Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:46][C@@H:47]2[CH2:49][O:48]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:46][C@@H:47]4[CH2:49][O:48]4)[CH3:21])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@@H]2CO2)c1=O

Procedure:
The subtitle compound was prepared using a similar method to Example 299a from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 252j) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]#[CH:28]>C(#N)C.C(N(CC)CC)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>[NH2:25][C:4]1[C:3]([C:28]#[C:27][CH2:26][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#CCNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 73.8 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate (166 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (303 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:33].[OH-].[Na+]>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:4]2[CH:5]=[C:6]([N:9]3[CH2:14][CH2:13][S:12](=[O:15])(=[O:16])[CH2:11][CH2:10]3)[N:7]=[CH:8][C:3]=2[C:1]([NH2:2])=[O:33])=[C:18]([CH3:24])[CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 100.7 %

Procedure:
A mixture of 5-cyano-4-(4-fluoro-2-methylphenyl)-2-(1,1-dioxo-thiomorpholin-4-yl)pyridine (14.80 g, 42.85 mmol), 15 mL of toluene, and 15 mL (27.6 g, 281 mmol) of concentrated sulfuric acid was heated in a 500-mL flask at 70° C. for 12 hours. The mixture was cooled and quenched with 150 mL cold H2O. A solution of 22.8 g (570 mmol) of sodium hydroxide in 200 mL of H2O was added dropwise at 25–30° C. over 15 minutes. The precipitate was filtered, washed with H2O, and dried to afford 15.68 g (100.7%) of 4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine-3-carboxamide as a colorless solid (2 wt % toluene remains).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1.[CH3:18][N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23]C(O)[CH2:21][C:20]1([CH3:29])[CH3:28].[NH2-].[Li+].CO>CCCCCCC>[CH3:18][N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23][CH:1]([O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]2[CH2:7][C:8]([CH3:16])([CH3:15])[N:9]([CH3:14])[C:10]([CH3:13])([CH3:12])[CH2:11]2)[CH2:21][C:20]1([CH3:29])[CH3:28]
Reactant: COC(=O)CNC1CC(C)(C)N(C)C(C)(C)C1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: CO
Solvent: CCCCCCC
Product: CN1C(C)(C)CC(NCC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Yield: 78.6 %

Procedure:
To the same flask as used in Example 1 were added 24.2 g (0.1 mole) of N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine methyl ester, 18.7 g (0.11 mole) of 1,2,2,6,6-pentamethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 30 g of N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine(1,2,2,6,6-pentamethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 79% based on N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine methyl ester. A pale yellow oily product was obtained by the subsequent column chromatographic separation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[CH:28][CH:27]=4)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.45) (0.158 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.032 g, 17%). MS (ISP) 374.0 [(M+H)+]; mp 199° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:5]=1.Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Yield: 100 %

Procedure:
To a solution of 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester (410 mg, 36.9 mmol) in methanol was added SnCl2 (1.36 g, 6.03 mmol) at room temperature. The reaction mixture was refluxed for 3 hours and then cooled. Solvent was removed in vacuo and the residue was dissolved in H2O and basified by Na2CO3 to pH=9. The mixture was extracted with CH2Cl2, and the organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (362 m g, 100%) as yellow oil. MS (M+H)=244.
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[C:15](#[N:17])[CH3:16].S(=O)(=O)(O)O.[Na]>C(O)(=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:4]([CH2:3][C:2]([CH3:14])([CH3:13])[N:17]=[C:15]2[CH3:16])=[CH:9][C:8]=1[OH:10]
Reactant: CC#N
Reactant: COc1ccc(CC(C)(C)O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)CC(C)(C)N=C2C
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a flask (ice cooled) containing acetic acid (1.2 ml) was added 5-(2-hydroxy-2-methylpropyl)-2-methoxyphenol (500 mg, 2.5 mmol) and acetonitrile (0.27 ml, 5.1 mmol). To this was added sulfuric acid (1.2 ml) slowly with stirring. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was poured onto ice-water and the aqueous solution neutralised with sodium C(Ar)bonate, then extracted with diethyl ether (2×) and ethyl acetate (2×) after saturation with sodium chloride. Purification (flashmaster: 20 g, 100% DCM to 100% EtOAc, then 30% MeOH/70% EtOAc) afforded the title compound (324 mg, 56%) as a pale brown solid. mp=160° C. dec. 1H NMR (270 MHz; CDCl3) 1.18 (6H, s, 2×CH3), 2.28 (3H, s, CH3), 2.59 (2H, s, CH2), 3.91 (3H, s, OCH3), 6.60 (1H, s, CH), 7.07 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 23.21 (CH3), 28.02 (2×CH3), 38.81 (CH2), 53.78 (C(CH3)2), 55.98 (CH3), 110.47 (CH), 112.35 (CH)<121.96 (C), 128.86 (C), 144.35 (C), 148.88 (C), 161.39 (C N). LC/MS (ES+) tr=1.2 min, m/z 219.95 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reaction time: 4 h
Yield: 76.3 %

Procedure:
To a mixture of 6-amino-2-oxindole (1 g) and acetyl chloride (0.79 g) in 10 ml of dichloromethane at 0° C. was added triethylamine (1 g). The mixture was brought to room temperature and stirred for 4 hours protected from atmospheric moisture with a dry-tube. The solvent was then evaporated and the residue was recrystallized from methanol to give 0.98 g (77%) of 6-acetylamino-2-oxindole as a beige solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:38][C:39]([F:50])([F:49])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([C:39]([F:50])([F:49])[F:38])[CH:45]=2)[C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 3-(trifluoromethyl)phenylboronic acid to afford the desired product as a colorless foam (67%). MS (ISP): 675.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(N)on1
Product: CC(C)(C)c1noc(N)c1Br
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-tert-butylisoxazole was prepared from 5-amino-3-tert-butylisoxazole and N-bromosuccinimide in 64% yield as described in Example 40a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]([CH3:16])[C:13](=O)[CH3:14]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]=[C:13]([CH3:14])[C:12]2([CH3:16])[CH3:11]
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2
Temperature: 100 °C
Yield: 45.4 %

Procedure:
A mixture of (4-methoxyphenyl)hydrazine (0.98 g, 7.1 mmol) and 3-methylbutan-2-one (1.53 g, 17.8 mmol) in 20 mL of HOAc was heated at 100° C. overnight. The mixture was concentrated and 1N NaOH was added until pH 9 to 10. The aqueous solution was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography to give 610 mg of 5-methoxy-2,3,3-trimethyl-3H-indole (45%). 1H NMR (CDCl3) δppm: 7.43 (dd, 1H), 6.81 (m, 2H), 3.83 (s, 3H), 2.26 (s, 3H), 1.28 (s, 6H). LC-MS (M+H): 190.16
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].I[CH2:18]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]1[C:3]2[C:4](=[O:5])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:18][O:1][C:2]=2[CH:16]=[CH:15][CH:14]=1
Reactant: ICI
Reactant: O=C(c1ccccc1O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OCOc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1 g, 49 mmol) was dissolved in dry N,N-dimethylformamide (180 ml). Dried finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added and the mixture was heated at 105° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate was collected by filtration after 0.5 h, washed with water on the filter and dissolved in a mixture of ethanol (80 ml) and 4 N sodium hydroxide (20 ml). The solution was stirred at reflux temperature for 1 h, cooled and diluted with water (300 ml). The formed crystalline precipitate was filtered off, washed with water (50 ml) and dried in vacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-12-one as a solid (9.5 g, 90%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:23]([F:25])[F:24])([CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15]CC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(Br)C1C=CC=CC=1.[CH:34]1([NH:40]C2CCCCC2)CCCC[CH2:35]1>CN(C)C=O>[C:1]([NH:4][C:5]([CH:23]([F:24])[F:25])([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH:34]([NH2:40])[CH3:35])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(=O)NC(CCCNC(=O)OCc1ccccc1)(C(=O)O)C(F)F
Agent: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NC(CCCNC(=O)C(C)N)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 0.5 g of 2-acetylamino-5-benzyloxycarbonylamino-2-difluoromethylpentanoic acid in 4 ml of dimethylformamide is added 0.27 g of benzylbromide and 0.4 ml of dicyclohexylamine. The reaction mixture is stirred for 12 hours and then the precipitate is filtered off. The filtrate is evaporated under reduced pressure, and the residue is partitioned between ethylacetate and water. The organic phase is washed with aqueous hydrochloric acid, water, 5% sodium bicarbonate, water and brine then dried over magnesium sulfate. The solvent is evaporated and the residue heated in 5 ml of trifluoroacetic acid for 1 hour at room temperature. The excess trifluoroacetic acid is then stripped off under reduced pressure. The residue is suspended in 5 ml of ether and a solution of N-benzyloxycarbonyl-O-ethoxycarbonylalanine (0.4 g) and triethylamine (0.2 g) in 5 ml of ether is added. Stirring is continued overnight at room temperature. The solvent is evaporated. The resulting syrupy residue is dissolved in glacial acetic acid, and the solution hydrogenated over Pd/C 10% (30 mg) for 12 hours. The catalyst is then filtered off. The filtrate is concentrated and the residue purified by ion exchange chromatography on an Amberlite 120 acidic column to give 2-acetylamino-5-(2-aminopropionylamino)-2-difluoromethylpentanoic acid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18](OC)=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH:23][CH3:24]>CO>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([N:23]([CH3:24])[CH3:22])=[O:19])(=[O:8])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Temperature: 35 °C
Yield: 76.8 %

Procedure:
115 g of N-tert.-butyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide (Example c) in 1500 ml of methanol are gassed with about 200 g of dimethylamine. The mixture is stirred at about 35° C. for one week. The solution is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively with dilute hydrochloric acid, saturated NaHCO3 solution and saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated. 92 g of N-tert.-butyl-2-dimethylaminocarbonyl-5-nitro-benzensulfonamide are obtained: m.p.: 138-141° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14].[CH3:18][C:19]1[CH:23]=[C:22]([NH2:24])[O:21][N:20]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]1[C:12]([C:13]#[N:14])=[C:15]([CH3:16])[NH:24][C:22]2[O:21][N:20]=[C:19]([CH3:18])[C:23]1=2
Reactant: Cc1cc(N)on1
Reactant: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F
Product: CC1=C(C#N)C(c2cc3cn[nH]c3cc2F)c2c(C)noc2N1

Procedure:
100 mg (0.44 mmol) (2E)-2-[(6-fluoro-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 13A) were treated with 3-methyl-1,2-oxazol-5-amine following the procedure described in Example 2. The crude material was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 55 mg (41% of th.) of the racemic title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([CH:2]=[O:3])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=CC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 248.9 %

Procedure:
To a suspension of 4.08 g of (methoxymethyl)triphenyl-phosphonium chloride in 20 mL of THF was added 8.11 mL of n-butyllithium(1.6 M in hexane) at 0° C. The reaction was stirred at 0° C. for 0.5 h. To the resulting solution was added 2.05 g of 1-benzyl-4-piperidone at 0° C. After stirring at rt for 1 h, the reaction was refluxed for 3 h. The reaction was cooled to rt and partitioned between EtOAc and H2O. The organic layer was washed with sat'd NaCl, dried over MgSO4 and concentrated to afford 5.48 g of viscous oil. The oil was dissolved in 20 mL of formic acid (96%). After stirring at rt for 4 h, the mixture was concentrated. The residue was dissolved in EtOAc and washed with sat'd NaHCO3 followed by sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 1:1 v/v hexanes/EtOAc followed by EtOAc to give 877 mg of the title compound.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[CH2:12]([CH:19]1[S:23][C:22](=[O:24])[NH:21][CH:20]1[C:25](O)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:25]([CH:20]1[CH:19]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:23][C:22](=[O:24])[NH:21]1)=[O:26])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(Cc2ccccc2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(Cc2ccccc2)S1
Yield: 64.2 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 210 mg of N-(2-nitrooxyethyl)-amine nitrate and 250 mg of 5-benzyl-2-oxothiazolidine-4-carboxylic acid, to obtain 220 mg of the title compound as pale yellow columnar crystals, melting at 123°124° C. (after recrystallization from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC(Cc1ccccc1Cl)C(=O)N1CCSC1
Product: O=C(NC(Cc1ccccc1Cl)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(2-chloro-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 214-216° C.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1.C1C=CC=CC=1>CCCCCC>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]2[CH2:7][CH2:6][CH2:5][S:4][CH:3]2[CH2:1][CH3:2])=[S:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CCC1NCCCS1
Reactant: S=C=Nc1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCC1SCCCN1C(=S)Nc1cccc(Cl)c1
Reaction time: 64 h

Procedure:
A mixture of 2.6 g. of 2-ethyltetrahydro-2H-1,3-thiazine, 3.4 g. of 3-chlorophenyl isothiocyanate, and 30 ml. of benzene was stirred, after an initial exotherm, at ambient temperature for about 64 hours. To the reaction mixture was added about 10 ml. of hexane, which caused white crystals to form. The mixture was cooled and filtered, and the solid was washed with hexane. The solid was recrystallized from about 500 ml. of 10:1 hexane:carbon tetrachloride to give N-(3-chlorophenyl)-2-ethyltetrahydro2H-1,3-thiazine-3-carbothioamide, m.p. 69°-73°. The following elemental microanalysis was obtained:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C1(C)COC(=O)N1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C2CCc3cc(O)ccc3C2)COC(=O)N1
Temperature: 20 °C
Yield: 84.5 %

Procedure:
A stirred solution of 100 grams of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one in 6 L dichloromethane was cooled to −80° C. under nitrogen. A solution of 177 g BBr3 in dichloromethane was added dropwise; during addition the reaction temperature was kept below −75° C. The reaction was stirred at 20° C. until the starting material was less than 2% by HPLC. Ice water was added to crystallize the solid, which was was filtered, washed with water, and the cake was slurried in methanol and dried to afford 80 g of 4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one, M=247.29, purity >98%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)[CH:16]=[CH:17][CH:18]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(-c2cccc(NC(=O)CNC(=O)OC(C)(C)C)c2)c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2cccc(NCCNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To methyl 3′-[(2-[[(tert-butoxy)carbonyl]amino]acetylamino)]-[1,1′-biphenyl]-3-carboxylate (1.6 g) 0° C. was added a 1.0 M solution of borane in tetrahydrofuran (30 mL). The mixture was warmed to room temperature and stirred for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate and concentrated to leave a cloudy liquid that was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The separated organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by silica gel chromatography provided the title compound (740 mg). Electrospray MS (positive ion): M+Na 393.0