Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O.CN(C)C=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([Cl:25])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.61 g (5.7 mmol) of 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (60 mL), and 3.5 mL (42 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (60 mL), and 0.71 g (6.3 mmol) of 1,3-cyclohexanedione and 0.97 mL (6.9 mmol) of triethylamine were added to the above solution. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 2.13 g of the title compound was obtained as a light yellow solid (yield: quantitative).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][C:12]([C:15]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][CH2:24][C:23]=3[CH:27]=2)[CH2:17][CH3:18])=[CH:11][CH:10]=1>C1COCC1>[O:26]1[C:22]2[CH:21]=[CH:20][C:19]([C:16]([CH2:17][CH3:18])=[C:15]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[C:12]3[CH:13]=[N:14][C:9]([O:5][CH2:4][CH2:3][NH:2][CH3:1])=[CH:10][CH:11]=3)=[CH:27][C:23]=2[CH2:24][CH2:25]1
Reactant: CNCCO
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2c(c1)CCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)nc1)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a stirred solution of 2-(methylamino)ethanol (875 mg, 10 eq) in 20 mL anhydrous THF was added NaH (373 mg, 8.0 eq) at 0° C., and the mixture was stirred at rt for 1 h, 4-(1-(6-Chloropyridin-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)but-1-enyl)phenol (440 mg, 1.0 eq) was added. The mixture was refluxed for 16 h, cooled, quenched with sat. NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (197 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=2.4 Hz, 0.5H), 7.60 (d, J=2.0 Hz, 0.5H), 7.32 (dd, J=8.4 Hz, 2.4 Hz, 0.5H), 7.07 (dd, J=8.4 Hz, 2.4 Hz, 0.5H), 7.03 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 0.5H), 6.78 (d, J=8.4 Hz, 1.5H), 6.69 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 0.5H), 6.59 (d, J=8.0 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.36 (d, J=8.4 Hz, 0.5H), 4.53 (t, J=8.4 Hz, 2H), 4.46 (t, J=5.2 Hz, 1H), 4.31 (t, J=5.2 Hz, 1H), 3.10 (t, J=8.4 Hz, 2H), 3.05 (t, J=5.2 Hz, 1H), 2.96 (t, J=5.2 Hz, 1H), 2.55 (s, 1.5H), 2.50 (s, 1.5H), 2.45 (q, J=7.6 Hz, 2H), 0.94 (t, J=7.2 Hz, 3H); m/z=417[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39]C)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([OH:39])=[O:38])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(OC)cc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N2CN(Cc3cccc(C(=O)O)c3)C(=O)C23CCN(CCCn2c(=O)[nH]c4ccccc42)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.32 g, 0.55 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.046 g, 1.1 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.15 g, 48%); 1H NMR (DMSO-d6): δ 1.64 (d, 2H, J=13.6 Hz), 1.77 (t, 2H, J=6.4 Hz), 1.95-2.02 (m, 2H), 2.31 (t, 2H, J=6 Hz), 2.57-2.67 (m, 4H), 3.68 (s, 3H), 3.79 (t, 2H, J=6.8 Hz), 4.34 (d, 4H, J=26.8 Hz), 6.84 (dd, 2H, J=4.8 and 2 Hz), 6.92-6.96 (m, 5H), 7.09-7.12 (m, 1H), 7.49-7.52 (m, 2H), 7.86-7.87 (m, 2H), 10.77 (s, 1H), 12.95 (br, 1H); MS for C32H35N5O5 m/z 570.04 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[O:13]=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:13])[C@H:5]([OH:6])[C:3]([C:2]([OH:8])=[O:1])=[O:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
In particular, the process of the invention may be applied to a methanolic solution of ascorbic acid or sodium ascorbate produced by esterification of 2-keto-L-gulonic acid in methanol, followed by cyclization with sodium bicarbonate to produce a feed composition to the solvent exchanger to produce an aqueous product of ascorbic acid or sodium ascorbate. The product may then be obtained from the aqueous stream by crystallization.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]([C:28]1[N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:30]([CH:33]=[O:34])=[CH:31][N:32]=1)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:28]1[N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:30]([CH:33]([OH:34])[CH:19]([CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:31][N:32]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: COC(=O)CCc1cccs1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCc1ncc(C(O)C(Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a solution of diisopropylamine (1.96 g, 0.0194 mol) in dry tetrahydrofuran (40 mL) held at -78° C. under argon was added n-butyl lithium (7.3 mL, 0.0183 mol of 2.5M in toluene), and the mixture was stirred for 10 minutes. Then, methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 mL) was added, and the mixture was stirred for 30 minutes at -78° C. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (3 g, 0.0111 mol) in tetrahydrofuran (4 mL) was added, and the resulting mixture was stirred at -78° C. for 30 minutes. The reaction was partitioned between saturated ammonium chloride solution and ether, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to 6.67 g of crude product. This was flash chromatographed over 70 g of silica gel with 4:1 ethyl acetate/hexanes to provide 4.03 g (81%) of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-[(2-thienyl)methyl]propanoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[C:5]([CH3:14])[C:6]=1C(OC(C)(C)C)=O.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=2)=[C:5]([CH3:14])[CH:6]=1
Reactant: Cc1c(-c2ccc(OC(F)(F)F)cc2)sc(N)c1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)sc1-c1ccc(OC(F)(F)F)cc1

Procedure:
The above thiophene (0.7 g) in 6 ml of trifluoroacetic acid is heated to 60° C. for 3 hr., cooled, diluted with toluene and concentrated in vacuo. The resulting oil is diluted and concentated twice more to afford 2-amino-4-methyl-5-(4-trifluoromethyloxyphenyl)thiophene trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C@@:2]1([C:8](O)=[O:9])[CH2:6][CH2:5][C:4](=[O:7])[O:3]1.O1CCCC1>O>[OH:9][CH2:8][C@@:2]1([CH3:1])[O:3][C:4](=[O:7])[CH2:5][CH2:6]1
Reactant: C[C@@]1(C(=O)O)CCC(=O)O1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]1(CO)CCC(=O)O1
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g. (102.7 mmol) of (S)-(-)-2-methyl-5-oxotetrahydro-2-furoic acid mp 84°-87° C.; [α]25D-16.56° in 70 ml. of dry tetrahydrofuran (THF) was added 10.1 ml. (8.1 g.; 106.7 mmol) of borane-methyl sulphide complex, dropwise, with stirring over a 0.5 hr. period. Occasional ice-bath cooling was employed to maintain the internal temperature below 30°. After stirring at room temperature for 1.5 hr., the reaction mixture was cautiously decomposed by the dropwise addition of 6.2 ml. of H2O. The mixture was then concentrated under water aspirator pressure and the residue was taken up in ethyl acetate and filtered. The solids were washed thoroughly with ethyl acetate and filtered. The solids were washed thoroughly with ethyl acetate and the filtrate and washes were combined and concentrated in vacuo giving (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone as a colorless oil (13.6 g.) which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].Cl.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]4[C:7]3=[O:16])[CH2:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C2=CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)cc1
Yield: 88 %

Procedure:
A solution N-(4-bromobutyl)phthalimide (0.85 g), 4-(4-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.63 g) and triethylamine (0.91 g) in dry acetonitrile (10 ml) was refluxed for 3 hours. After evaporation of the solvent, crude residue was dissolved in ethyl acetate, washed with water, sat. ammonium chloride solution and brine successively, dried over magnesium sulfate and evaporated to give a yellow solid of N-[4-{4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]phthalimide (0.99 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28]C(=O)C)[CH:26]=2)[N:21]=[CH:20][N:19]=1.CC(O)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([OH:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.9 g, 16.62 mmol) and acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester (4.62 g, 18.28 mmol) were dissolved in a 1:1 mixture of DCE:t-BuOH (50 mL). The reaction mixture was refluxed for 19 hours and then cooled to room temp. Solvent was removed via rotovap. The crude residue was then suspended in MeOH (80 mL) and NH4OH (8 mL, 30% in water) was added to the mixture. Stir for 15 hours at room temp. The reaction was heated to 100° C. and stirred for 1 hour. Cool to 0° C. and product was isolated by filtration and washed with cold MeOH to give 5 g (12.2 mmol, 67% over two steps) of desired product.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.O.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[S:18](=[O:28])(=[O:27])[N:17]=1>O>[Cl:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([NH:15][CH2:14][CH2:13][NH:12][CH:1]=[O:3])=[N:17][S:18](=[O:28])(=[O:27])[C:19]=2[CH:25]=1
Reactant: O=CO
Reactant: NCCNC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNCCNC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of formic acid (1 mL) and acetic anhydride (2 mL) was heated at 50° C. for 20 min. After cooling at room temperature, 3-(2-aminoethyl)amino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate (0.5 g) was added, and the reaction mixture was stirred for 2 h, then supplemented with water (20 mL) and stirred for 20 min. The precipitate was collected by filtration, washed with water and dried (yield: 0.3 g); m.p. 245-247° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].CN(C)C=O.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:6]=1
Reactant: N#Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Cl)c(Br)cn(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of 4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D of Example (16.4 g) and N,N-dimethylformamide (124 mL) was added N-bromosuccinimide (16.5 g) at 60° C., and the mixture was stirred for 40 hr. The reaction mixture was cooled to room temperature, and poured into water. The resulting solid was collected by filtration, and washed with water to give the title compound (20.9 g).
Reaction SMILES: [OH-].[Na+].[NH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]1.C(O)(=O)C>O>[NH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: CCOC(=O)c1cn(N)c2cc(Cl)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Sodium hydroxide (0.91 g, 0.0228 mole) was dissolved in 100 ml of water, and 2.6 g (0.0091 mole) of ethyl 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was added. The mixture was stirred on a steam bath for two hours and the hot solution was neutralized with acetic acid (1.6 ml). The suspension of solid was stirred at room temperature for about sixteen hours, and the solid was collected by filtration and washed with water. The product was recrystallized from dimethylformamide to give 2.0 g of 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, beige powder, m.p. 312°-315° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C)C=O>O>[Br:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
Mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (2.04 g) prepared in example 6, 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (2.69 g) and N,N-dimethylformamide (10 ml) was stirred at 50° C. for 20 hours. The reaction mixture was turned back to a room temperature, water (45 ml) was added, then extracted twice with ethyl acetate (15 ml). The organic layers were combined together, washed with water 3 times, dried over anhydrous sodium sulfate. Afer being filtrated under a reduced pressure, the residue thus obtained was purified by use of a silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (3.77 g, yield: 84%)
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH2:22][C:20](=[O:21])[O:19]1.CCN=C=NCCCN(C)C.O>CO.CN(C1C=CN=CC=1)C.[Pd]>[F:16][C:2]1([F:1])[CH2:3][CH:4]([C:6]([CH:22]2[C:23](=[O:24])[O:25][C:18]([CH3:26])([CH3:17])[O:19][C:20]2=[O:21])=[O:8])[CH2:5]1
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Product: CC1(C)OC(=O)C(C(=O)C2CC(F)(F)C2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A mixture of benzyl 3,3-difluorocyclobutanecarboxylate (28 g, 0.12 mol) and Pd/C (5 g) in methanol (150 mL) was hydrogenated for 2 h at ambient temperature. Pd/C was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane (200 mL) and cooled to 0° C. DMAP (30.8 g, 0.250 mol), Meldrum's acid (19.6 g, 0.140 mol) and EDCI (26.9 g, 0.140 mol) were added successively. The reaction mixture was stirred overnight at ambient temperature. Water (200 mL) was added and the resulting mixture was extracted with dichloromethane (300 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 20:1) to afford 5-(3,3-difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (24 g, 74% yield).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[N:27]=[CH:26][N:25](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:24]=5)[CH:21]=4)[N:16](C4CCCCO4)[N:15]=3)[CH:9]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:24]1[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[N:25]1
Reactant: O=C(NCC1CC1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 54.1 %

Procedure:
To a stirred solution of N-(cyclopropylmethyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.241 g, 0.352 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 4 h. The mixture was cooled and poured into aqueous saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) gave the title compound (0.0682 g, 54% yield). 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.45 (m, 1H), 8.19 (dt, 1H), 8.11 (d, 1H), 7.90 (dt, 1H), 7.69 (d, 1H), 7.66 (t, 1H), 3.30 (m, 2H), 1.18 (m, 1H), 0.55 (m, 2H), 0.32 (m, 2H). ES-MS (m/z) 359 [M+1]+
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Product: N#Cc1c(NCc2ccccc2)cccc1-c1ccccc1
Temperature: 150 °C

Procedure:
The product of example 1a above, 2-fluoro-6-phenylbenzonitrile, (0.118 g, 0.6 mmol), and benzylamine (0.5 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 150° C. for 24 hours. The residue was dissolved in methylene chloride (10 mL) and treated with an excess of polystyrene supported isocyanate resin for 30 minutes to remove the excess benzylamine. Filtration and evaporation gave the title product. ES (+) MS m/e=285 (MH+)
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10]>CN(C)C=O>[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([O:16][CH3:3])=[O:15])([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
390 mg (2.76 mmol) of methyl iodide and 320 mg (2.3 mmol) of powdered potassium carbonate were added to 940 mg (2.3 mmol) of 2-nitro-5-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid in 30 ml of dimethylforamide (freshly eluted through neutral alumina). After 1 hour, the mixture was poured into 300 ml of water, extracted with ether, the ether layer was washed with saturated sodium chloride solution, then dried and evaporated to 820 mg of light yellow oil (84%) diphenyl ether methyl benzoate having the following elemental analysis, calculated (found): C: 45.14 (47.54); H: 2.13 (2.69); Cl: 8.33 (6.19); F: 22.31 (21.26); N: 3.29 (2.72); O: 18.79.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]1[O:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=1>CN(C=O)C>[C:18]([O:17][C:16]([NH:15][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:30][C:31]1[O:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Reactant: COC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.3 %

Procedure:
To a stirred solution of (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)-carbamate (I8, 1 g, 3.34 mmol) in DMF (9.4 mL) at 0° C. under nitrogen was added K2CO3 (0.693 g, 5.01 mmol) followed by methyl 2-(chloromethyl)oxazole-4-carboxylate (0.586 g, 3.34 mmol). After 10 minutes at 0° C., the reaction was allowed to warm to room temperature and the stirring was maintained for 21 h. The reaction mixture was then partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic phases were dried over MgSO4, filtered then concentrated in vacuo to give the title compound (1.66 g) as an off-white solid. The residue was taken on to the next step without further purification. LCMS (Method 1): [MH+]=439 at 4.22 min.