Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:15]2=[O:29])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[CH3:1][C:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:23]3[CH2:28][CH2:27][N:26]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:25][CH2:24]3)[C:15]2=[O:29])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(Cn2c(=O)n(C3CCNCC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(Cn2c(=O)n(C3CCN(C(=O)OCc4ccccc4)CC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a mixture of 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-(3-piperidin-4-yl)-1,3-dihydrobenzimidazol-2-one prepared in Example 579 (90 mg, 0.23 mmol) and methylene chloride (5 ml), triethylamine (75 mg, 0.74 mmol) and benzyl chloroformate (126 mg, 0.74 mmol) were added in this order with cooling on ice-bath followed by stirring at room temperature for 3 hours. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=1/1) to afford benzyl 4-[3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]piperidine-1-carboxylate (25 mg, yield 21%) as a white powder.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:22]/[O:23][C:24]([C:27]([O:29]CC2C=CC([N+]([O-])=O)=CC=2)=[O:28])([CH3:26])[CH3:25])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH3:16])[N:14]([S:17]([O-:20])(=[O:19])=[O:18])[C:13]2=[O:21])=[O:10])[N:7]=1>O.O1CCCC1.[Pd]>[Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:22]/[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH3:16])[N:14]([S:17]([O-:20])(=[O:19])=[O:18])[C:13]2=[O:21])=[O:10])[N:7]=1
Reactant: C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Yield: 32.9 %

Procedure:
115 mg (0.19 mmol) of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(p-nitro-benzyloxycarbonyl)-1-methylethoxy]imino]acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 40 ml of water/tetrahydrofuran (1:1) and the solution is hydrogenated for 12 hours over 300 ml of 10% palladium/carbon. The catalyst is filtered off and the solvent is evaporated under reduced pressure. The oil obtained is chromatographed (230-400 mesh, chloroform/methanol/n-propanol/water (4:6:1:4) as the solvent]. There are obtained 28.6 mg (33%) of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy]imino]acetamido]-4-methyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=[O:4].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:3]=[O:4]
Reactant: CC(C=O)=CCC(C)CC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C=O)CCC(C)CC(C)(C)C
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
In a hydrogenation autoclave, 250 g (1.37 moles) of 2,5,7,7-tetramethyl-2-octenal, dissolved in 500 ml of methanol, were hydrogenated in the presence of 25 g of a 0.5% strength palladium/alumina catalyst at 80° C., initially under a hydrogen pressure of 25 bar, and after 2-3 h, under 55 bar. The total hydrogenation time was 10 h. The catalyst was filtered off, after which fractional distillation gave 245 g (1.33 moles) of 2,5,7,7-tetramethyloctanal (bp.=68° C./0.3 mbar; nD25 =1.4308), corresponding to a yield of 96% of theory. The compound was in the form of a diastereomeric mixture.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:14](O)(=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:9]([OH:11])(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]/[CH:1]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
A process for the production of purified azelaic acid by working up a reaction mixture containing C1-18 monocarboxylic acids, comprising pelargonic acid, and C4-16 dicarboxylic acids, comprising azelaic acid, obtained from the ozonolysis of oleic acid or a starting mixture containing oleic acid, all but <2% by weight of the monocarboxylic acids and part of the dicarboxylic acids with a chain length of <C9 and >C9 being separated off to obtain a prepurified product containing more than 75% by weight of oleic acid and the prepurified product being concentrated to more than 90% by weight of oleic acid in several process steps of which the last is an overhead distillation step, which comprises: (1), removing the dicarboxylic acids with chain lengths of <C9, present in the prepurified product, as an overhead product by a first fractional distillation; (2), reacting a bottom product from the first distillation with water to split carboxylic anhydrides present in the bottom product to form a reaction mixture and, (3), distilling the reaction mixture to recover as an overhead product the purified azelaic acid, the third process step (3) being carried out after or at the same time as the second process step (2).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][N:9]=1)[CH3:7].[CH2:17](O)[CH3:18]>O>[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][N:9]=1)[CH3:7]
Reactant: CCO
Reactant: CCc1cc(C(=O)O)ccn1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccnc(CC)c1
Reaction time: 64 h

Procedure:
2.35 ml of concentrated sulfuric acid are added to a solution of 5 g of 2-ethylpyridine-4-carboxylic acid in 75 ml of ethanol. The reaction mixture is refluxed with stirring for about 64 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 500 ml of water and then extracted with 500 ml of dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 5.08 g of ethyl 2-ethylpyridine-4-carboxylate are thus obtained in the form of an oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O1CCCC1.[CH2:11]([O:13][C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[C:25](=[CH:26][CH2:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][C@H:22]1[OH:35])[CH3:12].[NH4+].[Cl-]>C(OCC)C>[CH2:11]([O:13][C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[C:25](=[CH:26][CH2:27][C:28]([OH:34])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][C@H:22]1[OH:35])[CH3:12]
Reactant: [Li]CCCC
Reactant: CCCCCC(=O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(O)(CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC)CCCC

Procedure:
1.6 g. Butyl lithium, dissolved in 60 ml. tetrahydrofuran, is added dropwise to 3.7 g. 9β-hydroxy-15-oxo-12-prostenoic acid ethyl ester, dissolved in 150 ml. dry diethyl ether, with the exclusion of moisture, under argon and with stirring at -15°. The mixture is stirred for another hour, allowed to warm to 0° and mixed dropwise, with ice cooling, with 300 ml. saturated aqueous NH4Cl solution. The organic phase is separated, washed with water and dried over Na2SO4. The solvent is removed to obtain as residue 9β,15-dihydroxy-15-butyl-12-prostenoic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[O:14][CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1

Procedure:
reacting a 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone of the formula, ##STR14## wherein Bn is as hereinbefore defined with one equivalent of BnBr and one equivalent of triethlyamine in THF for 5 hours at 65--C to provide 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone of the formula, ##STR15## wherein Bn is as hereinbefore defined;
Reaction SMILES: Br[CH2:2][CH:3]=[C:4](C)[CH:5]([O:8][CH3:9])[O:6][CH3:7].C1N2CN3CN(C2)CN1C3.[Cl-].[Na+].[CH:23]([O:26]C(C)C)(C)C>O>[CH3:9][O:8][CH:5]([O:6][CH3:7])[CH:4]=[C:3]([CH3:2])[CH:23]=[O:26]
Reactant: COC(OC)C(C)=CCBr
Reactant: CC(C)OC(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(C=C(C)C=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
4-Bromo-1,1-dimethoxy-2-methyl-2-butene (2 g) was added to a solution of hexamine (1.7 g) and water (10 ml), and the mixture was stirred at room temperature for 14 hours. Dowex 50×8 (type H)(3 g) was previously treated with sodium chloride to convert it to type Na. Then isopropyl ether (20 ml) was added to the above reaction mixture, the type Na resin was added, and the mixture was stirred at 70° C. for 6 hours. The isopropyl ether layer was separated, concentrated and purified by column chromatography to give 4,4-dimethoxy-2-methyl-2-buten-1-al (0.92 g, 64%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:30]([Cl:31])=[CH:29][C:28]([NH:32][C:33](=[O:44])[C:34]([O:36]CC4C=CC=CC=4)=[O:35])=[CH:27][C:26]=3[Cl:45])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1.[H][H]>C(O)C>[OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:26]([Cl:45])=[CH:27][C:28]([NH:32][C:33](=[O:44])[C:34]([OH:36])=[O:35])=[CH:29][C:30]=3[Cl:31])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1
Reactant: [H][H]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)OCc3ccccc3)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: CCO
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
4-{4-[(2-benzyloxy-1,2-dioxoethyl)amino]-2,6-dichlorophenoxy}-2-isopropylphenyl 3,7,12(3α, 5β,7α,12α)-trihydroxycholan-24-oate (260 mg) and 26 mg of 10% carbon in 50 ml ethanol are treated with hydrogen on a Parr shaker. Catalyst is removed by filtering through Celite and the filtrate is stripped to give 4-{2,6-dichloro-4-[(2-hydroxy-1,2-dioxoethyl)amino]phenoxy}-2-isopropylphenyl 3,7,12(3α,5β,7α,12α)-trihydroxycholan-24-oate, as an amorphane monohydrate, m.p. 180°-92° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(=O)NNc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride (10.0 g, 46.8 mmol) by partitioning the solid between diluted Na2CO3 solution (10 ml saturated solution and 40 ml water) and AcOEt. The aqueous layer was extracted two more times with AcOEt, the organic extracts were dried (Na2SO4), the solvent was removed in vacuo, and the residue was taken up in dry toluene (100 ml). To this solution acetic anhydride (4.78 g, 46.8 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 15 min. Light petroleum (50 ml) was added, the mixture was cooled in the refrigerator (−20° C.), and the resulting crystals were collected on a sintered glass funnel and washed with cold petrol ether. Recrystallization from MeOH yielded (V) (8.30 g, 81%) as shiny white crystals, mp 179-182° C. (lit. 168-171° C.). TLC CHCl3/MeOH 9:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][CH:34]=[C:35]3[C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][CH:34]=[C:35]4[C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.050 g, 0.16 mmol), methyl 7-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.045 g, 0.16 mmol), triphenyl phosphine (0.042 g, 0.16 mmol) and diisopropyl azodicarboxylate (0.043 mL, 0.16 mmol) in dichloromethane (1.6 mL) was placed in microwave reaction tube and heated to 80° C. for 20 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.053 g, 58%). 1H NMR (DMSO-d6): δ 8.99 (s, 1H), 8.20 (d, J=8 Hz, 1H), 8.16 (d, J=7 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=9 Hz, 1H), 7.74 (d, J=8 Hz, 2H), 7.59-7.56 (m, 1H), 7.41 (d, J=8 Hz, 2H), 7.26-7.24 (m,1H), 7.16 (d, J=8 Hz, 2H), 4.99 (s, 2H), 3.94 (s, 3H), 3.39-3.20 (2 m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>Br>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: BrBr
Agent: Br
Product: O=C(CBr)c1ccncc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 18.2 g (150 mmol) 4-acetylpyridine (6-1) in 20 mL 48% HBr was added a 5 mL solution of 7.70 mL bromine in 48% HBr dropwise while heating in a 70° C. oil bath. A thick precipitate formed about midway through the addition, but the reaction was allowed to stir an additional 2 h at 70° C. The reaction was cooled and the precipitate was collected by filtration and washed 3×20 mL with a 1:1 methanol:Et2O solution to provide pure 2-bromo-1-pyridin-4-ylethanone (6-2) after drying under high vacuum: 1H NMR (400 MHz, DMSO-d6) δ 9.0 (d, J=3 Hz, 2H), 8.07 (d, J=3 Hz, 2H), 5.03 (s, 2H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].[C:18]([N:22]=[C:23]=[S:24])([CH3:21])([CH3:20])[CH3:19]>O.C(O)C>[C:1]([NH:4][CH:5]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[S:24])=[CH:13][CH:14]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)N=C=S
Reactant: CC(=O)NC(C(=O)O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(C(=O)O)c1ccc(NC(=S)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of α-acetamido-p-aminophenylacetic acid (1.04 g, 5 mmol) in water (5 ml) was added 10% NaOH until solution was effected. The solution was diluted with an equal volume of ethanol and then t-butyl isothiocyanate (1.64 g, 15 mmol) in ethanol was added. The reaction was stirred at room temperature overnight and then refluxed 24 hours. The ethanol was evaporated in vacuo and the aqueous phase was acidified and filtered. The aqueous filtrate was extracted with ethyl acetate. The dried extracts were evaporated to give α-acetamido-p-(3-t-butylthioureido)phenylacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]5)[N:16]=3)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH2:12]1[C:10]2([CH2:9][NH:8][CH2:11]2)[CH2:14][N:13]1[C:15]1[N:16]=[C:17]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]3)[CH:18]=[N:19][CH:20]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)n3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(-c3cncc(N4CC5(CNC5)C4)n3)ccc21
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 6-[6-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyrazin-2-yl]-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (example 28, 0.231 g, 0.53 mmol) in DCM (3 mL) was added TFA (0.605 g, 5.3 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was evaporated several times with toluene and then the residue was purified by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH—H2O (0.05% TEA) gradient to give the title compound (0.203 g, 99%) as a yellow solid (TFA salt). MS: 336.3 (M+H+).
Reaction SMILES: O1C=CC(NC[C@@H:8]2[O:12][C:11](=[O:13])N(C3C=CC(N4CC[C@H](NC(=O)C)C4)=C(F)C=3)C2)=N1.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)C(OCC(Cl)(Cl)Cl)=O)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1.ClC(OC)=O>>[CH3:8][O:12][C:11]([NH:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH:49][C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1)=[O:13]
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: COC(=O)Cl
Agent: Cl
Product: COC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S) -aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (360 mg, 0.63 mM) and methyl chloroformate gave the desired product (280 mg ). NMR (DMSO-d6) δ: 1.84 (hextet, 1H); 2.13 (hextet, 1H); 3.15 (m, 1H); 3.35 (m overlapped by H2O, ˜2H); 3.55 (s overlapping m, 4H); 3.84 (dd, 1H); 4.13 (overlapping m, 3H); 4.36 (dd, 1H); 4.98 (d, 1H); 5.04 (m, 1H); 5.08 (d, 1H); 6.73 (t, 1H); 6.89 (d, 1H); 7.08 (dd, 1H); 7.35 (dd, 1H); 7.43 (br, 1H); 8.93 (d, 1H). MS (ESP): 594 (MH+) for C22H23Cl3FN5O7
Reaction SMILES: [CH2:1]([C:8]#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][NH:11][CH2:12][CH2:13][NH2:14].C(=S)=S>C(OCC)(=O)C>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]=[C:8]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CNCCN
Reactant: CCCCCCCC#N
Solvent: CCOC(C)=O
Solvent: S=C=S
Product: CCCCCCCC1=NCCN1C
Temperature: 125 °C
Yield: 95.4 %

Procedure:
14.207 g (113.46 mmoles) of heptyl cyanide, 10.726 g (144.69 mmoles) of N-methylethylenediamine and 0.5 ml of carbon disulfide were mixed and heated at 125° C. for 24 hours. The solution was cooled, diluted with ethyl acetate and extracted with dilute hydrochloric acid. The acidic solution was basified with sodium hydroxide and extracted with ethyl acetate. The organic extracts were treated with charcoal, filtered, concentrated and Kugelrohr distilled at 105° C./1 2mm to give 19.73 g (77.3%) of the product.
Reaction SMILES: C[Si]([Br:5])(C)C.[CH2:6]([O:13][C:14]1[C:23]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:17]=[C:16]([CH2:24]O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]2[O:19][CH2:20][CH2:21][O:22][C:23]=12)[CH2:24][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1cc2c(c(OCc3ccccc3)c1)OCCO2
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: BrCc1cc2c(c(OCc3ccccc3)c1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.07 ml of trimethylsilyl bromide is added to a solution of 0.1 g of 5-benzyloxy-7-hydroxymethyl-1,4-benzodioxane in 5 ml of chloroform and the mixture is stirred for a further 15 minutes at room temperature and then concentrated by evaporation in a rotary evaporator. The residue is immediately dissolved in a small amount of ethyl acetate; the same volume of hexane is added and the mixture is filtered through 15 g of silica gel, followed by elution with a mixture (hexane/ethyl acetate=4:1). Concentration of the eluates by evaporation yields the title compound: Rf (hexane/ethyl acetate=3:1)=0.48.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: -5 °C
Yield: 60.7 %

Procedure:
Sodium hydride (60%, 0.16 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.20 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C. with stirring. To the reaction solution is added dropwise a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.80 g) in 1,2-dimethoxyethane (20 ml) at -5° C. for 10 minutes, which is further stirred for 15 minutes. On completion of the reaction, the reaction solution is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.10 g of desired compound (melting point: 47.0°-49.0° C.).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32]([OH:34])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:32](=[O:34])[C:31]3[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=[C:29]([CH3:28])[CH:30]=3)[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(C)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 3-methyl-5-trifluoromethylbenzoic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.