Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH3:19])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:17]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([NH2:1])[CH:5]=2)[CH2:18][CH3:19]
Reactant: [H][H]
Reactant: CCCn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1c2c(c3cc(N)ccc31)CCCC2
Yield: 95.8 %

Procedure:
A solution of the compound obtained in Step 1 (270 mg, 1.05 mmol) and 10% palladium on carbon (50% wet, 10 mg, 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl acetate (4 mL) was stirred at room temperature for 14 hr under 1 atm of hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9-propyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (230 mg, 1.006 mmol, 96%) as a brown oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O.O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH:24]=[CH2:23])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)c2c1CCC(=O)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(OC(C)=O)c2c1NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 Grams of 5-acetoxy-3,4-dihydro-8-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of dimethylformamide (DMF), to this solution were added 52 g of potassium carbonate powder and 50 ml of allyl bromide, the mixture thus obtained was stirred at room temperature for 8 hours. To this reaction mixture was diluted with 500 ml of water, extracted with 2 liter of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol, there was obtained 70 g of 5-acetoxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone as brown needle-like crystals.
Reaction SMILES: Br[C:2]1[CH:3]=N[N:5]([CH3:11])[C:6]=1[N:7]=[S:8]([CH3:10])[CH3:9].NC1N(C)N=C[C:14]=1[Br:19].N1C=CC=CC=1.ClS(C1N=C2N(C(OCC)=NC(F)=C2)N=1)(=O)=O>ClCCl>[Br:19][C:14]1[CH:3]=[CH:2][C:6]([N:7]=[S:8]([CH3:10])[CH3:9])=[N:5][CH:11]=1
Reactant: Cn1ncc(Br)c1N=S(C)C
Reactant: Cn1ncc(Br)c1N
Agent: CCOc1nc(F)cc2nc(S(=O)(=O)Cl)nn12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(C)=Nc1ccc(Br)cn1
Temperature: -10 °C
Yield: 428.9 %

Procedure:
A mixture containing about 53 mmol of N-(4-bromo-1-methyl-5-pyrazolyl)-S,S-dimethylsulfilimine in about 28 mL of dichloromethane solution prepared in Example 7 omitting the recovery step was cooled to -10° C. and 1.0 g (5.7 mmol) of 5-amino-4-bromo-1-methylpyrazole, 0.54 g (6.8 mmol) of pyridine, 11.8 mmol of 2-chlorosulfonyl-5-ethoxy-7-fluoro[1,2,4]triazolo[1,5-c]pyrimidine, and 5 mL of dichloromethane were added sequentially with stirring and cooling at about -10° C. The mixture was allowed to stir at ambient temperature for 2 days. The solids present were recovered by filtration, washed with a small amount of 2-propanol, and dried to obtain 5.7 g of the title compound as a white solid. A purer sample amounting to 4.6 g (26 percent of theory) was obtained dissolving this in dimethyl sulfoxide and then adding water to reprecipitate it.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]([CH3:15])[NH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][N:13]([CH3:15])[NH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: CN(C)N
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)Nc1ccc([N+](=O)[O-])c(N)c1
Temperature: 125 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (20 g, 116 mmol), N,N-dimethyl-hydrazine (44 mL, 580 mmol) and anhydrous potassium carbonate (17.6 g, 128 mmol) in N,N-dimethylacetamide (50 ml) were stirred at 125° C. under nitrogen for 3 days Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water (400 mL), stirred vigorously and incubated at 4° C. overnight. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(N′,N′-Dimethyl-hydrazino)-2-nitro-phenylamine (10.7 g, 47% yield) as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:22][C:23](O)=[O:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH:36]([CH3:38])[CH3:37])=[O:25])[C:6]1=[O:39].[C:40](OC(=O)C)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH:36]([CH3:38])[CH3:37])=[O:25])[C:6]1=[O:39])(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCN)c3ncccc23)c1
Solvent: c1ccncc1
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCNC(C)=O)c3ncccc23)c1
Reaction time: 0.67 h

Procedure:
N-[1-(3-Aminopropyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (50 mg, 0.1 mmol) was dissolved in pyridine (1 ml), and thereto was added acetic anhydride (0.5 ml). The mixture was stirred for 40 minutes, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (49 mg, 0.09 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]2=[O:43])[CH:29]=[CH:30][C:31]=1[F:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:28]6[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=6)[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)c(F)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
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: CC(=O)N(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)c(F)c1
Yield: 85.6 %

Procedure:
Using a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol) and 1-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (244 mg, 0.919 mmol) in N,N-dimethylacetamide (2.0 mL), HATU (350 mg, 0.919 mmol) and N,N-diisopropylethylamine (160 μL, 0.919 mmol) and in the same manner as in Example 44, the title compound (301 mg, 86%) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][CH:26]([NH2:34])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CC1[N:44](C(C2C=CC(Cl)=CC=2)=O)[C:43]2C=CC(OC)=CC=2C=1CC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][CH:26]([NH2:34])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[NH2:44][CH2:43][CH2:25][C:26]1[N:34]=[CH:30][NH:29][CH:27]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SCC(N)C(=O)NCC(=O)O)[C@@H](O)CCCC(=O)O
Product: NCCc1c[nH]cn1
Reaction time: 1 h

Procedure:
Antagonism for LTD4 was determined in isolated guinea-pig trachea prepared as spiral strip. Tracheal preparations were suspended under 1 g tension in 10 ml organ baths containing 5 μmol of indomethacin and they were incuated for 1 hr prior to use. Contractile responses to LTD4 (2×10-8 g/ml) were obtained after the maximal response to histamine (10-4M). Test compounds dissolved in 100% dimethyl sulfoxide were added to the organ baths (final concentration of 10-6 g/ml) 30 min prior to LTD4 addition, and then contractile responses to LTD4 were compared with those of control which was obtained from a paired trachea in the absence of test compounds. LTD4 -induced contractions were expressed as a percentage of the maximal response to histamine. The antagonism was determined as follows:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:14]([C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:19])=[C:13]([Cl:28])[CH:12]=[CH:11][C:10]=3[N:9]=2)[CH2:3]1.[Si:29]([O:36][CH2:37][CH:38]=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:28][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:38][CH2:37][O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:3]3)[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: N[C@H]1CCCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 50(a) using 2-[(3S)-3-amino-1-piperidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 51) (200 mg), activated 3 Å molecular sieves (0.20 g), (tert-butyldimethylsilyloxy)acetaldehyde (0.085 mL), dichloromethane (5.0 mL) and sodium triacetoxyborohydride (210 mg). Purification (SiO2, ethyl acetate:isohexane 1:1) gave the sub-titled compound (190 mg).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.C1C[O:21][CH2:20]C1>>[C:1]1([CH:20]=[O:21])[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: C1CCOC1
Reactant: c1ccc2c(c1)c1ccccc1c1cscc21
Product: O=Cc1scc2c3ccccc3c3ccccc3c12
Yield: 85.9 %

Procedure:
Phenanthro[9,10-c]thiophene (H. G. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a 85.9% yield of phenanthro[9,10-c]thiophene-1-carbaldehyde, mp 198°-199°, (C,H,S), (THF/95% EtOH).
Reaction SMILES: O.[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8](O)(=O)=O)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])O.[Na+]>CO>[S:8]1[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:2]([CH2:7][CH2:6][CH2:13][OH:16])=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCCc1csc2ccccc12

Procedure:
A solution of compound 80-2 (2.04 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (80 ml) was stirred at room temperature for 20 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (1.48 g) as a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH2:10][CH2:9][CH2:8][N:7]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[O:24][C:23]([CH3:25])=[N:22][CH:21]=5)=[C:16]([O:26][CH3:27])[CH:15]=4)=[N:12][N:13]=[C:6]23)[CH2:3][CH2:2]1.[OH2:36].[OH2:37].O.O.O.O.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][C:5]2([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:35])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[CH2:10][CH2:9][CH2:8][N:7]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[O:24][C:23]([CH3:25])=[N:22][CH:21]=5)=[C:16]([O:26][CH3:27])[CH:15]=4)=[N:12][N:13]=[C:6]23)[CH2:3][CH2:2]1
Reactant: O
Reactant: COc1cc(-c2nnc3n2CCCC3(CC2CC2)c2ccc(SC)cc2)ccc1-c1cnc(C)o1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(CC2CC2)c2ccc(S(C)(=O)=O)cc2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a mixture of 8-(cyclopropylmethyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-[4-(methylsulfanyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (86.0 mg) in DMF (1 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (87.4 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. Monoperoxyphthalic acid magnesium salt hexahydrate (87.4 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with aqueous sodium thiosulfate solution (1M) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (27.8 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II)chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (II) chloride (0.024 g), copper (1) iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40° C. for 24 hrs. The cooled mixture was concentrated, taken up in ethyl acetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate was combined with material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]1[CH2:14][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1>CO>[C:12]1(=[N:2][OH:3])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:14]1
Reactant: O=C1CCCc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=C1CCCc2ccccc21
Temperature: 22 °C
Yield: 63.9 %

Procedure:
Add hydroxylamine hydrochloride (71.0 g, 1.03 mol) to a solution of α-tetralone (100.0 g, 0.68 mol) in 300 mL of methanol and stir the resulting solution at reflux for 2 hours. Cool the mixture to 20-24° C. and concentrate under reduced pressure. Dilute the residue with 1 L of water and extract with dichloromethane. Wash the organic layer with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Crystallize the residue from isopropanol to provide the desired compound as an off-white solid (70.0 g, 63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([O:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.[C:20](O)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:18]([O:17][C@@H:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:5][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(CCN)cc1)OCC
Reactant: CCCCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCC(=O)NCCc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Ethyl (2S)-3-[4-(2-aminoethyl)phenyl]-2-ethoxypropanoate (320 mg 1.206 mmol) and heptanoic acid (157 mg, 1.206 mmol) were mixed in DCM (10 ml). EDC (243 mg, 1.266 mmol) was added and then DMAP (147 mg, 1.206 mmol) was added. The mixture was stirred at room temperature overnight. It was then washed with 1% hydrochloric acid, water, 1% sodium hydrogencarbonate aqueous solution, water and brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. Chromatography of the residue on a column (ISOLUTE, SI, 2 g/6 ml) using DCM, MeOH/DCM (0.5:99.5) and then MeOH/DCM (1:99) as eluant gave 166 mg desired product, yield 37%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-chlorosalicylic acid (75 g, 435.6 mmol) in anhydrous DMF (871 mL) was added Cs2CO3 (70.7 g, 217.8 mmol) and MeI (27.5 mL, 439.9 mmol) sequentially. The reaction mixture was stirred at room temperature overnight. Ice cold water (3 L) was added to the reaction mixture and the precipitated solid was filtered and dried to provide VII-1-I (75 g, 92% yield).
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[C:6]1=[O:19])(C)(C)C.C(O)(=O)C.O.[NH2:25]N>O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:19])[NH:25][N:5]=[CH:13]2)([CH3:18])([CH3:17])[CH3:16]
Reactant: NN
Reactant: CC(C)(C)c1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
In a 250 mL round-bottomed flask, 2,5-di-tert-butyl-3-hydroxyisoindolin-1-one (4.9 g, 18.7 mmol, Eq: 1.00) was combined with acetic acid (60 ml) to give a colorless solution. The reaction was heated to 90° C. Hydrazine monohydrate (1.61 g, 1.57 ml, 20.6 mmol, Eq: 1.1) was added dropwise. The reaction was stirred at 90° C. for 1 h. The reaction mixture was diluted with 24 mL H2O and slowly cooled to 25° C. over 3 h. The reaction mixture was concentrated but not quite to dryness. The reaction mixture was taken up in dichloromethane. The reaction mixture was poured into 75 mL sat NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. to give pure product as a white solid, which was purified by flash chromatography (silica gel, 80 g, 1% to 4% MeOH in DCM) to afford the desired product (3.7 g) as a white solid. (M+H)+=203 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.32 (s, 9 H) 6.58 (d, J=1.89 Hz, 1 H) 6.76 (dd, J=8.31, 1.89 Hz, 1 H) 7.06 (s, 1 H) 7.26 (d, J=8.31 Hz, 1 H) 9.19 (br. s., 1 H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[C:11]([NH:19][C:20](=[O:23])[CH2:21]Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.CO>[C:11]([NH:19][C:20](=[O:23])[CH2:21][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCl)NC(=O)c1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CSc1ccc(O)cc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 2.52 g (20 mmol) of 4-mercaptophenol, 1.32 g (20 mmol) of 85% potassium hydroxide and 50 ml of methanol were added at normal temperature. After confirming that potassium hydroxide had been dissolved, the inner temperature was cooled to 10° C. and 3.95 g (20 mmol) of N-benzoyl-chloroacetamide was added, followed by stirring at normal temperature for 3 hours. After the completion of the reaction, the reaction solution was acidified with hydrochloric acid and 50 ml of water was added, and then the deposited crystals were collected by filtration to obtain 5.0 g of N-benzoyl-(4-hydroxyphenylthio)acetamide. The yield was 87% and the melting point was 149–151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].O=S(Cl)[Cl:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(C(=O)Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dimethoxybenzoic acid (0.25 g, 1.4 mmol) in 5 mL of SOCl2 was warmed to reflux and was allowed to stir for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with 5 mL of toluene and concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to give the crude title compound which was used without additional purification or characterization.