Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[ClH:12].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:37][C:38]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([CH2:42][CH2:43][CH2:44][CH2:45][B:46]([OH:48])[OH:47])[C:39]([OH:41])=[O:40].C(N(CC)CC)C>CN(C=O)C.Cl>[ClH:12].[NH2:37][C:38]([CH:49]1[CH2:50][CH2:51][N:52]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:53][CH2:54]1)([CH2:42][CH2:43][CH2:44][CH2:45][B:46]([OH:48])[OH:47])[C:39]([OH:41])=[O:40]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 35 %

Procedure:
A solution of 4-fluorobenzeneacetic acid (126 mg, 0.816 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (156 mg, 0.816 mmol) and 1-hydroxybenzotriazole hydrate (125 mg, 0.816 mmol) in dry DMF (4 mL) was stirred for 30 minutes under an atmosphere of nitrogen. To the stirring solution was added a solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 150 mg, 0.371 mmol) in dry DMF (4 mL) in one portion. Triethylamine (0.31 mL, 2.23 mmol) was added and the resulting opaque mixture was stirred at room temperature for 1.75 hours. At the end of the reaction the solution was diluted with 1 N HCl and washed with ethyl acetate (2×), prior to concentration of the combined organic layers. The crude product was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water. Run 1—5% to 50% A over 24 min, then 50% to 100% A over 1 min. Run 2—5% to 40% A over 24 min, then 40% to 100% A over 1 min. Run 3—5% to 30% A over 24 min, then 30% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (4 mL)/acetonitrile (6 mL) and concentrated. The residue was once again treated with 0.5N HCl (4 mL)/acetonitrile (6 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-{1-[(4-fluorophenyl)acetyl]piperidin-4-yl}hexanoic acid hydrochloride (56 mg, 35%) as a white solid. 1H NMR (MeOH-d6, 400 MHz) δ 7.28 (m, 2H), 7.07 (m, 2H), 4.69 (m, 1H), 4.15 (m, 1H), 3.78 (m, 2H), 3.08 (m, 1H), 2.63 (m, 1H), 2.14 (m, 1H), 1.89 (m, 3H), 1.64 (m, 1H), 1.45 (m, 4H), 1.30-0.95 (m, 2H), 0.84 (bt, J=6.8 Hz, 2H). ESI+ MS found for C19H28BFN2O5 m/z 377.3 (M−18+H), 359.4 (M−2×18+H); ESI− MS m/z 393.4 (M−H), 375.4 (M−18−H).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([O:14][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Carboxylic acid 213 (0.010 g, 0.0193 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-aminomethylpyridine (0.004 g, 0.0386 mmol), triethylamine (0.008 mL, 0.058 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.074 g, 0.0386 mmol), 1-Hydroxybenzotriazole hydrate (0.0039 g, 0.029 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Dilute with dichloromethane, washed with 1M HCl solution, saturated brine solution, dried (Na2SO4), concentrated to give crude product. Chromatographed (0 to 8% methanol/dichloromethane) to give 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid (pyridin-2-ylmethyl)-amide 231 (0.007 g, 0.011 mmol, 59%.) 1H NMR (CDCl3) 8.94 (s, 1H), 8.45 (d, 2H), 8.05 (s, 1H), 7.70 (d, 4H), 7.57-7.17 (m, 12H), 7.05 (d, 2H), 4.78 (s, 1H), 4.69 (d, J=5 Hz, 1H), 4.38 (s, 1H). MS: 609 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[CH2:21][C:22](=O)[CH3:23]>CO>[CH3:2][O:3][N:4]=[C:22]([CH3:23])[CH2:21][C:14]1[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[Cl:12]
Reactant: CON
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of O-methyl-hydroxylamine hydrochloride (0.79 g, 9.4 mmol) in methanol (20 ml) was treated with triethylamine (1.32 ml, 9.4 mmol) followed by 1-(2,4,6-trichlorophenyl)-propan-2-one (1.5 g, 6.31 mmole). The resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was quenched with water and methanol was evaporated off. The resulting aqueous medium was extracted with ethylacetate (3×50 ml). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure (100 mbar; 45° C.). The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 2% ethyl acetate in hexane as elution system to give 1-(2,4,6-Trichloro-phenyl)-propan-2-one O-methyl-oxime (1.2 g, 76%), which was taken up for further reduction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Br-:21].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl.C(Cl)Cl>[Br:21][C:8]1[NH:9][C:10]2[C:6]([C:7]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:5][CH:4]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[C:2]=2[Cl:1]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a mixture of the methyl 7-chloro-3-cyclohexyl-1H-indole-6-carboxylate (1 g, 3.43 mmol) in a mixture of THF/CH2Cl2 (9 ml/9 ml) at r.t. under N2 was added pyridinium tribromide (1.33 g, 4.16 mmol, recrystallized from AcOH), and the reaction mixture stirred at r.t. for 2 hr. The mixture was then diluted with CH2Cl2 (40 ml), and the organics washed with NaHCO3 (30 ml, sat. aq.), followed by hydrochloric acid (30 ml, 1N) and brine (30 ml). After concentration of the organic layer, the residue was purified by Biotage flash chromatography (gradient elution, 0 to 20% EtOAc/Hexane) to gave methyl 2-bromo-7-chloro-3-cyclohexyl-1H-indole-6-carboxylate (841.8 mg, 66%) and to recover the starting material (201 mg). 1H NMR (500 MHz): (CD3OD) δ 7.67 (b d, J=8.5, 1H), 7.59 (d, J=8.5, 1H), 3.93 (s, 3H), 2.89 (m, 1H), 2.00-1.90 (overlapping m, 4H), 1.83-1.78 (overlapping m, 3H), 1.50-1.40 (m, 3H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=370.02, 372.03, 374.02, HPLC Rt=2.002 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:14]1([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc3ccccc3s2)cc1
Yield: 60 %

Procedure:
A solution of benzothiopheneboronic acid (1 g, 5.61 mmol) in ethanol (23 mL) was added to a mixture of iodobenzene (560 μL, 5 mmol), palladium tetrakis(triphenylphosphine) (460 mg, 0.4 mmol) and sodium carbonate (2.38 g, 22.4 mmol) in a mixture of toluene (15 mL) and water (15 mL). The reaction mixture was refluxed for 6 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The biphasic mixture was acidified with an aqueous solution of hydrochloric acid 1N until pH 2. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (2a) as a yellow oil (640 mg, 3 mmol, 60%).
Reaction SMILES: CN[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([N:12]([SiH3:16])C(C)C)(C)C>>[C:3]1([CH2:9][NH:12][SiH3:16])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CNc1ccccc1
Reactant: CC(C)N([SiH3])C(C)C
Product: [SiH3]NCc1ccccc1
Reaction time: 24 h
Yield: 89.4 %

Procedure:
In a 500 ml Schlenk flask, 64.2 grams (g) (0.6 mol) N-methylaniline and 131 g (1.0 mol) di-isopropylaminosilane were stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The relatively lower boiling point by-product di-isopropylamine was removed with vacuum at a pressure of 20 mmHg and room temperature (25° C.). The reaction mixture was stirred for another 24 hours. The end-product phenylmethylaminosilane (73.6 g, 89.5% yield) was obtained by vacuum distillation with a boiling point of 60° C. at 5 mm Hg. The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 1 and shows, among other things, peaks at 137, 122, 106, 91, and 77. The molecular weight of the phenylmethylaminosilane was 137.27.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=1[F:11]
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1F

Procedure:
In a round bottom flask, 3-amino-2-fluoro-benzoic acid (71, 2.51 g, 16.2 mmol) is dissolved in 100 mL of methanol and 1 mL of concentrated sulfuric acid is added. The reaction is heated to reflux for 24 hours and an additional 1 mL of concentrated sulfuric acid is added. The reaction is heated to reflux another 20 hours, then extracted with ethyl acetate and saturated aqueous sodium chloride. The organic layer is isolated and washed with water, sodium bicarbonate, and brine, then dried with magnesium sulfate, and filtered. The filtrate is concentrated under vacuum to provide the desired compound (72, 2.688 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCCC1>[CH3:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][N:5]=1
Reactant: C1CNCCN1
Reactant: Cc1nccc(Cl)n1
Solvent: C1CCOC1
Product: Cc1nccc(N2CCNCC2)n1

Procedure:
13 g of 4-chloro-2-methyl-pyrimidine were dissolved in 200 ml of tetrahydrofuran, and 17.5 g of piperazine were added. The reaction mixture was refluxed for 24 h. The precipitated piperazine hydrochloride was filtered off with suction and washed with tetrahydrofuran. Concentration of the solution in vacuo resulted in 19 g of 2-methyl-4-piperazino-pyrimidine, which was reacted without further purification.
Reaction SMILES: [NH2:1][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([CH3:4])[CH3:3].[C:13]1([CH2:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>O>[CH3:3][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([NH:1][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:4]
Reactant: O=CCc1ccccc1
Reactant: CC(C)(N)C(O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(NCCc1ccccc1)C(O)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 6.6 g. (0.03 mole) of α-(1-amino-1-methylethyl)benzenemethanol and 4.8 g. (0.03 mole) of phenylacetaldehyde in 75 ml. benzene is refluxed for 1 hour while 0.7 ml. of water separates in a Dean-Stark trap. The infrared absorption spectrum showed absence of the C=O function and the presence of a C=N function at 1650 cm-1. The solvent is removed in vacuo. The residue of the imino derivative was taken up with 60 ml. of methanol and 1.6 g. of KBH4 is added with stirring at 20°-25° C. After 20 hours, the solution is evaporated in vacuo. The residue is taken up with cold water, and the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration. Recrystallization from methanol gives pure α-{1-methyl-1-[(2-phenylethyl)amino]-ethyl}benzenemethanol as white crystals, m.p. 105°-106° C.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)(=O)C>[C:18]1([P:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2][C:3]#[N:4])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#CCBr
Solvent: CCOC(C)=O
Product: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 125.7 %

Procedure:
A solution of bromoacetonitrile (26.2 g, 218 mmol) and triphenylphosphine (52.0 g, 198 mmol) in ethyl acetate (240 mL) was stirred at 85° C. overnight, filtered and washed with petroleum ether. The filtrated cake was dried in air to give the title compound as a white solid (75 g), which was used without further purification. LCMS: rt=0.95 min, [M+H+]=302
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])/[CH:11]=[CH:12]/C2C=CC=CC=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].FC1C(F)=C2C(C=CC(=O)N2)=CC=1>>[F:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[C:5]=1[CH:12]=[CH:11][C:10](=[O:19])[NH:9]2
Reactant: O=C(/C=C/c1ccccc1)Nc1cc(F)cc(F)c1
Agent: O=c1ccc2ccc(F)c(F)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Product: O=c1ccc2c(F)cc(F)cc2[nH]1

Procedure:
The compound was prepared from (2E)-N-(3,5-difluorophenyl)-3-phenylacrylamide (Intermediate 26) (8.1 g, 31.2 mmol) and aluminium trichloride (21 g, 156 mmol) in a similar way as described for Intermediate 21. 3.47 g light brown solid (61%), mp 292-318° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.O1CCCC1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Mg]>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].C(OCC)C>[CH2:15]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(Br)n1
Agent: [Ni]
Agent: CC(C)P(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(Cc2ccccc2)n1

Procedure:
While stirring a mixture of 150 g of 2-bromo-6-methoxypyridine, 4.3 g of 1,3-bis(diphenylphosphino)propanenickel (II) chloride and 500 ml of tetrahydrofuran in an ice bath, Grignard reagent prepared from 123 ml of benzyl bromide, 30 g of magnesium and 400 ml of diethyl ether was added dropwise slowly. After stirring overnight as it was, the mixture was extracted with an aqueous ammonium chloride solution and hexane. The organic layer was washed with water and then with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography with (1% ethyl acetate/hexane and 1.5% ethyl acetate/hexane), to give 150 g of the title compound.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[C:9]([NH:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:10])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[C:9]([NH:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:10]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
2.0 mL of methanol, 2.0 mL of ethyl acetate and 3.0 mg of 5% palladium-carbon were added to 15 mg of 2-(3-nitrobenzamido)-4-phenylbenzoic acid at room temperature and stirred under hydrogen atmosphere at 40° C. for 2 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 5.1 mg of 2-(3-aminobenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1.C[Sn](C)C.C[Sn](C)C.[F-].[K+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:12][C:10]1([F:13])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[CH:3][CH:4]=2)([C:21]([O:23][CH3:24])=[O:22])[CH2:11]1
Reactant: COC(=O)C1(Cc2ccc(Br)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Palladium tetrakis(triphenylphosphine) (169 mg, 0.15 mmol) was added to a degassed, ambient temperature solution of 1-tert-butyl 2-methyl 2-(4-bromobenzyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (634 mg, 1.46 mmol), 2-bromo-5-fluoropyridine (257 mg, 1.46 mmol), and hexamethylditin (478 mg, 1.46 mmol) in 1,4-dioxane (5 mL). After stirring at 110° C. overnight, potassium fluoride (50% on celite) was added. After stirring vigorously for a further 1 h, the reaction mixture was filtered, washed with water, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-tert-butyl 2-methyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1,2-dicarboxylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15]([OH:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]1.[F-].[K+].Br[CH2:24][N:25]1[C:29](=[O:30])[C:28]2[C:31]([CH:37]([CH3:39])[CH3:38])=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=2[S:26]1(=[O:41])=[O:40]>CN(C=O)C>[CH:37]([C:31]1[C:28]2[C:29](=[O:30])[N:25]([CH2:24][O:16][C:15]3[N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[N:12]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:14]=3)[S:26](=[O:41])(=[O:40])[C:27]=2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=1)([CH3:39])[CH3:38]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccc2ccccc2n1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
A mixture of 1-(2-quinolinyl)-3-trifluoromethyl-5-hydroxypyrazole (533 mg; 1.91 mmol) and KF (220 mg; 3.8 mmol) in 35 ml of DMF was stirred under nitrogen at room temperature for 10 minutes and then 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (592 mg, 1.7 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes and diluted with ice/cold saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×) followed by the addition of ether, the organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with ethyl acetate/ether to yield a white solid, which was crystallized (from hot ethyl acetate/ether followed by methylene chloride/ether) and dried to afford 710 mg (76%) of 4-isopropyl-6-methoxy-2-[1-(2-quinolinyl)-3-(trifluoromethyl)pyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2-quinolinyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 124°-125° C.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC1[O:22]C2C=CC(CBr)=CC=2C=1C1C=CC=CC=1.CS.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([CH3:19])=[O:22])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Reactant: CSCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Agent: CS
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1ccc2oc(Br)c(-c3ccccc3)c2c1

Procedure:
To a stirred, cold solution of 7.8 g. of 2-bromo-5-methylthiomethyl-3-phenylbenzofuran (prepared by reacting 2-bromo-5-bromomethyl-3-phenylbenzofuran with methyl mercaptan according to the procedure of Example 18 hereof) in 100 ml. of chloroform is added dropwise 4.73 g. of 3-chloroperbenzoic acid in chloroform at 0° C. After three hours an addition 0.3 g. of the peracid is added and 30 minutes later the solution is washed with cold 5 percent sodium hydroxide solution, then with saturated sodium chloride solution and dried. Evaporation provides a residue which is recrystallized from a chloroform-hexane mixture to provide 2-bromo-5-methylsulfinylmethyl-3-phenylbenzofuran. The structural assignment is confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20](=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[OH:27][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20](=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(C(=O)CN2CCN(c3cccccc3=O)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(O)CN2CCN(c3cccccc3=O)CC2)cc1OC
Yield: 99.5 %

Procedure:
To a solution of 2-[4-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (1.33 g, described above) in methanol (20 ml) and chloroform (5 ml), sodium borohydride (0.31 g) was added portionwise over a period of one hr. The solvent was then removed under vacuum. The residue was taken up in chloroform, washed with water, ammonium chloride solution followed by water, dried and evaporated to give the title compound (1.33 g): mp 122°-124° C.; ir(CHCl3) 3420, 1565, 1260 and 1140 cm-1 ; uv max(MeOH) 352 (ε=10040), 256 (ε=15660) and 227 nm (ε=20250); nmr(CDCl3) δ2.6 (m, 6H), 3.3 (m, 4H), 3.85 (s, 6H), 4.7 (m,1H) and 6.8 (m,6H); and Anal. Calcd for C21H26N2O4 : C, 68.08% H, 7.08% N, 7.56% and Found: C, 67.78% H, 7.06% N, 7.36%.