Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=2)[NH:22][N:21]=1)[CH3:19].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C.CN(C=O)C>[CH:33]1([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=3)[C:20]([CH2:18][CH3:19])=[N:21]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: BrC1CCCC1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 337 mg (8.4 mmol) of NaH (60% in mineral oil), 1.7 mL (8.4 mmol) of 15-crown-5 and 42 mL of DMF was added 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. This mixture was stirred at room temperature for 3 hours and then 1.35 mL (12.6 mmol) of cyclopentyl bromide was added and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 40 mL ethyl acetate, washed with 30 mL of water and 30 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography over SiO2 using a step gradient of 10% ethyl acetate in hexanes until the first compound eluted and then 50% ethyl acetate in hexanes to provide 662 mg (2.4 mmol) of methyl 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate as a clear oil along with 144 mg (0.53 mmol) methyl 2-(cyclopentyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellow oil. 1H-NMR (CDCl3) δ 8.17 (s, 1H), 7.71 (dd, J1=8.4 Hz, J2=6.7 Hz, 2H), 5.0 (p, J=7.5 Hz, 1H), 3.97 (s, 3H), 3.00 (q, J=7.5 Hz, 2H), 2.16 (m, 4H), 1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>>[OH:6][C@H:3]1[CH2:4][CH2:5][N:1]([CH2:9][CH2:8][C:7]#[N:10])[CH2:2]1
Reactant: C=CC#N
Reactant: O[C@H]1CCNC1
Product: N#CCCN1CC[C@H](O)C1

Procedure:
By the reaction in the same manner as in Starting Material Synthesis Example 1 using (S)-(+)-3-pyrrolidinol (12.3 g) and acrylonitrile (10.2 mL), (S)-3-(3-hydroxypyrrolidin-1-yl)propionitrile (53 g) was obtained.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.05 g, 3.27 mmol) in N,N-dimethylformamide (15 mL) were serially added 2,2-diphenylethyl iodide (1.11 g, 3.60 mmol) and potassium carbonate (500 mg, 3.60 mmol) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl [[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate (1.11 g). To a solution of this compound (1.00 g, 1.99 mmol) in ethanol (45 mL)-water (5 mL) was added sodium periodate (0.51 g, 2.39 mmol) and the mixture was refluxed for 3 hours. To this reaction mixture were added ethyl acetate and water, and the resulting two layers were separated. The aqueous layer was extracted with ethyl acetate and the pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:8) and recrystallized from ethyl acetate to provide 0.64 g of the title compound. Yield 42%.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromo-4-methylpyridine
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:17])[NH:5]2.F[C:19]1C=C2C(NC(=O)C(C(OCC)=O)=N2)=C[CH:20]=1.C(I)C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:19]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]1=[O:17])[CH3:20]
Reactant: CCOC(=O)c1nc2cc(F)ccc2[nH]c1=O
Reactant: CCOC(=O)c1nc2ccc(F)cc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CCC(C)=O
Product: CCOC(=O)c1nc2ccc(F)cc2n(CC)c1=O

Procedure:
The mixture of 6-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester and 7-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (Example 22a) (2 g), ethyl iodide (4 g) and anhydrous potassium carbonate (5.9 g) in 2-butanone (200 ml) were heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated. The residual oil was chromatographed on silica using a mixture of petroleum ether (b.p. 60°-80°) and ethyl acetate (3:1) as eluent to give the required product, on evaporation of the later fractions, m.p. 99°-101.5°, (50%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CN(C)C=O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].[OH-].[Na+]>O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: [O-]c1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 110 °C
Reaction time: 44 h
Yield: 79.3 %

Procedure:
Sodium phenoxide trihydrate (7.50 g, 44.1 mmol) was dried under vacuum at 65° C. for 18 h at 0.6 mm Hg to yield 5.08 g of sodium phenoxide. Under a nitrogen atmosphere, 3,5-dibromopyridine (4.00 g, 16.9 mmol) and anhydrous N,N-dimethylformamide (40 mL) were added to the sodium phenoxide (5.08 g, 43.8 mmol). The resulting mixture was stirred at 110° C. for 44 h. After cooling to ambient temperature, water (75 mL) was added, and the pH was adjusted to 13.0 using 30% NaOH solution. The solution was extracted with diethyl ether (4×60 mL). The combined ether extracts were washed with saturated NaCl solution (50 mL), dried (NaSO4), filtered and concentrated by rotary evaporation to a brown oil (4.0 g). The oil was vacuum distilled, collecting a forerun (317 mg), bp 48°-65° C. at 0.05 mm Hg. Further distillation afforded 3.35 g (79.8%) of 3-bromo-5-phenoxypyridine as a pale-yellow oil, bp 75-112° C. at 0.05 mm Hg (lit. bp 110°-115° C. at 1.7 mm Hg, see K. Fujikawa, et al. Agr. Biol. Chem. 34:68 (1970).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][C@@H:48]([N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]2[CH:66]=[CH:65][C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH:58]=2)[C:49](=[O:52])[NH:50][CH3:51])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([C@@H:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:44]1[CH:43]=[CH:42][C:41]([F:40])=[CH:46][CH:45]=1)[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.22 g; 0.89 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.20 g; 1.02 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.53 g of (2-((((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylcarbamoylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)-methoxy)-1,1-dimethylethyl)carbamic acid tert-butylester.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]([CH3:12])([CH2:10][OH:11])[CH2:8][OH:9].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH3:6][C:7]([CH3:12])([CH2:10][O:11][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:8][OH:9]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CC(C)(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(C)(C)CO
Yield: 54.9 %

Procedure:
To an N,N-dimethylformamide solution (50 ml) containing 2.500 g of 2,2-dimethyl-1,3-propanediol was added an about 60% oil suspension containing 2.112 g of sodium hydride. After the reaction mixture was stirred under cooling with ice for 1 hour, 9.930 g of 1-bromo-octadecane was added dropwise thereto. After the reaction mixture was stirred at room temperature for 16.5 hours, water was added thereto and this mixture was extracted with hexane and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:0 to 20:1). Thus, 4.700 g of the title compound was obtained in the form of a white solid.
Reaction SMILES: C([C:6]1[C:7](=[O:17])[O:8][C:9]2[C:14](C=1)=CC=C(O)C=2)(OCC)=O.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>C(Cl)Cl>[CH2:18]([O:20][CH:21]([O:17][CH:7]([O:8][CH2:9][CH3:14])[CH3:6])[CH3:22])[CH3:19]
Reactant: C=COCC
Reactant: CCOC(=O)c1cc2ccc(O)cc2oc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(C)OC(C)OCC
Reaction time: 0.25 h
Yield: 26 %

Procedure:
To a slurry of 5.0 g (21 mMol) of 3-carbethoxy-7-hydroxycoumarin [H. Pechmann and E. Graezer, Chem. Ber. 34:378(1901)] in 100 mL of CH2Cl2 containing 5 mL of ethylvinyl ether was added 30 mg of p-toluenesulfonic acid. After 15 minutes, the reaction was poured into 100 mL of 10% potassium hydroxide (KOH) solution. The organic phase was separated, washed with H2O, dried and evaporated. The residue was taken up in toluene and precipitated with hexane to give 1.73 g (26% yield) of the 1-ethoxyethyl ether as a solid, m.p. 70°-71° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH3:26])[CH2:3][CH2:2]1.C(O[CH:30]=[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])C>>[CH:1]1([N:4]([CH:30]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH3:26])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2C)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1c([N+](=O)[O-])cc(F)c(N2CCN(C(=O)OCC)CC2)c1C)C1CC1)C(=O)OCC
Yield: 51.9 %

Procedure:
To N-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline (7.1 g) is added diethyl ethoxymethylenemalonate (4.6 g), and the mixture is reacted at 150°-170° C. for 17 hours. After cooling, the solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography (solvent, dichloromethane:n-hexane=2:1→dichloromethane) to give diethyl [N-cyclopropyl-N-[3-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate (5.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].O.P([O-])(O)(O)=[O:30].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[C:5]([OH:30])=[O:6]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 72 h

Procedure:
To a slurry of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (3.80 g, 10.1 mmol) and sodium dihydrogenphosphate hydrate (7.00 g, 50.7 mmol) in 40 mL 1:1 water/t-BuOH under nitrogen was added 2-methylbut-2-ene (37.6 mL, 355 mmol) and sodium chlorite (4.59 g, 50.7 mmol). The reaction mixture was allowed to stir rapidly for 3 days. The thick reaction mixture was concentrated in vacuo to remove the 2-methyl-2-butene, and the slurry diluted with water and filtered, rinsing water and MeOH. The resulting solid was dried in vacuo to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid as an off-white solid which was used without further purification. MS (ESI) m/z: Calculated: 390.1; Observed: 391.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:11][C:10]=1[N:26]([S:32]([NH:35]C(OC(C)(C)C)=O)(=[O:34])=[O:33])[CH2:27][C:28]([O:30]C)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][S:32]([N:26]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][C:28]([OH:30])=[O:29])(=[O:33])=[O:34]
Reactant: COC(=O)CN(c1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)COc1ccc(N(CC(=O)O)S(N)(=O)=O)c(OCc2ccccc2)c1

Procedure:
A solution of methyl N-(2-(benzyloxy)-4-{2-oxo-2-[2-(trimethylsilyl)ethoxy]ethoxy}phenyl)-N-{[(tert-butoxycarbonyl)amino]sulfonyl}glycinate (1.15 g, 1.84 mmol) in 20 mL of TFA/methylene chloride (1:1) is stirred at RT for 30 min. The solvent is removed under reduced pressure and the residue is dissolved in methylene chloride and the solvent evaporated (4×) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccnc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 2-chloro-pyrimidine-4-carboxylic acid methyl ester (0.62 g, 3.59 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.86 g, 4.31 mmol, 1.2 equiv; commercially available) and N-ethyl diisopropylamine (0.73 mL, 0.56 g, 4.31 mmol, 1.2 equiv) in acetonitrile (60 mL) was heated by microwave irradiation to 110° C. After stirring for 40 min, the reaction mixture was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.48 g (34%) of the title compound. MS (ISP): 337.5 [M+H]+.
Reaction SMILES: COC1C=C(C[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:21])C=C(OC)C=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:25]=1[CH:26]=O>>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:25]=1[CH2:26][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21]
Reactant: COc1cc(CCCc2ccc(O)cc2O)cc(OC)c1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Product: COc1cc(OC)c(CCCc2ccc(O)cc2O)c(OC)c1

Procedure:
Compound 31 was synthesized following a similar procedure as described for compound 28 above using as starting materials 2,4-dibenzyloxyacetophenone and 2,4,6-trimethoxybenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.822 (d, 1H, J=8.0 Hz), 6.250(d, 1H, J=2.5 Hz), 6.197(dd, 1H, J=2.5 & 8.0 Hz), 6.165(s, 2H), 3.768(s, 3H), 3.764(s, 6H), 2.562(t, 2H, J=7.5 Hz), 2.461(t, 2H, J=7.5 Hz), 1.617-1.653(m, 2H). 13C-NMR (MeOD, 125 MHz): δ 159.273(C), 158.729(2C), 155.556(C), 155.449(C), 129.655 (2CH), 120.426(C), 111.382(C), 105.789(CH), 101.968(CH), 90.285(CH), 54.655 (2CH3), 54.274(CH3), 29.716(CH2), 29.064(CH2), 22.142(CH2).
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][CH2:12][C@:13]1([CH3:24])[O:17][C:16]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:15]2[CH2:14]1>C(Cl)Cl>[OH:11][CH2:12][C@:13]1([CH3:24])[O:17][C:16]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:15]2[CH2:14]1
Reactant: COCOC[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CO)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 25 h
Yield: 46.3 %

Procedure:
Trifluoroacetic acid (15 ml) was added to a solution of (R)-2-methoxymethoxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 28 (3.1 g, 13 mmol) in methylene chloride (30 ml) followed by stirring at room temperature for 25 hours. The reaction mixture was concentrated under reduced pressure. Methanol was added to the solution, and the resulting mixture was concentrated under reduced pressure. To the residue, 2-propanol was added, and the precipitates were filtered off and washed with 2-propanol to afford (R)-2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (1.2 g, yield 46%) as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].[CH2:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>>[CH2:5]=[C:6]([CH2:10][C:11]([O:13][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:12])[C:7]([O:9][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:8]
Reactant: C=C(C)C
Reactant: C=C(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Product: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2-Methylprop-1-ene (50.3 mL) was added to 2-methylenesuccinic acid (10.0 g) at −78 C, then sulfuric acid (0.819 mL) was added dropwise at −78 C, and then, the obtained mixture was stirred at room temperature at 4.5 to 3.5 atm for 22 hours in a sealed tube. After removal of 2-methylprop-1-ene at room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and added to a saturated aqueous solution of sodium bicarbonate (100 mL) at 0 C, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (12.8 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([OH:29])=O)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C[N:34](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=2)[NH:15][C:14]([C:27]([NH2:34])=[O:29])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxylic acid (1.0 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.9 g), 1-hydroxybenzotriazole (0.6 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 min. 28% Aqueous ammonia solution (0.8 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was crystallized from a mixed solvent of ethanol-diethyl ether, and the obtained crystals were washed with diethyl ether to give the title compound (0.8 g, yield 83%) as colorless crystals. MS 445 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10](F)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2].[O:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2]
Reactant: N#Cc1cnc2cc(F)cc(F)c2c1O
Reactant: OC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cnc2cc(F)cc(OC3CCOCC3)c2c1O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (2.06 g), tetrahydro-2H-pyran-4-ol (1.02 g) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 30.0 ml) in anhydrous tetrahydrofuran (100 ml) was stirred and heated under nitrogen at 60° C. for 1.5 hours. Acetic acid was added until pH6 was reached and then the solution was evaporated to dryness. The residue was dissolved in aqueous sodium hydroxide solution (2.0M) and the resulting solution was filtered through a GF/A glass fibre pad. The filtrate was acidified to pH5 with acetic acid and the resulting oily precipitate allowed to stand 3 days when it had become solid. The solid was collected and washed with water then air-dried. (1.8 g, 62%); NMR spectrum: (DMSOd6) 1.67 (m, 2H), 1.92 (m, 2H), 3.50 (m, 2H), 3.91 (m, 2H), 4.76 (m, 1H), 6.81 (m, 1H), 6.94 (m, 1H), 8.52 (s, 1H); Mass spectrum: M+H+ 289.