Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[F:27][C:28]([F:40])([F:39])[C@@:29]([O:34][Si:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([I:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:30](=[O:31])[C@:29]([O:34][Si:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[C:28]([F:39])([F:27])[F:40]
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Reactant: Nc1ccc(I)c([N+](=O)[O-])c1Cl
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Solvent: ClCCl
Product: C[C@@](O[Si](C)(C)C)(C(=O)Nc1ccc(I)c([N+](=O)[O-])c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.4 %

Procedure:
4-Iodo-3-nitro-2-chloroaniline (Method 70) (1269 mg) and 2,6-di-t-butylpyridine (1.5 ml) were added to a solution of (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (6 mmol) in DCM (40 ml). The mixture was stirred for 3 days at ambient temperature. The volatile material was removed by evaporation and the residue was purified by chromatography eluting with 10% EtOAc in hexane to give the title compound (1160 mg). NMR: 0.27 (s, 9H), 1.70 (s, 3H), 7.70 (d, 1H), 8.05 (d, 1H), 9.72 (brs, 1H); m/z 509.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[C:14]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([Cl:33])[CH:26]=2)=[N:13][N:12]=1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>C(OCC)(=O)C>[ClH:10].[Cl:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][NH:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:11]([N:2]2[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]2)=[N:12][N:13]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: N#CC1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nnc(N3CCC(C#N)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of 1.2 g of the resulting 4-piperidinecarbonitrile hydrochloride, 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.8 g diisopropylethylamine, and 10 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 2 hr and 30 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. After it was dried over anhydrous sodium sulfate, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography. The resulting free compound was dissolved in ethyl acetate, then a solution of 4 N hydrochloric acid/ethyl acetate was added thereto, and the resulting crystals were collected by filtration to give 880 mg of the title compound as a yellow powder.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3C(C)=CC=C3C)=[CH:9][C:8]=2[F:21])[CH2:3][CH2:2]1.Cl.NO.C(N(CC)CC)C>C(O)C.C1COCC1>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:8]([F:21])=[CH:9][C:10]([NH2:14])=[CH:11][C:12]=2[F:13])[CH2:5][CH2:6]1
Reactant: Cc1ccc(C)n1-c1cc(F)c(C2=CCSCC2)c(F)c1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(F)c(C2=CCSCC2)c(F)c1

Procedure:
To a stirred solution of 1-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2,5-dimethyl-1H-pyrrole (0.828 g, 2.71 mmol) in 95% ethanol/THF (10:1, 55 mL) is added hydroxylamine hydrochloride (3.77 g, 54.2 mmol) and triethylamine (3.8 mL, 27.1 mmol). The reaction mixture is heated at reflux for 2 days and then concentrated under reduced pressure, diluted with CH2Cl2 (60 mL), washed with water (3×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 10-20% EtOAC/Hexanes, affords the title compound, MS (ESI+) for C11H11F2NS m/z 228 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 6.22 (m, 2 H), 5.91 (m, 1 H), 3.83 (m, 2 H), 3.33 (m, 2 H), 2.86 (t, 2 H), 2.53 (m, 2 H).
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[C:7]1([P:13](Cl)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CCOCC>[C:1]([P:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)(C)[Mg]Cl
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
466 ml of a 1.06 Molar titrated solution of 494 mmoles of t-butylmagnesium chloride in 466 ml of ether was added dropwise to a stirred solution of 88.4 g (494 mmoles) of phenyldichlorophosphine in 750 ml of anhydrous ether, maintained at +10° C. under an inert atmosphere. After the addition was complete the mixture was stirred for 15 minutes at +10° C., then the reaction mixture was allowed to gradually warm to ambient temperature. A Grignard mixture of 741 mmoles of phenylmagnesium bromide (prepared from 116.4 g of bromobenzene and 19.8 g of magnesium turnings in 450 ml of anhydrous ether) was added dropwise at +27° C., and the reaction mixture was then refluxed for 18 hours. The mixture was cooled to +18° C., and 340 ml of water was added dropwise at a temperature of between +18° C. and +36° C. After treatment with concentrated hydrochloric acid and ammonium hydroxide distillation gives t-butyldiphenylphosphine. 31P-NMR(delta)=17.53 ppm (relative intensity 1000.59), Yield=about 46%, BP=120°-125° C. at 0.2 torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[N:12]2[C:26](=[O:45])[C@@H:27]([CH2:33][N:34]([CH:43]=[O:44])[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[N:6][CH:7]=1.ClC1C=C(C(OO)=[O:54])C=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[N:12]2[C:26](=[O:45])[C@@H:27]([CH2:33][N:34]([CH:43]=[O:44])[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[N+:6]([O-:54])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)c[n+]2[O-])CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
To a solution of phenylmethyl (3S)-3-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-pyrazolidinecarboxylate (130 mg, 0.210 mmol) in dichloromethane (DCM) (4 mL) under nitrogen at 0° C. was added 3-chlorobenzenecarboperoxoic acid (141 mg, 0.629 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then warmed up to room temperature and stirred overnight. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted with DCM twice. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the crude product as a white semi-solid. The crude product was purified by RP-HPLC to provide phenylmethyl (3S)-3-{[(5-fluoro-1-oxido-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-pyrazolidinecarboxylate (103 mg, 77%). LCMS: (M+H)+: 636.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH2:14]([N+]1C=CN(C)C=1)C.[ClH:22]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:14][Cl:22]
Reactant: Cl
Reactant: Cc1ccc(C)cc1
Reactant: CC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: O
Product: Cc1ccc(C)c(CCl)c1
Temperature: 25 °C
Yield: 1844.6 %

Procedure:
53 g p-xylene, 4.9 g 1-ethyl-3-methylimidazolium tetrafluoroborate and 1.6 g concentrated hydrochloric acid whose concentration is 36% are added into a 500 ml four-neck flask and the temperature is raised to 80˜85° C. after well stirring. And the reaction solution is kept warm tor 0.5 h after the gas of hydrochloride is inflated, and then cooled to the room temperature, standing for layering. The upper layer is organic layer while the lower layer is water layer. The water layer is dehydrated trader vacuum and the gained ionic liquid can be recycled and reused. The organic layer is transferred into a 500 ml four-neck flask and is rectified under vacuum. Alter desolventizing. 70.6 g 2,5-dimethylbenzyl chloride is finally provided (91.3%) yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:19]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][NH:30][CH3:31]>Cl.O>[C:7]([C:6]1[N:5]([CH3:12])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][C:2]=1[N:1]=[N:19][N:30]([CH3:31])[CH3:29])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(N)nc(-c2ccccc2)n1C
Reactant: O=N[O-]
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(N=NN(C)C)nc(-c2ccccc2)n1C
Temperature: 0 °C

Procedure:
4-Amino-5-carbethoxy-1-methyl-2-phenyl imidazole (2.84) [made by the method of Cook et. al, Journal of the Chemical Society, 1950 (2775)] in 5N hydrochloric acid (24.0 ml) was cooled to 0° C and a cold solution of sodium nitrite (0.96 gm) in water (5 ml) added slowly, with stirring, keeping the mixture at 0° C. The resulting solution was added dropwise to a cold (0° C) mixture of sodium carbonate (120 mls of 30%) and dimethylamine (2.5 mls of 25% aqueous solution).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C([N:54]1[CH2:59][CH2:58][NH:57][C@H:56]([CH3:60])[CH2:55]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:54]5[CH2:59][CH2:58][NH:57][C@@H:56]([CH3:60])[CH2:55]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (R)—N′-Boc-2-methyl-piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (30 mg, 48.1%). LC-MS m/z 707 (M+H)+, 0.74 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.88 (d, J=6.27 Hz, 3H) 1.20 (t, J=7.53 Hz, 3H) 1.29-1.36 (m, 7H) 1.40-1.64 (m, 3H) 1.84-1.92 (m, 3H) 2.17 (s, 3H) 2.60-2.67 (m, 4H) 2.73-2.78 (m, 1H) 2.83 (q, J=7.36 Hz, 2H) 3.46 (s, 2H) 3.52 (td, J=11.36, 2.13 Hz, 2H) 3.80-3.87 (m, 2H) 4.04-4.11 (m, 1H) 4.21-4.44 (m, 6H) 6.74 (d, J=7.78 Hz, 1H) 7.04 (d, J=1.76 Hz, 1H) 7.07-7.11 (m, 1H) 7.14-7.21 (m, 3H) 7.26 (d, J=7.78 Hz, 1H) 7.34-7.38 (m, 1H) 7.99 (s, 1H) 8.43 (t, J=5.77 Hz, 1H) 9.02 (t, J=5.77 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][OH:13])[O:9]2)=[CH:4][CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH2:24]>N1C=CC=CC=1>[C:14]1([S:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][O:13][S:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:21])=[O:24])[O:9]3)=[CH:4][CH:3]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: Nc1ccc2c(c1)OC(CO)CC2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(c1)OC(COS(=O)(=O)c1ccccc1)CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of (7-amino-2-(hydroxymethyl)chroman (0.52 g, 2.9 mmol) in pyridine is treated with a solution of phenylsulfonyl chloride (0.81 mL, 6.4 mmol) in pyridine, stirred at ambient temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, ethyl acetate:hexane 1:1) to afford the title product as an off-white solid, 1.23 g (92% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].C(=O)[CH2:10][CH:11]([CH3:13])[CH3:12].CCCCCC.[C-:21]#[N:22].[K+]>O.N1CCCCC1>[CH2:10]([CH:4]([CH2:3][C:1]#[N:2])[C:21]#[N:22])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)CC#N
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCNCC1
Product: CC(C)CC(C#N)CC#N
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of ethyl cyanoacetate (733 g, 6.48 mol), isovaleraldehyde (613.9 g, 7.13 mol), piperidine (5.5 g, 0.065 mol), and hexane (0.5 L) was placed under reflux with continuous removal of water. When no additional water was collected, the mixture was cooled and distilled under vacuum to remove solvent. Isopropanol (1 L) was added to the remaining oil, followed by a solution of potassium cyanide (422 g, 6.48 mol) in water (2 L). The reaction mixture was maintained below 35° C. during addition of the potassium cyanide solution and then held at approximately 35° C. for 4 h. The reaction mixture was distilled at atmospheric pressure until a temperature of 95° C. was reached and then refluxed at this temperature for 5 h. The reaction mixture was cooled, diluted with water (0.5 L) and extracted with 1 L methyl tert-butyl ether (MTBE). The MTBE extract was washed with water (0.5 L), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give 873.4 g of 2-isobutyl-succinonitrile as an oil. Purified samples of 2-isobutyl-succinonitrile can be obtained by vacuum distillation (90° C. at 0.275 mm Hg).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[OH-].[Na+].[CH3:14][CH2:15]O>O>[CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([C:8]([O:10][CH2:14][CH3:15])=[O:9])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: CC1CCC(C(=O)O)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1CCC(C)NC1
Temperature: 25 °C

Procedure:
To 194.1 (1044 mg, 7.29 mmol) in EtOH (5207 μL) was added concentrated hydrochloric acid (405 μL, 7.29 mmol). The resulting solution was heated at reflux for 18 hours. The reaction mixture was then cooled to room temperature and poured onto water. The reaction was brought to pH 10 with 1N sodium hydroxide in water and was then extracted with EtOAc. The organic phase was then dried over anhydrous Na2SO4 and filtered to provide ethyl 6-methylpiperidine-3-carboxylate. ESI-MS M+H 172.2.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:25][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=O)c1ccc(C(C)=O)cc1
Yield: 54 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using 4-acetylbenzoic acid and dodecylamine gave the title compound as a white solid (54%). 1H NMR (CDCl3, 300 MHz) δ 8.00-7.90 (m, 2H), 7.85-7.71 (m, 2H), 6.05 (br s, 1H), 3.41-3.30 (m, 2H), 2.56 (s, 1.5H), 2.54 (s, 1.5H), 1.63-1.73 (m, 2H), 1.72-1.05 (m, 18H), 0.78 (m, 3H). M−(LC/MS(ESI)): 330.4; M+(LC/MS(ESI)): 332.4. HPLC (Condition A), Rt: 5.87 min (HPLC purity: 99.7%).
Reaction SMILES: CO.[F:3][C:4]1[CH:26]=[CH:25][C:7]([NH:8][C:9]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[NH2:22][C:20]1[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:9]([NH:8][C:7]2[CH:25]=[CH:26][C:4]([F:3])=[CH:5][CH:6]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a mixed solution of methanol 5.0 mL and ethyl acetate 5.0 mL of tert-butyl 2-(4-fluoroanilino)-4-nitrobenzoate 1.0 g, was added 5% palladium-carbon 0.20 g, and it was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble matter was filtrated, the solvent was removed under reduced pressure to give tert-butyl 4-amino-2-(4-fluoroanilino)benzoate 0.90 g of white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:21]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[C:7]([I:21])[C:6]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(F)(F)F)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(I)c(OCC(F)(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 96 %

Procedure:
2,4-Di-tert-butyl-1-(2,2,2-trifluoro-ethoxy)-benzene (5.06 g, 17.5 mmol), N-iodosuccinimide (4.74 g, 21 mmol) and p-toluenesulfonic acid monohydrate (1.33 g, 7 mmol) were combined in dichloromethane (50 mL) and heated at 38° C. for 19 h. The reaction was washed with 10% Na2S2O3 solution (2×40 mL). The aqueous was backwashed with dichloromethane (70 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide a yellow oil (6.96 g). The material was purified by flash chromatography using hexane to give 5.85 g (81%) of a light pink oil. 1HNMR (250 MHz, CDCl3): δ 7.67 (d, 1H, J=2.4), 7.37 (d, 1H, J=2.4), 4.45 (q, 2H, J=8.2), 1.40 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[C:26]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cccc(B(O)O)c1OC
Product: CCCNC(=O)c1nnc2c(-c3cccc(OC)c3OC)cccc2c1N
Yield: 87.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,3-dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were reacted to afford the title compound (106 mg, 89.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.78 (dd, J=7.1 Hz, J′=1.5 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.99 (m, 2H), 3.92 (s, 3H), 3.53 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.65 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.86 min.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]([CH3:40])[C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][CH2:17][C@H:18]3[O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[C:9]([CH3:39])[CH:8]=1)=[O:6]>C(O)C.O>[CH3:40][N:4]([CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH3:39])[C:10]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][CH2:17][C@H:18]3[O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[C:11]([CH3:13])[CH:12]=1)=[O:6]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N(C)C)cc5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)N(C)C)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH×H2O (11 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(4-(dimethylcarbamoyl)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (70 mg) in ethanol (2.6 mL) and water (0.5 mL) and the mixture is stirred for 24 hours at room temperature. After concentration the mixture is diluted with water, acidified with aqueous citric acid solution and extracted with dichloromethane. After concentration the mixture is partitioned between dichloromethane and citric acid. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield 21 mg, LC (method 20): tR=5.87 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7](=[CH2:12])C(OC)=O)[O:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[CH3:23][OH:24].O>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:12][CH2:23][OH:24])[O:4][N:3]=1
Reactant: CO
Reactant: C=C(C(=O)OC)c1cc(C)no1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C=CCO)on1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A 8 g quantity of methyl 3-methyl-5-isoxazolylacrylate was dissolved in 150 ml of dichloromethane. To the solution was added dropwise with cooling at -70° C. or lower 100 ml of a 25% solution of di-isobutyl aluminum hydride in toluene. After the addition, the reaction was effected for 30 minutes and then the excess of the reducing agent was decomposed with methanol-water. The organic layer was separated and dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation, giving 4.5 g of 3-methyl-5-isoxazolyl-allyl alcohol (Compound 4a) as an oil in a yield of 67.6%.