Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(O)C=CC=CC=1.C(O)(=O)C(O)=O.C=O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc2ccccc12
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)C(=O)O
Solvent: Oc1ccccc1
Product: c1ccc2ccccc2c1

Procedure:
One hundred parts of naphthalene-formaldehyde resin and 100 parts of phenol were reacted for 2 hours at 140° C. using 0.1 parts of p-toluenesulfonic acid as a catalyst. Then, 1 part of oxalic acid and 35 parts of 37% formalin were added, and the mixture was reacted for 2.5 hours at 100° C. Then, the reaction mixture was dehydrated under reduced pressure with heating. When the temperature reached 165° C., dehydration under reduced pressure was completed to obtain a naphthalene resin modified novolak-phenolic resin having a melting point of 125° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Br)C1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)[C@@H](N)CC1(Cc2ccccc2)C=CC=CC1

Procedure:
The synthesis of the benzylphenylalanine methyl ester is described in Scheme II-29. The imine is formed by treating phenylalanine methyl ester with benzaldehyde followed by deprotonation with lithium hexamethyldisilazide to generate the anion and alkylation with benzylbromide to give 1-benzylphenylalanine methyl ester 115. ##STR38##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>CO.O1CCCC1>[F:19][C:20]([F:27])([F:26])[C:21]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(Sc2ccc(CCN)cc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Sc2ccc(CCNC(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-[4-[(4-methoxyphenyl)thio]phenyl]-ethanamine (6.3 g) in methanol (45 ml) and tetrahydrofuran (10 ml) was added ethyl trifluoroacetate (2.89 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 2,2,2-trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl]acetamide (3.95 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[CH:4][N:3]=1.[C:11](OC(OCC)OCC)(=O)C>>[CH3:10][N:9]1[C:7](=[S:8])[N:6]2[N:5]=[CH:4][N:3]=[C:2]2[N:1]=[CH:11]1
Reactant: CNC(=S)n1ncnc1N
Reactant: CCOC(OCC)OC(C)=O
Product: Cn1cnc2ncnn2c1=S
Yield: 88 %

Procedure:
The synthesis method of Example 55 was applied. The compound (1.49 g) obtained in Example 29 and diethoxymethyl acetate (12 ml) were used as reagents. The mixture was reacted at 75° C. for 2 hours to give 1.39 g of white crystals (yield 88%). The crystals were subjected to recrystallization from acetone to give white crystals.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14].BrCC>>[CH2:9]([O:8][P:1]([CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CBr
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCCCCCCCCCCCCCCCCCOC(=O)CP(=O)(OCC)OCC
Temperature: 100 °C
Yield: 98 %

Procedure:
100 parts by weight of triethyl phosphite and 235 parts by weight of octadecyl bromoacetate were put into a reactor equipped with a distillation tube, and the inside of the reactor was substituted by nitrogen. Subsequently, the reactor was heated at 100° C. to start a reaction. Since bromoethane as a by-product began to distill out immediately, the reaction was maintained until the distillation-out of bromoethane slowed down. When the distillation-out of bromoethane became moderate, the reactor was further heated at 150° C. to continue the reaction for 3 hours. The reaction mixture was cooled to room temperature to obtain a precipitate. The precipitate was collected by filtration and recrystallized with acetone to obtain a white plate-like crystal (yield of 98%, melting point of 28 to 31° C.).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:24]
Reactant: CCOC(=O)CCBr
Reactant: O=C(O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1cccc(C(=O)O)c1
Reaction time: 0.08 h

Procedure:
A solution of 3-mercaptobenzoic acid (3.4 g) in DMF (50 mL) was treated with potassium carbonate (3.18 g) and stirred for 5 minutes. A solution of ethyl 3-bromopropionate (2.8 mL) in DMF (10 mL) was added dropwise over 30 minutes and the resulting mixture was stirred for a further 30 minutes. The mixture was partitioned between ethyl acetate and water, and the phases separated. The aqueous phase was acidified with aqueous HCl and extracted further with ethyl acetate. The organic phases were washed with water, dried, filtered and concentrated under reduced pressure to afford the subtitled compound. Yield 5.3 g.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(OCC)C>[N:25]([C@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
Into a solution of trans-2-diphenylmethylpyran-4-yl methanesulfonate 4a (0.33 g, 0.95 mmol) in dry DMF (40 ml) was added sodium azide (0.18 g, 2.85 mmol). The mixture was heated to 100° C. and stirred for 4 hr. The mixture was diluted with ethyl ether, washed with 2M aqueous NaHCO3 and brine, and then dried over anhydrous Na2SO4. Removal of the solvent and purification by flash chromatography (Hexane/Ethyl Acetate 9:1) afforded compound 5a (0.23 g, 82.7% yield) as a liquid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1/[CH:12]=[C:4]1\[C:5](=[O:11])[N:6](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[C:3]\1=[CH:2][CH:10]=[CH:9][CH:8]=2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: O=C1/C(=C\c2ccc[nH]2)c2ccccc2N1/C=C/c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (from Example 71 above) (500 mg, 1.49 mmol) in DMF (8 mL) and TEA (3 mL) was added styrene (0.34 mL, 2.98 mmol) (Aldrich), tri-o-tolylphosphine (361 mg, 1.19 mmol) (Aldrich) and Pd(OAc)2 (67 mg, 0.30 mmol) (Aldrich). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc 5:1) to 1,3-dihydro-(Z)-3-[(1H-pyrrol-2yl)methylene]-[(E)-2-phenylethenyl]-2H-indol-2-one. (Yield 371 mg, 80%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Oc1ccc(-n2cccc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(-n2cccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-pyrrol-1-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (27%, off-white crystals). HPLC-MS m/z=293.2 (M+1), Rt: 4.51 min.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH2:5][CH2:4]1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([CH3:16])([CH3:17])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN1CCC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-ethyl-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (0.28 g) and Pd/C (0.060 g, 10% wt) in 10 mL of EtOAc was placed under H2 which was provided by a balloon and stirred at RT overnight. Then the mixture was filtered through Celite®, condensed, and the residue was purified by flash column chromatography (2% of EtOAc in CH2Cl2). The titled compound was obtained as a pink oil. MS(ES+): 204.8 (M+H)+. Calc'd for C11H16N-204.31.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[CH2:7][CH2:8][NH2:9].[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][NH:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:4]([Br:10])[S:3][C:2]=1[Br:1]
Reactant: NCCc1cc(Br)sc1Br
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: OC(CNCCc1cc(Br)sc1Br)c1ccccc1

Procedure:
A solution of 2,5-dibromothiophene-3-ethylamine (31.6 g) and styrene oxide (13.3 g) in acetonitrile (135 ml) was heated under reflux for 24 hours. After standing at room temperature, brown crystals were filtered contaminated by traces of black tar. Recyrstallisation from acetonitrile (45 ml) with carbon treatment gave the title product (m.p. 94°) as tan crystals.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:6][CH:5]([N:7]2[C:11]([CH2:12][CH3:13])=[C:10]([O:14][C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:9]([CH2:23][CH3:24])=[N:8]2)[CH2:4]1>C(O)=O.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([Cl:21])[CH:18]=1)[O:14][C:10]1[C:9]([CH2:23][CH3:24])=[N:8][N:7]([CH:5]2[CH2:6][N:3]([CH3:1])[CH2:4]2)[C:11]=1[CH2:12][CH3:13]
Reactant: C=O
Reactant: CCc1nn(C2CNC2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCc1nn(C2CN(C)C2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
Paraformaldehyde (30 mg, 0.330 mmol) was added in one portion to a stirred solution of the pyrazole of Example 51 (120 mg, 0.330 mmol) in formic acid (2 ml) at room temperature. The mixture was heated at 100° C. for 5 hours, cooled to room temperature and concentrated under reduced pressure to leave a colourless oil. The oil was dissolved in ethyl acetate (50 ml) and the resulting solution was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (85 mg) as a colourless oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([NH:20][C:21]([N:13]2[CH2:12][CH2:11][N:10]=[C:9]2[CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(SCC2=NCCN2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN=C1CSc1ccccc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
2-Phenylthiomethyl-2-imidazoline (4.8 g; 0.025 mole) was dissolved in CH2Cl2 (200 ml) and the solution cooled to -15° C. before treating dropwise with fresh phenyl isocyanate (3.0 g; 0.025 moles) over 15 minutes. The mixture was allowed to warm to room temperature and stirring continued for a further 2 hours. The solvent was then evaporated in vacuo and the residue recrystallised from ethyl acetate, to give a solid, m.p. 117.4° to 119.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:21][CH:22]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)NCCCCSc2ccc(N)cc2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCCSc2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
A solution of 2.4 g of 4-methyl-N-[4-(4-aminophenylthio)butyl]benzenesulfonamide (Example 72) in 50 ml of pyridine is treated with 1.05 g of methane-sulfonyl chloride, and the solution stirred and heated on the steam bath for 6 hours. The pyridine is then removed in vacuo. The residue is shaken with 100 ml of water, and the mixture acidified below pH=2 with concentrated hydrochloric acid. The precipitate is collected, washed with water and dried. Recrystallization from 50% aqueous ethanol gives shiny white crystals after drying, m.p. 95°-96° C.; yield, 1.2 g.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]=1[OH:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([C:10]([F:12])([F:13])[F:11])[C:4]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(Br)cc(F)cc1C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: Fc1cc(Br)c(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.65 g (28 mmol) of sodium is dissolved in 35 ml of dry ethanol, 5.96 g (23 mmol) of 2-bromo-4-fluoro-6-(trifluoromethyl)-phenol is added and it is stirred for 20 minutes at room temperature, 7.17 g (42 mmol) of benzyl bromide is added and refluxed for 1 hour. Sodium bromide precipitates out crystalline from the solution The hot solution is filtered, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel 60 with dichloromethane/hexane. 6.29 g (18 mmol) =78.3% of the theoretical yield is obtained as a predominantly crystalline solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:14])[CH3:13]>CO.O1CCCC1>[CH2:12]([NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:13]
Reactant: CCN
Reactant: ClCCCOc1cccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CCNCCCOc1cccnc1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (1.00 g, 5.84 mmol) was dissolved in methanol (50 mL) and added to a 2.0 M solution of ethylamine in tetrahydrofuran (5 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 400 mg (38.1%) of an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:32][CH:31]5[C:33]([O:35]C)=[O:34])=[CH:26][CH:25]=4)[CH:17]=3)=[C:11]([CH3:37])[CH:10]=2)[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][C:27]([CH:30]5[CH2:32][CH:31]5[C:33]([OH:35])=[O:34])=[CH:28][CH:29]=4)[CH:17]=3)=[C:11]([CH3:37])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OC4CCS(=O)(=O)CC4)cc3C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(COc2ccc(C3CC3C(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a mixed solution of methyl 2-[4-({4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′- dimethylbiphenyl-3-yl}methoxy)phenyl]cyclopropanecarboxYlate (0.392 g, 0.733 mmol) in methanol (6 mL) and tetrahydrofuran (12 mL) was added 2 M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 2 hr. 1 M Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-90:10) and recrystallized from ethyl acetate-hexane to give the title compound (0.129 g, yield 34%) as colorless crystals.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]2[N:10]([CH3:36])[C:11](=[O:35])[N:12]([C:15]3[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)[CH:18]=[CH:19][C:20]=3[CH3:21])[C:13](=[O:14])[C:7]2=[CH:6][N:5]=1)=O.[CH3:37][NH2:38]>C1COCC1>[CH3:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)=[CH:16][C:15]=1[N:12]1[C:13](=[O:14])[C:7]2[C:8](=[N:9][C:4]([NH:38][CH3:37])=[N:5][CH:6]=2)[N:10]([CH3:36])[C:11]1=[O:35]
Reactant: CN
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-n1c(=O)c2cnc(S(C)=O)nc2n(C)c1=O
Solvent: C1CCOC1
Product: CNc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
N-[3-(7-Methanesulfinyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (30 mg, 58 μmol) is dissolved in 2 M methylamine solution (1 mL) in THF and the mixture is stirred for 1 h at 60° C. The reaction mixture is concentrated, dissolved in DMSO, and purified by preparative LCMS to give N-[4-Methyl-3-(1-methyl-7-methylamino-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (20 mg, 71%); 1H NMR 400 MHz (DMSO-d6) δ 10.70 (s, 1H), 8.95 (s, 0.33H), 8.85 (s, 0.66H), 8.39 (m, 3H), 8.11 (d, 1H), 7.93 (t, 1H), 7.84 (m, 2H), 7.49 (d, 1H), 3.65 (d, 2H), 3.58 (s, 1H), 3.08 (m, 3H), 2.17 (s, 3H); MS m/z 485.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14](O)=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14]([Cl:20])=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 99 %

Procedure:
To a suspension of 2-(4-nitrophthalimido)acetic acid (58.6 g) in toluene (250 ml) was added phosphorus pentachloride (48.8 g) and the mixture was refluxed for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. By addition of hexane to the residue, the title compound (62.3 g) was obtained as light yellow sharp-pointed needles.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:12][C:11]=2[N+:22]([O-])=O)[CH2:4][CH2:3]1>CCOC(C)=O.CO.[Pd]>[NH2:22][C:11]1[CH:12]=[C:13]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:1])([F:25])[CH2:7][CH2:6]1
Reactant: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Yield: 103.1 %

Procedure:
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)ethanesulfonamide (23.4 g) and Pd/C 10% in EtOAc (800 mL) were shaken together overnight under H2 atmosphere (50 PSI) in a Parr hydrogenation apparatus. The reaction mixture was diluted with MeOH (400 mL) and filtered over celite bed. The solvent was removed to provide the desired title product (22.2 g) as beige solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[C:6]([I:15])[CH:5]=1.Cl.O>CO>[F:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])=[C:6]([I:15])[CH:5]=1
Reactant: CC(=O)COc1cnc(F)cc1I
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)COc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Add NaBH4 (35 mg, 0.94 mmol) to a solution of 1-(6-fluoro-4-iodo-pyridin-3-yloxy) propan-2-one (240 mg, 0.81 mmol) in methanol (4 mL) slowly. Stir the mixture at RT for 3 h. Add 1 N HCl and water. Extract with methylene chloride. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a yellow solid. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound as a light yellow solid (240 mg, 99%). MS (ES) m/z 298 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.Br[CH2:10][CH2:11][CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:8][C@H:5]1[CH2:6][N:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C@@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: N#CCCCBr
Reactant: OC[C@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCN1C[C@H](O)C[C@@H]1CO

Procedure:
(3R,5R)-5-Hydroxymethylpyrrolidin-3-ol and 4-bromobutyronitrile are reacted in the presence of potassium carbonate in N,N-dimethylformamide to give 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile. In the same manner as in Example 1b (e) and using 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{3-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propyl}-5-methyl-2H-isoquinolin-1-one is obtained.