Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[C:8]=1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[N+:2]=[N-:3].C([N-]C(C)C)(C)C.[Li+].[CH:33](=[O:35])[CH3:34]>>[OH:35][CH:33]([CH:11]1[C:10](=[O:14])[N:9]2[CH:12]1[CH2:13][C:7]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[C:8]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH3:34]
Reactant: [N-]=[N+]=NCCOC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(OCCN=[N+]=[N-])CC12

Procedure:
Benzyl 3-(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is reacted with lithium diisopropylamide and acetaldehyde as described in Example 19 to provide benzyl 6-(1-hydroxyethyl)-3-(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:30]2[O:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OC(=O)C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][C:22]2[C:30]3[O:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:18]=1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)c1nc2cccc(CBr)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
1.8 g of 4-(2-quinolinylmethyloxy)phenol, 1.98 g of ethyl 7-bromomethylbenzoxazole-2-carboxylate and 1.0 g of potassium carbonate are combined in 100 ml of acetone and refluxed for 18 hours. The mixture is cooled, diluted with ethylacetate and filtered. The filtrate is concentrated and the crude product purified by flash chromatography on silica gel in 5% ethanol in chloroform/hexane (1:1) to give ethyl 7-(4-(quinolin-2-ylmethoxy)phenoxymethyl)benzoxazole-2-carboxylate.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2C)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 22 h
Yield: 55 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (37 mg, 0.09 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish III as a yellow oil (20 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]3)=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cc1

Procedure:
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with terephthalic acid monomethyl ester by method E. This resulted in the product with the molecular weight of 367.45 (C21H25N3O3); MS (ESI): 368 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[CH3:24][N:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][N:25]([CH3:30])[CH3:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: CN(C)CC(=O)O
Product: CN(C)CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 19, with the exceptions that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that N,N-dimethyl glycine was used instead of N-Boc glycine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:15](=[O:17])=[O:16].Cl>O1CCCC1>[CH3:12][C:7]1([CH3:13])[C:6]2[CH:14]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C=O
Reactant: CC1(C)CCCCc2ccc(Br)cc21
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCCCc2ccc(C(=O)O)cc21

Procedure:
The Grignard compound was prepared under an argon atmosphere from 4.00 g of 2-bromo-6,7,8,9-tetrahydro-9,9-dimethyl-5H-benzocycloheptene, as described in EP-A2-0315071, and 456 mg of Mg shavings in 20 ml of absolute tetrahydrofuran. After carrying out the metallation a vigorous CO2 stream was introduced at -10° C. The mixture was hydrolyzed with dil. HCl, extracted with ether and washed with a small amount of water. The acid was then purified by extraction in 1N NaOH, acidification to pH 1 (HCl) and re-extraction in ether. After washing with water, drying over Na2SO4 and evaporating there were obtained 2.64 g of 6,7,8,9-tetrahydro-9,9-dimethyl-5H-benzocycloheptene-2-carboxylic acid as colorless crystals of melting point 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:36].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:36][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.13 g) in acetic acid (12.2 mL) was added ammonium acetate (3.01 g), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (855 mg, yield 79%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 445 (MH+).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].C(CC(C)(C)C)(C)C>ClCCl>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.3 %

Procedure:
To a stirred solution of 42.5 g (0.25 mol) of phenyl ether in 200 mL of dichloromethane at −20° C. under argon was slowly added 23.3 g (0.20 mol) of chlorosulfonic acid. After the addition was complete, the reaction was allowed to slowly warm to room temperature. After 16 hours, 150 mL of isooctane was added and the solution was concentrated to an oily residue. Redissolution in 200 mL of 1:3 dichloromethane/isooctane and reconcentration with cooling to about 100 mL gave a solid. The supernatant was decanted, and the solid triturated with additional isooctane and then dried in vacuo to give 55.2 g of crude 4-phenoxybenzene sulfonic acid. The crude acid was dissolved in 200 mL of dichloromethane, and 22 mL (32 g, 0.25 mol) of oxalyl chloride was added, followed by 2.5 mL of N,N-dimethylformamide. After 2 days, the reaction solution was poured into 200 mL of ice water, and extracted with 400 mL of hexane. The organic layer was washed with 100 mL of water and 100 mL of brine, dried over magnesium sulfate, and concentrated. Recrystallization of the residue from dichloromethane/isooctane gave 38.5 g of 4-phenoxybenzenesulfonyl chloride as a white solid: mp 41.5° C.; 1H-NMR (CDCl3) δ 7.10 (apparent t, 4H, J=7 Hz), 7.28 (t, 1H, J=7 Hz), 7.46 (t, 2H, J=8 Hz), 7.98 (d, 2H, J=8.8 Hz).
Reaction SMILES: Br[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:33]1([C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=3)[CH:17]=2)=[C:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:7][CH2:8]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
To a solution of tert-butyl 4-(bromo(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (Example 71, Step 2) (91 mg, 0.18 mmol) in anhydrous toluene (3 mL) and ethanol (3 mL) was added phenyl boronic acid (43.7 mg, 0.358 mmol) and 2M Na2CO3 (0.53 mL, 1.08 mmol). This solution was degassed for 20 min and Pd(PPh3)4 (19 mg, 10 mol %) was added. The reaction was heated at 90° C. overnight. The reaction was cooled and extracted with EtOAc (3×). The organic layer was dried over MgSO4 and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) gave the title compound as a foam (60 mg, 66% yield).
Reaction SMILES: [CH2:1]([N:8]([CH3:33])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:29])([CH2:23]OS(C)(=O)=O)[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:30]([O-:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[CH2:1]([N:8]([CH3:33])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:29])([CH2:23][N:34]=[N+:35]=[N-:36])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[N+:30]([O-:32])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(COS(C)(=O)=O)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccc(C(C)(CN=[N+]=[N-])C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 6b from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-one and sodium azide in dimethylformamide.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:20]([O:19][C:18](=[O:24])[N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=2[F:26])[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[CH3:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: COc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-3-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere 100° C. for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:8]([OH:18])=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1)(=O)[CH3:5].[Cl-].[OH:20][NH3+:21].C([O-])(=O)C.[Na+]>O>[OH:18][C:8]1[C:7]([C:4](=[N:21][OH:20])[CH3:5])=[CH:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([CH3:17])[CH:9]=1
Reactant: [NH3+]O
Reactant: CC(=O)Nc1cc(C(C)=O)c(O)cc1C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(C(C)=NO)c(O)cc1C
Yield: 86 %

Procedure:
To an ethanol (560 ml)-water (180 ml) mixed solvent were added the compound (35.46 g, 171.1 mmol) obtained in step B, hydroxylammonium chloride (19.41 g, 279.3 mmol) and sodium acetate (22.83 g, 278.3 mmol), and the mixture was heated under reflux for 70 min. The reaction mixture was cooled, water (500 ml) was added, and the solution was concentrated under reduced pressure (about 300 ml) to allow precipitation of a solid. Water (500 ml) was added hereto again, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (32.7 g, yield 86%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C-:17]#[N:18].[K+].OS([O-])=O.[Na+]>C1COCC1.O>[C:17]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)#[N:18]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(O)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of phenylmethyl 3-oxo-1-pyrrolidinecarboxylate (1.0 g, 4.56 mmole) and KCN (0.81 g, 12.54 mmole) in THF (5 mL) and H2O (15 mL) at 0° C. was added NaHSO3 (1.14 g, 10.9 mmole) in H2O (5.0 mL). After 3 h, the reaction contents were concentrated in vacuo, extracted with CHCl3 (2×100 mL), and the organics dried over Na2SO4. Purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (0.92 g, 82%) as a light yellow oil: LC-MS (ES) m/e 247 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=O)[O:10][C:11]=1[CH3:12])=[O:5])[CH3:2].Cl.[NH2:16][NH2:17].CO>C([O-])([O-])=O.[K+].[K+]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=[O:10])[N:16]([NH2:17])[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1c(C)cc(=O)n(N)c1C
Temperature: 150 °C
Yield: 7 %

Procedure:
A mixture of 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (3.2 mL, 19 mmol) and hydrazine monohydrochloride (1.4 g, 20 mmol) in methanol (16 mL, 0.39 mmol) was heated under microwave irradiation for 2.5 hrs at 150° C. Reaction was taken up in sat. aq. K2CO3 (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phases were washed with brine, dried over MgSO4, evaporated and purified by flash chromatography. Yield 7%. 1H NMR (500 MHz, CDCl3): 6.35 (s, 1H), 5.12 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 2.21 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][NH2:44])[CH2:38][CH2:37]1>>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([NH:44][CH2:43][CH2:42][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(CCN)CC1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Product: CN1CCN(CCNC(=O)c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 269 using 268 (30 mg, 0.07 mmol) and 2-(4-methyl-piperazin-1-yl)-ethylamine to provide 271. LC-MS (M+H=576, obsd.=576).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=2)=O)=O)[CH:5]=[CH:6][C:7]=1[OH:8].C1C(O)=CC=CC=1C.S(O)(O)(=O)=O.[NH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([OH:42])=[N:39][C:40]=1[NH2:41].S(O)(O)(=O)=O>>[OH:1][C:2]1[CH:3]=[C:4]([C:9]2[N:34]=[C:35]3[C:40](=[N:41][C:11]=2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=2)[N:39]=[C:38]([OH:42])[N:37]=[C:36]3[OH:43])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(C(=O)c1ccc(O)c(O)c1)c1ccc(O)c(O)c1
Reactant: Nc1nc(O)nc(O)c1N
Agent: O=S(=O)(O)O
Solvent: Cc1cccc(O)c1
Product: Oc1nc(O)c2nc(-c3ccc(O)c(O)c3)c(-c3ccc(O)c(O)c3)nc2n1
Temperature: 50 °C

Procedure:
A 5-mL reaction vial with a stirring vane and a teflon cap was charged with 3,3′,4,4′-tetrahydroxybenzil (137 mg; 0.500 mmol) and 1.00 mL of m-cresol (Acros) which gives a yellow-brown slurry warming to ca. 50° C. The suspension is treated with sulfate 5,6-diamino-2,4-dihydroxypyrimidine sulfate (120 mg; 0.500 mmol; 1.00 equiv) which is insoluble in the reaction solution at room temperature and goes into solution on heating to ca. 200° C. to give homogeneous dark solution. Heating between 200° C. and 220° C. for an additional 2 h, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a light yellow precipitate. The solid was centrifuged, the supernatant decanted, the solid precipitate was washed with 4×40 mL of diethyl ether and dried in a vacuum dessicator to yield a yellow solid. MS (M+H+: calcd 381; found 381).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 9 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed in toluene (15 ml) for 4 hours in the presence of triethylamine (211 mg, 2.09 mmol). The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (84.1 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 9.0%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:34]([C:42]5[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=5)[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: COc1ccc(-c2c(-c3ccccc3)c(Cl)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)c(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc3ccccc23)cc1
Yield: 42.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.23 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-phenyl-4-(4-methoxyphenyl)quinoline (95 mg, 0.27 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography ethyl acetate eluent) to give 56 mg (43%) of the title compound as an off white solid. mp 239°-242° FDMS: m/e=570. α[D]589 =+45.00 (c=1.40, chloroform).
Reaction SMILES: O=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1C=CC=CC=1>[S:23]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Yield: 191.1 %

Procedure:
To a solution of t-butyl pyroglutamate (1a) (10.12 g, 54.6 mmol) in benzene (250 mL), was added Lawesson's reagent (11.05 g, 27.3 mmol). The mixture was stirred at reflux for 15.5 h, then concentrated. The resultant residue was purified by flash chromatography (0 to 2 to 3 to 4% MeOH/CHCl3) to afford 10.50 g (95%) of the title compound, 1b. 1H NMR (300 MHz, CDCl3) δ7.27 (br s, 1H), 4.46-4.39 (m, 1H), 3.03-2.84 (m, 2H), 2.58-2.46 (m, 1H), 2.37-2.23 (m, 2H), 1.49 (s, 9H).