Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:20](=[O:22])[NH2:21])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[CH:23]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:20]([OH:22])=[N:21][CH:23]=[N:1][C:2]=23)=[CH:12][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC([O-])[O-]
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1ncnc2c(-c3ccc(Cc4ccccc4)cc3)cnn12
Reaction time: 0.75 h

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl )-2-carbamoylpyrazole (1.00 g), ethyl orthoformate (0.61 ml) and N,N-dimethylformamide (0.86 ml) was stirred at 100° C. to 110° C. for 45 minutes. To the reaction mixture was added ethyl acetate (20 ml). After stirring at room temperature for 30 minutes, the precipitate was separated by filtration, washed with ethyl acetate, and dried to give the title compound (0.72 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[N:34]1[CH:39]=[CH:38][C:37]([CH:40]([S:42][C:43]2[C:48]([C:49]([OH:51])=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH3:41])=[CH:36][CH:35]=1.[Cl:52][C:53]1[CH:59]=[CH:58][C:56]([NH2:57])=[CH:55][CH:54]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:52][C:53]1[CH:59]=[CH:58][C:56]([NH:57][C:49]([C:48]2[C:43]([S:42][CH:40]([C:37]3[CH:36]=[CH:35][N:34]=[CH:39][CH:38]=3)[CH3:41])=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:51])=[CH:55][CH:54]=1
Reactant: CC(Sc1ncccc1C(=O)O)c1ccncc1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Sc1ncccc1C(=O)Nc1ccc(Cl)cc1)c1ccncc1
Yield: 14 %

Procedure:
N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol) were added to a solution of 2-[1-(4-pyridyl)ethylthio]pyridine-3-carboxylic acid (200 mg, 0.77 mmol, Reference compound No. 5-1) and 4-chloroaniline (110 mg, 0.85 mmol) in N,N-dimethylformamide (2.0 mL), then the mixture was stirred at room temperature for 13 hours. Ethyl acetate (30 mL) was added to the reaction mixture, the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (30 mL) twice and brine (30 mL) twice, then dried over anhydrous magnesium sulfate. The resulting residue by evaporated under reduced pressure was purified by silica gel column chromatography to give 41 mg of the target compound as a colorless solid. (Yield 14%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:37])=O.N1C=CC=CC=1.C(=O)(O)[O-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][Cl:37])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CCl)cc2)nn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (690 mg, 1.331 mmol) in 10 mL of DCM was added dropwise a solution of thionyl chloride (0.107 mL, 1.464 mmol) and pyridine (1.615 μL, 0.02 mmol) in 10 mL of DCM. The reaction mixture was stirred for 3 h at 40° C. and saturated aqueous bicarbonate solution was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic solution was dried over MgSO4, filtered and concentrated under vacuum to yield the crude product which was used in the next step without further purification. LCMS (Method A) RtA=1.681; [M+H]+=485.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][N:15]=[CH:16]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH2:21].[OH-:22].[Na+]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][N:15]=[CH:16]3)(=[O:22])=[O:21])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Sc2cccc3cnccc23)cc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
5-(4-Nitrophenylsulfanyl)isoquinoline 100 mg (0.4 mmol) was dissolved in concentrated sulfuric acid 2.0 ml, Beckman's reagent 3.0 ml (a mixture of K2Cr2O7 1 g-H2SO4 1 ml-H2O 9 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After water was added to the reaction mixture, the solution was neutralized with 4 N sodium hydroxide, and precipitates were filtered, washed with water, and recrystallized from methanol to give 5-(4-nitrophenylsulfonyl)isoquinoline 70 mg (63.6%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:10][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:12]([C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3](=[O:16])[N:4]([CH3:15])[C:5]=2[CH:10]=1)=[CH:17][C:18]1[CH:19]=[C:20]([CH3:21])[CH:23]=[CH:24][CH:25]=1)(=[O:14])[CH3:13]
Reactant: Cc1cccc(C=O)c1
Reactant: CC(=O)Cc1ccc2c(c1)n(C)c(=O)n2C
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cccc(C)c1)c1ccc2c(c1)n(C)c(=O)n2C
Reaction time: 18 h

Procedure:
1,3-Dimethyl-5-(2-oxo-propyl)-1,3-dihydro-benzoimidazol-2-one was diluted with toluene (30 mL) and treated with 3-methylbenzaldehyde (0.82 mL) and piperidine (0.3 mL). The mixture was placed in an oil bath set to a temperature of 145° C. and the flask was fitted with a pressure equalizing funnel containing 4 Å molecular sieves and equipped with a condenser. After 18 hours the mixture was allowed to cool and was concentrated. Chromatography on silica gel afforded 5-(1-Acetyl-2-m-tolyl-vinyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (1.077 g).
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([Cl:47])=[C:16]([NH:22][C:23]4[N:28]=[C:27]([N:29]([CH:39]5[CH2:41][CH2:40]5)CC5C=CC(OC)=CC=5)[C:26]5=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]5[N:24]=4)[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=3)[CH2:10][CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([Cl:47])=[C:16]([NH:22][C:23]4[N:28]=[C:27]([NH:29][CH:39]5[CH2:40][CH2:41]5)[C:26]5=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]5[N:24]=4)[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=3)[CH2:10][CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(C)=O)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CC(N2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1
Temperature: 50 °C
Yield: 55.6 %

Procedure:
To a solution of 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (110 mg, 0.169 mmol) in DCE (1.1 mL) and anisole (0.108 mL, 0.985 mmol) was added TFA (0.296 mL, 3.84 mmol) slowly drop wise at room temperature and the reaction mixture was heated at 50° C. for overnight. The reaction mixture was concentrated to remove solvent completely; the resultant residue was washed with hexane to remove anisole. The residue was diluted with Ethyl acetate, washed with aq. ammonia solution, brine, dried over Na2SO4 and concentrated. The crude material was purified by reverse phase HPLC, the fractions were concentrated and the resultant solid was dissolved in HPLC grade Chloroform (20 ml), washed with 10% NaHCO3 solution, brine, dried over Na2SO4 and concentrated. The solid was dissolved in Acetonitrile/water (1:3). Froze the mixture using a dry-ice acetone bath and then dried under lyophilization for 2 days. Lyophlization afforded 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) as a off white solid.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClC(Cl)Cl>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:26](=[O:27])[CH2:25][Cl:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
For protecting thiol groups, take 2-thioethylamine hydrochloride and triphenylmethanol as reactants and boron trifluoride-diethyl ether complex is used as a catalyst to get 2-[(triphenylmethyl)thio]ethylamine. The reaction temperature is 72 degrees Celsius and the reaction time is 4 hours. Step (2): Use 2-[(Triphenylmethyl)thio]ethylamine and chloroacetyl chloride to carry out the amidation reaction in trichloromethane solution so as to produce N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide. Step (3): Take 2-[(Triphenylmethyl)thio]ethylamine, N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide and use triethylamine used as a reagent to carry out the substitution reaction in dichloromethane solution. Thus an amine-amide-thiol ligand is produced. The reaction temperature of the substitution reaction is 55° C. and the reaction time is 48 hours. Step (4): Dissolve 6-bromohexanoic acid and thionyl chloride in absolute methanol solution to carry out the esterification reaction and get methyl 6-bromohexanoate. The reaction temperature of the esterification reaction is 25° C. and the reaction time is 24 hours. Step (5): Take the amine-amide-thiol ligand and methyl 6-bromohexanoate and use sodium hydroxide (NaOH) as a reagent to carry out the substitution reaction in acetonitrile solution and get methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate. The reaction temperature of the substitution reaction is 85° C. and the reaction time is 24 hours. Step (6): Hydrolyze methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate in alkaline methanol solution to get 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenyl-methyl)thio]dodecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.[C:12]([O-:15])(=[O:14])C.[Na+].[CH:17]1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:18]=1>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([O:15][C:12]([C:4]1[C:5]([O:9][CH3:10])=[C:6]([NH2:8])[N:7]=[C:2]([Cl:1])[N:3]=1)=[O:14])[CH3:18]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(N)nc(Cl)nc1Cl
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(Cl)nc(N)c1OC
Temperature: 110 °C
Yield: 232.5 %

Procedure:
2,6-Dichloro-5-methoxypyrimidin-4-ylamine (5.0 g, 26 mmol) was combined in 75 mL absolute ethanol with sodium acetate (2.1 g, 26 mmol), palladium acetate (280 mg, 0.91 mmol) and DPPB (1.1 g, 2.6 mmol) in a 300 mL stirred pressure reactor. The reactor was purged and pressurized to 300 psi with carbon monoxide, and heated at 110° C. for 7 h. The volatiles were removed under vacuum and the residue was taken up in ethyl acetate and water. The aqueous phase was extracted with an additional ethyl acetate; and the combined extracts were washed with brine, dried and evaporated. The residue was purified by flash chromatography on silica gel (0-30% ethyl acetate gradient in hexanes) to give the title compound (1.4 g, 23% yield): mp 118-119° C. 1H NMR (CDCl3) δ 6.18 (br s, 2H), 4.45 (q, 2H), 3.91 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.C1(N=C=NC2CCCCC2)CCCCC1.[OH:30][N:31]=[C:32]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCOCC>O1CCOCC1.C(Cl)(Cl)Cl>[OH:30][N:31]=[C:32]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][N:38]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:39][CH2:40]1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: ON=C(CCN1CCNCC1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)N3CCN(CCC(=NO)c4ccccc4)CC3)ccc2N1
Reaction time: 5 h
Yield: 15.1 %

Procedure:
One gram of 6-carboxy-3,4-dihydrocarbostyril, 1.3 g of dicyclohexylcarbodiimide and 1.47 g of (3-hydroxyimino-3-phenylpropyl)piperazine were suspended in 10 ml of dioxane, then the suspension was stirred at 60° to 70° C. for 5 hours. After the reaction was completed, the solvent was removed by evaporation, to the residue thus obtained was added ether so as to form crystals, then the crystals were removed by filtration. The mother liquor was concentrated, then the residue thus obtained was dissolved by adding chloroform, and the solution was washed with water and an aqueous solution saturated with sodium chloride, then dried with anhydrous potassium carbonate, and the solvent was removed by evaporation. The residue thus obtained was recrystallized from ethanol to yield 320 mg of 6-[4-(3-hydroxyimino-3-phenylpropyl)-1-piperazinylcarbonyl]3,4-dihydrocarbostyril.semihydrate. White powdery substance.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:14]1([CH:2]([CH3:1])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: CC(=O)Cc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(Cc1c[nH]c2ccccc12)N1CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

Procedure:
To a solution of indole-3-acetone (5.0 g, 29 mmol) in anhydrous 1,2-dichloroethane (100 ml) under an atmosphere of nitrogen was added piperidine (2.9 ml, 29 mmol), and glacial acetic acid (1.66 ml, 29 mmol) followed by sodium triacetoxyborohydride (6.8 g, 32 mmol). On complete addition the reaction mixture was stirred at room temperature for 17 hours. The mixture was basified by the addition of a saturated solution of sodium hydrogen carbonate, the layers were separated and the organic layer dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica elution with 5% CH3OH in CH2Cl2+0.5% 0.88 ammonia to give the title product (3 g, 43%); δH (360 MHz; CDCl3) 0.99 (3H, d, J 6.5 Hz, —CH3), 1.43-1.51 (2H, m, aliphatics), 1.60-1.69 (4H, m, aliphatics), 2.56-2.70 (5H, m, aliphatics+indole CHACHB), 2.87-2.99 (1H, m, indole CHAHBCH (piperidine)), 3.12 (1H, dd, J 13.9 and 3.6 Hz, indole CHACHB), 7.02 (1H, d, J 1.9 Hz, indole H2), 7.09 (1H, m, indole H6), 7.17 (1H, m, indole H5), 7.34 (1H, d, J 8.0 Hz, indole H7), 7.61 (1H, d, J 7.6 Hz, indole H4), 8.01 (1H, bs, indole NH); m/z (ES+) 243 (M++H, 100%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[C:13]=1[F:22]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl alcohol (29.4 mL) in DMF (300 mL) was added sodium hydride (60% oil, 11.3 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 1,2,3-trifluoro-4-nitrobenzene (20.0 g), and the mixture was stirred with heating at 80° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.1 g).
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[CH3:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=1/[CH:22]=[CH:23]/[C:24](/[CH3:33])=[CH:25]/[CH:26]=[CH:27]/[C:28](/[CH3:32])=[CH:29]/[CH2:30][OH:31]>C(Cl)Cl>[C:30]([O:31][CH2:30]/[CH:29]=[C:28](\[CH3:32])/[CH:27]=[CH:26]/[CH:25]=[C:24](\[CH3:33])/[CH:23]=[CH:22]/[C:15]1[C:16]([CH3:20])([CH3:21])[CH2:17][CH2:18][CH2:19][C:14]=1[CH3:13])(=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:15]\[CH:14]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:9][CH2:8][CH3:7]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCC/C=C/C=C\CCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride [EDCI] (0.71 g, 3.67 mmol) and anhydrous methylene chloride 15 ml were added to nitrogen filled, three mouth- round bottom flask and melted. The reaction mixture was cooled down into 0° C. Conjugated linoleic acid was added, and stirred for approximately 30 minutes. Retinol (0.87 g, 3.05 mmol) and N,N′-dimethylaminopyridine (DMAP) solubilized in anhydrous methylene chloride 7 ml were added into the reaction mixture, and stirred for 4 hours at room temperature. Organic phase were washed with water (20 ml×2) and brine (20 ml×2) and dried with anhydrous MgSO4, concentrated under low pressure and separated with column chromatography (solvent:ethylacetate/hexane=1/8).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: O=C1OCc2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(Cl)cc21

Procedure:
6-Chlorophthalide (7.66 gms; 0.0452 mole), N-bromosuccinimide (8.1 gms; 0.0452 mole) and azobisbutyronitrile (0.1 gm) were gently refluxed in dry carbon tetrachloride (150 ml.) for 11/2 hours. On cooling, the succinimide was filtered off and the solvent removed in vacuo to leave a yellow solid, which was used immediately. Yield 9.57 gms. 86.2%
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22].CCCCCC.C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:23][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:20])[CH3:22]
Reactant: CC(C)(CBr)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(COc1ccc2ccccc2c1Cl)NC(=O)OC(C)(C)C
Yield: 51 %

Procedure:
To a solution of 1-chloronaphthalen-2-ol (1.5 mmol) and Cs2CO3 (3 mmol) in acetonitrile was added tert-butyl (1-bromo-2-methylpropan-2-yl)carbamate (3 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-chloronaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-yl}carbamate as a pale oil (51% yield) which was dissolved in 5 mL of 4 M HCl solution in dioxane. The resulting mixture was stirred at room temperature for 18 h. After HPLC-MS control, the solvent was distilled off and the residue was dissolved in dichloromethane and wash 2 times with NaOH 1N to afford 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine as a pale oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][CH2:23][CH2:24][OH:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+].O>C(#N)C.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])[CH2:22][CH2:23][C:24]([OH:36])=[O:25])=[C:4]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CCCO)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N(CCC(=O)O)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 10 h
Yield: 115.8 %

Procedure:
To 2.63 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(3-hydroxypropyl)-3,4-dimethoxybenzenesulfonamide (Example 37) dissolved in 35 ml of acetonitrile are added, at room temperature, 0.069 g of ruthenium trichloride, 1.65 g of sodium periodate and 2.7 ml of water. The mixture is left for 10 hours at room temperature. The reaction medium is filtered through talc and then concentrated. The residue is taken up in dichloromethane and washed with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 3.13 g of the expected product.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH:58]1[CH2:62][CH2:61][O:60][CH2:59]1)=[O:56]>C(Cl)Cl>[O:60]1[CH2:61][CH2:62][CH:58]([O:57][C:55](=[O:56])[NH:3][CH:4]2[C:22](=[O:23])[N:21]3[CH:17]([CH2:18][CH:19]([O:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)[CH2:20]3)[C:16](=[O:35])[NH:15][C:14]3([C:36]([NH:38][S:39]([CH:42]4[CH2:43][CH2:44]4)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]3)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:59]1
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: O=C(Cl)OC1CCOC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O)OC1CCOC1
Yield: 52.6 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride (50 mg, 0.075 mmol), 44 μL (0.25 mmol) of DIPEA and 0.10 mL (0.1 mmol) of tetrahydro-furan-3-yl chloroformate (prepared by treating tetrahydrofuran-3-ol with phosgene) in DCM as described in the procedure above to give 28 mg (52%) of a white solid. Preparative HPLC condition: YMC ODS-A, S5, 30×50 mm, gradient: 50% B to 85% B, 8 min, hold 2 min, flow rate 45 ml/min. LC-MS (Method A, retention time: 3.05 min), MS m/z 710 (M++1).