Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:26]=2)=[N:10]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH:32]1[C:37]([OH:39])=[O:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[C:37]([OH:39])=[O:38])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 64.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.37 g, 0.65 mmol) was reacted with morpholine-3-carboxylic acid (0.1 g, 0.71 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.26 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O.[OH-].[Li+:3].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][CH2:56][CH3:57])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6].C(=O)=O>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][CH2:56][CH3:57])[N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:12]=1[C:13]([O-:15])=[O:14])([CH3:6])[CH3:7].[Li+:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 20 h

Procedure:
A solution of 2.65 g of lithium hydroxide monohydrate in 158 ml of water was added, whilst ice-cooling, to a solution of 30 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 18(a)] in 344 ml of dioxane, and the resulting mixture was stirred at 5°-10° C. for 20 hours. At the end of this time, small pieces of dry ice were added to the mixture, which was then concentrated by evaporation under reduced pressure to a volume of about 100 ml. Ethyl acetate and sodium chloride were added to the concentrate, and the mixture was stirred. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, to give lithium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as a glass. 6.08 g of potassium carbonate were added, whilst ice-cooling, to a solution of whole of this lithium carboxylate in 160 ml of N,N-dimethylacetamide, and then a solution of 11.2 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74% purity) in 26 ml of N,N-dimethylacetamide was added dropwise, whilst ice-cooling, to the mixture. The resulting mixture was stirred at 50° C. for 3 hours. At the end of this time, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was crystallized in diisopropyl ether, to give 29.3 g of the title compound as crystals, melting at 98°-100° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH:24]1([N:30]2[CH2:33][CH2:32][CH:31]2[C:34]([O-])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([CH:31]2[CH2:32][CH2:33][N:30]2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1CCN1C1CCCCC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCCCC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-cyclohexylazetidine-2-carboxylate 20A carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-cyclohexylazetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (69%). MS ISP (m/e): 519.2 (100) [(M+H)]]+.
Reaction SMILES: [SH:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([SH:11])[CH3:10].N.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.Cl>CO>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([S:11][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:10])=[CH:20][CH:19]=1
Reactant: CC(C)(S)CNCCNCC(C)(C)S
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: N
Solvent: CO
Product: COc1ccc(CSC(C)(C)CNCCNCC(C)(C)SCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of N,N'-bis(2-mercapto-2-methylpropyl)ethylene diamine (11.23 g, 47.5 mmol; see, DiZio et al., 1991, Bioconjugate Chem 2: 353 and Corbin et al., 1976, J. Org. Chem. 41: 489) in methanol (500 mL) was cooled in ice/water bath and then saturated with gaseous ammonia over 45 min. To this was added 4-methoxybenzyl chloride (17.0 mL, 125 mmol, 264 mol %). The reaction was allowed to warm to room temperature overnight with stirring under argon. The solution was concentrated to a paste and then partitioned between diethyl ether (150 mL) and 0.5 M KOH (200 mL). The aqueous layer was further extracted with diethyl ether (2×50 mL). The combined organic layers were washed with NaCl solution and concentrated to a clear colorless oil. The oil dissolved in diethyl ether (200 mL) and then acidified with 4.0 M HCl in dioxane until no further precipitation was seen. The white precipitate was collected by filtration and washed with diethyl ether. The white solid was recrystallized from hot water at a pH of ~2. The product was collected by filtration to afford 29.94 g as a mix of mono- and di- HCl salts. The HCl salts were partitioned between 1 M KOH (100 mL) and ethyl acetate (100 mL). The aqueous was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with NaCl solution, dried with Na2SO4 and concentrated to give pure product as the free base as a light yellow oil (18.53 g, 82% yield). Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH:19]1[C:50](=[O:51])[NH:49][CH:48]([CH:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[CH:41]([CH2:42][CH:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][CH:37]([CH:56]([OH:66])[CH:57]([OH:65])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:35](=[O:36])[NH:34][CH:33]([CH:67]([OH:69])[CH3:68])[C:31](=[O:32])[N:30]2[CH:26]([CH:27]([OH:71])[CH:28]([CH3:70])[CH2:29]2)[C:24](=[O:25])[NH:23][CH:22]([OH:72])[CH:21]([OH:73])[CH2:20]1)=[O:17].C(O)CCC.O>C(OCC)(=O)C.C(O)CCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:66])[C@@H:57]([OH:65])[C:58]2[CH:59]=[CH:60][C:61]([OH:64])=[CH:62][CH:63]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:67]([OH:69])[CH3:68])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:71])[C@@H:28]([CH3:70])[CH2:29]2)[C:24](=[O:25])[NH:23][C@H:22]([OH:72])[C@H:21]([OH:73])[CH2:20]1)=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)NC1CC(O)C(O)NC(=O)C2C(O)C(C)CN2C(=O)C(C(C)O)NC(=O)C(C(O)C(O)c2ccc(O)cc2)NC(=O)C2CC(O)CN2C(=O)C(C(C)O)NC1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
1.7 g. of crude aculeacins obtained in Example 2 dissolved in 5 ml. of n-butanol was charged on a silica gel column packed with a water-saturated solvent of ethyl acetate-n-butanol (4 : 1). The column was eluted with the same solvent and 10 g. fractions were collected. Each fraction was assayed by bio-assay and thin layer chromatograph to find the activity of Nos. 33 to 55 fractions. Vacuum drying gave 629 mg. of white powder. The powder was further purified by dissolving in n-butanol (50 ml.), and was washed three times with distilled water (each 10 ml.) and dried in vacuo. 577 mg. of purified aculeacin-A was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].CN(C)C=O>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: O=C([O-])c1cnccn1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A four-necked flask was charged with 127.5 g (0.873 mole) of sodium pyrazinecarboxylate, 119.3 g (0.792 mole) of chloromethyl pivalate and 146 g of dimethylformamide and the internal temperature was maintained under stirring at 105°-110° C. for 8 hours. The reaction mixture was then cooled and transferred to a separatory funnel. After addition of 500 g of toluene, the mixture was washed with 3 portions, or a total of 900 g, of water. From the toluene layer which separated the toluene was first distilled off and the residue was subjected to distillation under reduced pressure to give 147 g of pivaloyloxymethyl pyrazinecarboxylate. Yield: 78% (based on chloromethyl pivalate).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][NH:5][C:6]1[C:11](C2C=CC=CC=2)=[C:10]([NH:18][CH3:19])[N:9]=[C:8](N=NC2N=CC=CN=2)[N:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C[N:42](C)C=O>[OH-].[Na+]>[NH2:42][C:11]1[C:6]([NH:5][CH2:4][C:3]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:2]=2[Cl:1])=[N:7][CH:8]=[N:9][C:10]=1[NH:18][CH3:19]
Reactant: CN(C)C=O
Reactant: CNc1nc(N=Nc2ncccn2)nc(NCc2c(F)cccc2Cl)c1-c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CNc1ncnc(NCc2c(F)cccc2Cl)c1N
Yield: 79 %

Procedure:
In N,N-dimethylformamide (20 ml) and 2 N NaOH (5 ml) was dissolved 4-(2-chloro-6-fluorobenzyl)amino-6-methylamino-5-phenylazopyrimidine (1.112 g, 3 mmols), and sodium dithionite (3.27 g, 15 mmol; purity 80%) was added portionwise to the solution with stirring at 140°-150° C. The mixture was stirred at the same temperature for 30 minutes, after which it was concentrated to dryness under reduced pressure, and water was added to the residue. The mixture was adjusted to pH 12-13 by addition of 2 N NaOH, and extracted with ethyl acetate (150 ml, 100 ml). The extract was dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure, and the resultant residue was recrystallized from ethyl acetate-petroleum ether to give 5-amino-4-(2-chloro-6-fluorobenzyl)amino-6-methylaminopyrimidine as brown crystals (671 mg, yield 79%), m.p. 210°-213° C.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:25]([NH:31][CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:25]([N:31]([CH3:32])[C:9]([C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCNC
Reactant: CC(=O)c1ccc(C(=O)O)o1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCCN(C)C(=O)c1ccc(C(C)=O)o1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 4.6 g. (0.03 mole) of 5-acetylfuran-2-carboxylic acid in 150 ml. of dichloromethane was added 3.3 g. (0.033 mole) of N-methylmorpholine. The resulting solution was cooled to -20° C., and 3.6 g. (0.033 mole) of ethyl chloroformate was added dropwise, with stirring. Stirring was continued for 1 hour at -15° C. and then 3.8 g. (0.033 mole) of n-hexylmethylamine was added dropwise at -20° C. The resulting mixture was stirred for 1.5 hours while being allowed to warm to room temperature. The reaction mixture was then washed with water, dried (Na2SO4) and evaporated in vacuo to give 7.5 g. of an oil. This oil was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate, to give 5.6 g. of the title amide as an oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[CH:4]=[C:3]([C:10]([O:12]CC2C=CC=CC=2)=O)[CH:2]=1.[NH3:20]>>[C:10]([C:3]1[CH:2]=[N:1][CH:6]=[C:5]([CH:4]=1)[C:7]([OH:9])=[O:8])(=[O:12])[NH2:20]
Reactant: N
Reactant: O=C([O-])c1cncc(C(=O)OCc2ccccc2)c1
Product: NC(=O)c1cncc(C(=O)O)c1

Procedure:
Monobenzyl pyridine-3,5-dicarboxylate (compound G2) (1.92 g, 7.5 mmol) is heated in aqueous concentrated ammonia solution (40 mL, 25%) to 90° C. for 6 h. After cooling, the solution is evaporated and the residue is used as crude product without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)([OH:10])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.O.C(=O)(O)[O-].[Na+]>[OH:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3][CH2:4]1)([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH3:9]
Reactant: CC(O)(c1nccs1)[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(trans-4-aminocyclohexyl)-1-(1,3-thiazol-2-yl)ethanol (100 mg, 0.44 mmol) in dichlormethane (2.9 mL) and triethylamine (0.31 mL, 2.21 mmol) at 0° C. was added methanesulfonyl chloride (34 μL, 0.44 mmol) and the reaction was allowed to stir for 10 minutes at 0° C. and then diluted with water, dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate gradient in hexanes) to afford N-{trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}methanesulfonamide. MS ESI calc'd. for C12H21N2O3S2 [M+H]+ 305. found 305. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=3.2, 1H), 7.28 (d, J=3.2, 1H), 4.25-4.14 (m, 1H), 3.30-3.13 (m, 1H), 2.95 (s, 3H), 2.18-2.09 (m, 1H), 2.09-2.02 (m, 2H), 1.96-1.88 (m, 1H), 1.80-1.69 (m, 1H), 1.64-1.53 (m, 3H), 1.40-1.28 (m, 1H), 1.28-1.13 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH+]1C=CC=CC=1.CCOC(C)=O.CCCCCC.[Li+].[Br-]>C1COCC1.CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2c1c1ccccc1n2Cc1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a mixture of 9-Benzyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (3.89 g, 14.13 mmol), THF (20 mL) in THF (20 mL) and DMF (15 mL) is added pyridinium hydrobromide perbromide (5.42 g, 16.96 mmol) as a solution in DMF (5 mL). After stirring for 5 h at room temperature, TLC (EtOAc-hexane, 20/80) showed little or no reaction had occurred, so the mixture is stirred at 70° C. for 4 h and then allowed to cool (and stir the remainder of the night). The solvents then are removed and the residue is partitioned between Et2O and brine, dil. Na2S2O3, and brine. The aqueous layer is removed and CH2Cl2 is added to the organic layer (from which solids had begun to precipitate). The organic layers are dried over MgSO4 and taken to dryness. Without further purification, the crude product is stirred with LiBr (2.67 g, 31 mmol) and Li2CO3 (2.07 g, 28 mmol) in DMF (50 mL) at 100° C. for 45 min, and then at reflux for 3 h. After cooling, the solvent is removed and the residue is partitioned between CH2Cl2 and water. The organic layers are dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (250 mL) using EtOAc-heptane (15/85)/CH2Cl2 (6:1) as eluent to give 2.78 g of solid; mp 119-121.5° C.; IR (drift) 3353, 1602, 1485, 1458, 1337, 1328, 1279, 1230, 1138, 1104, 780, 748, 735, 714, 700 cm−1; 1H NMR (CDCl3) δ5.32, 5.50, 6.60, 6.97, 7.14, 7.26, 7.3-7.4, 8.33. Anal. Calcd for C19H15NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 82.35; H, 5.51; N, 5.06.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C(OC(C)C)(C)C>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.584 mol, content: 90.7%, water: 8.5%) and trimethylcetylammonium chloride (0.084 g) was stirred in diisopropyl ether (500 ml), and 36% conc. hydrochloric acid (18.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.1 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (17.2 g) in diisopropyl ether (88 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 900 g of the solvent was distilled away under reduced pressure while continuously introducing diisopropyl ether (1000 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (95.8 g, yield: 93.1%) and 2-keto-L-gulonic acid (0.9 g, residual ratio: 0.8%). Quantitative analysis of diisopropyl ether in the distillate and filtrate showed that the recovery ratio was not less than 99%.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.[NH4+].[Cl-]>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OC1(c2nccs2)CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOC1(c2nccs2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a solution of the alcohol 2-[(1-Hydroxy)cyclobutyl]thiazole from Step 1 (5 g, 32 mmol) and Hunig's base (10.4 mL, 60 mmol) in dichloromethane (100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5 mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 1 h, was heated at reflux temperature for 3.5 h and finally was stirred at room temperature for 15 h. Sat. aq. NH4Cl was added and the resulting mixture was extracted with dichloromethane (3×). The combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of-the residue (silica gel; dichloromethane to dichloromethane/ethyl acetate 95:5) provided 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole (2 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][O:27][CH2:28][C:29]([N:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:30])(=[O:19])=[O:18])=[C:12]([CH3:44])[CH:11]=1>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][O:27][CH2:28][C:29]([N:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)=[O:30])(=[O:18])=[O:19])=[C:12]([CH3:44])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazine-1-carboxylate (Example 101) (1 eq.) in dichloromethane (10 ml/mmol). The reaction mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The crude product was used in the next synthesis step without being purified further.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1>CO.Cl>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2([CH3:22])[C:6](=[O:23])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:9][C:8]2=[O:12])=[CH:18][CH:17]=1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)ccc2C1=O
Agent: Cl
Solvent: CO
Product: CC1(c2ccc(N)cc2)C(=O)Nc2cc(Cl)ccc2C1=O
Yield: 87.6 %

Procedure:
To a solution of 7-chloro-3-methyl-3-(4-nitro-phenyl)-1H-quinoline-2,4-dione (0.98 g, 2.96 mmol) in methanol (10 mL) was added SnCl2-2H2O (2.0 g, 8.88 mmol). The resulting solution was stirred at reflux temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to produce pale yellow residue. The residue was diluted with 1N HCl solution (200 mL) and extracted with ethyl acetate (200 mL×3). The organic layer was washed with brine (200 ml×2) and water (200 ml×2) and dried over anhydrous MgSO4. After evaporation of the solvent, the objective compound (0.78 g, 88%) was obtained as pale yellow solid by purifying the residue with recrystallization (n-hexane:EtOAc=1:1): 1H NMR (200 MHz, CDCl3) δ 1.79 (s, 3H, CH3), 3.67 (br s, 2H, NH2), 6.57 (d, J=8.6 Hz, 2H, ArH), 6.92 (d, J=2.0 Hz, 1H, ArH), 7.03-7.09 (m, 3H, ArH), 7.83 (d, J=8.8 Hz, 1H, ArH), 9.01 (br s, 1H, NH); m.p. 155-156° C.; MS(EI) m/e 300 [M+].