Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37]([O:39]C(C)(C)C)=[O:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:35][C@H:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([OH:39])=[O:38])=[O:32])=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)O)c1ccccc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.40 g, 0.827 mmol) was dissolved in CH2Cl2 (40 ml) and tert-butyl (2R)-amino(phenyl)acetate (0.206 g, 0.993 mmol) and N-methylmorpholine (0.251 g, 2.48 mmol) were added. After 10 minutes, TBTU (0.345 g, 1.076 mmol) was added. The reaction was stirred overnight. The resulting tert-butyl ester was concentrated and purified on silica gel (eluted with EtOAc/CH2Cl2 25/75). The pure fractions were collected and concentrated. CH2Cl2 (25 ml) and TFA (3 ml) were added. The mixture was stirred for 5 days and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-70% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions gave the title compound as a colourless solid. M/z: 615.50 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 4.35 (d, 1H), 4.36 (d, 1H), 4.40 (d, 1H), 4.53 (d, 1H), 4.58 (d, 1H), 4.94 (d, 1H), 5.19 (d, 1H), 6.97-7.40 (m, 15H), 8.02-8.06 (m, 2H), 8.26-8.32 (m, 1H).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[C:11]3[O:13][CH2:14][O:15][C:10]3=[CH:9][C:8]=2[C:16]2([OH:23])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=N1.Cl>>[CH3:22][N:19]1[CH2:20][CH2:21][C:16]2([C:8]3[C:7](=[CH:12][C:11]4[O:13][CH2:14][O:15][C:10]=4[CH:9]=3)[C:4](=[O:5])[O:23]2)[CH2:17][CH2:18]1
Reactant: CN1CCC(O)(c2cc3c(cc2C2=NC(C)(C)CO2)OCO3)CC1
Agent: Cl
Product: CN1CCC2(CC1)OC(=O)c1cc3c(cc12)OCO3

Procedure:
Treatment of 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)-4,5-methylenedioxyphenyl]-4-hydroxy-1-methylpiperidine with hydrochloric acid by the method described in Example 1d provides 1,3-dihydro-1'-methyl-5,6-methylenedioxyspiro[isobenzofuran-1,4'-piperidine]-3-one.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33]5[N:34]=[C:35]([O:38][CH3:39])[N:36]=[CH:37][C:32]=5[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33]5[N:34]=[C:35]([O:38][CH3:39])[N:36]=[CH:37][C:32]=5[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ncc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of 0.54 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)carbamate in 15 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. A 2 mol/L aqueous sodium hydroxide solution was added under cooling with ice to adjust pH at 13, dichloromethane was added thereto, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=10:1 to obtain 0.34 g of 8-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][NH2:21]>C1COCC1.C1(C)C=CC=CC=1>[NH:21]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c2n(c3ccccc13)CCCN2
Reaction time: 0.33 h

Procedure:
A solution of methyl 2-chloroindole-3-carboxylate (D11a, 1.5 g, 0.0071 mole) in THF (30 ml) under argon was treated with sodium hydride (215 mg of 80% oil dispersion, 0.0071 mole) and stirred for 20 minutes. The resulting solution was treated with a solution of 3-bromopropylamine (0.0093 mole) in toluene (15 ml) and a white gelatinous precipitate formed. This mixture was diluted with more THF (30 ml) and heated under reflux for 18 h, then concentrated in vacuo and the residue shaken well with ethyl acetate (40 ml) and 10% Na2CO3 solution (30 ml). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a beige solid. This was chromatographed on silica gel eluting with ether/60-80 petrol (1:1) to afford unreacted starting material (600 mg) and the title compound (D18) as a white solid (110 mg, 6%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C([Li])CCC.[C:13](=[O:15])=[O:14].Cl>C(OCC)C>[CH2:1]([C:3]1[O:4][C:5]([C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1)[CH3:2]
Reactant: CCc1ccco1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1ccc(C(=O)O)o1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
2-Ethylfuran (9.1 g) was dissolved in diethyl ether, and the mixture was cooled to -70° C. under nitrogen atmosphere. n-Butyllithium (1.6M in hexane, 60 ml) was slowly added dropwise. The mixture was stirred at room temperature for 2 hours, and then cooled to -70° C. The mixture was stirred for 30 minutes with introducing carbon dioxide gas, and then warmed to room temperature. The mixture was stirred at room temperature for 30 minutes, poured into ice-water, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was crystallized from water and collected by filtration to give 5-ethyl-2-furancarboxylic acid (9.0 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:34])([F:33])[CH:5]([CH3:32])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:24](=[O:25])[CH2:23][O:22][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:20]2)=[CH:14][CH:13]=1)[C:7]([O:9]CC)=[O:8]>O1CCOCC1>[F:34][C:4]([F:3])([F:33])[CH:5]([CH3:32])[CH:6]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:24](=[O:25])[CH2:23][O:22][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:20]2)=[CH:16][CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C(C(=O)O)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
11.4 ml (11.4 mmol) of 1 N aqueous sodium hydroxide solution were added to a solution of 1283 mg (2.86 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoate in 10 ml of dioxane, and the mixture was stirred at 80° C. overnight. After the reaction had gone to completion, the dioxane was removed under reduced pressure and the solution that remained was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 1058 mg (2.52 mmol, 88% of theory) of the title compound as an isomer mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]([CH3:21])[N:13]=1.S(Cl)([Cl:25])(=O)=O>C(O)(=O)C.O>[Cl:25][C:16]1[C:12]([C:3]2[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])=[N:13][N:14]([CH3:21])[C:15]=1[C:17]([F:18])([F:19])[F:20]
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Reaction time: 6 h

Procedure:
To 5.00 g of 3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole dissolved in 50 ml of acetic acid was added 15 ml of sulfuryl chloride. The mixture was mildly refluxed with 2 ml portions of sulfuryl chloride added every 15 minutes. After 6 hours, the mixture was cooled, then diluted with water and extracted with ether. The ether was washed 3 times with water, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed to give a quantitative yield of 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:29]
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].C(NC(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:15]2[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)N1CCN(c2ccc(C(=O)CCc3ccc(N)cc3)cc2)CC1
Temperature: 105 °C

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (1.1 g, 4.52 mmol) (prepared as described in Example 1b),1-ethoxycarbonylpiperazine (2.15 g, 13.57 mmol), and diisopropylamine (6.5 g, 4.98 mmol) in dimethylsulfoxide (10 mL) was heated at 100-110° C. for about 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (150 mL), washed with cold water and brine. The organic layer was separated, dried, and evaporated in vacua. Purification by silica gel chromatography, eluting with 60% ethyl acetate/hexane, gave the title compound, m.p. 106.3-106.7° C. Analysis for C22H27N3O3: Calcd.: C, 69.27; H, 7.13; N, 11.02. Found: C, 69.13; H, 7.04; N, 11.03.
Reaction SMILES: CC(C[CH:5](NC(C(NC(CNC(CN[C:29]([CH:31]([NH2:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)=[O:30])=O)=O)CC1C=CC=CC=1)=O)[C:6](O)=[O:7])C.CN(CCCN)C.C(N1C=CN=C1)(N1C=CN=C1)=S.[CH3:60][N:61]([CH2:63][CH2:64][CH2:65][NH:66][C:67]([NH2:69])=[S:68])[CH3:62].FC(F)(F)C(O)=[O:73]>O>[NH2:40][C@H:31]([C:29]([OH:30])=[O:73])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[CH3:60][N:61]([CH2:63][CH2:64][CH2:65][N:66]1[CH2:5][C:6](=[O:7])[NH:69][C:67]1=[S:68])[CH3:62]
Reactant: CN(C)CCCNC(N)=S
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)C(N)Cc1ccc(O)cc1)C(=O)O
Agent: CN(C)CCCN
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: O
Product: CN(C)CCCN1CC(=O)NC1=S
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Yield: 95 %

Procedure:
Reaction of YGGFL with Dimethylaminopropylamine and Thiocarbonyldiimidazole. Dimethylaminopropylamine (1 μmol in 50 μl of DMF) was added to 1,1'-thiocarbonyldiimidazole (1 μmol in 50 μl DMF) and allowed to react for five minutes at 25° C. The pentapeptide, YGGFL (100 nmol in 50 μl DMF), was added and allowed to react for twenty minutes at 25° C. The sample was then taken to dryness in a vacuum centrifuge, redissolved in 0.1% trifluoroacetic acid in water (100 μl), and analyzed by reversed phase HPLC (FIG. 6). The expected peptide product (the N-terminal dimethylaminopropylthiourea derivative; peak B) was identified by FAB/MS (MH+=700) and obtained in approximately 95% yield. Peak A is the starting peptide, YGGFL (MH+=556). Peak B was then treated with 50 μl of anhydrous trifluoroacetic acid for ten minutes at 50° C., dried in a vacuum centrifuge, redissolved in 0.1% trifluoroacetic acid in water (100 μl), and analyzed by reversed phase HPLC. The shortened peptide (GGFL) (MH+=393) and the dimethylaminopropyl thiocarbamyl amino acid (MH+=326) were found in quantitative yield. No dimethylaminopropyl thiohydantoin tyrosine was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCC[CH2:20]1.C([Li])CCC.COS(OC)(=O)=O>C([Li])CCC.O>[CH3:20][C:16]1[S:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(-c2ccc(-c3cccs3)s2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSc1ccc(-c2ccc(-c3ccc(C)s3)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.82 gram (0.003 mole) of 5-(4-methylthiophenyl)[2,2'-bithienyl] in 100 ml of freshly distilled tetrahydrofuran was cooled to 0° C. and 1.4 ml of n-butyllithium (2.6M in hexanes) was added dropwise via syringe during a ten minute period. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes, then at ambient temperature for three hours. The reaction mixture was recooled to 0° C. and an additional five drops of n-butyllithium was added. The reaction mixture stirred at 0° C. for one hour then 0.32 ml (0.0034 mole) of dimethylsulfate was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was taken up in 70 ml of water and the organic layer was separated. The aqueous layer was washed with three 25 ml portions of chloroform. The organic layers were combined and washed, first with water, then with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 0.78 gram of 5'-methyl-5-(4-methylthiophenyl)[2,2'-bithienyl]; m.p. 145°-147° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:6](Br)[CH:7]=1.[Cu](C#N)[C:32]#[N:33].CN1CCCC1=O>O>[F:1][C:2]1[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:6]([C:32]#[N:33])[CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Br)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 175 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A mixture of 75 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]bromobenzene, 27 mg of copper cyanide and 0.5 ml of N-methyl-2-pyrrolidone was stirred at 170 to 180° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 57 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]cyanobenzene.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[S:12]1[CH:16]=[C:15]([CH:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[C:14]2[CH:36]=[CH:37][CH:38]=[CH:39][C:13]1=2>CCOC(C)=O>[Br-:1].[S:12]1[CH:16]=[C:15]([CH:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N+:23]([CH2:2][C:3]([C:5]4[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=4)=[O:4])([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[C:14]2[CH:36]=[CH:37][CH:38]=[CH:39][C:13]1=2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1csc3ccccc13)C2)c1ccc(O)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (54.8 mg, 0.25 mmol) was added portionwise to a solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (C19) (100 mg, 0.25 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with ethylacetate and then it was triturated with CH3CN to obtain (R)-3-(2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane bromide (101 mg, 65.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[CH:13][CH:12]=2)=[N:6][CH:5]=1.[CH2:31]([N:33](CC)[CH2:34]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:19](=[O:20])[N:33]([CH3:34])[CH3:31])=[CH:13][CH:12]=2)=[N:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)nc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
The compound 17 (2.2 g, 5.28 mmol) was dissolved in CH2Cl2 and stirred at room temperature under an atmosphere of argon. Triethylamine (0.883 mL, 6.33 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 2.5 g, 5.80 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 13.2 mL, 26.4 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 18 (1.3 g, ˜98%). 1H NMR (400 MHz, DMSO-d6): 8.67 (br, 1H), 8.29 (dd, J=8.8 and 2.4 Hz, 1H) 7.31 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.57 (m, 1H), 3.85 (s, 3H), 2.93 (s, 3H), 2.85-2.75 (m, 2H), 2.80 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:8][C:9]1([CH3:16])[CH2:14]CC[CH2:11][C:10]1=[O:15])([CH3:4])([CH3:3])[CH3:2].CC(C(C)C)=O>>[C:21]([C:18]1[CH:17]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:19]=1[OH:20])[CH2:8][C:9]([C:10]([CH3:11])=[O:15])([CH3:14])[CH3:16])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC1(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCCCC1=O
Solvent: CC(=O)C(C)C
Product: CC(=O)C(C)(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 65 %

Procedure:
If, in this example, the 2-methylcyclohexanone is replaced by an equivalent quantity of isopropyl methyl ketone, an otherwise identical procedure gives methyl [1-(3,5-ditert.-butyl-4-hydroxybenzyl)-isopropyl] ketone, melting point 75° C., in a yield of 65%.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=2[O:14]1>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[O:23]1[C:22]2[CH:21]=[CH:20][C:17]([CH2:18][N:4]3[C:5](=[O:6])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[S:1]3(=[O:2])=[O:3])=[CH:16][C:15]=2[O:14][CH2:13]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
To saccharin (5.0 g, 0.0273 mol) in DMF (10 mL) was added Nail (1.15 g, 60% in oil, 0.0288 mol) with ice bath cooling. After stirring for 10 minutes. a solution of 3,4-methylenedioxybenzyl chloride in methylene chloride, 50% by weight, (10 g, 0.0293 mol) was added and the mixture stirred for 16 hours. The mixture was diluted with ethyl acetate (200 mL) containing 10% methylene chloride and washed with IN HCl (2×100 mL). The organic phase was washed with brine and dried over MgSO4. The mixture was concentrated until crystals were apparent. After standing for 16 hours the product was collected by filtration (4.2 g, 49%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:4][CH:3]=1.[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[NH:41][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCN(CCCNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCN(CCCNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a mixture of 4-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (20 mg, 0.041 mmol) and benzenesulfonamide (7.0 mg, 0.045 mmol) in CH2Cl2 (1 ml) were added WSC.HCl (8.6 mg, 0.045 mmol) and DMAP (5.5 mg, 0.045 mmol), and the mixture was stirred at RT for 18 h. The reaction mixture was purified by preparative normal phase HPLC using linear gradients of (A) chloroform and (B) methanol (2-4% B, in 0-2 min; 4-5% B, in 2-6 min; 5% B, in 6-12 min) at a flow rate of 12 ml/min. Fractions containing the major peak were pooled and concentrated to afford 3-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-[(phenylsulfonyl)carbamoyl]propane (5.4 mg, 21%): MS(ES+) m/e 627 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.05 (m, 2H), 7.50 (m, 3H), 7.44 (d, J=8.8 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.23 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 4.72 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.21 (m, 1H), 2.96 (m, 1H), 2.79-2.65 (m, 5H), 2.57 (m, 1H), 2.17 (m, 1H), 2.03 (m, 1H), 1.94-1.66 (m, 4H).