Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[C:16](F)[CH:17]=1>CN1C(=O)CCC1>[CH2:1]([O:8][C:16]1[CH:15]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[CH:13]=[C:12]([F:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: OCc1ccccc1
Product: O=C(O)Cc1cc(F)cc(OCc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To benzyl alcohol (1.4 g, 12.8 mmol) in NMP (30 mL) was added sodium hydride (60% in mineral oil; 0.5 g, 12.8 mmol), and the mixture was stirred for 20 minutes. 3,5-Difluorophenylacetic acid (1.0 g, 5.8 mmol) was added, and the reaction was stirred at 100° C. for 2 hours, and then 60° C. overnight. The mixture was worked-up to give the desired product, plus ˜30% of benzyl alcohol impurity (2.0 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]1.[CH2:23]([NH:26][C:27]1[CH2:31][S:30][C:29](=[O:32])[N:28]=1)[C:24]#[CH:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16](/[CH:19]=[C:31]2/[C:27]([NH:26][CH2:23][C:24]#[CH:25])=[N:28][C:29](=[O:32])[S:30]/2)[CH2:15][CH2:14]1
Reactant: C#CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)phenyl]piperidine-4-carbaldehyde (1.61 g) in 2-propanol (20 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1.15 g) and piperidinium acetate (0.72 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/heptane to give the title compound (1.45 g).
Reaction SMILES: O[CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([NH:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7].[H][H]>C(O)C.[Pd]>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2([C:18]([OH:20])=[O:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][C:3]=1[CH2:2][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)c1ccccc1C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1Cc1ccccc1C
Yield: 81.3 %

Procedure:
The compound of example 241 (32 mg, 0.074 mmol) was dissolved in ethanol (10 ml), palladium (10%) on charcoal (10 mg) was added, and the mixture was hydrogenated at room temperature for 1 h at a hydrogen pressure of 5 bar. After completion of the reaction, the mixture was filtered over silica gel and evaporated to dryness. The residue was triturated with diethyl ether, filtered and dried in vacuo to yield 25 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[C:19](=[O:20])[NH:18][C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=2)[CH:13]=1.Cl.[Cl:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30]Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:18]2[C:19](=[O:20])[C:14]([N:12]3[CH:13]=[C:9]([CH3:8])[N:10]=[CH:11]3)=[CH:15][CH:16]=[C:17]2[C:21]1=[O:23]
Reactant: ClCCNCCCl
Reactant: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccc3n(c2=O)CCN(CCCl)C3=O)cn1
Reaction time: 0.17 h

Procedure:
Potassium carbonate (195.4 g, 1414 mmol) was added to a mixture of 5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid, hydrochloride salt (C3) (34.5 g, 135 mmol) and 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (37.8 g, 212 mmol) in N,N-dimethylformamide (670 mL), and the reaction was stirred for 10 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 83.5 g, 219 mmol) was added and stirring was continued for an additional 3 hours and 40 minutes. The reaction mixture was then poured into water (4 L) and stirred for 30 minutes. After extraction with dichloromethane (3×1 L), the combined organic layers were washed with saturated aqueous sodium chloride solution (3×3 L), dried over magnesium sulfate, filtered and concentrated in vacuo. Finally, most of the DMF was removed by using a methanol/liquid nitrogen cooler. The residue was stirred in ethyl acetate (approximately 50 mL) for 30 minutes. The solids were collected by filtration and washed with ethyl acetate and pentane, providing the title compound as a yellow solid. Yield: 23.0 g, 75.0 mmol, 56%. LCMS m/z 307.1 (M+1). 1H-NMR (300 MHz, CDCl3) δ 2.29 (br s, 3H), 3.80-3.93 (m, 6H), 4.38-4.44 (m, 2H), 7.13-7.16 (m, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 8.24 (d, J=1.0 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9][C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([O-:18])=[O:17].[Na+]>S(=O)(=O)(O)O>[N+:16]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:11](=[O:12])[C:10]([CH3:13])([CH3:14])[NH:9][C:8]2=[O:15])=[CH:6][CH:5]=1)([O-:18])=[O:17]
Reactant: CC1(C)NC(=O)N(c2ccccc2)C1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
17.0 g (83 mmol) of 3-phenyl-5,5-dimethylhydantoin were dissolved in 160 ml of concentrated sulphuric acid and 7.07 g (83 mmol) of sodium nitrate were slowly added with stirring, at 0° C. over a 40 minute period. After the addition was completed, maintained stirring at 0° C. was continued for 20 minutes with the reaction mixture. The mixture was allowed to warm to room temperature and stirring was continued for 4 hours. The mixture was then poured onto ice water and then extracted with methylene chloride. The extract was dried over sodium sulphate. The methylene chloride was evaporated and the resulting product was crystallized from methylene chloride/petroleum ether. The recrystallized product was dried for 16 hours, under greatly reduced pressure, to yield 3-(4-nitrophenyl)-5,5-dimethylhydantoin, m.p. 176°-177° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([CH2:29][CH2:30][CH2:31][CH3:32])[C:24]([O:26]CC)=[O:25])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([CH2:29][CH2:30][CH2:31][CH3:32])[C:24]([OH:26])=[O:25])[CH:8]=2)[N:3]=1
Reactant: CCCCC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1.0 g of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoate are dissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 50° C. for 4 h and subsequently evaporated in vacuo. The mixture is then adjusted to pH2 using 25% hydrochloric acid with ice-cooling, with yellow crystals precipitating. The precipitate obtained is filtered off and dried in vacuo. Yield: 550 mg (59%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoic acid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([NH:28]C(=O)C)[CH:23]=4)[CH2:18][CH2:17]3)[C:11]3[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=4)[CH2:20][CH2:21]3)[C:11]3[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCn3c(-c4ccc(Cl)cc4)nc4ccccc43)CC2)c1
Agent: Cl
Solvent: CO
Product: Nc1cccc(C2CCN(CCCn3c(-c4ccc(Cl)cc4)nc4ccccc43)CC2)c1
Yield: 86.8 %

Procedure:
1.5 g (3.08 mmol) of 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole obtained in Example 4 was dissolved in 30 ml of methanol, and 10 ml of 5N—HCl aqueous solution was added to the resulting solution, followed by mixing the solution at 50° C. for 3 hours. The resulting solution was concentrated under a reduced pressure and 60 ml of water was added thereto. Then, pH of the solution was adjusted to 8 or more. The reaction mixture was extracted with ethylacetate (80 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=1/3) to obtain 1.19 g (yield 87%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]([CH:20](Cl)[CH3:21])=[CH:8]2.CN(C=O)C.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]([CH:20]([N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])[CH3:21])=[CH:8]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)Cl
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 8-chloro-3-(1-chloroethyl)-2-(2-methylpyridin-3-yl)-quinoline hydrochloride (1.3130 g, 3.712 mmol) in DMF (18.56 m/L, 3.712 mmol) at 100° C. was added potassium phthalimide (1.719 g, 9.281 mmol) at 100° C. and the mixture was stirred at 100° C. After 1.5 h, the mixture was concentrated under reduced pressure and triturated with water (50 mL). The resulting solid was filtered and washed with 2 N NaOH (50 mL) and then with water (500 mL), and air-dried to give 2-(1-(8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione as a tan solid: LC-MS (ESI) m/z 428.0 [M+H]+. The impure product was carried on crude without purification for the next step.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:4].C(Cl)(Cl)Cl.CC(C)=O>B([O-])([O-])[O-]>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:4]
Reactant: COC(=O)CCCCCNC(=O)C(F)(F)F
Agent: [O-]B([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=C(O)CCCCCNC(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Next, after dissolving Methyl 6-trifluoroacetamidohexanoate (3.7 g, 15.4 mmol) in 10 mM of a borate buffer pH8.0 (3000 ml), a porcine liver derived carboxylesterase (2160U, 1.2 ml) was added, and a reaction performed at 30° C. After 72 hours had passed since the start of the reaction, after boiling for 10 minutes at 100° C. and stopping the reaction, the reaction solution was concentrated and applied to a silica gel column chromatography (2.0×30 cm) equilibrated (10 ml/min) with chloroform:acetone=8:2. After fractionating into 20 ml per tube, the product was confirmed using a phosphomolybdic acid color reaction using TLC (development solution chloroform:acetone=8:2). After concentrating a fraction which is No. 5-15 (100-300 ml) including the desired product, the product was freeze dried and 6-Trifluoroacetamidohexanoic acid was obtained (weight: 3.1 g yield: 89%).
Reaction SMILES: [C:1]1([P:7]([CH2:14][S:15]C(=O)C)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([P:7]([CH2:14][SH:15])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)SCP(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: SCP(c1ccccc1)c1ccccc1
Yield: 94 %

Procedure:
Compound 11b (17.27 g, 63.0 mmol) was dissolved in anhydrous methanol and Ar(g) was bubbled through the solution for 1 h. Sodium hydroxide (2.52 g, 63 mmol) was then added, and the mixture was stirred under Ar(g) for 2 h. Solvent was then removed under reduced pressure, and the residue was dissolved in methylene chloride. This solution was washed twice with 2 N HCl and once with brine. The organic layer was dried over MgSO4(s) and filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography (alumina, 25% v/v ethyl acetateinhexanes) to afford 1b as a clear oil in 94% yield. Alternatively, phosphinothiol 1b can be used in its crude form for formation of phosphinothioesters. Spectral data. 1H NMR (CDCl3, 300 MHz) δ 7.41-7.38 (m, 4 H), 7.33-7.26 (m, 6 H), 3.02 (d, J=7.8 Hz, 2 H), 1.38 (t, J=7.5 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 132.54 (d, J=17.1 Hz), 128.86, 128.36, 128.14, 20.60 (d, J=21.7 Hz) ppm; 31P NMR (CDCl3, 121 MHz) δ—7/94 ppm; MS (EST) m/z 232.05 (MH+=233.0, fragments at 183.0, 155.0, 139.0, 91.2).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12.C(N(C(C)C)C(C)C)C.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][C:34](ON1C(=O)CCC1=O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][C:34]([NH:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1cnn2c1NCC2
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (2.22 g) and N-ethyldiisopropylamine (2.84 g) in methylene chloride (70 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (3.15 g). The mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 7-[3-(tert-butoxycarbonylamino)propionyl]amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.2 g) as a solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=4)[CH2:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.C1(O)C=CC=CC=1.C(O)(=O)CC.[BrH:51]>>[BrH:51].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=4)[CH2:20][NH:19][CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cc(-c4ccc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc(F)c3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Cc1c(-c2cc(F)c3c(c2)CNC3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In 3.0 ml of 47% hydrobromic acid was suspended 0.30 g of 1-cyclopropyl-7-[7-fluoro-2-(p-toluenesulfonyl)isoindolin-5-yl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, followed by adding thereto 0.16 g of phenol and 1.8 ml of propionic acid, and the resulting mixture was heated at 100° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, after which ethanol was added to the resulting residue and the crystals were collected by filtration to obtain 0.21 g of colorless 1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrobromide. The hydrobromide obtained was suspended in 1.3 ml of ethanol and dissolved in 2.6 ml of a 0.5 N aqueous sodium hydroxide solution, after which carbon dioxide was bubbled into the resulting solution and the crystals were collected by filtration to obtain 0.10 g of colorless 1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCOC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCOC1
Yield: 70 %

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (254 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (207 mg), tetrakis(triphenylphosphine)palladium(0) (77.0 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (181 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To 1-[2-(4-nitrophenoxy)ethyl]imidazole (0.64 g) was added 85% ethanol solution (19.2 ml), calcium chloride (0.15 g) and reduced iron (0.77 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with. Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[2-(imidazol-1-yl)ethoxy]aniline (0.31 g).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46]C=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CO>CN(C=O)C>[C:43]([C:44]1([NH:49][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:7]=[C:8]3[C:31](=[CH:32][CH:33]=2)[C:12]2=[N:13][O:14][C:15]([C:16]4[C:20]([C:21]([F:22])([F:23])[F:24])=[C:19]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[O:18][N:17]=4)=[C:11]2[CH2:10][CH2:9]3)[CH2:46][CH2:45]1)#[N:48]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: N#CC1(NC(=O)C(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Preparation 131B, Isomer 2, 25 mg, 0.055 mmol) in DMF (1 mL) was added 1-aminocyclopropanecarbonitrile, HCl (9.74 mg, 0.082 mmol), HATU (24.99 mg, 0.066 mmol), and N-methylmorpholine (0.036 mL, 0.329 mmol). The reaction mixture was stirred for 1 h at room temperature. Methanol was added and it was purified by prep HPLC (Phenomenex 21.2×250 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 30 min, 20 mL/min, 220 nM) to yield N-(1-cyanocyclopropyl)-2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (11 mg, 0.021 mmol, 38.2% yield) as a white solid: product HPLC ret. time=9.96 min (condition G); LC/MS M+1=521.06; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (1H, s), 7.89 (1H, d, J=7.92 Hz), 7.80 (2H, d, J=7.26 Hz), 7.63-7.76 (3H, m), 7.41-7.51 (2H, m), 6.43 (1H, d, J=4.18 Hz), 5.02 (1H, d, J=3.74 Hz), 3.05 (4H, s), 1.46 (2H, q, J=2.79 Hz), 1.07-1.24 (2H, m).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.C(N(CC)CC)C.[CH2:28]([O:30][SiH:31]([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])[CH3:29]>CCOCC>[CH2:28]([O:30][Si:31]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCO[SiH](OCC)OCC
Reactant: O=C(c1ccccc1)c1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
[Rh(cod)(MeCN)2]BF4 (11.0 mg, 0.0300 mmol, 0.0300 equiv) and 4-iodobenzophenone (307 mg, 1.00 mmol, 1.00 equiv) were charged in 10 mL vial capped with a rubber septum. The vial was evacuated and backfilled with nitrogen. To this vial, DMF (4 mL), triethylamine (0.420 mL, 3.00 mmol, 3.00 equiv) and triethoxysilane (0.360 mL, 2.00 mmol, 2.00 equiv) were added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to 23° C. The mixture was diluted with ether (50 mL) and washed three times with water (3×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Kugelrohr distillation to give 275 mg of the title compound as a colorless oil (80% yield). Rf=0.45 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 7.82−7.77 (m, 6H), 7.59 (t, J=7.5 Hz, 1H), 7.48 (dd, J=7.5 Hz, 7.5 Hz, 2H), 3.90 (q, J=7.0 Hz, 6H), 1.27 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 196.84, 139.05, 137.29, 136.34, 134.66, 132.54, 130.11, 129.00, 128.28, 58.91, 18.21. Mass Spectrometry: HRMS-FIA (m/z): Calcd for [M+Na]+, 367.13361. Found, 367.13347.