Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([N:34]([CH3:36])[CH3:35])=C(C#N)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].[CH3:41][C:42]([OH:44])=[O:43].CS(C)=O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([N:34]([CH3:35])[CH3:36])=[C:41]([C:42]([OH:44])=[O:43])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)c1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CN(C)c1c(C(=O)O)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 70 °C

Procedure:
To a suspension of 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (31.8 mg, 0.06 mmol) in EtOH (1 mL) was added NaOH (0.2 mL of a 5M aq. solution, 1 mmol). The reaction was heated at 70° C. for 60 hours and then cooled to room temperature. HOAc (60 μL, 1 mmol) was added followed by DMSO (1.5 mL). After sonication and filtration to remove solids, the filtrate was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (TFA salt). MS ESI calc'd for C26H37ClN6O3 [M+H]+=553. found=553. 1H NMR (600 MHz, DMSO-d6) δ 8.75-8.77 (m, 2H), 8.27 (m, 1H), 3.93 (dd, J=12.0, 1.8 Hz, 1H), 3.75-3.81 (m, 2H), 3.47-3.52 (m, 2H), 3.38 (m, 1H), 3.15 (s, 6H), 3.03 (m, 1H), 2.81 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H), 1.69 (m, 1H), 1.51-1.63 (m, 2H), 1.31-1.41 (m, 2H), 1.13 (m, 1H), 1.05 (m, 1H), 0.83 (m, 1H), 0.64-0.73 (m, 6H), 0.34-0.46 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetic acid are dissolved in 2 ml dichloromethane. 100 μl acetic anhydride are added and the mixture is stirred overnight at ambient temperature. The volatile constituents are eliminated in vacuo and the residue is purified by chromatography on silica gel with dichloromethane/methanol (99:1 to 85:15). The product thus obtained is extracted from diethyl ether/diisopropylether. The solid is suction filtered and dried in vacuo.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH:4]1[N:3]=[CH:1][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=CNCc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccn2cncc2c1
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-Formamidomethylpyridine (39 g., 0.29 mole) was dissolved in 150 ml. of benzene. Phosphorus oxychloride (100 ml.) was added dropwise at such a rate that the reaction began to reflux. By external heating, reflux was maintained for 3.5 hours. After standing approximately 16 hours at room temperature, the reaction was concentrated to an oil. The oil was poured onto approximately 300 g. of ice, the mixture made basic (approximately pH 10) with 10 N sodium hydroxide, and extracted with three 300 ml. portions of methylene chloride. The aqueous was made more basic and extracted with a further three 300 ml. portions of methylene chloride. All of the extracts were combined, back-washed with 75 ml. of water and concentrated to yield crystalline imidazo[3,4-a]pyridine (29 g., Rf 0.25 on thin layer chromatography on silica gel with ethyl acetate/5% acetic acid as eluant).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[F:27][C:28]1[C:36]2[C:35](=O)O[C:33](=O)[C:32]=2[CH:31]=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH2:35][N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[CH2:33]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6cccc(F)c6C5)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 4-fluoro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [OH-].[K+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH:4]1C(OC)=O.O1C2C=CC=CC=2C(=O)C1C(OCC)=O.Cl>O.C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4]1
Reactant: COC(=O)C1Oc2ccccc2C1=O
Agent: CCOC(=O)C1Oc2ccccc2C1=O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1COc2ccccc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution is prepared from 8.2 l of water and 8262 g (125.4 mol) of potassium hydroxide (85% pure), 12.5 l of ethanol are added at 50-60° C. and 9079 g of the water-moist mixture, obtained in the 1st stage described above, of methyl benzofuran-3-one-2-carboxylate and ethyl benzofuran-3-one-2-carboxylate (24.79 mol in total) are then added. The mixture is heated under reflux for 45 minutes and 7.3 l of water are then added. This solution is cooled to 20° C. and introduced into a mixture, heated at 55° C., of 17.5 l of concentrated hydrochloric acid and 20 l water in the course of 60 minutes, vigorous evolution of gas taking place. Residues of the alkaline solution are rinsed out with 3 l of water and also introduced into the hydrochloric acid. The mixture is stirred at 60° C. for a further 30 minutes (end of the evolution of gas) and cooled to 20° C. The product is filtered off with suction, rinsed with 6 l of water and dried at 35° c. in a vacuum drying cabinet. 3250 g (94% of theory) of benzofuran-3-one are obtained. HPLC: logP=1.26.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][C:22]#[N:23].C1C=CC=CC=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[C:22]#[N:23]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: N#CC(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1Cl
Temperature: -5 °C
Reaction time: 10 h

Procedure:
To a solution of 39 parts of potassium hydroxide in 39 parts of pyridine is added a solution of 17 parts of 1-chloro-4-nitrobenzene in 46 parts of pyridine. The whole is cooled to -5° C and there is added dropwise a solution of 22 parts of 2,4-dichlorobenzeneacetonitrile in pyridine, while still cooling at -5° C. Upon completion, stirring is continued for 10 hours at 0° C. After the addition of 90 parts of benzene, the product is precipitated. It is filtered off, washed on the filter with benzene and taken up in water. The aqueous mixture is treated with acetic acid, whereupon the product is separated as an oil. The latter is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of methanol, 2,2' -oxybispropane, petroleumether and trichloromethane, yielding 2,4-dichloro-α-(4-nitrophenyl)benzeneacetonitrile; mp. 81°- 82.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:30]=[CH:29][C:28]([C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:38][CH:37]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
1-(4-Aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (99.6 mg, 0.39 mmol) and 2-(4-benzoylphenoxy)acetic acid (100 mg, 0.39 mmol) were combined in pyridine (10 mL). The mixture was warmed until homogeneous and then allowed to cool. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (82 mg, 0.43 mole) was added. The reaction mixture was maintained at ambient temperature overnight and then concentrated under vacuum. The residue was partitioned between chloroform and saturated potassium carbonate solution. The layers were separated. The aqueous layer was extracted with chloroform. The organic layers were combined, dried over magnesium sulfate and then concentrated under vacuum to provide a gold oil. The oil was purified by column chromatography (silica gel eluting with 10% methanol in dichloromethane) to provide about 70 mg of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-benzoylphenoxy)acetamide as a white solid, m.p. 73-98° C. 1H NMR (500 MHz, DMSO-d6) δ8.22 (t, J=6.0 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.42 (dt, J=8.0, 1.0 Hz, 1H), 7.25 (t, J=8.0, 1.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.58 (broad s, 2H), 4.61 (t, J=7.0 Hz, 2H), 4.56 (s, 2H), 3.18 (q, J=6.0 Hz, 2H), 1.86 (quintet, J=7.0 Hz, 2H), 1.50 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 493.2106 (493.2114 calcd for C29H27N5O3).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:24])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][C:15]([Cl:23])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])=[CH:5][CH:6]=1.C([O-:27])C.O>>[CH2:13]1[CH:12]2[CH:11]([NH:10][C:8]([C@H:7]([NH2:24])[C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[O:9])[C:18](=[O:19])[N:17]2[C:16]([C:20]([OH:22])=[O:21])=[C:15]([Cl:23])[CH2:14]1.[OH2:27]
Reactant: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Reactant: CC[O-]
Solvent: O
Product: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Reaction time: 0.5 h

Procedure:
Loracarbef ethanolate, (4.0 g, 97.1% potency), was slurried in 56 ml of water (containing 0.004 eq sodium, ~0.02 g editate) at 50° C. for 2 hours. Within 30 minutes the slurry became very thick, indicating conversion to monohydrate.
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH2:14][C:15](=O)[CH3:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>C1COCC1.[Pd]>[CH3:16][C:15]1[NH:1][C:4]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CC(C)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cc(C)[nH]c12
Yield: 85.5 %

Procedure:
A mixed solution of methyl 2-nitro-3-(2-oxo-n-propyl)benzoate (0.33 g) and 10% Pd/C (50% wet, 0.33 g) in THF (20 ml) was stirred under H2 atmosphere at room temperature for 2.5 hours. After removal of insoluble materials by filtration, the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give methyl 2-methylindole-7-carboxylate as a pale yellow syrup (0.225 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH3:7].[C:13]([O-])(O)=[O:14].[Na+].[OH-].[Na+]>ClCCl.CN(C=O)C>[CH2:6]([C:8]1[CH:12]=[C:11]([CH:13]=[O:14])[S:10][CH:9]=1)[CH3:7]
Reactant: O=C([O-])O
Reactant: CCc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
31.5 ml of phosphorus oxychloride was added dropwise to 26.0 ml of DMF and stirring carried out for 1 hour. 25.0 g (223 mmol) of 3-ethylthiophene was added dropwise thereto and, after stirring for 1 hour, stirring was conducted at 100° C. for 1 hour. After cooling to room temperature, dilution was carried out with dichloromethane and the mixture poured into saturated bicarbonate of soda solution and neutralization performed with aqueous sodium hydroxide solution. Extraction was then carried out with dichloromethane, followed by drying and concentrating. The residue was distilled and 25.7 g (183 mmol, 0.1 mmHg, 48-49° C). of an approximately 3:1 mixture of 3-ethylthiophenealdehyde and 4-ethylthiophenealdehyde was obtained as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[S:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]=2[N:17]=[N:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24]([C:22]2[CH:21]=[CH:20][C:19]3[S:15][N:16]=[N:17][C:18]=3[CH:23]=2)=[O:25])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc2snnc2c1

Procedure:
50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to benzo-1,2,3-thiadiazole-5-carboxylic acid via Procedure G. The crude product was purified via reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)benzo[d][1,2,3]thiadiazole-5-carboxamide. MS (Q1) 367 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:13][C:14](O)=[O:15].C([Li])CCC.Cl>C(OCC)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:12]2[C:3]3[C:4](=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][CH:2]=3)[C:14](=[O:15])[CH2:13]2)=[CH:22][CH:21]=1
Reactant: O=C(O)CC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1CC(c2ccc(F)cc2)c2ccc(C(F)(F)F)cc21
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a solution of 40 grams of 3-(2-bromo-4-trifluoromethylphenyl)-3-(4'-fluorophenyl)-propanoic acid in 750 milliliters of dry diethylether were added dropwise 90 milliliters of butyllithium (20% in hexane). The temperature was kept between -2 and -5 degrees Centigrade, and the addition time was about 10 minutes. The reaction mixture was stirred at zero degrees Centigrade for 11/2 hours; and then 400 milliliters of 2 N hydrochloric acid were added. The orgranic phase was separated and extracted twice with a 10% solution of sodium carbonate in water, then washed with water and dried over anhydrous potassium carbonate. After filtration and evaporation there was obtained 23 grams of crude 3-(4'-fluorophenyl)-6-trifluoromethyl-1-indanone. The oil was distilled in vacuo, and there was obtained 17 grams (57%) of pure 3-(4'-fluorophenyl)-6-trifluoromethyl-1-indanone boiling at 140 degrees Centigrade /0.2 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17]CC1C=CC=CC=1)[CH:10]=2)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CCOC(C)=O.CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2cc(O)ccc2c1O

Procedure:
1-Cyano-4,7-dihydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared by heating a mixture of 175 mg (0.50 mmol) of 7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (example 52h), 630 mg (10 mmol) of ammonium formate, and 40 mg of 10% Pd/C in 3 mL of 1:1 EtOAc and EtOH at reflux temperature for 40 min. The resultant mixture was cooled, filtered through a celite pad to remove solids, and concentrated to a crude solid. The solid was triturated with hot ethanol to give 56 mg of off-white solid upon drying; MS (ESI+): 259.3 e/z (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([C:20]([CH2:27][CH3:28])([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:21](=[O:22])[C:20]([CH2:27][CH3:28])([CH2:18][CH3:19])[C:24](=[O:25])[O:9]2)=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)NO)cc1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(C)cc2)C1=O
Yield: 34.1 %

Procedure:
A mixture consisting of 1.51 g (0.0100 mol) of 4-methylbenzohydroxamic acid, mp 148-150° C. (dec.) (lit. mp 148° C. dec. , Beilstein Handbook of Organic Chemistry, series H, vol 9, p. 491), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 1.977 g (0.0100 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 2 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 mL portions of water, three times with 50 mL portions of 5% hydrochloric acid, and two times with 50 mL portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 0.94 g (34.2%) of crude 2-(4-methylbenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from methanol gave pure 2-(4-methylbenzoly)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 92-93° C.; IR (Nujol) 1805 (s,C=0), 1747 (s, C=0) 1695 cm-1 (s, C=0);H1NMR (400 MHz, CDCl3) δ7.70 (d,2H), 7.29 (d,2H), 2.43 (s,3H), 1.95 (q. 4H), 1.00 (t, 6H); High resolution MS, calc'd for: C15H17NO4 : 275.1157. Found: 275.1163. Anal. Calc'd for: C15H17NO4 : C, 65.44; H, 6.23; N 5 09. Found: C, 65.24; H, 6.45; N, 5.28.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.13 g, 0.33 mmol) was added to a solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-bis-(2-hydroxyethyl)acetamide 26 (0.09 g, 0.3 mmol), triethylamine (0.12 mL), and ethanol (1.7 mL). The reaction mixture was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The residue was triturated with water and then purified by flash chromatography (silica gel, 20–10:1:0–0.2 CH2Cl2/methanol/concentrated ammonium hydroxide, v/v) to provide 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide 27 (0.1 g, 64%) as a yellow solid. mp 114–116° C. 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.60 (m, 2H), 3.32 (m, 2H), 3.50 (m, 4H), 3.70 (m, 4H), 4.81 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H). m/z (ESI): 523 [C22H31ClN8O5+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:10])[CH3:9].[Br:11]Br.C(OC)(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[Br:11][C:5]1[S:4][C:3]([CH2:7][CH:8]([NH2:10])[CH3:9])=[C:2]([Cl:1])[CH:6]=1
Reactant: BrBr
Reactant: CC(N)Cc1sccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(N)Cc1sc(Br)cc1Cl
Temperature: 15 °C

Procedure:
In a sulfonation flask 5 g (0.028 mol) 2-(3-chlorothiphen-2-yl)-1-methylethylamine is dissolved in 70 ml of acetic acid. The mixture is then cooled to 15° C. and 4.8 g (0.30 m) of bromine is added under stirring (internal temperature 15-17° C.). After warming up to rt, the mixture is stirred for 16 hours. Then the mixture is poured to a mixture of tert. butylmethylether (ca. 250 ml) and 2N sodiumhydroxide. The final pH is 11. After washing with brine, drying with sodium sulphate and evaporation of the solvent the crude material is obtained. Purification is achieved by column chromatography over silicagel (eluent: tert. butylmethylether/EtOH 10:1). Yield: 5.4 g (75% of theory) of a colourless oil (1H-NMR: 1.18/d/3H, 2.68-2.87/m (diasterotopic protons)/2H, 3.2/m/1H, 6.87/s/1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:29]([F:40])[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:33][C:32]1[C:27]([NH:26][C:12]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[O:14])=[CH:28][C:29]([F:40])=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Cn1cc(C(=O)O)c2ccc(F)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3cc(F)ccc23)cc1F
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a suspension of 6-fluoro-1-methylindole-3-carboxylic acid (500 mg, 2.59 mmol) and DMF (0.02 ml, 0.26 mmol) in methylene chloride (15 ml) was added dropwise oxalyl chloride (0.25 ml, 2.85 mmol) under stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (10.0 ml), followed by the dropwise addition to a solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (600 mg, 2.59 mmol) and triethylamine (1.08 ml, 7.77 mmol) in methylene chloride (5.0 ml). After completion of the dropwise addition, the reaction mixture was heated under reflux for 10 hours. After the reaction mixture was cooled to room temperature, the precipitated crystals were removed under reduced pressure. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane:ethyl acetate (2:1, v/v) eluate fractions, ethyl (5-chloro-2-fluoro-4-((6-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (665 mg, 63%) was obtained as a yellow solid.