Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][C:6]([OH:19])([CH3:18])[CH2:5]1)=[N+:2]=[N-:3].Cl[C:21]1[N:25](C)[N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].[F-].[K+].O>C(Cl)Cl.FC(F)(F)C(O)=O.CS(C)=O>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:24]([CH3:23])[N:25]=[CH:21][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:7][C:6]([CH3:18])([OH:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC1(O)CC(N=[N+]=[N-])CCN(C(=O)OC(C)(C)C)C1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(C)(O)C1
Temperature: 70 °C

Procedure:
A solution of tert-butyl 5-azido-3-hydroxy-3-methylazepane-1-carboxylate (0.8 g, 3 mmol) in DCM (15 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 1.5 hr and then concentrated under reduced pressure. The residue was dissolved in the minimum volume of DCM, loaded onto an SCX column, washed with DCM and MeOH and eluted with 1 N ammonia in MeOH. The solvent was removed under reduced pressure. To a solution of the residue in anhydrous DMSO (10 mL) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (574 mg, 3.56 mmol) and potassium fluoride (675 mg, 12.7 mmol). The mixture was heated at 70° C. for 16 hr under nitrogen, then cooled and poured into water (300 mL). The mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with water (100 mL) and brine (50 mL), separated, dried over MgSO4 and concentrated to give a brown gum. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-azido-3-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol as a mixture of four diastereoisomers (0.38 g, 47% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 4.12-3.90 (m, 1H), 3.85 and 3.74 (2s, 3H), 3.60-3.40 (m, 1H), 3.40-3.30 (m, 1H), 3.25-3.10 (m, 1H), 3.00-2.60 (m, 2H), 2.30-2.10 (m, 2H), 2.00-1.70 (m, 2H), 1.35-1.15 (m, 3H). LCMS (ES+) m/z 296 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH3:13].[CH:14]([B-](F)(F)F)=[CH2:15].[K+]>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH:14]=[CH2:15])[CH3:13]
Reactant: C=C[B-](F)(F)F
Reactant: CCc1c(Br)ccc2c1COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc2c(c1CC)COC2=O

Procedure:
A mixture of 5-bromo-4-ethyl-2-benzofuran-1(3H)-one (1.81 g, 7.51 mmol), potassium vinyltrifluoroborate (1.21 g, 9.01 mmol) and Pd(dppf)Cl2 (200 mg) in 20 mL of TEA and 20 mL of EtOH was heated to reflux under N2 overnight and then concentrated. The resulting oil was purified by column chromatography to give 4-ethyl-5-vinyl-2-benzofuran-1(3H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:24]=[O:25]>C1COCC1.[Cl-].[NH4+]>[CH2:13]([N:12]([CH2:15][CH3:16])[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCN(CC)c1ccnc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of (6-bromo-quinolin-4-yl)-diethylamine (0.510 g, 1.59 mmol) in THF (10 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (0.765 mL, 1.92 mmol, 1.2 equiv.) at −70° C. During the addition, the color of the solution was turned into red and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.246 mL, 3.19 mmol) in THF (1 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.205 g (48% yield) of 4-(diethylamino)-quinoline-6-carbaldehyde as a white solid: EI-LRMS m/e calcd for C14H16N2O (M+) 229.1, found 229.1.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:13][O:14][C:15]([CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[O:16].O>N1C=CC=CC=1.N1CCCCC1>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][C:15]([O:14][CH3:13])=[O:16])[CH:20]=1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Reactant: COC(=O)COc1cccc(C=O)c1
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)[nH]c2=O)c1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
In a mixture of 9 ml of pyridine and 150 μl of piperidine were dissolved 0.75 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone and 0.75 g of 3-[(methoxycarbonyl)methoxy]benzaldehyde, and the solution was heated under reflux for 4 hours. After cooled to room temperature, 20 ml of water was added, precipitated crystals were filtered, washed with water, washed with tetrahydrofuran, and dried to obtain 0.42 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (7a)] as a yellow crystal.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[CH2:16][C:17]([O:19]C)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:16][C:17]([OH:19])=[O:18])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCl
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1.16 g of 5-acetylsalicylic acid, methyl ester in 10 mL of N,N-dimethylformamide is added 1 g of chloroacetic acid, methyl ester and 1.2 g of potassium carbonate. After stirring this mixture at ambient temperature for 16 hours the reaction is filtered, diluted with ethyl acetate, and washed once with water and twice with brine. The ethyl acetate is dried with magnesium sulfate, filtered, and evaporated to give 5-acetyl-2-(carboxymethoxy)benzoic acid as a crude product. Crystallization from methanol at -15° C. gives 0.6 g of white crystals. 1H-NMR (CDCl3): 8.5 ppm (1H, d), 8.1 ppm (1H, dd), 6.9 ppm (1H, d), 4.8 ppm (2H, s), 4.0 ppm (3H, s), 3.8 ppm (3H, s), 2.6 ppm (3H, s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[N+:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[C-:11].CCOCC>COCCOCCOC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]1[N:6]=[CH:11][NH:10][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: CCOC(C#N)OCC
Reactant: [C-]#[N+]CC(=O)OC
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(OCC)c1nc[nH]c1C(=O)OC
Temperature: 75 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a stirred suspension of 30-35% KH (7.90 g) in 40 mL anhydrous diglyme at −20° C. was added a solution of diethoxyacetonitrile (Intermediate 1A, 6.20 g, 46.6 mmol) and methyl isocyanoacetate (4.96 g, 65.2 mmol) in 25 mL of anhydrous diglyme. The resulting mixture was heated to 70-80° C. and stirred overnight. The mixture was cooled to room temperature and quenched with saturated NH4Cl solution. DCM was added and the layers were separated. The mixture was further extracted with DCM. The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give brown oil. Cold ether was added to the residue and the resulting white precipitate was filtered, washed with cold ether and dried to give the desired product Intermediate 1B (5.65 g, 53%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](S(C)(=O)=O)=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.[CH2:40]([O:42][C:43]1[CH:44]=[C:45]([OH:49])[CH:46]=[CH:47][CH:48]=1)[CH3:41].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH2:40][CH3:41])[CH:44]=3)=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1
Reactant: CCOc1cccc(O)c1
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Oc2nc3c(C#N)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n(Cc4ccccc4Cl)c3c(=O)n2C)c1

Procedure:
A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate (110 mg), 3-ethoxyphenol (31 μl) and potassium carbonate (39 mg) in N,N-dimethylformamide (2 ml) was stirred at 50° C. for 1 hour. After the reaction solution was allowed to cool, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (86 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 1.5 g of ethyl 3-aminopropionate monohydrochloride and 1.7 g of 2-{(tert-butoxycarbonyl)amino}acetic acid in 50 ml of chloroform, 1.6 g of 1-hydroxybenzotriazole monohydrate, 2.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 1.4 ml of triethylamine were added at room temperature by the order stated, and stirred for 2 hours at the same temperature. The reaction liquid was diluted with chloroform, and washed successively with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated saline solution, by the order stated, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/4) to provide 2.0 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]2[N:7]([N:17]=[CH:18][C:19]=2[C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:10]=1.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>O1CCCC1>[CH3:3][O:4][C:5]1[C:6]2[N:7]([N:17]=[CH:18][C:19]=2[C:20]2[CH:21]=[N:22][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:24]=2)[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:10]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(-c3cn[nH]c3)c12
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)cn2ncc(-c3cnn(Cc4ccccn4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 0.004 g, 0.1 mmol) in tetrahydrofuran (2.0 mL) was added a solution of 4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-(1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine (15 mg, 0.05 mmol) in tetrahydrofuran (1.0 mL) at 0° C. The resultant slurry was then stirred at ambient temperature for 15 min followed by the addition of 2-(chloromethyl)pyridine (0.007 g, 0.055 mmol) in tetrahydrofuran (1.0 mL). The reaction mixture was heated to 60° C. After 8 hours, the reaction mixture was cooled and quenched with ice water and the organic components were extracted with ethyl acetate (2×10 mL) and the combined organic layers were concentrated. The crude material was purified by flash column chromatography (methanol/dichloromethane gradient) to afford 4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-(1-pyridin-2-ylmethyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine. 1H NMR (400 MHz, CD3OD) δ 8.56 (bs, 2H), 8.34 (s, 1H), 8.07-8.02 (m, 2H), 7.91 (s, 1H), 7.86-7.83 (m, 2H), 7.38 (bs, 1H), 7.17 (bs, 1H), 6.79 (s, 1H), 5.51 (s, 2H), 4.01 (s, 3H), 3.96 (s, 3H). LRMS (ESI) calculated for C21H19N7O [M+H]+, 386.2; found 386.5. The compounds in the following table were prepared according to the procedure described in scheme 6 and for compounds 6-1 to 6-4. The compounds were prepared as free bases.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9](=[S:18])[NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[H-].[K+].Br[CH:22](Br)[CH3:23].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]2[C:9]([S:18][CH2:22][CH2:23]2)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CC(Br)Br
Reactant: S=c1[nH]c(-c2ccccn2)c(-c2ccccn2)[nH]1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3n(c2-c2ccccn2)CCS3)nc1
Reaction time: 2 h

Procedure:
A mixture of 16.57 g (0.065 m) of 4,5-di(2-pyridyl)-1H-imidazole-2-thione in 150 ml of dimethylformamide was stirred at -15° (ice-methanol-dry ice) under nitrogen and 27 ml (6.2 g, 0.15 m) of a 24% suspension of potassium hydride in mineral oil was added gradually. After about 2 hours, a solution of 11.8 g (5.42 ml, 0.0634 m) of dibromoethane in 60 ml of dimethylformamide was added dropwise. The reaction mixture was allowed to attain room temperature overnight. The mixture was poured into 600 ml of water. The aqueous mixture was extracted with 3×200 ml portions of methylenechloride. The combined extracts were washed with 5×100 ml water, brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated under 25 ml of low boiling petroleum ether. The product was separated, dissolved in 50 ml of ethanol. The solution was chilled until crystallization was complete, filtered, and the product was washed with a small portion of cold ethanol and air dried. Yield 9.1 g, m.p. 140°-142°. Crystallization three times from ethanol gave an analytical sample of 5,6-di-(2-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 142°-143°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]3([CH2:15][CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12][CH2:11]3)[CH2:9][N:8]([CH3:26])[C:7]=12>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][N:8]([CH3:26])[C:7]=12
Reactant: CN1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2cccc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Product: CN1CC2(CCNCC2)c2cccc(Cl)c21
Yield: 104.2 %

Procedure:
A solution of benzyl 7-chloro-1-methyl-spiro[indoline-3,4′-piperidine]-1′-carboxylate (1.1 g, 2.96 mmol) in trifluoroacetic acid (10 mL) is refluxed for 3 hours. The reaction mixture is concentrated, the pH of the residue is adjusted with 10% NaHCO3 (20 mL) to basic and extracted with EtOAc (3×20 mL). The combined extracts are washed with 10% NaHCO3 (20 mL), water (20 mL), and brine solution (20 mL), dried with a drying agent, filtered, and evaporated to dryness to give the title compound as a brown liquid (0.73 g, 103.9% crude). ESI/MS m/z 237.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.NO.N1C=CC=CC=1>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([NH2:15])[C:3]=1[NH2:18]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask was charged with 1 (680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), pyridine (0.25 mL, 3.0 mmol) and ethanol (10 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 289.2 (MH+), tR=2.06 min.
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][O:8][C:9]1[C:10]2[O:22][CH2:21][O:20][C:11]=2[CH:12]=[C:13]2[C:18]=1[CH:17]=[N+:16]([CH3:19])[CH:15]=[CH:14]2.B.[Na].C(Cl)Cl.Cl>O>[CH3:7][O:8][C:9]1[C:10]2[O:22][CH2:21][O:20][C:11]=2[CH:12]=[C:13]2[C:18]=1[CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2
Reactant: COc1c2c(cc3cc[n+](C)cc13)OCO2
Agent: B
Agent: COS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1c2c(cc3c1OCO3)CCN(C)C2
Reaction time: 2 h
Yield: 79 %

Procedure:
8-Methoxy-2-methyl-6,7-methylenedioxyisoquinolinium methyl sulfate (6) in an amount of 1.47 g (4.47 mmol) was dissolved in 20 ml of water, to which 0.34 g (9 mmol) of sodium boron hydride was portionwise added under cooling with water. After stirring the mixture for two hours, 10 ml of methylene chloride was added and the solution was rendered acidic with concentrated hydrochloric acid. The solution was separated and the methylene chloride layer was extracted with 2N hydrochloric acid. The aqueous layers were combined and rendered basic with 25% aqueous solution of sodium hydroxide. This was extracted with 15 ml and then 10 ml of methylene chloride successively, washed with 10 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 780 mg of 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (7) (hydrocotarnine) with a yield of 79%.
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.[CH3:15][O:16][CH2:17][CH2:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:18][CH2:17][O:16][CH3:15])(=[O:21])=[O:20])=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COCCS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: COCCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
A mixture of 500 mg of methyl 4-mercaptobenzoate, 1.6 g of potassium carbonate, 1.2 g of 2-bromoethylmethylether and 329 mg of tetrabutylammonium iodide in 10 mL of acetone was refluxed for 16 h. The reaction mixture was diluted with ethyl acetate, washed with H2O and concentrated. Purified by silica gel chromatography (0-50% ethyl acetate/hexane) to yield 4-(2-methoxyethylthio)benzoate. 240 mg of 4-(2-methoxyethylthio)benzoate was reacted via Procedure R to give 4-(2-methoxyethylsulfonyl)benzoate. 120 mg of 4-(2-methoxyethylsulfonyl)benzoate was hydrolyzed via Procedure M to yield 4-(2-methoxyethylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-methoxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-methoxyethylsulfonyl)benzamide. MS (Q1) 431.0 (M)+.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:37])[NH2:36])[CH:31]=2)[CH:26]=1)=[O:23])=O)C1C=CC=CC=1.CS(O)(=O)=O.[H][H]>[C].[Pd].CN(C)C=O>[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:36])[NH2:37])[CH:31]=2)[CH:26]=1)=[O:23]
Reactant: [H][H]
Reactant: N=C(N)c1ccc2cc(OC(=O)CCCCCNC(=O)OCc3ccccc3)ccc2c1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)CCCCCN)ccc2c1
Yield: 36.6 %

Procedure:
To 40 ml of anhydrous dimethylformamide, were added 4.2 g of 6-amidino-2-naphthyl ε-benzyloxycarbonylaminocaproate methanesulfonate, 1.0 g of methanesulfonic acid, and 0.2 g of 10% palladium-carbon. Hydrogen was passed for 4 hours through the vigorously stirred mixture. After removing the palladium-carbon by filtration, the filtrate was poured into stirred ethyl ether. An oily substance which separated out was washed with ethyl ether and recrystallized from ethanol to obtain 0.87 g of white crystals of 6-amidino-2-naphthyl ε-aminocaproate dimethanesulfonate.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[S:31]1[C:35]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1>>[S:31]1[C:35]2[CH:36]=[C:37]([S:40]([N:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]3)(=[O:41])=[O:42])[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3ncsc3c2)c1
Yield: 85.4 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (135 mg), sodium hydride (60% in oil, 38.3 mg), 15-crown-5 (0.18 mL) and 6-benzothiazolesulfonyl chloride (206 mg), a procedure as in Reference Example 219 was performed to give the title compound as white crystal (yield 248 mg, 85%).
Reaction SMILES: [CH2:1]([C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])[CH:17]=[CH:18][CH:19]=2)[N:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([N:8]4[CH2:7][CH2:6][C:5]([OH:11])([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]4)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CC(C)CC1(O)CCNCC1
Reactant: Nc1ccc2cccc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4ccc(N)nc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-isobutylpiperidin-4-ol (70 mg, 0.44 mmol), 4-(2-aminoquinoline-8-sulfonamido)benzoic acid (100 mg, 0.44 mmol), and HBTU (134 mg, 0.53 mmol) in DCM (5 mL) was added DIPEA (1 mL) dropwise at room temperature, and then the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated, purified by a standard method to yield the title compound. 1H NMR (CHLOROFORM-d) δ: 8.10-8.20 (m, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.69-7.82 (m, 1H), 7.06-7.26 (m, 5H), 6.80 (d, J=9.1 Hz, 1H), 5.41 (s, 2H), 4.33 (br. s., 1H), 3.41-3.19 (m., 3H), 1.82 (dt, J=12.9, 6.4 Hz, 1H), 1.63-1.46 (m, 4H), 1.40 (d, J=5.9 Hz, 2H), 0.97 (d, J=6.7 Hz, 6H). LCMS (m/z): 483.7 (M+1)+