Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=4)[C:30]([OH:32])=O)=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[C:43]1([NH2:46])[CH2:45][CH2:44]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=4)[C:30]([NH:46][C:43]4([C:38]5[N:39]=[CH:40][CH:41]=[CH:42][N:37]=5)[CH2:45][CH2:44]4)=[O:32])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])cc1C(=O)O
Reactant: NC1(c2ncccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])cc1C(=O)NC1(c2ncccn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)-6-nitrobenzofuran-5-yl)-2-methoxybenzoic acid (300 mg, 0.634 mmol) and 1-(pyrimidin-2-yl)cyclopropanamine hydrochloride (131 mg, 0.760 mmol) in DMF (15 mL) at room temperature under a nitrogen atmosphere was added triethylamine (TEA) (0.442 mL, 3.17 mmol). The mixture was cooled to 0° C. and added with BOP reagent (420 mg, 0.951 mmol). The reaction mixture was then stirred at rt overnight, and then diluted with water. The solid was filtered and dried under suction to obtain the title compound as a light yellow solid. Yield: 350 mg (94%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.52 (br. s, 1H) 8.93 (s, 1H) 8.70 (s, 2 H) 8.49 (s, 1H) 8.00-8.14 (m, 2H) 7.88 (d, J=2.51 Hz, 1H) 7.74 (s, 1H) 7.52 (dd, J=8.53, 2.51 Hz, 1H) 7.34-7.43 (m, 4H) 7.20 (s, 1H) 3.89 (s, 3H) 1.54-1.68 (m, 2H) 1.36-1.49 (m, 2H). LCMS: (ES+) m/z=591.39 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 μm); Mphase A: 5 mM Ammonium Acetate:MeCN (95:5); Mphase B: 5 mM Ammonium Acetate: MeCN (5:95)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8]O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[C:16]([Si:19]([CH3:21])([CH3:20])[CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([NH2:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)([CH3:18])([CH3:17])[CH3:15]
Reactant: Nc1ccc(OCCO)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)CCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
2-(4-amino-3-nitro-phenoxy)-ethanol Compound 18a (0.5 g, 2.52 mmol) was treated with TBSCl (0.42 g, 2.52 mmol) and imidazole (0.173 g, 2.52 mmol) in DMF (10 mL) at room temperature overnight. DMF was removed under vacuum and the residue was diluted with AcOEt, washed with H2O and saturated aqueous NH4Cl and dried over Na2SO4. The solvent was evaporated to dryness to provide 4-[2-(tert-butyl-dimethyl-silanyl)-ethoxy]-2-nitro-phenylamine Compound 18b (0.787 g) as a golden solid. LCMS single peak, 3.93 min, MS (ESI) m/z 313.2 (M+H+). 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1 H), 7.00 (d, 1 H, J=9.0 Hz), 6.66 (d, 1 H, J=9.0 Hz), 3.94-3.84 (m, 4 H), 0.81 (s, 9 H), −0.01 (s, 6 H).
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[Cl:21][C:22]1[CH:44]=[C:43]([F:45])[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[CH:41][C:23]=1[C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([C:38]([OH:40])=O)[CH:28]=1)=[O:25].C(N(CC)C(C)C)(C)C.[CH2:61]([CH2:63][NH2:64])[OH:62]>CN(C=O)C>[Cl:21][C:22]1[CH:44]=[C:43]([F:45])[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[CH:41][C:23]=1[C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([C:38]([NH:64][CH2:63][CH2:61][OH:62])=[O:40])[CH:28]=1)=[O:25]
Reactant: NCCO
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
TPTU (510 mg, 1.72 mmol) and 5-(2-chloro-4-fluoro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 108, 500 mg, 1.14 mmol) were dissolved in DMF (2.5 mL) at 0° C. N,N-diisopropylethylamine (0.6 mL, 3.43 mmol) was then added and the mixture stirred at 0° C. for 15 minutes. Ethanolamine (99.5 mL, 1.65 mmol) was then added and the mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the resulting brown solid triturated with dichloromethane/TBME/heptane (4:2:0.5, 5 mL) to give a white solid, which was further triturated with MeOH (5 mL) to afford the title compound as a white solid (262 mg, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:18])=[C:6]([N+:15]([O-:17])=[O:16])[C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].CN(C)C=O.C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[CH3:31]>C(OCC)C>[CH2:30]([O:18][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:31]
Reactant: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1OCC

Procedure:
5-Ethoxy-4-hydroxy-2,3-dinitro-benzaldehyde (3.77 g), N,N-dimethylformamide (35 ml), K2CO3 (3.877 g) and ethyl bromide (50 ml) were refluxed 24 hours. To the reaction solution was added diethyl ether (100 ml) and then it was washed with water and 1M sodium hydroxide. The solution was dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Cl)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.63 (s, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.94 (dd, J=2.1, 8.3 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.[CH3:32]O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:32][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: CO
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (Example I5) (10 g) in toluene (150 ml) and dimethylformamide (0.1 ml) at ambient temperature was added dropwise thionyl chloride (3.5 ml). The reaction mixture was stirred at 50° C. for 2 hours. The solution was then cooled to 0° C. and methanol (2 ml) added slowly. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and aqueous sodium hydrogen carbonate (saturated) (50 ml) added to the residue. The mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over sodium sulfate and concentrated to afford 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester as a yellow solid (11.5 g). 1H-NMR (CDCl3, 400 MHz): 7.95 (d, 1H), 7.55 (m, 4H), 7.45 (s, 1H), 4.10 (d, 1H), 3.90 (s, 3H), 3.70 (d, 1H), 2.60 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:25][NH2:26].O>O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:4]2[N:5]=[C:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:7]=[C:2]([NH:25][NH2:26])[N:3]=2)=[CH:18][CH:19]=1
Reactant: Fc1cccc(F)c1-c1nc(Cl)nc(Nc2ccc(Cl)cc2)n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1nc(Nc2ccc(Cl)cc2)nc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 165.6 %

Procedure:
General Method 1A Step 3A.1 part a. To a solution of 151 mg (0.4 mmol) of triazine (XXVI) in 4 mL of 1,4-dioxane was quickly added 100 uL (2 mmol) of hydrazine monohydrate. The reaction was stirred at room temperature for 12 hours and 30 mL of water was added and the mixture stirred for an additional 30 minutes. The resultant solid was collected by filtration and washed with several portions of water. The white solid was dried overnight to afford 231 mg of N-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-hydrazinyl-1,3,5-triazin-2-amine (XXVII). If the hydrazine did not form a solid that could be filtered, then the mixture was extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield the hydrazine intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C:19]2=[O:24])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:36]=[CH:35]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([NH:17][N:18]2[CH2:23][CH2:22][N:21]([S:42]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[CH:40][CH:41]=[C:32]([Cl:31])[CH:33]=4)[CH:38]=3)(=[O:43])=[O:44])[CH2:20][C:19]2=[O:24])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-benzyloxycarbonyl-2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide (840 mg) and 10% Pd/C (500 mg) in methanol (35 ml) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain N-(2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide as a colorless syrup. A solution of the resultant 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]-N-(2-oxo-1-piperazinyl)acetamide in ethyl acetate (40 ml) and a 10% aqueous solution of sodium carbonate (40 ml) was combined at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (470 mg) and stirred at room temperature for 30 minutes. The organic phase was separated, washed with brine, dried and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (ethyl acetate) and crystallized from ethyl acetate to obtain the title compound (420 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18]Cl)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-:22].[K+].[K+].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[CH:32][C:31]=1[C:44]([F:47])([F:46])[F:45])([O-:29])=[O:28]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][O:43][C:40]4[CH:39]=[CH:38][C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[C:31]([C:44]([F:45])([F:46])[F:47])[CH:32]=5)=[CH:42][CH:41]=4)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: ClCCN1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a solution of 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-4-(2-chloroethyl)piperazine (200 mg, 0.61 mmol) in acetonitrile (5 ml) was added potassium carbonate (139 mg, 1.01 mmol, 1.6 eq.), 4-[4-nitro-3-(trifluoromethyl)phenyl]aminophenol (200 mg, 0.67 mmol, 1.1 eq.) and KI (56 mg, 0.34 mmol, 0.6 eq.) with stirring for 3 hours at 70° C. (oil bath). The reaction mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 2% dichloromethane in methanol to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethan-1-one as a orange solid (150.3 mg, 36%); (ES, m/z): [M+H]+ 591.15; 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J=9.0 Hz, 1H), 6.91-7.11 (m, 4H), 7.08 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 2H), 6.92 (dd, J=2.7, 9.0 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 4.93-5.09 (m, 1H), 4.75 (s, 2H), 3.65-3.78 (m, 4H), 3.28 (dd, J=9.3, 15.9 Hz, 1H), 2.97 (dd, J=8.1, 15.6 Hz, 1H), 2.79 (dd, J=7.5, 13.5 Hz, 1H), 2.60-2.75 (m, 5H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4]>C(O)C>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:9]([OH:10])[C@@H:7]([OH:8])[CH:5]([OH:6])[C@H:3]([OH:4])[CH2:2][OH:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@@H](O)C(O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The parent strain 3118 (ura+ version of 3099 prior to marker loopout) and the insertion site control strain 3862 produced 20-21 g/L ethanol in 55 hours, whereas strain 3082 produced 28 g/L in the same period (FIG. 33). In all three strains, glucose was depleted by nine hours. The additional ethanol formation in strain 3082 was correlated with an increased consumption of xylose. Strain 3082 produced less xylitol throughout the fermentation, and higher levels of glycerol and arabitol. Metabolite formation is summarized in Table 9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[C:7]=1[CH3:8].Cl[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.O>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]([O:18][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[O:17]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1cccc(Nc2ccccc2C(=O)O)c1C
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Nc2ccccc2C(=O)OCC(=O)N(C)C)c1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of mefenamic acid (2.41 g, 0.01 mole), 2-chloro-N,N-dimethylacetamide (1.6 g, 0.013 mole), triethylamine (1.6 ml, 0.011 mole) and sodium iodide (0.15 g, 0.001 mole) in N,N-dimethylformamide (10 ml) was stirred at 90° C. for 2 h. Water (50 ml) was added and the mixture allowed to stand at 4° C. for 5 h. The title compound was isolated by filtration, washed with water and recrystallized from ethanol-water (3.0 g, 92%). Mp 85°-86° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)[CH:23]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (2.5 g), (5-chloro-3-thienyl)methanol (2.48 g) and tributylphosphine (5.63 g) in THF (150 ml) was added 1,1′-(azodicarbonyl)dipiperidine (7.03 g), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed With brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then ETOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (1.15 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21]C)C.ClC(OC1C=CC=CC=1)=[O:27]>O1CCCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:21]([N:20]3[CH2:18][CH2:24][CH2:23]3)=[O:27])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC1
Temperature: 25 °C

Procedure:
4-(4-Nitrophenoxy)pyridin-2-ylamine (100 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere, triethylamine (0.181 ml) and phenyl chloroformate (0.163 ml) were added while stirring and cooling in an ice water bath. The reaction mixture was allowed to warm up to room temperature and stirred for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The separated organic layer was washed with water (30 ml) and brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added N,N-dimethylformamide (5 ml), and azetidine monohydrochloride (203 mg) and triethylamine (0.483 ml) were added, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure, the resultant residue was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The separated organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:3, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to provide the roughly-purified titled compound as a pale yellow solid (118.7 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:20]=[C:10]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[N:11]=2)[CH:14]=1)[CH3:19]
Reactant: [H][H]
Reactant: C=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Yield: 99.2 %

Procedure:
A solution of 60 mg of N-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide in 15 ml of methanol is hydrogenated at 25° C. for 45 minutes under 1 bar of hydrogen in the presence of 24 mg of 10% palladium-on-charcoal. As the reaction is incomplete, the product is recycled under the same conditions. After filtering, the reaction mixture is concentrated to dryness under reduced pressure. The residue is taken up in 50 ml of ethyl acetate. The organic phase is washed with water, separated by settling, dried and concentrated to dryness under reduced pressure to give 60 mg of 6-ethyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24](OCC)=[O:25])=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:25])[NH:33][N:32]=3)=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3)c(F)c2)CC1

Procedure:
In a 250 mL round bottom flask, 4-[4-(3-ethoxycarbonyl-propionyl)-3-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 9.68 mmol), and hydrazine monohydrate (0.97 mL, 19.4 mmol), in isopropanol (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 945 mg (25%). Mp 146-148° C. MS m/z 392 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[Na+].C1C2C(=CC=CC=2)C=CC=1O.[C:24](=[O:26])=[O:25].OC1C=CC2C(=CC=CC=2)C=1C(O)=O>O>[OH:11][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C=O
Agent: O=C(O)c1c(O)ccc2ccccc12
Agent: Oc1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 0.03 %

Procedure:
An autoclave was charged with 498 g of light oil (boiling at 250°-350° C.) and 166 g of sodium β-naphtholate, and with stirring, 72 g of β-naphthol was added. The mixture was reacted with carbon dioxide under a pressure of 5 kg/cm2.G at a reaction temperature of 270° C. for 4 hours. The reaction mixture was added to 830 ml of water, and heated at 100° C. for 30 minutes to decompose a 2-hydroxynaphthalene-1-carboxylic acid salt. The mixture was then separated into a light oil layer and an aqueous layer at 85° C. From the light oil layer, β-naphthol was extracted as an aqueous solution of sodium β-naphtholate by using an aqueous solution of sodium hydroxide. The pH of the aqueous layer was adjusted to 5.5 with hydrochloric acid, and the tarry layer that sedimented was separated at 85° C., and β-naphthol was recovered from the tarry layer by vacuum distillation. Water (500 ml) was added to the aqueous layer, and the mixture was extracted with 650 ml of toluene at 80° C. From the toluene layer, β-napthol was extracted as an aqueous solution of sodium β-naphtholate by using an aqueous solution of sodium hydroxide. The pH of the aqueous layer was adjusted to 2.0 with hydrochloric acid, and the mixture was cooled to 40° C., followed by filtration. Thus, 79.9 g of 2-hydroxynaphthalene-3-carboxylic acid (melting range 220°-221° C.; purity 99.6%; β-naphthol content 0.03%) was obtained.