Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]([C:11]1[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:14][CH:15]=1)=[O:10])[CH3:7].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>O1CCCC1>[CH2:6]([O:8][C:9]([C:11]1[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[S:14][C:15]=1[CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[O:25][CH3:24])=[O:10])[CH3:7]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)OC(C)(C)C)sc1C(O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.3 %

Procedure:
Butyl lithium (2.5 M, 53 mL, 132 mmol) was slowly added to a solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid ethyl ester (16.4 g, 60 mmol) in anhydrous tetrahydrofuran (250 mL) at −78° C. under a nitrogen atmosphere. A solution of 2-methoxybenzaldehyde (10.89 g, 79.99 mmol) in tetrahydrofuran (50 mL) was then added dropwise at −78° C. The mixture was warmed slowly to room temperature and stirred for 15 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (500 mL). The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was then purified by column chromatography to yield the pure product (12 g, 29 mmol, 48%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1C(O)=O.C([N:22](CC)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)(C)C>[CH3:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[NH2:22]
Reactant: Cc1c(C(=O)O)ccn2nc(-c3ccccc3)nc12
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(N)ccn2nc(-c3ccccc3)nc12
Yield: 25.4 %

Procedure:
To a suspension of 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (710 mg, 2.81 mmol) and triethylamine (1.17 ml, 8.42 mmol) in tert-butanol (20 ml) is added diphenyl phosphorazidate (909 μl, 4.21 mmol) at 25° C. After the addition the white suspension is refluxed for 24 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% and then ethyl acetate/methanol 10% as eluent affording 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (160 mg, 25.4%) as a white solid. mp.: 213-5° C. MS: m/z=225.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH2:20][CH2:19][CH:18]=[CH:17][C@@H:16]2[CH2:36][C@@:15]2([C:37]([O:39]CC)=[O:38])[NH:14][C:13](=[O:42])[C@@H:12]2[CH2:43][C@@H:44]([O:46][C:47]([N:49]3[CH2:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][C:55]=4[F:58])[CH2:50]3)=[O:48])[CH2:45][N:11]2[C:10]1=[O:59])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOCC>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH2:20][CH2:19][CH:18]=[CH:17][C@@H:16]2[CH2:36][C@@:15]2([C:37]([OH:39])=[O:38])[NH:14][C:13](=[O:42])[C@@H:12]2[CH2:43][C@@H:44]([O:46][C:47]([N:49]3[CH2:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][C:55]=4[F:58])[CH2:50]3)=[O:48])[CH2:45][N:11]2[C:10]1=[O:59])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-14a-carboxylate (1.45 g, 1.72 mmol) in THF (22 mL) was added 0.4 N NaOH solution (10.8 ml, 4.30 mmol) in water. The reaction was stirred at rt for 6 days. Water (5 mL) and ether (15 mL) was added. The aqueous layer was separated and acidified by saturated potassium hydrogen sulfate solution to pH=2˜3. The aqueous layer was extracted with EA (2×30 mL). the combined organics were washed with brine and dried over sodium sulfate. After removal of solvent, it gave (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-14a-carboxylic acid as white solid (1.40 g, 99%). MS: Calcd.: 814; Found: [M+H]+ 815. 1H NMR (400 MHz, d6-DMSO) δ11.24 (s, 1H), 8.84 (s, 1H), 8.01 (m, 2H), 7.86 (m, 2H), 7.36 (m, 1H), 7.10-7.26 (m, 3H), 5.49 (m, 1H), 5.39 (m, 1H), 5.27 (m, 1H), 4.67 & 4.66 (s, 4H), 4.40 (m, 1H), 4.27 (m, 1H), 3.97 (m, 1H), 3.66 (m, 1H), 3.31-3.53 (m, 2H), 3.23 (m, 1H), 2.96 (m, 1H), 2.55 (m, 1H), 2.25 (m, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 0.96-1.69 (m, 11H).
Reaction SMILES: N[C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.N([O-])=O.[Na+].[Cl-:27].[Na+]>C(O)C.O.Cl>[Cl:27][C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12
Reactant: [Cl-]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled solution of t-butyl 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid and sodium nitrite (1.18 g, 0.017 mol) were added portionwise over 15-20 minutes. The reaction mixture was stirred at 0°-5° C. for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried (Na2SO4) and concentrated to give 3.1 g (73%) of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:23]1([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])=[CH:6][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(OCCN2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
To a 50 mL vial which contained a solution of 2-(4-Hydroxy-phenyl)-isoindole-1,3-dione (239 mg, 1 mmol) and 1-(2-chloroethyl) piperidine hydrochloride (390 mg, 2 mmol) in DMF (15 mL) was added K2CO3 (600 mg, 4.5 mmol) at rt. The reaction mixture was heated to 85° C. and stirred at 85° C. for 72 h. After cooled to rt, the reaction mixture was poured into 50 mL ice-water mixture and then was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel to yield the title product, (90 mg, 28%); LCMS; 97%, ESI+; Calcd: 350.4; Found m/z: 351.6 (M+1); 1HNMR (400 MHz, CDCl3) δ 1.40-1.68 (m, 6H), 2.52 (br, 4H), 2.80 (t, J=6.0 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 7.02 (d, J=9.2 Hz, 2H), 7.32 (d, J=9.2 Hz, 2H), 7.77-7.79 (m, 2H), 7.84-7.96 (M, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH:29](O)([OH:33])[C:30]#[C:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:32][C:31]#[C:30][CH2:29][OH:33])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC#CC(O)O
Product: O=C1c2ccccc2C(OCC#CCO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and butynediol (435 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (271 mg, 58%). 1H NMR (300 MHz, CDCl3): 8.05-7.93 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.61-7.54 (m, 2H, Ar—H), 7.36-7.33 (m, 2H, Ar—H), 7.24-7.16 (m, 5H, Ar—H), 4.60 and 4.52 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.20-4.18 (m, 2H, HO—CH2), 3.83 and 3.52 (dt: AB, J=1.8, 15.3 Hz, 2H, O—CH2), 2.42 (t, J=6.0 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 169.24, 148.20, 145.18, 137.24, 135.88, 133.78, 132.49, 131.29, 130.78, 129.43, 128.79, 124.81, 124.43, 124.14, 95.88, 86.01, 81.28, 54.04, 52.97, 51.55, 43.60. m/z (ES): 463 [M+H]+. Anal.: calc. for C25H19ClN2O5+0.2 H2O: C, 64.36; H, 4.20; N, 6.01. Found: C, 64.11; H, 3.72; N, 5.53.
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C>O1CCOCC1.Cl>[F:35][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:32]=[CH:31][C:30](=[O:33])[NH:29][CH:28]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2ccccc2c(-c2ccc(=O)[nH]c2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 90 °C

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(6-methoxypyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (100 mg, 0.210 mmol) was dissolved in a mixture of 1.2 mL of 1,4-dioxane and 0.6 mL of 4M aqueous hydrochloric acid. The solution was heated at 90° C. for 2 hours. The crude reaction mixture was quenched with one equivalent of triethylamine and was then evaporated to dryness. The crude product was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, and a portion of the material was purified on 12 g of silica gel utilizing a gradient of 0-10% methanol in dichloromethane to yield 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)-N-(1-(6-oxo-1,6-dihydropyridin-3-yl)isoquinolin-3-yl)cyclopropane-carboxamide as a white solid. ESI-MS m/z calc. 461.1. found 461.9 (M+1)+. Retention time 1.67 minutes.
Reaction SMILES: Cl[CH:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]1[CH:7]=[C:6]([CH3:8])[S:5][C:4]=1[CH3:9].[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:10]1([CH:2]([NH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[C:3]2[CH:7]=[C:6]([CH3:8])[S:5][C:4]=2[CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1cc(C(Cl)C2CCCCC2)c(C)s1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-2,5-dimethylthiophene (653 mg) synthesized above, methyl 4-aminobenzoate (813 mg), sodium iodide (806 mg) and N,N-dimethylacetamide (15 mL) was added sodium carbonate (570 mg), and the mixture was stirred overnight at 100° C. under an argon atmosphere. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred with heating under reflux overnight, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), 1N hydrochloric acid (10 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (815 mg, 88%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH:27]=[O:28])=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1/C=C/c1ccc(/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1C=Cc1ccc(/C=C/C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of (E,E)-3-[4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]phenyl]-2-propenol (2.80 g), activated manganese dioxide (8.40 g) and chloroform (150 ml) was stirred at room temperature for 16 hours. After the manganese dioxide was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to yield (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]cinnamaldehyde (2.50 g, 90%) from the fraction eluted with chloroform, which was then recrystallized from dichloromethane-methanol to yield light yellow prisms having a melting point of 213°-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:7]=[C:6]2[C:20]1[N:28](S(C2C=CC(C)=CC=2)(=O)=O)[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:7]=[C:6]2[C:20]1[NH:28][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=1
Reactant: COC(=O)CCn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCC(=O)O)c2cc1OC
Yield: 87.8 %

Procedure:
3-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridine-2-yl)indol-1-yl]propionic acid is prepared by following the procedure described in example 88a, but using 1 g of methyl 3-[5,6-dimethoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propionate and a solution of 74 ml of methanolic potassium hydroxide (0.1 g/ml; 1.78M). 0.601 g of 3-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propionic acid is obtained, the characteristics of which are as follows:
Reaction SMILES: [Na].CC[O-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([CH:41]=[CH:42][CH:43]=1)[CH:12]=[C:13]([C:38]([CH3:40])=O)[C:14]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:15])([O-:8])=[O:7].Cl.[C:45]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])(=[NH:47])[NH2:46]>C(O)C>[NH2:47][C:45]1[NH:46][C:38]([CH3:40])=[C:13]([C:14]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:21][CH2:20]2)=[O:15])[CH:12]([C:11]2[CH:41]=[CH:42][CH:43]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[C:48]=1[C:49]([O:51][CH2:52][CH3:53])=[O:50]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
Sodium (0.20 g) was dissolved in dry ethanol (10 ml) and the thus-obtained sodium ethylate solution was added dropwise to a solution of 2-(4-benzhydryl-1-piperazinyl)ethyl 2-(3-nitrobenzylidene)acetoacetate (4.37 g) and ethyl amidinoacetate hydrochloride (1.42 g) in dry ethanol (10 ml) with stirring under reflux over a period of about 15 minutes. The mixture was further refluxed for 5 minutes. The resulting NaCl was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g). From the eluate with ethyl ether-ethyl acetate (10:1, v/v), there was obtained 5-[2-(4-benzhydryl-1-piperazinyl)ethyl] 3-ethyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate as a yellow powder. Yield 3.22 g. To a solution of 2.48 g of this product in ethanol was added a solution of oxalic acid in ethanol to give the oxalate as crystals. Yield 2.52 g. Recrystallization from ethanol-ethyl ether gave yellow crystals (1.83 g). m.p. 152°-153° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]2=[O:28])=[CH:13][CH:12]=1.CO.[Li+].[OH-].Cl>O>[F:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:28])[C:18]2=[CH:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
6-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid methyl ester (410 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (305 mg, 77% yield) as a brown solid. LC-MS (m/z) 397 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:8][C:7]1[C:2]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)CO
Reactant: Clc1nccnc1Cl
Product: CCOC(=O)COc1nccnc1Cl

Procedure:
The title compound was synthesized from 2,3-dichloropyrazine and ethyl 2-hydroxyacetate in the same manner as in Example 19.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]=[N:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[Mg+2].[Br-].[Br-].C[Si](C)(C)[O:20][C:21]([O:29][CH2:30][CH3:31])=[C:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:8]([NH:7][CH:6]([CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[C:21]([O:29][CH2:30][CH3:31])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C(CC1CCC1)=NCc1ccccc1
Reactant: CCOC(OCC)=C(OCC)O[Si](C)(C)C
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)C(OCC)(OCC)C(CC1CCC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
N-(2-cyclobutylethylidene)-1-phenylmethanamine (1.00 g, 5.3 mmol) was dissolved in 23 mL toluene, MgBr2.0Et2 (2.07 g, 8.0 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Trimethyl(1,2,2-triethoxyvinyloxy)silane (1.83 g, 7.4 mmol) was added, and the mixture was stirred at room temperature. After 3 hours, the reaction was quenched with water (30 mL) and acidified to pH=2 with hydrochloric acid. The organic phase was washed with sat. NaHCO3, dried over Na2SO4 and the solvent was removed under vacuum to yield the crude product. Column chromatography (silica, cyclohexane:ethyl acetate 10:1) yielded 1.1 g ethyl 3-(benzylamino)-4-cyclobutyl-2,2-diethoxybutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(CO)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 92.5 %

Procedure:
A mixed solution of 4-(4′-methoxyphenyl)benzylalcohol (1.20 g, 5.60 mmol), manganese dioxide (2.0 g) and tetrahydrofuran (25 ml) was stirred at room temperature for 72 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:tetrahydrofuran=5:1:1) to give the object compound (1.1 g) as colorless crystals. Melting point: 99-100° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>[Pd].CO>[NH2:1][C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cccc([N+](=O)[O-])c3N2)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc(N)c3N2)cc1
Yield: 200.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 5-nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-ylmethyl ester (3.64 g, 10.0 mmole), p-toluenesulfonic acid monohydrate (3.8 g, 20.0 mmole) and 0.50 g of 10% palladium on carbon in 140 mL of methanol was treated with 50 psi of hydrogen on a Parr shaker for 1 hour. The catalyst was filtered and washed with additional methanol. The solvent was evaporated in vacuum to yield 6.7 g of the p-toluenesulfonate salt of the title compound as a pink solid. This compound was used for the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9](=[N:18][OH:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17].[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>C(OCC)C>[CH:20]([S:23]([O:19][N:18]=[C:9]([Cl:8])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:25])=[O:24])([CH3:22])[CH3:21]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)S(=O)(=O)ON=C(Cl)c1c(Cl)cccc1Cl

Procedure:
A 3.6 (0.036 mol) sample of triethylamine was added slowly to a cooled mixture (ice bath) of 7.8 g (0.035 mol) alpha-chloro-2,6-dichlorobenzaldoxime (U.S. Pat. No. 3,234,255) and 5.5 g (0.035 mol) isopropylsulfonyl chloride in 125 ml diethyl ether. The reaction was slightly exothermic. The reaction mixture was filtered to remove a small amount of salts and the filtrate was evaporated under reduced pressure to give a yellow oil. The oil was chromatographed through a silica gel column with hexane/dichloromethane elution. O-isopropylsulfonyl-alpha-chloro-2,6-dichlorobenzaldoxime (white solid, m.p. 48°-50° C.) was eluted from the column with dichloromethane. Elemental analysis for C11H12Cl3NO3S showed: %S, calc. 9.3, found 8.1; %Cl, calc. 30.9, found 32.8.