Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-3-pyridinecarboxaldehyde (50 mg, 0.36 mmol; prepared according to the method of Comins and Killpack, J. Org. Chem., 1990, 55, 69-73) in t-butanol (0.5 ml) was added a solution of potassium permanganate (81 mg) in water (1.0 ml). The mixture was stirred at room temperature for two hours, and then saturated sodium sulphite solution was added until the purple colour disappeared. Reaction mixture was extracted with chloroform several times as it was gradually acidified with dilute HCl (2N). Chloroform extracts were concentrated in vacuo to yield the title compound (42 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:5]([CH3:31])[CH:4]=1)#[N:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[C:10]2[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:5]([CH3:31])[CH:4]=1)(=[O:33])[NH2:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C#N)cc1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred suspension of ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28B) (120 mg, 0.28 mmol) and potassium carbonate in DMSO (0.2 mL) was added dropwise 30% H2O2 at 0° C. The mixture was allowed to warm to room temperature and stirred 3 h. After water (2 mL) was added, some precipitate appeared, which was separated by centrifuge, rinsed with water (0.5 mL) and dried in vacuum to afford ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28C) as a white solid (100 mg, 80%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:22])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C1CCC(=O)N1Cc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
1-Benzyl-5-oxo-2-pyrrolidinecarboxylic acid (9.69 g, 44.2 mmol) in methanol (75 mL) was treated with sulfuric acid (0.5 mL) and refluxed for 2.5 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate phase was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[C:6]([O:15][CH3:16])=[C:5]([CH2:17][CH:18]2[CH2:23][CH2:22][C:21]([CH:25](O)[CH3:26])([OH:24])[CH2:20][CH:19]2[C:28]([O:30]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[K+].[Br-].[OH2:53]>CN(C)C1C=CN=CC=1>[OH:53][CH:25]([C:21]1([OH:24])[CH2:22][CH2:23][CH:18]2[CH:19]([C:28](=[O:30])[C:4]3[C:5]([CH2:17]2)=[C:6]([O:15][CH3:16])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH2:20]1)[CH3:26]
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2c(OC)cccc12
Reactant: O
Agent: CN(C)c1ccncc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c2c(c(OC)c3c(OC)cccc13)CC1CCC(O)(C(C)O)CC1C2=O
Yield: 49 %

Procedure:
0.48 g of 1-(1,4,5-trimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane, prepared as described in Example 5, was treated with acetic anhydride and pyridine in the presence of 4-dimethylamino-pyridine. After a night at room temperature the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The crude product was dissolved in methanol and refluxed with cyclohexene in the presence of 10% by weight palladium-on-carbon. The catalyst was then filtered off and the solution, concentrated to a small volume, was treated at 0° C. for 60 minutes with trifluoroacetic anhydride and trifluoroacetic acid. Then the solution was diluted with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and with water, dried and concentrated to dryness under vacuum. The residue was dissolved in methanol in the presence of catalytic amount of sodium methylate. After conventional work-up and purification by chromatography 0.18 g of the title compound was obtained (yield 49%): m/z 400 (M+.); IR (KBr): 3450 cm-1 (OH), 1675 cm-1 (C=O benzylic ketone); PMR (CDCl3): inter alia δ (1.2 (d, CH3 --CH), 3.7-3.9 (s, three OCH3) and 6.4-8.0 (m, three aromatic hydrogen).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>N1C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:7]2[C:8](=[O:9])[NH:1][C:2](=[S:3])[NH:4][C:5]=2[OH:6])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C1CC(=O)NC(=S)N1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1c(O)[nH]c(=S)[nH]c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-thiobarbituric acid (14.4 g) was suspended in pyridine and 4-fluorophenyl isocyanate (13.7 g) was added thereto. The reaction mixture was maintained at 90° C. for one hour, and thereafter left overnight at room temperature. The solids formed were collected, washed with pyridine, re-suspended in ethanol, and again collected and dried. A pale pink powder product was thereby obtained, mp >250° C. (dec.), NMR (DMSO) 7.0-7.7δ (multiplet, integral 4); 10.7-11.4δ (overlapping broad singlets, combined integral 4). MS, M/e 281 (Calc., 281).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([CH3:23])[C:15]=1[CH:16]=O>CS(C)=O.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:16]([C:15]3[C:14]([CH3:13])=[CH:21][C:20]([OH:22])=[CH:19][C:18]=3[CH3:23])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)[nH]c2c1
Reaction time: 120 h

Procedure:
3.65 g of methyl 3,4-diaminobenzoate and 3.3 g of 2,6-dimethyl-4-hydroxybenzaldehyde were stirred in 25 ml of DMSO at room temperature. A solution of 170 mg of FeCl3 in 5 ml of DMSO was added by pipet and the reaction was stirred at the same temperature for 5 days. The reaction was then diluted with water and the resulting precipitates were collected by filtration. The filter cake was washed with water and heptane, and dried by air in the suction funnel to afford the title compound. LCMS retention T=1.01 min. (M+H)+=297.01, Method 10.
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]([O:23]C(=O)C)[C@@H:11]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C>CO>[CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@@H:11]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 7 (2.00 g, 3.3 mmol) was dissolved in methanol (90.0 ml), and triethylamine (10.0 ml) was added to the solution, followed by stirring for 48 hours at room temperature. The reaction mixture was concentrated through distillation under reduced pressure, and the residue was purified by means of silica gel column chromatography (silica gel 200 ml, eluent; n-hexane:ethyl acetate=1:1), to thereby yield a white powdery compound (Compound 8; 1.72 g, 3.06 mmol, 92.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]([CH3:25])[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:24][CH2:23][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl-propylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](F)(=[O:24])=[O:23])=[CH:18][C:17]=1N>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: COc1ccc(S(=O)(=O)F)cc1N
Product: COc1ccc(S(=O)(=O)Oc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
3,4,5-trimethoxyphenol (504 mg) was processed as described in Example 43 (substituting 4-methoxybenzenesulfonyl chloride for 4-methoxymetanilyl fluoride) to provide 500 mg of the desired product.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1(O)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])[CH3:7].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][SH:23]>O>[CH2:6]([C:8]1([S:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH3:15])[CH3:7]
Reactant: CCCCCCS
Reactant: CCC1CCCCC1(O)CC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCSC1(CC)CCCCC1CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a cooled (0° C.) mixture of water (13 ml.) and 27 mg. concentrated sulphuric acid was added dropwise 1,2-diethylcyclohexanol (12 g., 77 mmole) and then n-hexylthiol (9.1 g., 77 mmole). The mixture was stirred at 0° C. for 6 hours and at room temperature for 1 hour. The mixture was then poured into 1 liter of cold water and extracted with ether. The ether extract was washed with 2N sodium hydroxide and water and dried (MgSO4). The solvent was removed by distillation and the residue was distilled under reduced pressure to give n-hexyl 1,2-diethylcyclohexyl sulphide (15 g.) as a colourless liquid, b.p. 110°-4°/0.03 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccc(Cl)cc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(2,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.03 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which precipitates is filtered and air-dried, yield 5.5 g., m.p. 215°-226°C. Recrystallizations from ethanol gives material with m.p. 224.5°-227°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][NH:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C1CNCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (0° C.) solution of tert-butyl 3-(2,6-dimethoxyphenyl)-5-oxo-4-(4-(trifluoromethoxy)-benzyl)piperazine-1-carboxylate (540 mg; 1.05 mmol) in anh. DCM (10 ml) was treated dropwise with 4 M HCl in dioxane (4.00 ml; 16.00 mmol), and the resulting mixture was further stirred at rt, under nitrogen, for 16 h. The reaction mixture was concentrated to dryness under reduced pressure, the resulting residue was dissolved in DCM, and washed successively with 1 M aq. NaOH, aq. sat. NaHCO3, and brine. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=10/1) afforded 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperazin-2-one as an orange oil. LC-MS (conditions D): tR=0.85 min.; [M+H]+: 411.13 g/mol.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[C:21](Cl)(=[O:29])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:21](=[O:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:1][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(CO)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a mixture of 2-hydroxy-4′-trifluoromethyl acetophenone (24.0 g), pyridine (10.3 g) and tetrahydrofuran (200 ml) was added dropwise phenyl chlorocarbonate (20.4 g) under ice-cooling, which was stirred at room temperature for 1 hour. The reaction mixture was concentrated, which was poured into water (500 ml), and extracted with ethyl acetate (150 ml×2). The organic layer was washed with water and then a saturated aqueous solution of sodium chloride, which was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to crystallization by addition of isopropyl ether (100 ml) to give crystals of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.9 g, 53%). Melting point 134-135° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@H:7]([CH2:16][CH2:17][OH:18])[NH:8]C(OC(C)(C)C)=O)([CH3:4])(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.[ClH:59]>O1CCCC1.C(O)C>[ClH:59].[CH2:1]([O:5][C:6](=[O:19])[C@H:7]([CH2:16][CH2:17][O:18][C:43]1[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=1)[NH2:8])[CH3:4]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N)CCOc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of BOC-L-homoserine t-butyl ester (3.2 g, 11.6 mmol) in tetrahydrofuran is added triphenylphosphine (7.59 g, 29 mmol), p-fluorophenol (2.08 g, 18.6 mmol) and 1,1′-azobis(N,N-dimethylformamide) (3.2 g, 18.6 mmol). The mixture is stirred overnight, washed with brine, dried over MgSO4, and the solvent is removed to give an orange oil. The oil is purified by flash chromatography (SiO2, 85% hexane/15% ethyl acetate) to give a clear oil which is dissolved in ethanol (100 mL) and the solution is saturated with HCl gas, then stirred overnight. The mixture is concentrated to give O-(4-fluorophenyl)-L-homoserine ethyl ester hydrochloride as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][O:32][C:33]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:33]=3[O:32][CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(C(=O)Cl)c1OC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OC(C)=O)[C@@H](COC(C)=O)O3)c2=O)c1OC
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
15.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 15 ml of triethylamine were dissolved in 75 ml of dry dioxane, and the resulting solution was cooled with ice. To the solution was added 13.6 g of 2,3-dimethoxybenzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 30 minutes and then at 90° C. for 30 minutes. The crystals produced were filtered off, and the filtrate was concentrated under reduced pressure. To the oily residue was added 200 ml of ethanol. Upon heating, the mixture began to separate crystals while the oily residue was dissolved. After dissolving the oily residue completely, the mixture was cooled, and there was obtained 2'-deoxy-3',5'-di-O-acetyl-3-(2,3-dimethoxybenzoyl)-5-fluorouridine as crystals. Recrystallization of the product from ethanol afforded 19.65 g (yield: 88.4%) or colorless needles having a melting point of 139 to 141° C. The structure was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCNc2cc(N)ccc2C1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCNc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc2C1=O
Temperature: 120 °C
Yield: 13.5 %

Procedure:
Into a microwave vial, 8-amino-4-ethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.100 g, 0.000487 mol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.14 g, 0.00046 mol), 10-camphorsulfonic acid (0.22 g, 0.00092 mol) and isopropyl alcohol (1.3 mL, 0.017 mol) were added and heated in the microwave at 120° C. for 40 minutes. The solvent was removed under vacuum. The solid was dissolved in EtOAc and washed with saturated NaHCO3. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via Gilson prep-HPLC to give a TFA salt (30 mg, 13%). 1H-NMR (CDCl3, 400 MHz): δ10.97 (bs, 1H), 9.52 (bs, 1H), 7.75 (s, 1H), 7.70 (bs, 1H), 7.28-7.50 m, 4H), 6.90 (d, 1H), 6.28 (bs, 1H), 3.44-3.65 (m, 7H), 3.01 (d, 1H), 1.25 (t, 3H). LC/MS (ESI+) 484.21 (M+H).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N+:16]([O-])=[CH:15][CH:14]=1>ClCCl.C([O-])([O-])=O.[Na+].[Na+].O>[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[NH:16][C:15](=[O:8])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1ccc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reaction time: 1 h

Procedure:
p-Toluenesulfonyl chloride (628 mg, 3.293 mmol, 1.5 equip) was added to a biphasic mixture of 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide in dichloromethane (6 mL) and 10% Na2CO3 (42 mL) and the resulting mixture stirred for 1 h. The reaction mixture was diluted with dichloromethane and water, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[NH:9][N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[NH:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl>[C:19]1([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4]([C:3]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[CH:28][C:2]=2[NH:1][C:50]([C:46]2[NH:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[O:5])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(N)c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(NC(=O)c3ccc[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
2-Amino-N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide (245 mg, 0.5 mmol) was suspended in dichloromethane (10 mL), treated first with neat N,N-diisopropylethylamine (0.35 mL, 2 mmol) then with solid 1H-pyrrole-2-carbonyl chloride (258 mg, 2 mmol). The reaction was stirred at room temperature overnight then treated with additional acid chloride (258 mg) and N,N-diisopropylethylamine (0.35 mL). After two hours the solvent was removed under reduced pressure and the crude was taken up with tetrahydrofuran (30 mL) and treated with 2N NaOH (10 mL). After stirring overnight the solvent was removed and the solid was filtered and washed thoroughly with water. The crude was purified by flash chromatography over silica gel (eluent: ethyl acetate/methanol/aq.33% NH4OH in 9:1:0.1 ratio) to give 60 mg of title compound.