Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:24]([CH:26]=[CH2:27])=[O:25].O>O1CCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:24]([OH:25])[CH:26]=[CH2:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
10.3 g (40 mmol) of 1-(phenylsulfonyl)indole (synthesized analogous to T. Sakamoto; Y. Kondo; N. Takazawa; H. Yamanaka; J. Chem.Soc.Perkin Trans. 1; 16; 1996; 1927–1934) in 110 ml tetrahydrofuran were cooled to −20° C. To the stirred solution 30 ml of 1.6 M n-butyllithium were added at −20° C. within 20 min. The resulting suspension was warmed to 10° C. and stirred at 10° C. for 4 hours. The mixture was again cooled to −20° C. and a solution of 3.4 g acrolein (61 mmol) in 20 ml THF was added dropwise within 20 min at −20° C. The solution was stirred at 20° C. for 16 hours. 150 ml water was added dropwise, the mixture was vigorously stirred for 10 min. The phases were separated, and the water phase was extracted with 3×100 ml of methyl-t-butyl-ether. The combined organic phases were washed with 100 ml of brine, dried on sodium sulfate and rotary evaporated (35° C., 20 mbar). The residue was purified by liquid chromatography (eluent toluene/ethyl acetate 6:1), the pure fractions were collected and rotary evaporated (40° C./15 mbar).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[N:18]([N:20]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:22]=2)[CH:19]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH:12][S:23]([C:21]1[N:22]=[C:17]2[N:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]2[N:20]=1)(=[O:24])=[O:25]
Reactant: Cc1cnc2nc(S(=O)(=O)Cl)nn2c1
Reactant: COC(=O)c1cccc(C)c1N
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2ncc(C)cn2n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methyl 3-methylanthranilate (2.1 g, 13 mmol) was dissolved in 4 ml pyridine and 6-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After a mild exothermic reaction subsided the reaction mixture was stirred at 50° C. for 24 hours. The pyridine was removed by evaporation at reduced pressure and the residue was treated with in 10% aqueous sodium bicarbonate. Insouble material was collected by filtration, washed with ether and dried to yield 2.9 (63%) of the desired product as a solid, mp 198.5°-205° C. An analytical sample was prepared by recrystallization from ethanol to yield a crystalline solid, mp 208.5°-210.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1>O1CCCC1>[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=3)=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(-n3ccnc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5.0 g of p-tetradecyloxyphenylacetyl chloride in 50 ml of tetrahydrofuran is added to a solution of 4.31 g of pyridine and 2.36 g of 4-(2-methyl-1H-imidazol-1-yl)benzenamine in 50 ml of tetrahydrofuran over 5 minutes. The mixture is stirred at ambient temperature for 1 hour, heated to reflux and allowed to stir at room temperature for 2 hours. The solvent is evaporated to a residue which is partitioned between chloroform and dilute sodium bicarbonate. The organic layer is separated, washed with water, dried and filtered through a pad of magnesium silicate. The solvent is evaporated to an oil which crystallizes from methyl alcohol:water to give 4.0 g of white solid which is chromatographed on silica gel using ethyl acetate containing 0.1% ammonium hydroxide to give 3.9 g of the desired product as a white solid, m.p. 106°-109° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH2:13]>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]([CH:12]=[O:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2ccccc2cc1O
Reactant: O
Solvent: Cc1ccccc1C
Product: O=Cc1nc2ccccc2cc1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
3-Hydroxy-2-methyl-quinoline (0.46 g) was suspended in xylene (30 ml), zelene dioxide (2.55 g) was added to the suspension, and the mixture was stirred at 130° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 3-hydroxyquinoline-2-carbaldehyde (124 mg, yield 25%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.[OH:16][CH:17]([C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)C>[OH:16][CH:17]([C:25]1[CH:26]=[C:27]([O:33][CH3:34])[C:28]([C:31]#[N:32])=[CH:29][N:30]=1)[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:14][CH:12]([OH:13])[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:15])[O:3][C@@H:2]([CH3:1])[CH2:11]3)[CH2:23][CH2:24]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: COc1cc(C(O)CN2CCNCC2)ncc1C#N
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3)C[C@H](C)OC4=O)CC2)ncc1C#N
Temperature: 140 °C

Procedure:
A Pyrex® vessel was charged with magnetic stirring bar and 3-(S)-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 23) (78 mg, 0.38 mmol), and isomer A of 6-(1-hydroxy-2-piperazin-1-yl-ethyl)-4-methoxy-pyridine-3-carbonitrile (INTERMEDIATE 38) (100 mg, 0.38 mmol), and 2 mL of ethanol. The resulting mixture was heated in the microwave at 140° C. for 1 hour. The mixture was cooled to room temperature and the solvent was evaporated and the resulting residue was purified by preparative TLC eluting with 10% methanol/dichloromethane. The resulting mixture of two diastereomers was separated to the individual isomers by SFC-HPLC using a Chiralcel® AD-3 column.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([I:34])[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([I:34])[CH:27]=1
Reactant: NCc1ccc(F)cc1I
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-iodophenyl)methanamine. White solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.66 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2,), 4.57 (2H, d, J=6.6 Hz, NCH2), 7.05 (1H, m, aromatic), 7.3-7.38 (3H, m, aromatics), 7.42 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.53 (2H, m, aromatics), 7.56 (1H, dd, J=2.6 Hz and J=8.0 Hz, aromatic), 8.05 (1H, broad t, NH). HRMS (ESI+) calculated for C24H24FIN3O4 [M+H+]: 564.0796; found: 564.0809.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].[C:15]([OH:18])(=[O:17])C>[C].[Rh]>[C:5]([O:18][C:15]([N:7]1[CH2:6][C@@H:5]([C:3]([OH:2])=[O:4])[CH2:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:17])([CH3:6])([CH3:10])[CH3:3]
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Reactant: CC(=O)O
Agent: [Rh]
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@H](C(=O)O)C1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Dimethylpyridine-3,5-dicarboxylate (62.8 g) was dissolved in acetic acid (300 mL), 5% rhodium-carbon (6 g) was added and the mixture was stirred under hydrogen pressurization (5 atm) at 50° C. for 20 hr. The reaction mixture was allowed to cool to room temperature, the rhodium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (300 mL), and triethylamine (180 mL) and di-tert-butyl bicarbonate (105 g) were successively added under ice-cooling. The reaction mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the mixture was adjusted to pH 3 with 6M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extraction layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (300 mL), and 8N aqueous sodium hydroxide solution (161 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 20 hr, and methanol was evaporated under reduced pressure. The concentrate was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with diethyl ether. The basic aqueous layer was acidified (pH 3) with 6M hydrochloric acid. The precipitated powder was collected by filtration, washed with water and air-dried to give the object product (80.5 g) as a powder.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]#[N:15].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CCO.N1CCCCC1>[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]#[N:15])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1c(Nc2cccnc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(Nc2cccnc2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 53 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 4-hydroxybenzaldehyde (31 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (40 mg, 53% yield).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9]Br.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CC(C)=O>[S:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:9][CH2:8]1
Reactant: Nc1ccccc1S
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(c1)NCCS2
Reaction time: 8 h
Yield: 66.1 %

Procedure:
K2CO3 (4.4 g, 31.9 mmol) and 1,2-dibromoethane (0.69 mL, 8.0 mmol) were added to a solution of 2-aminothiophenol (1.0 g, 8.0 mmol) in 20 mL of acetone at room temperature. The reaction mixture was stirred overnight. The insoluble material was filtered off and the solvent was removed under reduced pressure. The residue was purified on silica gel column to provide 3,4-dihydro-2H-1,4-benzothiazine (0.8 g, 66%). MS (ES+): 152 (M+1). (208b) K2CO3 (5.2 g, 37.7 mmol) and methyl 4-(bromomethyl)benzoate (2.8 g, 12.6 mmol) were added to a solution of 208a (1.9 g, 12.6 mmol) in 20 mL of anhydrous DMF. The reaction mixture was heated to 80° C. overnight. After cooling down, the solid was filtered off and rinsed with DMF. The solvent was removed under reduced pressure and the residue was purified on silica gel column to provide methyl 4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoate (3.02 g, 80%). MS (ES+): 300 (M+1). (208c) A solution of Oxone® (2.2 g, 3.54 mmol) in 20 mL of H2O was added slowly to a solution of 208b (2.12 g, 7.1 mmol) in 20 mL of MeOH. Upon completion of the reaction, the solution was diluted with ethyl acetate, washed with saturated NaHCO3 and dried over MgSO4. After filtration and concentration, the residue was purified on silica gel column to provide methyl 4-[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoate (1.39 g, 65%). MS (AP+): 316 (M+1). (208d) A solution of KOH (1N, 7.5 mL) was added to a solution of 208c (1.25 g, 3.8 mmol) in 40 mL of MeOH and 40 mL of H2O. The reaction mixture was heated to 60° C. overnight. Upon completion, the aliquot was neutralized with HCl (1N, 1.2 mL). The solvent was removed and the residue was dissolved in MeOH. After filtration and concentration, 4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoic acid was obtained in quantitative yield. MS (AP+): 318 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:49])([F:48])[CH:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:30]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:37])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([C:16]([NH:47][CH:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:39]([F:38])([F:48])[F:49])=[O:17])[CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(c1ccccc1)C(F)(F)F
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)NC(c2ccccc2)C(F)(F)F)c1)S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI, 10.0 mg, 0.019 mmol) and (2,2,2-trifluoro-1-phenylethyl)amine (7.6 mg, 0.056 mmol) in DMF (500 μL) were added BOP reagent (10.0 mg, 0.022 mmol), ethyl(diisopropyl)amine (5.0 μL, 0.028 mmol). After sitting at rt for 4 hr, the reaction was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl {1-benzyl-1-methyl-2-[(3-[(methylsulfonyl)(propyl)amino]-5-{[(2,2,2-trifluoro-1-phenylethyl)amino]carbonyl}benzyl)oxy]ethyl}carbamate which was taken up in HCl(g) saturated EtOAc (1 mL). After 15 hr, it was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to provide 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]-N-(2,2,2-trifluoro-1-phenylethyl)benzamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.61-7.55 (m, 2H), 7.46-7.40 (m, 3H), 7.34-7.24 (m, 3H), 7.20-7.15 (m, 2H), 6.04-5.96 (m, 1H), 4.72 (A of AB, d, J=13.8 Hz, 1H), 4.68 (B of AB, d, J=13.8 Hz, 1H), 3.71 (t, J=7.1 Hz, 2H), 3.45 (A of AB, d, J=10.0 Hz, 1H), 3.40 (B of AB, d, J=10.0 Hz, 1H), 3.08 (A of AB, d, J=13.4 Hz, 1H), 2.96 (s, 3H), 2.87 (B of AB, d, J=13.4 Hz, 1H), 1.51-1.41 (m, 2H), 1.25 (s, 3H), 0.90 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([O:3][CH:4]=[CH2:5])=[CH2:2].[CH3:6][O:7][C:8](=[O:15])[CH2:9][C:10]1CCCC=1.C([O-])(=O)C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:6][O:7][C:8](=[O:15])[CH2:9][CH:10]1[CH2:2][CH:1]2[O:3][CH:4]2[CH2:5]1
Reactant: C=COC=C
Reactant: COC(=O)CC1=CCCC1
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CC1CC2OC2C1
Temperature: 35 °C
Yield: 66.5 %

Procedure:
Preparation of a vinyl ether compound having the formula: ##STR51## A) 43.46 g (0.31 mol) of cyclopentenylacetic acid methyl ester are dissolved in 80 ml of chloroform. After the addition of 4 g of sodium acetate, 82.51 g of a 40% solution of peracetic acid in acetic acid are added dropwise thereto, with stirring, the temperature being maintained at about 35° C. The reaction mixture is then stirred for a further 5 hours at 35° C. The reaction mixture is extracted with 5% sodium hydrogen carbonate solution and then twice with water. The organic phase is then separated off and dried and residual peroxide is destroyed with sodium sulfite. After distillation of the organic phase there are obtained 32.3 g of 3,4-epoxycyclopentylacetic acid methyl ester (66.5% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(C)ccc2OCC1=O

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (1.7 g) is alkylated with 3-(4-phenylpiperazin-1-yl)propylchloride in the same manner as described in Example 1 to give methyl 7-methyl-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (0.9 g) as a colorless oil.
Reaction SMILES: CN(C)CCN.[CH3:7][O:8][CH2:9][CH2:10][O:11][N:12]1[C:16](=O)[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2C1=O.C(O)(=O)C.C([C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[NH:42][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:45])=[O:44])(=O)C1C=CC=CC=1>CCO>[Cl:41][C:39]1[CH:40]=[CH:35][C:36]([NH:42][S:43]([C:46]([F:49])([F:47])[F:48])(=[O:45])=[O:44])=[C:37]([C:16](=[N:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[C:15]2[CH:14]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:38]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: COCCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: COCCON=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.2 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H; 8.87, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.54-7.31, m, 13H; 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H; 4.33, m, 4H; 3.67, m, 4H; 3.46, s, 3H; 3.38, s, 3H. HRMS (M+) 436.0465.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21]>C1COCC1.C(OC)(C)(C)C.[Pd]>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[NH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CN=[N+]=[N-]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1ccccc1CN
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 78.0 g (0.312 mol) 2-azidomethylphenylacetic acid t-butyl ester in 1.36 L THF was added 7.8 g (50% water wet) 5% Pd on C and the mixture shaken mechanically in a 2 L heavy-walled flask under H2 at 45 psi for 2 h. The catalyst was removed by filtration through a bed of celite, rinsing with 250 mL THF. To the filtrate was added a solution of 31.25 g (0.347 mol) oxalic acid in 500 mL methyl tert-butyl ether, and the resultant suspension stirred at room temperature for 30 min. The solid was collected on a filter and washed with 300 mL methyl tert-butyl ether (the filtration was very slow, requiring about 3 hours). Drying under reduced pressure at 60° C. for 18 h gave 42.4 g (39% overall from 2-bromomethylphenylacetic acid) tert-butyl [2-(aminomethyl)phenyl]acetate oxalate salt as a white powder. The product is unstable as the free base, and will cyclize to the amide over several hours at room temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl(3-nitrophenyl)carbamate (17.1 g, 71.7 mmol) in ethanol (90 mL)/tetrahydrofuran (30 mL) was added 10% palladium-carbon (1.53 g), and the mixture was stirred at room temperature under a hydrogen atmosphere (3 atm) for 9 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether/hexane mixture to give the title compound (14.7 g, 98%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.O>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O)C1
Temperature: 110 °C
Yield: 81.2 %

Procedure:
A mixture of 2-chloro-5-nitroanisole (0.59 g, 3.1 mmol) and 3-hydroxy pyrrolidine (0.55 g, 6.2 mmol) was heated neat to 110° C. over night. Reaction mass was diluted with ethyl acetate and the organic layer was given water and brine wash, dried over Na2SO4, concentration yields dark red solid (0.6 g, 82% yield). LC-MS, [M+H]+=239.