Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>S(=O)(=O)(O)O.CC(C)=O>[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:1])=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O
Reactant: OCCCCCCCCCCCCC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCCCC1CCCCC1
Yield: 58.7 %

Procedure:
CrO3 (VI) (3.204 g, 32.04 mM) was dissolved in sulfuric acid (2.76 ml), followed by stirring for a time, and then water (4.8 ml) was added to yield a solution. This solution was added drop by drop to a solution of 12-cyclohexyldodecanol (5.36 g, 20 mM) in acetone (300 ml) under ice cooling conditions, followed by stirring for 1 hour. To the mixture, iso-prapanol (about 2 ml) was added and then concentrated to dryness under reduced pressure. To the resulting residue, water (50 ml) and chloroform (50 ml) were added, followed by vigorous stirring, after which the chloroform layer was separated. The chloroform layer was dryed over anhydrous sodium sulfate, purified by silica gel colum (50 g) (methanol-chloroform (1:49)) to yield the title compound (5.3 g, yield 58.7%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Fc1ccc(C2CCCN2)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(F)c(Cl)c1

Procedure:
The title compound, off-white solid, m.p. 119° C. and MS: m/e=374.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:7]([N:8]=[C:15]=[S:16])=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(N2CCCCC2)c1N
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(N2CCCCC2)c1N=C=S

Procedure:
Reaction of 6-methyl-2-piperidinoaniline (6.4 g) in dioxan (20 ml) and water (65 ml) with thiophosgene (5.7 g) at 0° C. for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothiocyanate as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:25][CH3:26])=[CH:22][CH:21]=[CH:20][CH:19]=2>CN(C)P(N(C)C)(N(C)C)=O.C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:26][NH:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Cc1cc(C(=O)O)on1
Reactant: CNc1c(N)cnc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNc1c(NC(=O)c2cc(C)no2)cnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 245 mg of 3-methylisoxazole-5-carboxylic acid in 20 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 226 mg of thionyl chloride at -5°-0° C. After stirring at the same temperature for 30 minutes, 330 mg of 3-amino-4-methylaminoquinoline A15 is added and stirred at 0°-5° C. for 5 hours. The mixture is diluted with 50 ml of ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 361 mg (67%) of 4-methylamino-3-[(3-methylisoxazole-5-ylcarbonyl)amino]quinoline. It is suspended in 4 ml of hexamethylphosphoramide and 1 ml of acetic acid and stirred at 180° C. (bath temperature) for 40 minutes. The cooled mixture is poured into ice-water and neutralized with aqueous sodium bicarbonate. The resulting solid is filtered, washed with water and chromatographed on silica gel with dichloromethane-methanol (25:1 v/v) as eluent. The product obtained is recrystallized from dichloromethane-methanol to give 294 mg of C102 as white crystals melting at 281°-284° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@H:29]([NH:32][C:14](=[O:16])[C@@H:9]([N:8]([CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4R,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 240 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.40-7.43 (m, 2H), 7.31-7.37 (m, 3H), 7.23-7.30 (m, 1H), 4.82-4.89 (m, 1H), 4.35-4.42 (m, 1H), 3.35 (d, J=12.9 Hz, 1H), 2.95 (s, 3H), 2.68-2.78 (m, 2H), 2.42-2.50 (m, 1H), 2.26-2.36 (m, 3H), 1.89 (ddd, J=14.1, 8.2, 5.9 Hz, 1H), 1.71-1.82 (m, 2H), 1.60-1.70 (m, 3H), 1.48-1.51 (m, 1H), 1.48 (s, 9H), 1.22-1.35 (m, 1H), 0.88-0.98 (m, 6H); MS (ESI+) m/z 444 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:23])[C@@:11]([CH3:22])([CH2:14][O:15]CC[Si](C)(C)C)[CH:12]=[CH2:13])([CH3:3])[CH3:2].F[B-](F)(F)F.[Li+]>C(#N)C.O.O.C(OCC)C>[OH:15][CH2:14][C@@:11]([CH3:22])([CH:12]=[CH2:13])[C:10]([N:5]1[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])=[O:23]
Reactant: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1C(C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: C=C[C@](C)(CO)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a stirred solution of (R)-4-isopropyl-3-[(R)-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoyl]-oxazolidin-2-one (2.93 g, 8.58 mmol) in a mixture of acetonitrile (86 mL) and water (1.72 mL) was added lithium tetrafluoroborate (1 M in acetonitrile, 42.9 mL, 42.9 mmol). The mixture was heated at reflux under nitrogen for 5 h and allowed to cool to ambient temperature. More lithium tetrafluoroborate (1 M in acetonitrile, 8.6 mL, 8.6 mmol) was added and the mixture heated at reflux for a further 75 minutes and allowed to cool to ambient temperature. The mixture was diluted with water/diethyl ether (2:3, 100 mL) and the organic layer was separated and washed with water. The combined aqueous washes were back-extracted with diethyl ether and the combined organic extracts dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (1.89 g, 91%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.35 (s, 3H), 2.36-2.47 (m, 1H), 2.56-2.70 (br s, 1H), 3.47-3.54 (m, 1H), 3.91 (d, J=11.6 Hz, 1H), 4.22-4.31 (m, 2H), 4.47-4.53 (m, 1H), 4.97 (d, J=17.8 Hz, 1H), 5.17 (d, J=10.7 Hz, 1H), 6.09 (dd, J=17.8, 10.7 Hz, 1H). LCMS (m/z) 242.2 [M+H], Tr=1.82 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:5]1([NH:8][C:14]2[CH:15]=[CH:16][C:11]([NH2:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(NC2CCCCC2)cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and cyclohexylamine
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:25])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(OC)(C)C.C(O)(C)C>[CH3:24][O:23][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[C:9](=[O:25])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2c(OC)c1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4)CC3)c(C)c2c(OC)c1OC
Yield: 49 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,6,7-trimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 34) and 1-phenylpiperazine; yield 49%; m.p. 136°-137° C. (from TBME/isopropanol).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][N+:15]([O-:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][N+:15]([O-:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
(4-Acetamidophenylsulphonyl)nitromethane (obtained as described in J Het. Chem., 1977, 14, 1415) (10.0 g, 38.8 mmol) was added in one portion to a boiling mixture of concentrated hydrochloric acid (20 ml), water (100 ml) and ethanol (40 ml). The mixture was stirred at reflux until a clear solution formed (about 20 minutes) and then for a further 5 mins. The hot reaction mixture was poured into an excess of ice-cold saturated sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and the solvent was removed by evaporation. There was thus obtained (4 aminophenylsulphonyl)nitromethane as a pale yellow solid (5.2 g, 62% yield), m.p. 132°-133° C., microanalysis, found: C, 39.2; H, 3.8: N, 12.9%; C7H8N2O4S requires: C, 38.9; H, 3.7; N, 12.95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH:11]([C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1=NN(c2ccc(Cl)cc2)C(=O)C1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1C(=O)Nc1ccc(F)cc1
Reaction time: 8 h

Procedure:
The suspension of 3.1 g of 1-(p-chlorophenyl)-3-methyl-2-pyrazolin-5-one in 100 ml of benzene is treated with 1.8 g of triethylamine, warmed until dissolution and combined with 2.1 g of p-fluorophenylisocyanate while stirring. After standing overnight at room temperature it is evaporated, the residue taken up in methanol and the solution treated with the mixture of 10 ml of 5 N hydrochloric acid and 250 ml of water. The mixture is extracted with ethyl acetate, the extract washed with water, dried and evaporated. The crude solid is dissolved in 2 N aqueous sodium hydroxide, the solution filtered and acidified with 5 N hydrochloric acid. The precipitate is collected, washed with water and recrystallized from ethyl acetate-petroleum ether, to yield the 1-(p-chlorophenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one melting at 240°-242° with decomposition.
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[CH:9][C:10](I)=[C:11]([CH:13]=1)[NH2:12].C(N(CC)CC)C.C#CCC>C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:5]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:13][C:11]=1[NH2:12])#[C:1][CH2:2][CH3:3]
Reactant: C1CCOC1
Reactant: Nc1cc(F)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: C#CCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC#Cc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
160 mL of THF were placed in the flask and degassed with argon. Then 10 g (45 mmol) 5-fluoro-2-iodo-aniline, 1.5 g (2.1 mmol) PdCl2(PPh3)2 and 0.40 g (2.1 mmol) copper iodide were added and the flask was rinsed with argon. Then 18 mL (0.13 mol) triethylamine were added and 3.0 g (55 mmol) 1-butyne (in gaseous form) were passed through the solution. The reaction mixture was stirred for 3 h at RT, then diluted with diethyl ether, filtered through kieselguhr and evaporated down.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14][N:15]=2)[CH2:7]1.[OH-].[Na+]>C1COCC1.CO>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH2:7]1
Reactant: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboxylate (1.2 g, 3.2 mmol) and 1M aqueous NaOH (6.4 mL, 6.4 mmol) in THF-MeOH (1:1, 24 mL) was heated at 80° C. bath for 2 h. Volatile solvents were removed in vacuo. The residue was diluted with H2O, acidified with 1M HCl (7 mL) and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (Na2SO4), concentrated and triturated with Et2O to give the title compound as white solid. 1H NMR (400 MHz, acetone-d6): δ 7.84 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.51 (s, 1 H), 3.95 (m, 1 H), 3.81-3.60 (m, 3 H), 2.60-2.40 (m, 2 H).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH2:17]>N1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH:17][C:1](=[O:5])[CH:2]=[CH:3][CH3:4]
Reactant: C/C=C/C(=O)Cl
Reactant: Cc1ccc2[nH]nc(N)c2c1
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2ccc(C)cc12
Reaction time: 12 h

Procedure:
0.33 cm3 of crotonyl chloride is added to 560 mg of 5-methyl-1H-indazole-3-amine, prepared as described in patent EP 909 720, in 30 cm3 of pyridine. The medium is allowed to return to about 19° C. over 12 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 25 cm3 of tetrahydrofuran, 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 2×25 cm3 of distilled water. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 50 mg of N-(5-methyl-1H-indazol-3-yl)-2-butenamide (E form) are obtained in the form of a white solid melting at about 218° C.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CN(C)C=O.Br[CH2:20][CH2:21][C:22]([CH3:30])([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CO.O>[CH3:30][C:22]([CH3:29])([CH2:21][CH2:20][NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)(C)CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)CCNS(=O)(=O)c1ccccc1
Temperature: 70 °C

Procedure:
Benzenesulphonamide (9.6 g, 61.1 mmol) was added to a stirred solution of sodium methoxide (1.6 g, 29.6 mmol) in methanol (100 ml). The clear solution was evaporated to dryness, then dimethyl formamide (100 ml) and ethyl 5-bromo-3,3-dimethyl-pentanoate (7.0 g, 32.8 mmol) were added and the mixture was heated for eight hours at 70° C. The solution was then poured into water (600 ml), the mixture was extracted with ether and the ether phase, after being dried over sodium sulphate, was evaporated. Treatment of the solid residue with a mixture of toluene and cyclohexane (9:1) left most of the unreacted benzenesulphonamide undissolved. After filtration, the solution was evaporated and the residue was purified by chromatography on silica gel with a mixture of methylene chloride and ethanol (98:2). Yield: 4.6 g (50% of theory), oily substance, nD20 =1.5083.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([CH:9]1[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH2:10]1)([OH:8])[C:4]([F:7])([F:6])[F:5].[NH2:19][CH:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:21].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:21][CH:20]([NH:19][C:14]([C:11]1[CH2:10][CH:9]([C:3]([OH:8])([C:2]([F:18])([F:1])[F:17])[C:4]([F:5])([F:6])[F:7])[O:13][N:12]=1)=[O:16])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1
Reactant: CCCCCC(C)N
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: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCCCC(C)NC(=O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1
Yield: 65.2 %

Procedure:
A solution of 5-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4,5-dihydroisoxazole-3-carboxylic acid from example 8-2 (84 mg, 0.3 mmol), 2-aminoheptane (69 mg, 0.6 mmol), 4-methylmorpholine (121 mg, 1.2 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (265 mg, 0.6 mmol) in DMF (0.5 ml) was stirred at r.t. for 17 h. The reaction mixture was diluted with EtOAc, washed with water, 1 M citric acid and brine, then dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc:Haxanes, 2:1) to afford the title compound as a clear oil (74 mg, 65%). 1H NMR δ 0.86 (t, 3H), 1.16 (d, 3H), 1.27-1.45 (m, 8H), 3.39 (dd, 1H), 3.65 (dd, 1H), 3.99 (m, 1H), 5.11 (t, 1H), 6.36 (d, 1H). ESIMS: m/z 377 (M−H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].C(OCC)(=[O:18])C>O>[OH:18][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 100 %

Procedure:
3-chloro-2-nitrobenzoic acid (30 g, 0.15 mol) and KOH (120 g, 2.14 mol) were dissolved in water (150 mL). The mixture was heated at reflux for 12 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The pH of mixture was adjusted to 3. The resulting mixture was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (40 g, 100%) as a brown solid. 1H NMR (400 MHz, DMSO): δ 11.193 (s, 1H), 7.476 (t, 1H), 7.367 (d, 1H), 7.268 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:32]([O:39][C:40](=[O:53])[CH2:41][CH2:42][NH:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH2:51])[CH:46]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:53])[CH2:41][CH2:42][NH:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH:51][C:22](=[O:24])[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:46]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Reactant: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)cc1

Procedure:
For the preparation of the ester starting material, MS: 756 (15, M+H), N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanine and N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate are coupled to give N-[m-[[N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanyl]amino]benzoyl]-β-alanine benzyl ester, MS: 605 (15, M+H), and this is converted with hydrogen sulphide and triethylamine in pyridine into N-[m-[[N-(benzyloxycarbonyl)-3-[p-(thiocarbamoyl)phenyl]-DL-alanyl]amino]benzoyl]-β-alanine benzyl ester, m.p. 145°-146° C. (from ethyl acetate). The latter is then reacted with methyl iodide in acetone and subsequently with ammonium acetate in methanol and treated with benzyl chloroformate and triethylamine in THF.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[CH3:16][NH:17][O:18][CH3:19].FC1C=CC(C(Cl)=O)=CC=1>C(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]([O:18][CH3:19])[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-fluorobenzoic acid (20 g, 143 mmol) in thionyl chloride (130 g; 1.1 mol) was stirred under reflux for 6 h: vigorous evolution of gas, clear solution after about 10 min, deepening of the color from yellow to orange. Excess thionyl chloride was removed by distillation (initially atmospheric pressure/40° C., then membrane pump vacuum/400° C.). From the distillation residue, 4-fluorobenzoyl chloride was distilled off under membrane pump vacuum at 90° C. over a short column. The reaction product crystallized on storing in a fridge (n20D 1.5315; m.p. 9° C., yield 20 g/89%). Freshly distilled triethylamine (29 ml) was added to a suspension of N,O-dimethylhydroxylamine hydrochloride (9.0 g; 92 mmol) in CH2Cl2 (75 ml). The reaction mixture was stirred at room temperature for 2 h and then cooled to −10° C. With cooling, 4-fluorobenzoyl chloride (13.5 g; 85 mmol) was, over a period of 6 min, added dropwise to the initial charge. After the addition had ended, cooling was removed and the reaction mixture was stirred at room temperature for 1.5 h. The light-brown suspension was poured into H2O (100 ml). The organic phase was removed and the aqueous phase was extracted with diethyl ether (2×). The combined extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated. The oily brown residue crystallized on cooling and scratching. The crude product was dried using an oil pump (residual triethylamine!) and reacted without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:30])[C@H:26]([CH2:28][OH:29])[NH2:27])C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:22][O:24][C:25](=[O:30])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH2:28][OH:29]
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.556 g (10 mmol) of L-serine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.