Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=2[O:8][CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[N:3]=[CH:2]1.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=2[O:8][CH2:9][CH:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[OH:11])[N:3]=[CH:2]1
Reactant: O=C(COc1ccccc1-c1c[nH]cn1)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(COc1ccccc1-c1c[nH]cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a mixture 2-(2-(1H-imidazol-4-yl)phenoxy)-1-cyclohexylethanone (130 mg, 0.457 mmol) in MeOH (4 mL) at 0° C., was added NaBH4 (52 mg, 1.37 mmol) and the solution was allowed to stir at room temperature for 1 h. The solvent was distilled off and the crude was acidified with dil HCl (2 N) and again basified by saturated aqueous NaHCO3 solution, the product was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried, and concentrated under reduced pressure to afford the final product (118 mg, 0.413 mmol, 90%). 1H NMR (DMSO-d6): 1.04-1.21 (m, 5H), 1.49-1.50 (m, 1H), 1.61-1.68 (m, 4H), 1.85 (d, 1H, J=12.4 Hz), 3.62-3.65 (m, 1H), 3.96 (d, 1H, J=9.6 Hz, 6.4 Hz), 4.07 (dd, 1H, J=10 Hz, 3.2 Hz), 4.97 (br s, 1H), 6.93 (t, 1H, J=7.2 Hz), 7.03 (d, 1H, J=7.6 Hz), 7.12 (d, 1H, J=7.2 Hz), 7.67 (s, 1H), 7.70 (s, 1H), 8.03 (s, 1H), 12.01 (br s, 1H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][CH:5]=1>O1CCOCC1.C(Cl)(Cl)Cl>[Br:1][C:21]1[C:20]2[C:15]([C:14]3[NH:13][S:12](=[O:25])(=[O:24])[N:11]([CH3:26])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[C:23]=3[CH:22]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: BrBr
Reactant: CN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CN1C(c2ccc(F)cc2)c2cc(Br)c3cccnc3c2NS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
Bromine (7.48 μl, 0.15 mmol) was added to a solution of 1-(4-fluoro-phenyl)-2-methyl-1,4-dihydro-2H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 382 (50 mg, 0.15 mmol) in dioxane:chloroform (1:1, 4 ml) at 0° C. and the mixture was stirred at 0° C. for 1 h. The resulting precipitate was collected by filtration and dried. The resulting solid was triturated from MeOH to give the title compound (17 mg, 28%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CCOC(C)=O.OS([O-])(=O)=O.[Na+]>C1COCC1>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:14])[CH3:2]
Reactant: CCOC(CCNC(=O)CCCCCl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(CCN1CCCCC1=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of N-[3,3-bis(ethyloxy)propyl]-5-chloropentanamide (10 g, 38 mmol) in THF (400 mL) was treated with lithium hexamethyl disilazide (LiHMDS, 1.0 M in THF) (40 mL, 40 mmol) at ambient temperature. After stirring for 15 min., an additional 10 mL of LiHMDS was added and the reaction was stirred an additional 30 min. After TLC (EtOAc) showed the absence of starting material, the reaction was poured into a sep. funnel containing EtOAc (500 mL) and 1N NaHSO4 (500 mL). Back extracted the aqueous with EtOAc then combined the organics, washed them with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide the product as a clear viscous oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.02 Hz, 6 H), 1.63-1.74 (m, 6 H), 2.17 (t, J=6.11 Hz, 2 H), 3.20-3.28 (m, 4 H), 3.42 (dq, J=9.55, 7.07 Hz, 2 H), 3.56 (dq, J=9.55, 7.07 Hz, 2 H), 4.47 (t, J=5.62 Hz, 1 H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][CH:11]2[O:16][CH:15]([CH2:17][OH:18])[CH:14]([OH:19])[CH:13]([OH:20])[CH:12]2[OH:21])[CH:2]=1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[O:10]([C:3]1[CH:2]=[CH:1][C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=1)[CH:11]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]1[OH:21]
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(OC2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 1 h

Procedure:
A colorimetric pNPG (p-nitrophenyl-β-D-glucopyranoside)-based assay was used for measuring β-glucosidase activity. In a total volume of 100 μL, 20 μL clear media supernatant containing β-glucosidase enzyme was added to 4 mM pNPG (Sigma-Aldrich, Inc. St. Louis, Mo.) solution in 50 mM sodium phosphate buffer at pH6.5. The reactions were incubated at pH 6.5, 45° C. for 1 hour. The reaction mixture was quenched with 100 μL of 1M sodium carbonate pH 11 solution. The absorbance of the solution was measured at 405 nm to determine the conversion of pNPG to p-nitrophenol. The release of p-nitrophenol (ε=17,700 M-1 cm-1) was measured at 405 nm to calculate β-glucosidase activity. Detectable β-glucosidase activity was observed under high throughput screening conditions (pH 7, 50° C.).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[CH3:27]>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][C:19]=1[CH3:27]
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: Cc1cc(B(O)O)ccc1F
Product: CCC(=O)NC1CCCc2c(-c3ccc(F)c(C)c3)cncc21
Yield: 82 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-fluoro-3-methylphenylboronic acid to give the title compound as light yellow foam in 82% yield. MS: 313.5 (M+H+).
Reaction SMILES: C([O:3][P:4]([CH:10]([OH:28])[CH:11]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:12][NH:13]C(OC(C)(C)C)=O)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])C>Cl>[ClH:27].[NH2:13][CH2:12][CH:11]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:10]([P:4]([CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[OH:5])[OH:28]
Reactant: CCCCP(=O)(OCC)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Product: CCCCP(=O)(O)C(O)C(CN)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 0.35 g of ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl(n-butyl)phosphinic acid in 10 ml of 5.0M aqueous hydrochloric acid is heated to reflux for 24 hours. The reaction is cooled to room temperature and washed with 3×50 ml dichloromethane and 1×50 ml ether. After evaporation of the aqueous layer the residue is co-evaporated with water (3×50 ml) and absolute ethanol (3×50 ml) and dried in high vacuum to afford 3-amino-2-(4-chlorophenyl)-1-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[C:6]([NH:8][C:9]1[C:10]([NH:23][C:24](=[O:34])[C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:11][C:12]([O:15][Si](C)(C)C(C)(C)C)=[CH:13][CH:14]=1)=[O:7])#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[C:6]([NH:8][C:9]1[C:10]([NH:23][C:24](=[O:34])[C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-(dimethyl-t-butylsiloxy)-1,2-benzenediamine (1.57 g, 3.05 mmol) THF (30 mL) at 0° C. was added a THF solution of TBAF (3.1 mL, 3.1 mmol). After 1 h, the reaction was quenched with water (35 mL) and extracted with ether (2×200 mL). The combined organic layers was MgSO4 dried, filtered, and concentrated. The residue was chromatographed (1:1 EtOAc/hexanes) to give the title compound as a solid (1.10 g, 91%); IR(KBr): 3277, 1629, 1600, 1535, 1478, 1299 cm−1; NMR(300 MHz, d6-DMSO): δ10.02 (s, 1H), 9.70 (s, 1H), 9.56 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=7.5, 1H), 8.01 (d, J=7.2, 1H), 7.79 (d, J=8.1, 2H), 7.70 (m, 1H), 7.34-7.21 (m, 4H), 6.63 (d, J=9.0, 1H), 2.90 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H); MS(FD): 399.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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]>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Oc1cccc(-c2ccco2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
3-Bromophenol (500 mg, 2.86 mmol) and furan-2-boronic acid (420 mg, 3.76 mmol) were dissolved in dimethoxyethane/water=5 mL/2.5 mL. Pd(dppf)Cl2 (118 mg, 0.14 mmol) and sodium carbonate (919 mg, 8.67 mmol) were added thereto, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (hexane:ethyl acetate=9:1) to obtain 3-(furan-2-yl)phenol (191 mg, 41%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11].C(O[C:16](=O)[CH2:17][N:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19])C>O1CCOCC1>[CH2:20]([N:18]([CH2:17][C:16]1[O:3][C:4]2[C:5]([C:10](=[O:12])[CH:11]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccccc1O
Reactant: CCOC(=O)CN(C)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)Cc1cc(=O)c2ccccc2o1
Temperature: 80 °C
Reaction time: 19 h
Yield: 74.2 %

Procedure:
To a suspension of sodium hydride (16.4 g) in absolute dioxane (700 ml) stirred at 80° C., was slowly added a mixture of o-hydroxyacetophenone (31.0 g) and N-benzyl-N-methylglycine ethyl ester (40 g) in dioxane (100 ml), and the resulting solution was boiled for 19 hours before being evaporated in vacuo. The residue was dissolved in ethanol and the mixture was saturated with dry HCl and stirred at room temperature for 18 hours. After evaporation the residue was taken up in chloroform and washed with water. Evaporation of the dried organic extracts yielded an oil (40 g) which was chromatographed on alumina eluting with chloroform to give the title chromone as a yellow oil (17.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[CH:38](F)OC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:38][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH:34]([F:36])[F:35])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)F)cc1)CCC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)F)cc2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 537.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 4-difluoromethoxy-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)=[CH:18]\[CH2:19][O:20][C:21]2[C:26]3[O:27][CH:28]=[CH:29][C:25]=3[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:4]1([CH2:1][C:2]#[C:3][C:11]2[CH:12]=[CH:13][C:14](/[C:17](/[C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=3)=[CH:18]\[CH2:19][O:20][C:21]3[C:26]4[O:27][CH:28]=[CH:29][C:25]=4[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Temperature: 0 °C
Reaction time: 120 h

Procedure:
N-Propargylmorpholine (0.64 g, 5.1 mmol) was added under nitrogen atmosphere to a degassed solution of ethyl (Z)-[7-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyacetate (0.68 g, 1.09 mmol) in a mixture of tetrahydrofuran (20 mL) and triethylamine (10 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (0.17 g, 0.147 mmol) and copper(I) iodide (0.03 g, 0.16 mmol) were added. The reaction mixture was stirred at ambient temperature for 120 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding ethyl (E)-[7-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]benzo[b]furan-4-yl]oxyacetate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[CH3:16])(=O)C.[OH-].[Na+].O>CO>[CH3:16][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1c(C)ccc([N+](=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of 2,6-dimethyl-3-nitrobenzyl acetate (26.9 g) in methanol (266 ml) was added 1N sodium hydroxide solution (133 ml) at ambient temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added water, and the resulting precipitates were collected by filtration to give 2,6-dimethyl-3-nitrobenzyl alcohol (18.0 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([O:13]C)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.B(Br)(Br)Br>ClCCl.CO>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: COc1cc2c(c(Cl)c1O)c(=O)c(C(=O)O)cn2C1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cn(C2CC2)c2cc(O)c(O)c(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of 5-chloro-1-cyclopropyl-6-hydroxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.5 g, 27.4 mmol) in Dichloromethane (DCM) (100 mL) was added BBr3 (6.49 mL, 68.6 mmol) at −78° C. The mixture was allowed to warm up to rt. and stirred at rt overnight. LCMS indicated completion of the reaction. The mixture was diluted with MeOH and concentrated to dryness. This procedure was repeated several times to afford 5-chloro-1-cyclopropyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7.8 g, 26.4 mmol, 96% yield) as yellow solid. LCMS: [M+H]+: 296.1.
Reaction SMILES: [Cl-].[CH:2]1([NH2+:10][CH2:11][CH2:12]Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:10]([CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:26]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]C1CCCCCCC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C1CCCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=[C:8]([CH:13]=O)[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+].Cl.[CH3:25][O:26][NH2:27]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=[C:8]([CH:13]=[N:27][O:26][CH3:25])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1cc(NC(=O)OC(C)C)cc(C=O)c1OCC
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(NC(=O)OC(C)C)cc(C=NOC)c1OCC
Reaction time: 12 h
Yield: 93 %

Procedure:
Isopropyl N-(3,4-diethoxy-5-formylphenyl)carbamate (0.6 g) was dissolved in ethanol (20 ml). To the solution was added an aqueous solution (10 ml) containing sodium hydroxide (0.32 g) and methoxyamine hydrochloride (0.66 g). After being allowed to stand for 12 hours, the reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The resultant solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give isopropyl N-(3,4-diethoxy-5-methoxyiminomethylphenyl)carbamate (Compound No. 191) (0.61 g) in a yield of 93%. M.P., 110°-111.5° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([CH:16]([OH:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1>CS(C)=O>[NH2:8][C:9]1[N:10]=[C:11]([Cl:26])[C:12]([C:16](=[O:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:13]([Cl:15])[N:14]=1
Reactant: CC1(C)OCC(CC(O)c2c(Cl)nc(N)nc2Cl)O1
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
Acetic anhydride (149 ml) was added dropwise to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-ol (74.70 g) and dimethyl sulfoxide (600 ml) at room temperature over 15 minutes under cooling in an ice bath. The reaction mixture was then stirred at the same temperature as above for 18 hours. After the disappearance of the materials had been confirmed, the reaction solution was poured into ice water. The precipitated solid was collected by filtration, so as to obtain the title compound (68.26 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3
Reactant: OC1CCNCC1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCC(O)CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 31 %

Procedure:
7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.5 g) and 4-hydroxypiperidine (1.0 g) are suspended in N-methylpyrrolidone (5 ml), and the mixture is heated at 110°-120° C. for 5 hours. The reaction mixture is concentrated to dryness under reduced pressure, and to the residue is added ethanol. The resulting crystals are separated by filtration and recrystallized from N,N-dimethylformamide to give 7-amino-8-fluoro-9-(4-hydroxy-1-piperidyl)-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.2 g) as yellow cubic crystals. m.p. 287°-292° C. (decomp.)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Temperature: 120 °C

Procedure:
4′-Methoxy-4-nitro-biphenyl (4.55 g, 19.8 mmol), prepared in the previous step, in a mixture of glacial acetic acid plus 65 mL of 48% HBr was heated at approximately 120° C. until the reaction was complete by TLC. The reaction was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The organic layer was separated, dried (Na2SO4) and the solvent removed under reduced pressure to give 4′-hydroxy-4-nitro-biphenyl.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:31])=[O:30]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 5 °C

Procedure:
The crude oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol, from Example 8 is dissolved in 200 ml of methylene chloride and to that mixture is added 13.2 g of triethylamine. The reaction mixture is cooled to 5° C. and 11.0 g of methanesulfonyl chloride is added slowly, maintaining the temperature between 5°-10° C. The precipitation of triethylamine hydrochloride crystals is observed. After the addition of the methanesulfonyl chloride has been completed, the reaction mixture is stirred for an additional one-half hour. Then the solution is filtered to remove the triethylamine hydrochloride crystals and the filtrate is poured into 200 ml of water. The organic layer is separated and dried over magnesium sulfate. Evaporation of the organic layer under reduced pressure yields 30.4 g of crude 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: Cc1cccc(Nc2ccccc2C(=O)O)c1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1cccc(C)c1C
Yield: 86 %

Procedure:
A suspension of 2-[(2,3-dimethylphenyl) amino]benzoic acid (mefenamic acid) 35 g, 145 mmol) in methanol (600 ml) and concentrated sulfuric acid (15 ml) is heated at reflux for two days. The reaction mixture is cooled in an ice bath. The resulting solid is collected by filtration and recrystallized from methanol to give 2-[(2,3-dimethylphenyl)amino]benzoic acid, methyl ester (32.0 g, 86%); mp 98°-100° C.