F:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[S:14]2)[C@H:10]1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(CCF)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3aR,5S,6S,7R,7aR)-6,7-bis(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (400 mg, 0.73 mmol) in THF (20 mL) was added methylmagnesium chloride (1 mL, 3M in THF). After stirred for 3 hours at 0-5°C., the resulting solution was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 20% ethyl acetate in petroleum ether to give compound 73 as a yellow oil (0.37 g, 90%, diasteromers' ratio is 1:4). (ES, m/z) [M+H]+ 561.0; 1H NMR (300 MHz, CDCl3) δ 7.25-7.44 (m, 10H), 6.13-6.15 (d, J=6.9 Hz, 1H), 4.73-4.78 (m, 2H), 4.54-4.68 (m, 2H), 4.28-4.49 (m, 4H), 4.07-4.25 (m, 2H), 3.75-3.97 (m, 2H), 3.12-3.17 (m, 1H), 1.54 (s, 9H), 1.22-1.24 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH:13]=O)[CH2:9][C:10](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#C>C(OC(=O)C)(=O)C>[CH2:1]([N:8]1[CH:9]=[CH:10][C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCC
Reactant: O=CN(CC(=O)O)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(Cc2ccccc2)c1
Yield: 94 %

Procedure:
Using 1.93 g (10 mmol) of N-benzyl-N-formylglycine, 3.65 g (37.2 mmol) of ethyl propiolate and 10 ml of acetic anhydride, a reaction and post treatment were conducted in a similar manner as, in Referential Example 1. The resulting brown oil was purified by silica gel column chromatography [silica gel: “No.9385”, product of Merck & Co., Inc. (the same silica gel was also used in the subsequent referential examples and examples); eluent: ethyl acetate/hexane=1/3], whereby 2.156 g of the title compound were obtained (yield: 94.0%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][C:25]=1[N+:34]([O-:36])=[O:35]>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:32])=[O:31])=[CH:26][C:25]=1[N+:34]([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNS(=O)(=O)c3ccc(Cl)c([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-chloro-3-nitrobenzenesulfonyl chloride: ESMS m/e: 523.1 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][CH:6]=[CH:5][CH:4]2[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH2:13][CH2:12]2)[O:2]1.[H][H]>C(O)C.[Pd]>[CH2:27]1[CH2:1][O:2][C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=3)[CH2:15][CH2:16]2)[O:26]1
Reactant: Fc1cc(C2CCC(CCC3C=CCCC34OCCO4)CC2)cc(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1cc(C2CCC(CCC3CCCCC34OCCO4)CC2)cc(F)c1F
Yield: 92 %

Procedure:
Pd/C (5% ) (1 g) was added to a solution of 1,1-ethylenedioxy -(2'-(4"-(3'",4'",5'"-trifluorophenyl)cyclohexyl)-ethyl)-3-cyclohexene (6.7 g) in ethanol (200 ml), followed by carrying out catalytic reduction in a hydrogen gas atmosphere, filtering off the catalyst after completion of the reaction and distilling off the solvent from the organic layer under reduced pressure, to obtain 1,1 -ethylenedioxy-(2'-(4"-(3'",4'",5'"-trifluorophenyl)cyclohexyl)ethyl)cyclohexane (6.2 g).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]1CCC(N)CC1>>[CH3:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][N:24]([CH3:23])[CH2:4][CH2:5]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: CN1CCC(N)CC1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCN(C)CC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-methylpiperidin-4-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68 (bs, 4H) 1.85 (s, 3H) 2.13 (bs, 3H) 2.57 (bs, 3H) 2.66 (bs, 2H) 3.13 (d, J=11.82 Hz, 2H) 3.81 (bs, 1H) 4.52 (d, J=5.91 Hz, 2H) 6.52 (s, 1H) 7.15-7.22 (m, 1H) 7.27 (d, J=7.79 Hz, 1H) 7.70 (d, J=7.66 Hz, 1H) 8.48 (d, J=4.03 Hz, 1H); MS (ESI) m/z 327.5 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[C:17](OC)(OC)(OC)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO.C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([CH3:18])[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (2.50 g, 8.89 mmol) in methanol (25 mL) and THF (100 mL) was added trimethyl orthoacetate (16.77 ml, 133.4 mmol) and TsOH (153.14 mg, 0.89 mmol). The reaction mixture was stirred at 70° C. for 1 hr then allowed to cool to RT overnight. Saturated aqueous sodium bicarbonate (30 mL) was introduced and the resulting precipitous solution filtered. The filtrate was extracted into DCM (3×100 mL extractions). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The orange/yellow solid residue was then triturated from a mixture of DCM and MeOH to give the title compound as a pale yellow powder (400 mg): 1H NMR (500 MHz, DMSO) delta 2.89 (3H, s), 7.46 (1H, dd, J=8.5, 1.9 Hz), 7.57 (1H, d, J=8.4 Hz), 8.02 (1 H, s), 8.10 (1H, s), 8.61 (1H, d, J=1.8 Hz), 8.64 (1H, s); LC-MS: m/z=+306.7 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1.[F:13][C:14]([F:21])([F:20])C1C=NNC=1>>[F:13][C:14]([F:21])([F:20])[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: O=C(O)C1(n2cc(F)cn2)CC1
Product: O=C(O)C1(n2cc(C(F)(F)F)cn2)CC1

Procedure:
The title compound was prepared by a method analogous to Intermediate 4 but using 4-(trifluoromethyl)-1H-pyrazole in Step 1. 1H NMR (400 MHz, CDCl3) δ 1.60-1.79 (m, 2H), 1.83-1.95 (m, 2H), 7.75 (s, 1H), 7.78-7.89 (m, 1H), 11.82 (br s, 1H).