Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[NH2:7])[CH3:2].C([O-])(O)=O.[Na+].[N+]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](Cl)(=[O:36])=[O:35])([O-])=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[NH:7][S:34]([C:26]1[CH:25]=[CH:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][CH:27]=1)(=[O:35])=[O:36])[CH3:2]
Reactant: CCOC(=O)C[C@H](N)c1ccc(OC)nc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Reaction time: 12 h

Procedure:
A solution of aminoester 16-5 (3.0 g, 13.0 mmol) in CH2Cl2 (20 mL) was treated with aq NaHCO3 (4.4 g in 20 mL H2O). 2,4-Dinitrobenzenesulfonyl chloride (4.3 g, 16 mmol) was added and the reaction mixture stirred for 12 h. The solution was extracted with CH2Cl2 (3×40 mL) and the combined organic solutions washed with satd aq NaHCO3 (40 mL) and brine (40 mL). The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (97:3 CH2Cl2/MeOH) to give the desired product 16-6.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:17]=1N)=[O:12])[CH3:9].[ClH:26]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:17]=1[Cl:26])=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(CCOCCOC)c1N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(CCOCCOC)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of t-butyl nitrite (8.5 mL, 64.5 mmol), anhydrous cuprous chloride (6.54 g, 66.1 mmol) and anhydrous acetonitrile (80 mL) was added 5-amino-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (10.38 g, 40.3 mmol) over 10 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 h, then at 70° C. for 2 h. The mixture was then cooled to room temperature and poured carefully into 6.0 N aqueous HCl (45 mL). The aqueous phase was extracted with methylene chloride (3×150 mL). The combined organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide the crude material as an oil. The product was purified by column chromatography on silica gel (eluting with ethyl acetate/hexanes, using a gradient of 1:3 to 1:0) to provide 5-chloro-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid ethyl ester as a light yellow oil (3.43 g, 30%). Mass spectrum: m/z: 277.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O1CCCC1>[Pd].C(OCC)(=O)C>[C:14]([CH2:13][C:7]1[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:4]([NH:1][C:16](=[O:18])[CH3:17])=[CH:5][CH:6]=1)#[N:15]
Reactant: N#CCc1ccc([N+](=O)[O-])c2ccoc12
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(CC#N)c2occc12
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
Add (4-nitrobenzofur-7-yl)acetonitrile (600 mg, 2.96 mmol), acetic anhydride (600 mg, 5.88 mmol), and 5% palladium on carbon (300 mg) to tetrahydrofuran (25 mL). Stir under hydrogen (1 atm) for 45 minutes. Dilute with ethyl acetate, filter through a pad of Celite®, and concentrate under reduced pressure. Chromatograph on flash silica using 75% ethyl acetate, 25% hexane gives 430 mg (67%) of the title compound as an off-white solid. HRMS (M+H)=215.0816.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[NH2:17][CH2:18][C:19]([N:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:22])=[O:20].ClC1C(C)=C(C)N=C(C2C=CC=CC=2)N=1.NCC(N(CCC)CCC)=O>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][C:2]2[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:3]=2)=[CH:28][CH:27]=1
Reactant: CCc1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CN(C(=O)CN)c1ccc(Cl)cc1
Agent: CCCN(CCC)C(=O)CN
Agent: Cc1nc(-c2ccccc2)nc(Cl)c1C
Product: CCc1c(C)nc(-c2ccccc2)nc1NCC(=O)N(C)c1ccc(Cl)cc1

Procedure:
The same procedures as Example 1 are repeated except that 4-chloro-5-ethyl-6-methyl-2-phenylpyrimidine and 2-amino-N-(4-chlorophenyl)-N-methylacetamide are used instead of 4-chloro-5,6-dimethyl-2-phenylpyrimidine and 2-amino-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from isopropanol to give the desired compound, m.p. 142-143° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7]1.[N+:24]([C:27]1[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33](Cl)=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N+:24]([C:27]1[CH:28]=[CH:29][C:30](/[CH:31]=[CH:32]/[C:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=3)[CH2:7]2)=[O:34])=[CH:36][CH:37]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
A mixture of 2-(4-aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (400 mg, 1.14 mmol), trans-4-nitrocinnamoyl chloride (240 mg, 1.14 mmol) and triethylamine (0.2 ml, 1.37 mmol) in dichloromethane (6 ml) was shaken at room temperature for 18 h. Saturated aqueous potassium carbonate (5 ml) was added and shaking resumed for 15 mins. The organic layer was chromatographed on silica using 10-100% ethyl acetate-hexane gradient elution to afford the title compound as a yellow gum (490 mg, 82%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:37])[CH2:12][NH:13][C@H:14]([CH3:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(=O)OCC2C=CC=CC=2)[CH:7]=[CH:8][C:9]=1[OH:10])=[O:2].[H][H]>CO.[Pd]>[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:13][CH2:12][C@@H:11]([C:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH:3][CH:1]=[O:2])[CH:5]=1)[OH:37])[CH3:36]
Reactant: C[C@H](CCCCCCCCCCNC(=O)OCc1ccccc1)NCC(O)c1ccc(O)c(NC=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(CCCCCCCCCCN)NC[C@H](O)c1ccc(O)c(NC=O)c1
Yield: 100.4 %

Procedure:
A mixture of compound 23 (0.54 g, 1.05 mmol) dissolved in methanol (30 mL) and palladium catalyst (0.15 g, 10% Pd on carbon, 50% we) was stirred overnight at room temperature under one atmospheric hydrogen pressure. The catalyst was removed by filtration and washed with methanol (3×10 mL). The filtrate and washings were combined and concentrated under vacuum to complete dryness, affording the desired product 24 (0.40 g, 91% yield) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 1.31 (m, 15H), 1.48-1.58 (m, 4H), 1.75 (m, 2H), 260-2.80 (m, 5H), 4.66 (m, 1H), 5.09 (s, 2H), 6.82 (d, 1H), 7.00 (d, 1H), 8.02 (s, 1H), 8.30 (s, 1H); m/z (ESI) 380 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1)(C(OC)=O)C(OC)=O)#[N:2].[Li+].[OH-]>CO.O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCCc1ccc([N+](=O)[O-])cn1
Yield: 92.9 %

Procedure:
To a solution of compound 76 (3.3 g, 10.7 mmol) in CH3OH (100 mL) was added a solution of LiOH (15.4 g, 64.2 mmol) in H2O (100 mL) at room temperature with stirring. The mixture was stirred at room temperature for 2 h. Methanol was removed in vacuo and the residual aqueous solution was washed with EtOAc (two times), then was acidified to pH=2 with 1N HCl. The aqueous phase was extracted with EtOAc. The combined organic extract was dried over Na2SO4, then was stirred at 50° C. for overnight. The solution was concentrated to afford compound 77 (1.9 g, 95%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH:27]([CH3:31])[CH2:26]2)=O)[C:17]2[O:21][CH:20]=[CH:19][C:18]=2[CH:22]=1)(=[O:13])=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].[ClH:38]>C1COCC1>[ClH:38].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH2:23][N:25]2[CH2:30][CH2:29][NH:28][CH:27]([CH3:31])[CH2:26]2)[C:17]2[O:21][CH:20]=[CH:19][C:18]=2[CH:22]=1)(=[O:12])=[O:13]
Reactant: COc1ccc(C)cc1NS(=O)(=O)c1cc(C(=O)N2CCNC(C)C2)c2occc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(C)cc1NS(=O)(=O)c1cc(CN2CCNC(C)C2)c2occc2c1
Reaction time: 1 h

Procedure:
To the obtained 7-(3-methyl-piperazin-1-carbonyl)-benzofuran-5-sulfonic acid (2-methoxy-5-methyl-phenyl)-amide (30 mg, 0.07 mmol; Step 1) was added LiAlH4 (9.0 mg, 0.24 mmol) in dry THF (4 mL) and the mixture was warmed to reflux. After 1 h, HPLC analysis showed 15% product and the remaining impurities. Added mixture to 2 M HCl, concentrated and purified by preparative HPLC (Gilson; gradient of 30-70% MeCN). The pure fractions were stripped, HCl/ether added and concentrated to give the title compound as a colourless solid. Yield: 1.3 mg (5%). HPLC 90% RT=1.17 min (System A; 30-80% MeCN over 3 min), 1.13 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (d, J=7.0 Hz, 2H) 2.21 (s, 3H) 2.72 (m, 1H) 2.86 (m, 1H) 3.38 (s, 4H) 3.43-3.64 (m, 4H) 4.30 (d, J=6.59 Hz, 2H) 6.62 (d, J=8.30 Hz, 1H) 6.81-6.88 (m, 1H) 6.99 (d, J=2.44 Hz, 1H) 7.25 (d, J=1.95 Hz, 1H) 7.76 (br s, 1H) 7.94 (d, J=2.20 Hz, 1H) 8.08 (d, J=1.71 Hz, 1H). MS (ESI) for C22H27N3O4S m/z 430 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1[N:36]([C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[F:33])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1F
Reactant: O=C(COCc1ccccc1)NNC(=O)c1ccc(-c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-n1c(COCc2ccccc2)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To biphenyl-4-carboxylic acid N′-(2-benzyloxyacetyl)hydrazide (9.38 g) was added phosphorus oxychloride (30 ml), and stirred at 100° C. for one hour. After the reaction solution was cooled to ambient temperature, the reaction solution was concentrated under reduced pressure. To the resulting residue was added ethyl acetate, and the separated organic layer was washed with aqueous 1 mol/liter sodium hydroxide solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford an oily product. Subsequently, 2-fluoroaniline (5 ml) and p-toluenesulfonic acid·monohydrate (200 mg) were added to the resulting oily product, and stirred at 140° C. for 4 hours. After the reaction solution was cooled to ambient temperature, ethyl acetate was added to the reaction solution. The separated organic layer was washed with aqueous 1 mol/liter sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=3/1–1/1), to afford the entitled compound 3-benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole as pale yellow solid (6.60 g, 58%). The physico-chemical values are as follows.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[F:30])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]([C:17]2[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=2)=[C:22]([F:30])[CH:23]=1
Reactant: COc1cc(C(N)C(N)=O)c(F)cc1Cl
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 17.2 g of sodium carbonate and 61 ml of water was added dropwise 10.9 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 84 ml of water and then 7.10 g of 2-amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 9.2 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 3.61 g (yield, 37%) of the desired compound, 3-(4-chloro-2-fluoro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1008).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.O1CCCC1.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O>[Br:7][C:5]1[S:4][C:3]([C:8]([NH2:10])=[O:9])=[C:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:6]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)c1sc(Br)cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)c1sc(Br)cc1NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added cyclohexanecarbonyl chloride (0.18 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide. To 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (0.90 mL) and ethanol (2.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL)) was added, and the precipitate was collected by filtration to give the title compound (252 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cccc(Oc2cncc(Cl)n2)c1
Yield: 85 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 3-chlorophenol (193 μL, 1.86 mmol, d=1.24 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (346 mg). Yield: 85%. 1H NMR (250 MHz, DMSO-d6) δ 7.32 (dd, 1H, Harom 4, Jo=8.2 Hz, Jm=1.9 Hz), 7.43 (d, 1H, Harom 6, J=8.0 Hz), 7.50 (d, 1H, Harom 2, Jm=1.9 Hz), 7.56 (t, 1H, Harom 5, J=8.1 Hz), 8.59 (s, 1H, HPz 5), 8.62 (s, 1H, HPz 3). m/z: 241.1 [(M+H)+, calcd for C10H6Cl2N2O 240.0].
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH:34]=O)=[CH:4]1)[CH3:2].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([CH2:34][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C=O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCn1cc(CN2CCCC2)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (10 g, 21.12 mmol) in Dichloromethane (DCM) (150 mL) was added pyrrolidine (2.61 mL, 31.7 mmol), sodium triacetoxyborohydride (8.95 g, 42.2 mmol) and AcOH (0.060 mL, 1.056 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS showed completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF), using a 120 g column and eluting with MeOH/DCM (0-20%). The product was further purified with reverse phase automatic silica column chromatography (Combiflash RF), using a 150 g golden column and eluting with acetonitrile/water (0-60%) to afford 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (4.6 g, 8.70 mmol, 41.2% yield) as a pale yellow solid. LCMS: (M+H)+: 529.4.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC(OC)=O.C(N(CC)CC)C.[NH2:26][C:27]([CH3:34])([CH:31]([CH3:33])[CH3:32])[C:28]([NH2:30])=[O:29]>O1CCCC1.O>[C:28]([C:27]([NH:26][C:1](=[O:13])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:34])[CH:31]([CH3:33])[CH3:32])(=[O:29])[NH2:30]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)C(C)(N)C(N)=O
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of quinaldic acid (20 g, 0.116 mol) in tetrahydrofuran (500 ml) cooled to -9° C. is added methyl chloroformate (8.92 ml, 0.116 mol) followed by triethylamine (18.4 ml, 0.139 mol). After 20 minutes 2-amino-2,3-dimethylbutyramide (15.1 g, 0.116 mol) is added and the mixture stirred overnight at room temperature. Water is added and the solution is reduced to 200 ml of a rotorvap. A white solid separates and is filtered off, water washed and dried. Recrystallization from absolute ethanol gives the product mp 179°-180° C., 26.86 g (87%). Anal. calcd. for C16H19N3O2 : C, 67.34; H, 6.73; N, 14.72. Found: C, 67.14; H, 6.17; N, 14.72.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15]CC)=[O:14])[CH:3]=1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 8 h
Yield: 65 %

Procedure:
2 g (8.65 mmol) of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate are dissolved in 20 ml EtOH and 20 ml of 1M NaOH solution are added. The mixture is stirred overnight, the solvent removed in vacuo and the crude product subject to HPLC chromatography: Yield: 65%
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11].[NH2:20]OS(O)(=O)=O>C(O)=O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][NH:20][C:2]2=[O:1])[CH2:9][C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(CC(=O)O)C2CCCCC2=O)cc1
Reactant: NOS(=O)(=O)O
Solvent: O=CO
Product: Cc1ccc(C(CC(=O)O)C2CCCCNC2=O)cc1
Temperature: 25 °C

Procedure:
The title material of Example 201 in formic acid is added to a solution of hydroxylamine-O-sulfonic acid in formic acid over a 5 min. period with stirring under N2. The mixture is heated under reflux for 3 hours and then cooled to room temperature. The reaction is quenched with cold water and the solution is neutralized with 6N NaOH. It is then extracted three times with CH2Cl2. The combined organic layers are dried over MgSO4 and the solvent is removed on a rotary evaporator. The desired products are purified and isolated by HPLC to give both the 3- and 7-substituted title products.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.[Mg].II.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1)[CH3:20]
Reactant: COc1c(C)cc(Br)cc1C
Reactant: CCOC(=O)Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c(OC)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,6-dimethylanisole (PREPARATION 1, 12.98 g) in tetrahydrofuran (40 ml) is added drop by drop to a mixture of magnesium turnings (1.87 g) in tetrahydrofuran (5 ml). The Grignard reaction is initiated with iodine crystals. After the addition is complete, the mixture is refluxed for 2 hours. The Grignard reagent is cooled to about 10° and then a solution of ethyl chloroformate (7.5 ml) in tetrahydrofuran (40 ml) is added in a 2 minute period. The mixture is stirred for 45 minutes at ice-water temperature and then at 20°-25° for 2 hours. The reaction is quenched with a saturated solution of ammonium chloride and diluted with ether. The phases are separated, the organic phase is washed with water and then with saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.[BrH:14]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][Br:14]
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Reactant: Br
Product: O=[N+]([O-])c1cc(CBr)cc(O)c1O

Procedure:
12.2 g of 3,4-dihydroxy-5-nitrobenzyl alcohol was dissolved in 100 ml of 47% hydrobromic acid at 50° C. After cooling the product was filtered and washed with 47% hydrobromic acid. The crude product was dissolved in dichloromethane and dried over Na2SO4. The mixture was filtered and the solvent was evaporated in vacuo. Yield 7.1 g.