Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>CO.C(Cl)(Cl)Cl>[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:17]=[N:16][C:15]4[C:14]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:13][C:12]([C:24]5[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[N:28][CH:29]=5)=[N:11][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NS(=O)(=O)c5ccc(F)cc5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a 25 mL flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (Example 7, Step 2) (0.1 g, 0.0002 mol) and pyridine (4 mL) were added. To the same flask, 4-fluorobenzenesulfonyl chloride (0.038 g, 0.0002 mol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 10% methanol in chloroform and washed with water. The organic layer was washed with brine, dried over sodium sulfate and was evaporated to provide the crude product. The crude product was purified by flash column chromatography (3% methanol in chloroform) to obtain the title compound (0.06 g, 45%). 1H NMR (300 MHz, DMSO-d6): δ 10.57 (s, 1H), 10.42 (s, 1H), 9.48 (s, 1H), 8.98 (d, J=2.1 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.91 (dd, J′=5.1 Hz, J″=3.9 Hz, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.45 (dd, J′=8.7 Hz, J″=1.5 Hz, 3H), 7.23 (d, J=7.8 Hz, 1H), 4.57 (br s, 4H), 3.83 (br s, 4H), 1.49 (s, 9H). LC-MS (ESI): Calculated mass: 658.2; Observed mass [M+H]+: 658.9 (RT=1.69 min).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N)C1C=CC=CC=1.C(O)(=O)C>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:14](/[C:13](=[O:20])[CH2:12][Cl:11])\[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)/C(=C\c1ccc(Cl)cc1Cl)C(=O)CCl

Procedure:
A solution 2,4-dichlorobenzaldehyde (4.6 g, 26.1 mmol), ethyl 4-chloro-3-oxobutanoate (4.5 g, 27.4 mmol), benzylamine (165 mg, 1.5 mmol), and acetic acid (118 mg, 2.0 mmol) in isopropyl alcohol (30 mL) stirred at ambient temperature for 96 h. The mixture was diluted with isopropyl alcohol to give a total volume of 50 mL and was saved as a stock solution of Example 1B (0.52 mmol/mL).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.N1CCCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CCCc2ccc(Br)cc21
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1C(=Cc2cccnc2)CCc2ccc(Br)cc21
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 7-bromo-1-tetralone (11.25 g), pyridin-3-carboxaldehyde (5.35 g), acetic acid (5 ml) and piperidine (6 ml) was heated on a stream bath for 6 hours and then allowed to stand for 18 hours. The volatile material was evaporated and the residue was dissolved in ethyl acetate. The solution was extracted several times with dilute hydrochloric acid and the combined extracts were made just alkaline with dilute sodium hydroxide solution. The solid was filtered off, washed with water and crystallised from methanol to give 7-bromo-2-(3-pyridylmethylene)-1-tetralone (12.8 g), m.p. 124°-125°.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)=[C:16]([Cl:27])[N:15]=[C:14]([Cl:28])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.Cl>CCO.[Fe]>[ClH:27].[CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)=[C:16]([Cl:27])[N:15]=[C:14]([Cl:28])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1c(-c2cccc([N+](=O)[O-])c2)c(Cl)nc(Cl)c1=O)OCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2c(Cl)nc(Cl)c(=O)n2CC(=O)OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
The pyrazinone, 1-benzyloxycarbonylmethyl-3-dichloro-6-(3-nitrophenyl)pyrazinone (EX-100A), (15.01 g, 34.6 mmol) was taken up in 325 mL of 50% EtOH (w/w) and heated to 75° C. EtOAc was added until the solution was homogeneous (about 80 mL). Iron powder (9.4 g, 168 mmol) was added, followed by 0.57 mL of 12 M HCl (6.8 mmol) in about 0.6 mL of 50% EtOH. The reaction was monitored by TLC (80% EtOAc/hexanes) and was complete within 40 minutes. The reaction mixture was cooled to room temperature, and the iron was removed by filtration through Celite. The yellow solution was diluted with 600 mL of EtOAc and 300 mL of water. Saturated NaCl was added to help separate the layers. The organic phase was washed with saturated NaHCO3 (2×250 mL), saturated NaCl (1×250 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was taken up in 20–25 mL of 3.4 M HCl in EtOAc. Additional EtOAc (about 25 mL) was added, and the mixture was heated to dissolve all of the compound. The volatile components were removed under reduced pressure. The residue (crusty solid) was taken up in EtOAc and slowly dripped into hexanes. The pale yellow solid that precipitated was filtered and dried under vacuum at room temperature to yield 12.19 g (80% yield) of 1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-aminophenyl)pyrazinone hydrochloride (EX-100B) as a pale yellow solid: 1H NMR (300 MHz, CD3OD) δ 4.61 (AB q, 2H, J=17 Hz), 5.20 (AB q, 2H, J=12 Hz), 7.31–7.51 (m, 7H), 7.63–7.67 (m, 2H); HPLC purity (retention time): 91% (3.0 min); LRMS m/z 404 (M++H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]([O:18]C)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Li+].[OH-]>CO>[CH3:15][O:14][C:12]([C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][O:9][C:10]=1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)noc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of dimethyl 3-phenylisoxazole-4,5-dicarboxylate (770 mg, 2.95 mmol) in MeOH (15 mL)/water (5.00 mL) at rt was added LiOH, hydrate (124 mg, 2.95 mmol) and the reaction mixture was allowed to stir at rt for 1 hr. The MeOH was removed in vacuo and the remaining aqueous solution was diluted with water (5 mL). The pH was adjusted to <1 with 1N HCl and the mixture was extracted with EtOAc (40 mL). The organic layer was washed with brine (25 mL), dried (MgSO4) and concentrated to afford 4-(methoxycarbonyl)-3-phenylisoxazole-5-carboxylic acid (709 mg, 2.87 mmol, 97% yield) as a colorless oil. HPLC retention time=1.99 minutes (YMC Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=248.13. 1H NMR (400 MHz, chloroform-d) δ ppm 3.89 (s, 3H) 7.51 (m, 5H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].O=[C:12]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1.[OH-].[Na+]>C1COCC1.CCOCC.O>[C:27]1([N:24]2[CH2:23][CH2:22][N:21]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)[CH2:26][CH2:25]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of LiAlH4 (3.32 g, 0.0875 mol) in dry THF (125 mL) at 0° was treated with a solution of AlCl3 (40 g, 0.03 mol) in dry Et2O (125 mL) and stirred for 30 minutes. Over a 10-minute period, a solution of trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine (10.54 g, 0.035 mol) in THF (150 mL) was added, and the reaction mixture was allowed to warm to room temperature. After 20 hours, the reaction mixture was cooled in ice-water and treated with THF (50 mL) containing H2O (3 mL), then with 50% NaOH (3 mL) and H2O (6 mL). The inorganic material was filtered off through a Celite pad, and the solids were washed thoroughly with THF. The combined filtrates were evaporated to dryness, and the residue was taken up in CH2Cl2, dried (Na2SO4), and concentrated to yield trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexylamine as a white solid, 9.64 g (96%), which was used without further purification; mp 65-70° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[O:20]1[CH:24]=[CH:23][C:22]([CH:25]2[NH:30][CH2:29][CH2:28][NH:27][CH2:26]2)=[CH:21]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][CH2:29][NH:30][CH:25]([C:22]5[CH:23]=[CH:24][O:20][CH:21]=5)[CH2:26]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cc(C2CNCCN2)co1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccoc4)C3)c(F)cc2c1=O
Temperature: 120 °C
Yield: 24.3 %

Procedure:
A mixture of 365 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 593 mg of 3-(3-furanyl)piperazine and 10 ml of pyridine was heated in a pressure bottle at about 120° C. for 2 days, then allowed to cool and the solvent removed. The residue was purified by flash silica gel column chormatography eluting with chloroform:methanol:water:triethylamine (95:5:1:1). This product was then triturated with methanol-ether and the solid, washed with methanol, then ether and dried in vacuo, giving 125 mg of the desired product, mp 202°-204° C.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([S:18]([OH:21])(=O)=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([S:18]([Cl:24])(=[O:21])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)O)cc1OC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)Cl)cc1OC(=O)c1ccccc1

Procedure:
A solution of 3-benzoyloxy-4-methoxybenzenesulfonic acid (7.69 g) in dry toluene (70 mL) is treated with thionyl chloride (9 mL), and ,the mixture is heated at reflux for 6 hours. Concentration gives 3-benzoyloxy-4-methoxybenzenesulfonyl chloride (8.4 g), in the form of a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Product: CC(C)(C)OC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Dissolve tert-butyl-N-(2-hydroxyethyl)-carbamate (10 mL, 64.5 mmol) in anhydrous THY (500 mL) at 0° C. Add sodium hydride (60% in mineral oil, 3.1 g, 77.4 mmol) and stir for 30 min at 0° C. Add benzyl bromide (9.2 mL, 77 mmol) followed by tetrabutylammonium iodide (3.7 g, 10 mmol) and stir at ambient temperature overnight. Quench with water (500 mL), extract with diethyl ether (3×100 mL), wash the combined organic extracts with brine, dry over MgSO4, filter, and evaporate to give the desired intermediate (5 g), that was used without further purification.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:35][CH2:36][O:37]C)[N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]3[N:26]=[CH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl.C(#N)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:35][CH2:36][OH:37])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]3[N:26]=[CH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1cc2ccccc2cn1
Agent: BrB(Br)Br
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CCO)n2CCCNC(=O)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Boron tribromide (5.50 mL of 1 M in dichloromethane) was added dropwise to a chilled (0° C.) suspension of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide (1.0 g, 2.2 mmol; U.S. Pat. No. 6,756,382, Example 192) in dichloromethane (20 mL). The reaction mixture was stirred at 0° C. for 45 minutes and then allowed to warm to ambient temperature. After 5 hours the reaction mixture was concentrated under reduced pressure and the residue was allowed to stand over the weekend. The residue was diluted with methanol (20 mL) and then heated to 50° C. Hydrochloric acid (about 10 mL of 6 N) was added and the mixture was stirred for about 2.5 hours. The mixture was made basic with aqueous sodium hydroxide and then extracted with ethyl acetate (×2). The combined extracts were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid. This material was suspended in hot acetonitrile, allowed to cool, and then the solvent was decanted. The resulting material was dried under vacuum to provide about 400 mg of N-{3-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide as a white solid, mp 245-246° C. Anal calcd for C25H24N6O2: % C, 67.73; % H, 5.59; % N, 18.80. Found: % C, 67.38; % H, 5.54; % N, 18.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:11]2[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[C:33](O)[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:28][C:29]1[CH:34]=[C:33]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11]3[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=3)=[CH:25][CH:24]=2)[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CC(C)c1csc(N(CCc2ccc(F)cc2)Cc2ccc(CO)cc2)n1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccc(F)cc3)c3nc(C(C)C)cs3)cc2)cc1F
Yield: 64.2 %

Procedure:
A solution of (4-{[[2-(4-fluorophenyl)ethyl](4-isopropyl-1,3-thiazol-2-yl)amino]methyl}phenyl)methanol (510 mg), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (280 mg), triphenylphosphine (420 mg) and diethyl azodicarboxylate (40% toluene solution, 750 mg) in toluene (3 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (490 mg, yield 64%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](S(C)(=O)=O)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].B(O)(O)[C:36]1C=CC(C)=CC=1.BrC1C=CC([C@H](N[C@H](C(NC2(C#N)CC2)=O)CCC)C(F)(F)F)=CC=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:36])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(C)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between p-tolylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex. MS (+ESI): 430 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: CCN
Product: CCNC(=O)c1cc(/C=C/c2c(-c3ccc(F)cc3)noc2C)n[nH]1
Yield: 33 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using ethylamine instead of morpholine, to the title compound (8.9 mg, 33%) which was obtained as an off white solid. MS: m/e=341.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:18]=1[CH2:35][CH2:36][CH:37]([CH3:52])[CH2:38][C@H](C)C(N1[C@H](C(C)C)COC1=O)=O>CN(C=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][O:28][C:19]1[C:18]([CH2:35]/[CH:36]=[C:37](\[CH3:52])/[CH2:38][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:17]([O:16][CH3:15])[C:25]([CH3:26])=[C:24]2[C:20]=1[C:21](=[O:27])[O:22][CH2:23]2
Reactant: CCOC(=O)CP(=O)(OC)OC
Reactant: COCCOCOc1c(CCC(C)C[C@H](C)C(=O)N2C(=O)OC[C@H]2C(C)C)c(OC)c(C)c2c1C(=O)OC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2)P(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° was added 50% NaH/oil (33 mg), and the mixture stirred for 10 minutes. (E) 4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (600 mg) was added at the same temperature and allowed to reach room temperature in 30 minutes. The reaction was poured onto water and extracted with EtOAc. The organic layers were washed with water, dried over sodium sulfate, and evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by BtOAc) to obtain ethyl (E) 6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(dimethylphosphono)-4-methyl-4-hexenoate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CCCCC[C@H](O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a flask containing (S)-1-(4-Bromo-phenyl)-hexan-1-ol in CH2Cl2 at ambient temperature (˜23° C.) was added imidazole and t-butyldimethylsilyl chloride. The reaction mixture was stirred at ambient temperature for a period of time until all starting material was consumed before quenching with a mixture of MeOH and water. The organic layer was washed with deionized water and concentrated under reduced pressure to give the product as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:14].[K+]>[OH-].[K+].O.OCC(CO)O>[OH:14][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: O
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
4-Isopropyl-benzoic acid (5.00 g, 30.0 mmol) was dissolved in 20 mL of 10% potassium hydroxide in water solution. To this solution was added 480 mL of 0.2 N aqueous potassium hydroxide solution, followed by a solution of potassium permanganate (9.65 g, 60.0 mmol) in 500 mL of water. The mixture was stirred at 70° C. for one hour. To the reaction mixture was added a few drops of glycerol, and the resulting mixture was cooled to 0° C. Solid residues were removed by filtration, and the filtrate was acidified to pH 1 and extracted twice with ether. The ether extracts were combined, rinsed once with brine and dried over magnesium sulfate and concentrated in vacuo. The concentrate was washed with carbon tetrachloride and recrystallized from water to give 2.2 g (12.2 mmol) of 4-(1-hydroxy-1-methyl-ethyl)-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16][CH2:17]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(F)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of 3-fluoro-4-methylbenzoic acid (13.23 g, 85.85 mmol) in EtOH (200 mL) at 0° C. was added SOCl2 (3 mL) dropwise. The reaction mixture was heated at 60° C. overnight, then cooled to room temperature, concentrated under reduced pressure and diluted with DCM. The organic layer was washed with 1N NaOH (100 mL×2), dried (MgSO4) and concentrated to give ethyl 3-fluoro-4-methylbenzoate (15.02 g, 96%).