Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[I-].[Na+].[Cl:10][C:11]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:12]=1[CH2:13][CH:14]([O:23][C@@H:24]1[O:29][C@@H:28]([CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C)C=O>[Cl:10][C:11]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:12]=1[CH2:13][CH:14]([O:23][C@@H:24]1[O:29][C@@H:28]([CH2:30][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:27][CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(Cc2ccc(Cl)cc2Cl)O[C@H]2CCC[C@H](COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(Cc2ccc(Cl)cc2Cl)O[C@H]2CCC[C@H](Cn3cncn3)O2)cc1
Yield: 11.9 %

Procedure:
97.5 mg of 1,2,4-triazole and 62 mg of 55% sodium hydride, 142 mg of sodium iodide, 533 mg of trans-6-[α-(2,4-dichlorobenzyl)-4-methoxybenzyloxy]-2-tosyloxymethyltetrahydropyran and 6 ml of dimethylformamide were reacted and treated essentially as described in Example 3(b) and then the product was purified by column chromatography through silica gel eluted with a 1:2 by volume mixture of benzene and ethyl acetate, to give 244 mg of an isomer of lesser polarity, 109 mg of an isomer of greater polarity and 52 mg of a mixture of the two isomers (in which the ratio of the isomers of lesser to greater polarity was about 2:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([S:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)([C:20](OCC)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]([CH2:20][OH:21])([S:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cccc(SC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a slurry of lithium aluminum hydride (0.25 g, 6.6 mmol) in anhydrous diethyl ether (60 mL) at 0° C., a solution of ethyl N-tert-butoxycarbonyl-4-(3-tolylsulfanyl)piperidine-4-carboxylate (2.25 g, 5.9 mmol) in diethyl ether (5 mL) was added dropwise with the temperature of the reacting mixture maintained below 10° C. The resulting mixture was stirred at 0° C. for 1 h., and quenched with successive addition of water (0.25 mL), 15% aqueous NaOH (0.25 mL), and water (10.75 mL). The resultant slurry was stirred at room temp. for one h., and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1Br.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccc(N)c(C)c1
Reactant: Cc1ccc(Br)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2ccc(C)cc2C)c(C)c1
Temperature: 100 °C
Yield: 84 %

Procedure:
A mixture of 2,4-dimethylaniline (6.05 g, 50 mmol), 2,4-dimethylbromobenzene (9.25 g, 50 mmol), Pd(dppf)Cl2 (0.88 g, 1.2 mmol), sodium tert-butoxide (KOBut) (9.6 g, 0.1 mmol) in toluene (120 mL) was degassed and heated at 100° C. overnight. The resulting mixture was worked up with dichloromethane/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1. After removal of solvent, a liquid was obtained (9.45 g, in 84% yield).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:4].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].[Na+].Cl>COCCO.O>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4])[C:6](=[O:17])[O:7]2)=[CH:12][CH:11]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2ccc(Cl)cc2oc1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(Cl)cc2oc1=O

Procedure:
A suspension of 350 mg of 7-chloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (1.38 mmol) and 670 mg of sodium glycinate (6.9 mmol) in 13 mL of 2-methoxyethanol was heated at reflux temperature for 10 hours. The mixture was cooled acidified with 1N HCl and diluted with 10 mL water. The resultant white solid was collected on a glass fritted filter and washed twice with water and once with methanol. The solid was triturated with methanol to give 124 mg. MS: (+) m/z 298.03/300.02 (M+1, 35/37Cl)
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]1([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][C:4]4[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:5]=43)=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(-c3ccccc3)ccc1C2
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
A solution of 2.5 g of (RS)-2-(2-oxoethyl)-6-phenyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.5 g (52%) of (R)-1-(7-phenyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])[CH3:30].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:29]([C:32]1[CH:37]=[C:36]([N:8]2[C:9](=[O:27])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][C:13]=3[F:26])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:28])[CH:35]=[CH:34][CH:33]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (2.0 g), (3-acetylphenyl)boronic acid (2.0 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (40 mL) was added copper(II) acetate (2.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.99 g, 76%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH2:27][OH:28])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH2:27][O:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][O:26][S:39]([CH3:38])(=[O:41])=[O:40])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CO)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(COS(C)(=O)=O)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropane-1,3-diol (79.4 mg, 0.192 mmol) and Et3N (80 uL, 0.574 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (37.4 uL, 0.48 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method J): RT 2.98 min [M+H]+ 570.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30])(=[O:12])=[O:11].[N:33]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:38][CH2:39][CH2:40][NH:41][C:29]([C:28]2[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=2/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Reactant: NCCCN1CCCC1
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1

Procedure:
2-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid was coupled with 3-pyrrolidin-1-yl-propylamine to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12]Cl.[OH:14][C:15]1([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][N:18]1[CH2:19][CH2:20][C:15]([OH:14])([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: Cc1ccc(OCCCCl)c(C)c1
Product: Cc1ccc(OCCCN2CCC(O)(c3cnc4ccccc4c3)CC2)c(C)c1
Yield: 44.6 %

Procedure:
Beginning with 0.235 gm (1.2 mMol) 3-chloropropyl 2,4-dimethylphenyl ether and 0.270 gm (1.2 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.209 gm (45%) of the title compound were recovered as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C1(C)C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>CO.CCOCC.CCCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1csc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCCCCCC
Solvent: CCOCC
Product: COc1ccc(-c2csc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Mix 3-bromobenzo[b]thiophene (5.83 g, 27.4 mmol), tetrakis(triphenylphosphine)palladium (O) (1.00 g, 0.865 mmol) and toluene (60 mL) and purge with nitrogen. Rapidly, add a 2 M aqueous solution of sodium carbonate (27 mL) and purge with nitrogen. Add a solution of 4-methoxyphenylboronic acid (4.57 g, 30.1 mmol) in methanol (13 mL), purge with nitrogen and heat at a gentle reflux for 4.5 hours. Let cool and stir at room temperature, overnight. TLC (30% dicloromethane in heptane) shows that all starting material is consumed. Dilute reaction mixture with ethyl acetate (100 mL). Wash with 2 M sodium carbonate (75 mL), water (75 mL), saturated sodium chloride (75 mL), dry (MgSO4) and concentrate (in vacuo) to give a residue. Purify the residue by column (silica) chromatography (20% dichloromethane in heptane) to give a mixture as a residue. Dissolve the residue in 30% ether in heptane, filter, evaporate and dry (0.5 mm Hg, room temperature) to give the title compound as a clear oil (5.47 g, 83% Yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C(OC1C=C(CCN)C=CC=1)CCC.C(N(CC)CC)C.[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH:38]=[CH:39][C:40](Cl)=[O:41]>C(#N)C.O>[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH:38]=[CH:39][C:40]([NH:13][CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1)=[O:41]
Reactant: CCCOc1cccc(CCN)c1
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Agent: CCCCOc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCOc1cccc(CCNC(=O)C=Cc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(3-propyloxyphenyl)ethylamine prepared in a manner analogous to that described in Example 1E (2.69 g) in acetonitrile (40 cm3) was added triethylamine (3 cm3). A solution of 2-chlorocinnamoyl chloride (3.6 g) in acetonitrile (20 cm3) was added slowly, the reaction mixture being cooled in an ice bath. When addition was complete, the mixture was stirred at room temperature for 40 minutes, treated with water (60 cm3) and SVM (2 cm3) and stirred well. The resulting precipitate was filtered off, washed and air-dried (5.49 g) m.p. 96°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C[O-].[Na+:17]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[Na+:17]
Reactant: O=C(O)CCCSc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C([O-])CCCSc1ccc(Cl)cc1

Procedure:
A hot solution of 13.8 g of 4-(p-chlorophenylthio)butyric acid was added to a hot solution of 3.2 g of sodium methoxide in 50 ml of isopropanol. The resulting mixture was cooled and filtered. The air-dried solid weighed 14.4 g.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188d) (20 mg, 0.07 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (15 mg, 0.07 mmol) were dissolved in DMA (2 ml). WSC hydrochloride (40 mg, 0.21 mmol) and HOBt (10 mg, 0.07 mmol) were added, and the mixture was stirred at 70° C. for one hour and at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0, 9, 17%) to obtain 16 mg of the title compound as a glassy solid.
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=[C:6]=[O:7])=O.[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:14]([OH:16])=[O:15]>O1CCOCC1>[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:6](=[O:7])[NH2:5])[CH:18]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Solvent: C1COCCO1
Product: CON=C(C(=O)O)c1cccc(OC(N)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trichloroacetyl isocyanate (70 ml) was dropwise added over 6 minutes at ambient temperature to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40 g) in dry dioxane (200 ml), and the resulting mixture was stirred for 5 hours at ambient temperature. Dioxane was distilled off and to the residue were added ethyl acetate (200 ml) and by small portions water (200 ml) under ice-cooling. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3-trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5 hours at ambient temperature keeping the pH value of the mixture at 6.0 to 6.4 by adding an aqueous solution of sodium bicarbonate. The resulting mixture was washed twice with ethyl acetate. The aqueous layer was adjusted to pH 2 with a 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and precipitating crystals were collected by filtration to give colorless crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl)acetic acid (syn isomer) (15 g), mp 163° C. (dec.). The same compound (5.4 g) was obtained from the mother liquor.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:3]=1.P(Br)(Br)([Br:25])=O>O>[Br:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:3]=1
Reactant: O=c1c2ccccc2c(O)nn1-c1cccc(C(F)(F)F)c1
Reactant: O=P(Br)(Br)Br
Solvent: O
Product: O=c1c2ccccc2c(Br)nn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
4-Hydroxy-2-(3-trifluoromethylphenyl)-2H-phthalazin-1-one (0.50 g, 1.6 mmol) and phosphorus oxybromide (1.9 g, 6.5 mmol) were stirred at 150° C. for 2 h. H2O (100 ml) was added after cooling to room temperature. The precipitated solid was collected by filtration and washed with H2O. Drying of the solid in vacuum gave the title compound (0.4 g, 66% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.39 (1H, d), 7.95–8.12 (5H, m), 7.79–7.99 (2H, m); MS (ESI+)=370.98 (M+H)+.
Reaction SMILES: CN(C=O)C.[CH2:6]1[N:13]([CH2:14][CH2:15][N:16]2[CH2:23][C:21](=[O:22])[O:20][C:18](=[O:19])[CH2:17]2)[CH2:12][C:10](=[O:11])[O:9][C:7]1=[O:8].[OH2:24].[NH4+].[OH2:26]>>[CH2:15]([N:16]([CH2:23][C:21]([OH:20])=[O:22])[CH2:17][C:18]([OH:26])=[O:19])[CH2:14][N:13]([CH2:12][C:10]([OH:9])=[O:11])[CH2:6][C:7]([OH:24])=[O:8]
Reactant: O
Reactant: O=C1CN(CCN2CC(=O)OC(=O)C2)CC(=O)O1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into 200 ml of N, N-dimethylformaldehyde, 35.3 g of ethylenediamine tetraacetic dianhydride was added and dissolved through the application of heat at 80° C. Into thus-obtained liquid solution, 0.4 g of cotton cloth (unbleached cotton knit) was soaked and heated at 80° C. for 6 hours. Next, the cotton cloth was soaked into 500 ml of distilled water. In this state, pH of the distilled water was adjusted to about 10 using ammonium water, and the water was stirred for 3 hours to dissolve and remove the unreacted ethylenediamine tetraacetic acid. Then, the cotton cloth was soaked into 500 ml of 0.1 normal sulfuric acid aqueous solution and was stirred for 3 hours. After that, the cotton cloth was repeatedly washed with distilled water until the washing distilled water was neutralized, and then was dried at 60° C. for 5 hours. As a result, 0.54 g of cotton-EDTA type chelate forming fiber was obtained (substitution rate: 35 weight percent).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCCCCC.C(OCC)C>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][C:14]3[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=3)=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of the aniline produced in Example 1 (168 mg, 0.574 mmol) in CH2Cl2 (3 mL) was added 4-chlorobenzenesulfonyl chloride (157 mg, 0.746 mmol, commercially available from Aldrich) at once. After 20 minutes, an additional amount (48 mg, 0.230 mmol) of 4-chlorobenzenesulfonyl chloride was added and the solution was stirred overnight. The product was isolated following column chromatography (1:1 hexane/diethyl ether). Yield: 160 mg (60%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=O)OCCCl.[OH-].[K+].[C:20](O)(=[O:22])C>O>[OH:22][CH2:20][CH2:12][NH:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1c(NC(=O)OCCCl)cccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(NCCO)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
25.8 g of the β-chloroethyl N-(2-methyl-3-nitrophenyl)-carbamate prepared under Example 3, stage 1, are initially introduced into the reaction vessel in 250 ml of water. The reaction mixture is heated to 80° C. and 35 g of 50% strength aqueous potassium hydroxide solution are then added in the course of one hour. After the mixture has been subsequently stirred at 75° C. for 3 hours, its pH is brought to 8 with glacial acetic acid, and the reaction mixture is cooled slowly. The product which has precipitated is filtered off with suction, washed with water, and dried at 50° C. in a vacuum drying cabinet.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:8]([O:12][CH2:13][CH2:14][OH:15])(=[O:11])[CH:9]=[CH2:10].COC1C=CC(O)=CC=1>>[C:8]([O:12][CH2:13][CH2:14][O:15][C:6](=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:11])[CH:9]=[CH2:10]
Reactant: CCCCN=C=O
Reactant: C=CC(=O)OCCO
Agent: COc1ccc(O)cc1
Product: C=CC(=O)OCCOC(=O)NCCCC

Procedure:
145.3 grams of butyl isocyanate and 180.7 grams of 2-hydroxyethyl acrylate, stabilized with 400 ppm of hydroquinone monomethyl ether, were reacted together for 6 hours at 75° C. to give 1-butane carbamic acid 2-acryloyloxyethyl ester.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(OCC)(=O)C.[Pt]=O>[C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][NH:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Cc2ccccc2)c2cccnc12
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(Cc2ccccc2)c2c1NCCC2
Reaction time: 4 h
Yield: 102.6 %

Procedure:
To a solution of 702.8 mg (2.99 mmol) of 5-(phenylmethyl)-8-quinolinol in 40 ml of methanol and 8 ml of ethyl acetate under nitrogen was added 200 mg of platinum oxide and the mixture was hydrogenated at 40 PSI for four hours. Filtration through a 0.4 μm polyester membrane filter followed by evaporation yielded 733.8 mg of a dark tan solid. Recrystallization from dichloromethane:hexane and then flash chromatography on 50 g of silica eluted with 3:7 ethyl acetate:petroleum ether provided 534.5 mg: melting point 135°-136° C.