Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:7][C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)(C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1>CCO.O>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])/[CH:35]=[CH:17]/[C:14]3[CH:15]=[CH:16][C:11](/[CH:10]=[CH:9]/[C:8]([OH:7])=[O:19])=[N:12][CH:13]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)c1cccc(CN2CCN(C)CC2)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 47.4 %

Procedure:
1.7 M KOH (0.634 ml) was added dropwise to a stirred mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (see Example 11 STEP A-D, 250 mg, 1.078 mmol) and 1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 14, 250 mg, 1.078 mmol) in EtOH (15 ml). The resulting solution was stirred at 0° C. for 7 h and then diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatographic column (eluent: DCM/MeOH/NH4OH from 97:3:0.1 to 95:5:0.2) and the desired intermediate was dissolved in DCM (4 ml) and TFA (1 ml). The mixture was stirred at room temperature for 6 h and then the solvent was removed in vacuo to give 200 mg of (E)-3-(5-{(E)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its tris-trifluoroacetate salt. The crude mixture was used in the next step without further purifications.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].S1[C@@H]2CC(=[O:46])N2CC=C1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH3:1][O:2]/[N:3]=[C:4](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14](=[O:46])[C@H:9]12)=[O:6]
Reactant: O=C1C[C@H]2SC=CCN12
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1cscn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS(=O)[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product (0.2 g) obtained in Example 3, i.e. a mixture of pivaloyloxymethyl 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate and 2-cephem isomer thereof, was dissolved in chloroform (1 ml). To this solution was added dropwise a solution of m-chloroperbenzoic acid (0.059 g) in chloroform (1 ml). The mixture was stirred for 1.5 hours at room temperature. Precipitated crystals were filtered, washed with chloroform (2 ml), and dried under reduced pressure to give the title compound (0.092 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[C@@H:19]([CH3:21])[CH2:18][C:17]([O:24][CH3:25])([O:22][CH3:23])[C@@H:16]3[OH:26])[CH:13]=[C:12]([O:27][CH3:28])[CH:11]=[CH:10]2)(=O)=O.C(N(CC)CC)C.C(O)=O>O1CCOCC1>[CH3:28][O:27][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[C:15]3[C:20](=[CH:7][N:8]=2)[C@@H:19]([CH3:21])[CH2:18][C:17]([O:22][CH3:23])([O:24][CH3:25])[C@@H:16]3[OH:26])[CH:13]=1
Reactant: COc1ccc2nc(OS(=O)(=O)C(F)(F)F)c3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc2ncc3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Temperature: 23 °C
Yield: 96.9 %

Procedure:
Tetrakistriphenylphosphine palladium (778 mg, 673 mmol, 0.04 equiv) was added to a deoxygenated solution of (7S, 10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-6,10-phenanthridinediol 6-(trifluoromethanesulfonate) (13, 7.60 g, 16.8 mmol, 1 equiv) and triethylamine (9.40 mL, 67.3 mmol, 4.00 equiv) in dioxane (300 mL) at 23° C. The resulting solution was deoxygenated by alternately evacuating the reaction vessel and flushing with argon (5×). Formic acid (1.70 mL, 43.8 mmol, 2.63 equiv) was added slowly over 5 min via syringe and the resulting solution was heated at reflux for 20 min, then was allowed to cool to 23° C. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (300 mL) and ethyl acetate (300 mL). The aqueous layer was separated and further extracted with ethyl acetate (2×300 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (ether initially, grading to 20% ethyl acetate-ether) to provide (7S, 10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-10-phenanthridinol (15) as a white foam (mp 135°-136° C., 4.94 g, 97%).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
To a suspension of 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide (150 mg, 0.37 mmol, 1.00 eq) in 1,4-Dioxane (4.00 mL, 26.67 V) and water (0.50 mL, 3.33 V) was degassed with nitrogen for 15 minutes, then to this 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (101.25 mg, 0.44 mmol, 1.20 eq), cesium carbonate (362.17 mg, 1.10 mmol, 3.00 eq) and [1,1-bis(diphenyl phosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (30.15 mg, 0.04 mmol, 0.10 eq) were added, then the reaction mixture was heated in pressure tube at 100° C. for 5 h. After completion of the reaction by TLC, the reaction mixture was cooled to room temperature, and filtered through celite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to provide the crude compound, which was purified by column chromatography to afford the title compound (90 mg, 0.17 mmol, 47.5%) as a dark brown solid. m/z: 434.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=O)=[CH:6]2.[CH:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](/[CH:12]=[CH:16]/[CH:14]=[O:15])=[CH:6]2
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(/C=C/C=O)cc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 26.3 %

Procedure:
5-Methoxyindole-2-carboxaldehyde (1.5 g, 8.5 mmol) was dissolved in dry toluene (30 ml) and treated with (formylmethylene)triphenylphosphorane (3 g, 9.8 mmol). The reaction mixture was stirred at 85° C. for 5 h, allowed to cool and chromatographed over silica gel using hexane/EtOAc (7:3). Evaporation of the solvent yielded 0.45 g (26 %) of (E)-3-(5-methoxy-2-indolyl)-2-propenaldehyde, m.p.=145-147° C.
Reaction SMILES: [F:1]F.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([F:1])[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)C(=O)Cc1ccc(Cl)cc1
Reactant: FF
Solvent: CC#N
Product: COC(=O)C(=O)C(F)c1ccc(Cl)cc1

Procedure:
In the same manner as in Example 1, methyl 3-(4-chlorophenyl)pyruvate is dissolved in acetonitrile (500 ml) and reacted with fluorine at -10° C. After the same work-up as in Example 1, the resulting crude product is rectified to give syrupy methyl 3-(4-chlorophenyl)-3-fluoropyruvate (7.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[C:4]([O:14][CH3:15])[CH:3]=1.C(OCC)(=[O:18])C>C(O)(=O)C.O.CCCCCC.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[C:4]([O:14][CH3:15])[CH:3]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]2([CH3:12])[CH3:13]
Reactant: CCOC(C)=O
Reactant: COc1cc(Br)cc2c1CCCC2(C)C
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: COc1cc(Br)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A solution of 7-bromo-5-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 63, 5.6 g, 20.81 mmol) in glacial acetic acid (20 mL) was cooled to 0° C. and treated with a solution of chromium trioxide (6.16 g, 61.6 mmol) in acetic acid and water (25 mL). The reaction mixture was then allowed to warm to ambient temperature and stirred for 48 h. It was diluted with water and extracted with diethyl ether (×2). The combined organic phase was washed with water (×3), saturated aqueous sodium bicarbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil. Flash column chromatography over silica gel (230-400 mesh) using 10-20-100% ethyl acetate in hexane as the eluent afforded the title compound (2 g, 33%) as a yellow oil and recovered starting material (2.2 g, 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].CO>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([C:9]3[S:10][C:6]4[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:31]=[CH:30][C:7]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc([N+](=O)[O-])cc4s3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3nc4ccc([N+](=O)[O-])cc4s3)cn2)CC1
Temperature: 70 °C

Procedure:
To tert-butyl 4-[5-(6-nitro-1,3-benzothiazol-2-yl)pyridin-2-yl]piperazine-1-carboxylate (0.29 g) in DCM (15 mL) was added TFA (1.5 mL) before stirring o.n. at r.t. The solvent was thereafter removed by blowing with nitrogen and the residue, crude 6-nitro-2-(6-piperazin-1-ylpyridin-3-yl)-1,3-benzothiazole (MS m/z [M+H] 342.), was used directly in the next step. To this residue in methanol (3 mL), was added formaldehyde (37% aq., 0.25 mL) and sodium cyanoborohydride (74 mg), followed by heating at 70° C. for 5 minutes. A thick solid formed and additional methanol (3 mL) was added. The mixture was stirred at r.t. for 1 h, then filtered. The solid was washed with ice-cold methanol and was then dried under vacuum over P2O5, to give intermediate 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-6-nitro-1,3-benzothiazole trifluoroacetate (0.26 g) as a solid. MS m/z (M+H) 356. This intermediate (0.26 g) was dissolved in methanol (8 mL) and ammonia (7M in methanol, 2 mL) was added. The flask was evacuated and flushed with argon. Palladium (10% on carbon, 30 mg) was added and the flask was evacuated and filled with hydrogen gas. The reaction mixture was shaken under an atmosphere of hydrogen o.n. at r.t. The mixture was thereafter filtered through diatomaceous earth and evaporated in vacuo, to give the title compound (0.22 g) as a white solid. 1H NMR (CHLOROFORM-d) δ 8.67 (d, 1H) 8.05 (dd, 1H) 7.70 (d, 1H) 7.04 (d, 1H) 6.74 (dd, 1H) 6.63 (d, 1H) 3.33-4.01 (m, 6H) 2.42-2.55 (m, 4H) 2.30 (s, 3H); MS m/z (M+H) 326.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:23])[NH:9][C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:12][CH:13]=[N:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].IC.[C:26](=O)(O)[O-].[Na+]>O1CCCC1>[C:3]([O:7][C:8](=[O:23])[N:9]([CH3:26])[C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:12][CH:13]=[N:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C([O-])O
Reactant: Cc1ccccc1-c1ncncc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ncncc1N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (75 mg, 1.87 mmol) was added to a stirring solution of (4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert-butyl ester (410 mmol, 1.44 mmol) in tetrahydrofuran (10 mL) under Argon atmosphere. After 10 min., iodomethane (117 μL, 1.87 mmol) was added. The reaction mixture was stirred for 16 hours and then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by removal of volatiles gave the crude product. Flash chromatography on silica gel (33% ethyl acetate in n-hexane) gave the product as a yellow solid (242 mg, 56%) which was pure enough for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34].[Cl-].[NH4+].[N-:37]=[N+:38]=[N-:39].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]3[NH:39][N:38]=[N:37][N:33]=3)=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]
Reactant: Cc1cc(C#N)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nnn[nH]2)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-cyano-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (47 mg) in N,N-dimethylformamide (1.5 mL) were added ammonium chloride (0.1 g) and sodium azide (0.12 g), and the mixture was stirred at 60° C. for 1 hour, and then stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=3/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (33 mg).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:26])[C:9]([S:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1.CO>[CH:1]1([NH:7][C:8](=[O:26])[C:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)COc1ccc(SC(C)(C)C(=O)NC2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(OCC(=O)O)cc1)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl (4-{[2-(cyclohexylamino)-1,1-dimethyl-2-oxoethyl]thio}phenoxy)acetate (prepared as example 72) was dissolved in THF/MeOH and treated with an aq. LiOH/H2O solution. The reaction mixture was stirred at rt for 16 h. The volatiles were removed in-vacuo and the residual aq. solution was acidified to pH=2 with a 1 N HCl solution. EtOAc was added and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated to provide the desired carboxylic acid as a white solid. LCMS: (M+H)+=352.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:19])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2nc(Cl)ccc2[nH]1
Yield: 59.8 %

Procedure:
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid 11-b (25.20 g, 128.18 mmol) was added to a refluxing mixture of sulfuric acid (20 ml) and methanol (400 ml). The mixture was refluxed overnight. The mixture was then evaporated and a cold NaHCO3 solution was added until basic pH. The precipitate was filtered off and dried, yielding 16.15 g of the desired product (59.8%). m/z=211.17 (M+H)+, Cl pattern.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[CH3:10][C@H:11]1[CH:15]=[CH:14][C@H:13]([CH3:16])[N:12]1[CH2:17][C:18](OC)=[O:19].Cl>C(O)C.C(OCC)(=O)C>[NH2:4][C:3]([NH2:5])=[N:2][C:18](=[O:19])[CH2:17][N:12]1[C@@H:13]([CH3:16])[CH:14]=[CH:15][C@@H:11]1[CH3:10]
Reactant: N=C(N)N
Reactant: COC(=O)CN1[C@@H](C)C=C[C@@H]1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H]1C=C[C@H](C)N1CC(=O)N=C(N)N
Reaction time: 18 h

Procedure:
A solution of guanidine hydrochloride (2.3 g., 0.024 mol) and sodium ethoxide (from 0.55 g, 0.024 mol of sodium) in absolute ethanol (24 cm3) was stirred at room temperature for 1 h. The precipitated sodium chloride was removed by filtration and washed with ethanol (4 cm3). Methyl (trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetate (3.4 g., 0.02 mol) was added to the combined filtrate and washings obtained above and the solution stoppered and stirred for 18 h. The reaction mixture was then evaporated and the residue crystallised from ethanol to give the product (1.25 g.). The base was suspended in ethanol and acidified with ethanolic hydrogen chloride, the clear solution thus obtained was diluted with ethyl acetate and concentrated by evaporation to precipitate the title compound as the dihydrochloride (1.6 g.) m.p. 210°-11° C.(d).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[C:12]([C:15]1[O:19][CH:18]=[N:17][C:16]=1[CH3:20])(=[O:14])[CH3:13].O>C(OCC)C>[CH3:20][C:16]1[N:17]=[CH:18][O:19][C:15]=1[C:12]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)([OH:14])[CH3:13]
Reactant: CC(=O)c1ocnc1C
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ncoc1C(C)(O)c1ccsc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Bromothiophene (4.23 g) in diethylether (10 ml) was added dropwise to n-butyllithium (2.5M solution in hexane, 10.4 ml) in dry diethylether (20 ml) at -70° C. under a nitrogen atmosphere. After 3 hours 5-acetyl-4-methyloxazole (2.5 g) in diethylether (10 ml) was added dropwise. After a further 2.5 hours at -70° C., the mixture was allowed to warm to room temperature and then left overnight. The mixture was poured into water and extracted with ether. The product thus obtained was crystallised from diethylether to give 1-(4-methyl-5-oxazolyl)-1-(3-thienyl)ethanol, m.p. 87°-89° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.II.[OH-].[Na+]>CCOCC.CCCCCC.O>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[N:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc2nccc(Cl)c2c1
Agent: II
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(-c2cc(Cl)c3cc(C)ccc3n2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4.3 g (25 mmol) of p-bromotoluene in 50 ml of ether cooled to 5° was dropwise added 15 ml of a 1.6M solution of butyl lithium in hexane, while maintaining the temperature below 5°. This mixture was stirred at 5° for 10 min and at 30° for 10 min. and then cooled to -20°. A solution of 4.0 g (22 mmol) of 4-chloro-6-methylquinoline, prepared as in Example 25, in 20 ml of ether was added while maintaining the temperature at -20°. It was then allowed to stir at room temperature for 15 min. To the reaction mixture was then added 10 ml of water and 5 g of iodine, and 60 ml of 3N sodium hydroxide. After 20 min of stirring the organic layer was separated. The aqueous phase was extracted with an equal volume of ether. The organic phases were combined, washed with water, dried over sodium sulfate, and concentrated in vacuo to leave the above-named 4-chloroquinoline as a yellow oil. A solution of this oil in methylene chloride was filtered through a plug of alumina. The filtrate was concentrated in vacuo to give 3.22 g of the above-named product, mp 40°-50°.
Reaction SMILES: F[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(OC(N1CCC(OC2C=C3C(=CC=2)C=NC=C3)CC1)=O)(C)(C)C>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:2]2[C:3]([N+:12]([O-:14])=[O:13])=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1c(F)ccc2cnccc12
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2[N+](=O)[O-])CC1

Procedure:
90 mg (0.47 mmol) 6-Fluoro-5-nitro-isoquinoline (152) were treated with 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester following the method described for the preparation of compound 154.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Na+].CC(O)=O>CCO>[CH3:15][N:14]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2ccncc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(C(=O)O)cc2ccncc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
NaH (60% dispersion in mineral oil, 51 mg, 1.26 mmol) was added to a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (200 mg, 1.05 mmol) in anhydrous DMF (10 mL) at 0° C. The mixture was stirred for 1 h, before being treated with MeI (79 μL, 1.26 mmol) and allowed to warm to 20° C. After 16 h, saturated aqueous NH4Cl (10 mL) was added, then the suspension was stirred vigorously for 1 h. The mixture was partitioned between H2O (10 mL) and EtOAc (30 mL), then the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated, then the residue was purified by flash chromatography (IH-EtOAc, 1:1) to provide 1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester: δH (CDCl3): 1.45 (t, 3H), 4.20 (s, 3H), 4.42 (q, 2H), 7.25 (s, 1H), 7.58 (d, 1H), 8.36 (d, 1H), 8.95 (s, 1H). A solution of this ester (36 mg, 180 μmol) in EtOH (3 mL) was treated with 2 M NaOH (270 μL, 540 μmol), then the mixture was stirred at 60° C. for 4 h. On cooling to ambient temperature, the mixture was treated dropwise with dilute AcOH to adjust the pH to 4. The resulting suspension was allowed to stand at ambient temperature for 7 d, then the precipitated solid was collected, washed with H2O, and dried to furnish the title compound: δH(CD3OD): 4.23 (s, 3H), 7.20 (s, 1H), 8.01 (d, 1H), 8.17 (d, 1H), 9.12 (s, 1H).