Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[N+:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:14]([S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:12])=[O:13])[CH:15]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Cc1cccc2c1c([N+](=O)[O-])cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To acetic anhydride (5 mL) at 0° C. was added 90% nitric acid (0.183 mL, 3.90 mmol) and the resulting mixture was aged for 10 min, then added dropwise to a solution of tert-butyl [1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step B (1.00 g, 2.69 mmol) in acetic anhydride (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 6 h, then aged at −20° C. for 16 h, then quenched with H2O and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=361 (M-C4H7).
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:11][C:12](=[O:44])[C:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)C(OCC)=O)[CH3:10]>C(OCC)(=O)C.S(=O)(=O)(O)O>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:22]1[CH:21]=[C:20]([CH2:19][CH:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[C:12]([O:11][CH2:9][CH3:10])=[O:44])[O:24][N:23]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)C(=O)OCC
Reaction time: 8 h

Procedure:
Sodium hydroxide, 1M, (21.5 mL, 21.5 mmol) was added in portions over 30 minutes to a dioxane (22 mL) solution of 2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (10.95 g, 21.5 mmol). After stirring overnight, the reaction had not gone to completion. An additional 0.2 equivalents of 1M sodium hydroxide (4.2 mL, 4.2 mmol) was added and stirring continued for 3 hours. The reaction was diluted with ethyl acetate (50 mL) and 1M sulfuric acid (23 mL) was added dropwise at 0° C. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate and concentrated in vacuo to give a the title compound. The crude product was used directly in the next step without separation of the unreacted diester. MS (Cl) m/z 382.2 (M−99).
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:20][CH:21]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3cccc(F)c3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(-c3cccc(F)c3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(4-{2-[(3′-Fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester obtained in Example 68-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (151 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2ncc3c(n2)C(OS(C)(=O)=O)CCC3)ccc1-n1cnc(C)c1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)C(N2CCCC2)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a suspension of methanesulfonic acid 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-8-yl ester (61 mg, 0.14 mmol) in tetrahydrofurane (1.4 mL) was added under nitrogen at 0° C. pyrrolidine (20 mg, 0.28 mmol) and triethyl amine (29 mg, 0.28 mmol). The reaction was stirred at room temperature over night, heated to reflux for 2 hours. A few drops of dimethylformamide were added and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, dissolved in water and extracted twice with ethyl acetate. The combined organic layers were washed with dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol/concentrated aqueous ammonia (19:1:0.2 v/v/v) as eluent to yield the title compound (24 mg, 42%) as a yellow solid. MS ISP (m/e): 234.3 (100), 334 (24), 405.3 (69) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.61 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.38 (d, 1H), 7.20 (d, 1H), 7.02 (s, 1H), 3.80 (s, 3H), 2.55-2.80 (m, 4H), 2.14 (s, 3H), 2.04 (m, 2H), 1.60-1.80 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].O>O1CCCC1.CCCCCC>[CH2:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]([O:27][CH2:28][CH3:29])=[O:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)OCC
Reactant: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11 g of 4-(4-bromophenyl)-1-benzyl-1,2,3,6-tetrahydropyridine in 200 ml of tetrahydrofuran was added 27 ml of a 2.5 M solution of n-butyllithium in hexane at −78° C. and the resulting mixture was stirred at the same temperature for 15 minutes. Into the reaction mixture was dropped 42 ml of diethyl carbonate and the mixture was heated to room temperature over 15 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 2.8 g of the title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH2:6][CH2:7]3)=[N:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Clc1ccc2c(Cl)ncnc2c1
Product: Clc1ccc2c(c1)N(c1ncnc3cc(Cl)ccc13)CC2
Yield: 50 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 50% yield from 6-chloro-indoline and 4,7-dichloro-quinazoline. (M.P. 189° C.; LC-MS: 316 (MH+)).
Reaction SMILES: [O:1]=[C:2]1[C@H:10]2[C@H:5]([C@@H:6]3[CH2:11][C@H:9]2[CH:8]=[CH:7]3)[C@@H:4](N[C@@H](CC(C)C)C(OCC2C=CC=CC=2)=O)[O:3]1.[OH2:28]>>[OH:28][C@@H:4]1[C@@H:5]2[C@@H:10]([C@H:9]3[CH2:11][C@@H:6]2[CH:7]=[CH:8]3)[C:2](=[O:1])[O:3]1
Reactant: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1
Reactant: O
Product: O=C1O[C@H](O)[C@@H]2[C@H]1[C@@H]1C=C[C@H]2C1
Temperature: 55 °C

Procedure:
2.2 g of the product of Step A were added to a mixture of 1.8 ml of 22° Be hydrochloric acid in 18 ml of water and the mixture was heated at 55° C. for 17 hours and was then cooled to 20° C. The mixture was extracted with ethyl acetate and the organic phase was washed with 2N aqueous sodium hydroxide solution. The alkaline aqueous phase was washed with methylene chloride, with ethyl acetate and was acidified to a pH of 3.5 by addition of 2N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was taken up in ether and the mixture was vacuum filtered to obtain 0.450 g of (3S,3aS,4R,7S,7aR) 3-hydroxy-3a, 4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one melting at 133° C. and having specific rotation of [α]D20 =- 44° (c=1% in benzene).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:40][CH2:41][C:42](Cl)=[O:43])(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:19]([NH:23][C:41](=[O:40])[CH2:42][OH:43])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)CO)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To a stirred solution of (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine (91a, 13 mg, 0.03 mmol) in dry THF (1 ml) were added, at r.t., triethyl amine (28 μl, 0.2 mmol) and 2-chloro-2-oxoethyl acetate (10.8 μl, 0.1 mmol). The reaction was stirred over night. The solvent was removed under reduced pressure. To the crude solid was added Methanol (300 μl) and ammonium hydroxide (100 μl, 28%). The solution was stirred over night.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[C:12]([NH:14][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[CH:13]=1)=[O:7].C(N(C(C)C)CC)(C)C.[CH3:44][C:45]([CH3:51])([CH2:49][CH3:50])[C:46](Cl)=[O:47]>C(Cl)Cl>[CH3:44][C:45]([CH3:51])([CH2:49][CH3:50])[C:46]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)=[C:12]([NH:14][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[CH:13]=1)=[O:7])=[O:47]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CNCCNC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)C(=O)N(C)CCNC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)c1
Temperature: 12.5 °C
Reaction time: 4 h

Procedure:
Furan-2-carboxylic acid [5-{2-[(2,2-dimethyl-butyryl)-methyl-amino]-ethylcarbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (compound no. 133) was prepared as follows: To a solution of furan-2-carboxylic acid [5-(2-methylamino-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.04 g, 0.086 mmol) and diisopropylethylamine (0.5 mL) in CH2Cl2 (2.0 mL), 2,2-dimethyl butyryl chloride (0.173 mmol) was added at 0° C., and the reaction was stirred at 0-25° C. for 4 h. Reaction was diluted with CH2Cl2 and washed with a solution of saturated NaHCO3. Organic layer was concentrated and dissolved in ACN and purified on preparative HPLC using water/MeOH (0.1% TFA) as eluent to give the product (0.01 g, 21% yield).
Reaction SMILES: [C:1]1(CO)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(O)(=O)CC[C:14](C)=[O:15].C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:3]1([CH2:14][OH:15])[C:4]([CH2:7][OH:8])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: CC(=O)CCC(=O)O
Reactant: OCc1ccc(CO)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: OCc1ccccc1CO
Reaction time: 8 h
Yield: 191 %

Procedure:
In a flask with dichloromethane (ca. 25 ml), 1,4-phenylenedimethanol (5 g, 0.036 mol) and levulinic acid (8.36 g, 0.072 mol) were mixed. The flask was then cooled in an ice water bath. Diisopropyl carbodiimide (9.09 g, 0.072 mol) and the catalyst DMAP (ca. 100 mg) were then added slowly to the solution. The mixture was allowed to come to room temperature and was stirred overnight. The mixture was then filtered and washed with 1M HCL brine. It was then dried over MgSO4 and concentrated in vacuo to afford a white solid as the product (9.5 g). Its purity was ascertained using 1H NMR (300 MHZ in CDCL3): δ 7.34 (s, 4H), 5.11 (s, 4H), 2.77 (t, 4H), 2.62 (t, 4H), 2.18 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9]S[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[C:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[C:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][C:5]([C:16]([O:18][CH3:19])=[O:17])=[C:6]2[N:7]1[CH:8]=[CH:9][C:11]1[CH:15]=[CH:14][S:13][C:12]=12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC=C2
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12

Procedure:
4.4 g of methyl 8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate were heated under reflux and under argon together with 90 ml of xylene until the reaction was completed. The solution was evaporated in vacuo and the residue was treated with 100 ml of n-hexane, whereupon the product was removed by filtration. By recrystallization from ethyl acetate, there was obtained methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate as yellow crystals of m.p. 153°-156°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].C([O-])=[O:14].[Na+]>CO>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CO)c1ccc(Cl)c(Cl)c1
Yield: 41.9 %

Procedure:
A mixture of 2-bromo-3′,4′-dichloroacetophenone (78.0 g), sodium formate (68.0 g) and methanol (300 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was concentrated and poured into water (1 L). The solid precipitates were filtered, washed with water and then isopropyl ether, and air-dried. The residue was dried under reduced pressure to give crystals of 2-hydroxy-3′,4′-dichloroacetophenone (25.0 g, 42%). Recrystallization from ethyl acetate-hexane gave pale yellow prisms. Melting point 115-118° C.
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].Cl[C:14]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O>[CH3:19][O:18][C:16]([C:15]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:14]=1[O:10][N:9]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2])=[O:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(=NO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1ON=C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A solution of 17.25 g of acetophenone oxime in 100 ml of dimethylformamide is added dropwise to a suspension of 5.92 g of 62.5% sodium hydride in 400 ml of dimethylformamide under ice-cooling. The mixture is stirred at the same temperature for 1.5 hours. A solution of 25.04 g of methyl 2-chloro-5-nitrobenzoate in 150 ml of dimethylformamide is added to the mixture, the mixture is stirred for 1 hour. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from isopropanol to give 26.7 g of acetophenone O-(2-methoxycarbonyl-4-nitrophenyl)oxime as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: COc1ccc(N)c(CO)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN2CCCCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-piperidine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and piperidine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][P:30]([Cl:32])[O:29][C@@H:28]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][P:30]([Cl:32])[O:29][C@@H:28]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OP(Cl)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OP(Cl)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-chloro-1,3-dioxaphosphorinan-4-yl)acetate.
Reaction SMILES: [CH3:1]C(OC(N(C)C)N(C)C)(C)C.[CH3:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([CH3:23])[C:15]=1[Br:24]>CN(C=O)C.[Zn]>[Br:24][C:15]1[C:16]([CH3:23])=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:1][NH:20]2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1Br
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]ccc2c1Br
Temperature: 122.5 °C
Yield: 29 %

Procedure:
Bredereck's reagent (tert-butoxybis(dimethylamino)methane—16 g, 91 mmol) is added at room temperature to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 ml). The reaction mixture is heated at 120-125° C. under N2 for 5 hours or until starting material is mostly consumed according to TLC. The reaction mixture is allowed to cool to room temperature, poured into water (300 ml), and extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of enamines as a dark brown oil. This material is carried on to the next step without purification. The crude mixture is dissolved in acetic acid/water (250 ml of 4:1), cooled to 0° C. and treated with zinc dust (57 g, 870 mmol) added slowly in portions. After complete addition, the reaction mixture is heated at 110° C. for 4 h. Zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica get (EtOAc/Hexane 1:20) to obtain 4-bromo-5-methylindole (5.3 g) (21) as a light purple oil.
Reaction SMILES: [Cl:1][C:2]1[C:13]([OH:14])=[CH:12][C:5]2[C:6](=O)[C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:13]([OH:14])=[CH:12][C:5]2[C:6](=[S:24])[C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[CH:3]=1
Reactant: CC1(C)Oc2cc(Cl)c(O)cc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc(Cl)c(O)cc2C1=S
Temperature: 25 °C

Procedure:
A solution of 20 mmol 6-chloro-5-hydroxy-2,2-dimethyl-benzofuran-3-one in 30 ml toluene is admixed with 10 mmol Lawesson's reagent and heated for 3 hours to boiling under reflux. After cooling to room temperature it is filtered on 50 g silica gel. The red fraction of the filtrate is collected. After removing the toluene by distillation a red oil remains.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(C)=O>[C:37]([O:39][CH2:40][CH2:41][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][CH2:14][C:12]2[N:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[OH:1])[O:10][C:11]=2[CH:26]([CH3:28])[CH3:27])=[CH:19][C:20]=1[CH3:25])(=[O:38])[CH3:36]
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)cc1C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
The obtained 3-[2-(2-hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (378 mg, 0.95 mmol) was dissolved in acetone (20 mL). To the solution, potassium carbonate (158 mg, 0.95 mmol) and ethyl bromoacetate (158 mg, 0.95 mmol) were added while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the mixture was washed with acetone to remove the solvent. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (315 mg) as white solid (yield 69%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[Br:28]>>[Br:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[NH:21][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Product: Cc1noc(NS(=O)(=O)c2ccsc2CCc2ccc3c(c2)OCO3)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]-thiophene-3-sulfonamide was prepared in the same manner as described in Example 10. By reacting 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene with 5-amino-4-bromo-3-methylisoxazole and purifying the crude product by HPLC, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide was obtained in a 30% yield, m.p. 180° (dec.).