Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([CH2:5][CH2:6][NH:7][C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:10]([O:12][CH3:13])=[O:11])(=O)=O.ClCCl.S([O-])(=O)(=O)C.[Br-:27].[Li+]>O>[Br:27][CH2:5][CH2:6][NH:7][C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: [Br-]
Reactant: COC(=O)C=C(CC(=O)OC)NCCS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C=C(CC(=O)OC)NCCBr
Temperature: 35 °C
Reaction time: 19 h
Yield: 86.7 %

Procedure:
Dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate (156.3 g, 529 mmol) was added to a 2 L three-neck flask, which was fitted with a mechanical stirrer, thermometer, and reflux condenser. Dichloromethane (750 mL) was added and stirred until the mesylate had completely dissolved, anhydrous lithium bromide (69.0 g, 794 mmol) was added, and the mixture stirred at 35° C. for 19 hours. The mixture was cooled to 0° C. and water (250 mL) added, then stirred for 5 minutes and the phases separated. The organic phase was washed with water (3×250 mL) and brine (150 mL), and dried over anhydrous potassium carbonate for 15 minutes. Rotary evaporation of the solvent under reduced pressure (50° C.) gave 128.4 g of crude dimethyl 3-(2-bromoethylamino)-2-pentenedioate as a yellow oil, which quickly solidified to a yellow solid. The crude material was purified by extraction into boiling hexane (5×750 mL) and recrystallization from hexane, and the pot residues extracted and recrystallized, to give a total of 90.8 g (61.2% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as white needles. An NMR spectrum in CDCl3 indicated an Z/E isomer ratio of 19:1, and remeasurement of the CDCl3 solution after three days indicated an Z/E ratio of 4:1. The two isomers were not separated.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[CH3:25][CH:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCOCC>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH:26]([CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCC(C)O
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)OC(=O)c1ccc(OC(C)=O)cc1F

Procedure:
To 10.8 g (0.06 mol) of 4-acetoxy-2-fluorobenzoic acid was added 60 ml of thionyl chloride, and the mixture was allowed to react under reflux for 7 hours. Then, excess thionyl chloride was distilled off, and 10 ml of pyridine and 5.3 g (0.0402 mol) of 2-octanol were added dropwise. The resultant mixture was stirred at room temperature for a whole day, and then diluted with 200 ml of ether. An organic layer was washed with dilute hydrochloric acid, with a 1N sodium hydroxide aqueous solution and with water in this order, and dried over magnesium sulfate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Cl:19])[C:6]=1SC)=O.[CH3:22][NH:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:7]1[CH2:8][CH2:9][CH2:10][C:5]2[C:3](=[O:2])[N:23]([CH3:22])[NH:24][C:6]1=2
Reactant: CNN
Reactant: COC(=O)C1=C(SC)N(c2c(C)cc(C)cc2Cl)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (4.99 g), methylhydrazine (16.4 mL), p-toluenesulfonic acid monohydrate (2.91 g), and methanol (75 mL) were combined in a glass vessel sealed with a Telfon™ screw cap. The reaction mixture was stirred in a 130° C. oil bath for 24 h, then cooled to room temperature and concentrated on the rotary evaporator. The residue was chromatographed on silica gel using a methanol/dichloromethane gradient to give 3.21 g of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one, mp 95.9–99.9° C.
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=5)[C:20]4=[O:31])[CH2:14][CH2:13]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)C>CO.O>[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=5)[C@H:20]4[OH:31])[CH2:14][CH2:13]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A slurry of 1-phenyl-8-[(1,2,3,4-tetrahydro-7-methoxy-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (10.0 g, see example 195) in 150 ml of methanol is cooled in ice and treated dropwise with 4.5 g of sodium borohydride in 25 ml of water. The resulting mixture is stirred over a 60-hour period at room temperature under nitrogen. The reaction mixture is diluted with water and extracted with methylene chloride. Concentration of the dried methylene chloride solution yields the crude product. Trituration with absolute ethanol gives 8.1 g of the title compound, melting point 216°-218° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][N+:12]([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=C[N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-methoxy-benzaldehyde (1 equivalent) was dissolved in MeOH and chilled in an ice bath. Nitromethane (1 equivalent) was added. NaOH (1.05 equivalents) in water was added dropwise to the nitromethane/aldehyde solution, such that the temperature did not rise above 15° C. The reaction was then allowed to stir at 0° C. for 15 minutes. The reaction mixture was poured into concentrated HCl diluted with water. Product was extracted with EtOAc and washed with water, brine, and dried (Na2SO4). Solvent was removed to yield a yellow oil which was freeze-dried in 90% MeCN/H2O to give the product 2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:34][CH2:35][CH:36]([OH:39])[CH2:37][CH3:38]>ClCCl>[OH:39][CH:36]([CH2:37][CH3:38])[CH2:35][NH:34][C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCC(O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(O)CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
23.20 g (103.93 mmol) 3-benzyloxycarbonylamino-propionic acid, 14.10 g (104.35 mmol) 1-hydroxybenzotriazole, 18.80 ml (135.07 mmol) triethylamine and 21.00 g (135.27 mmol) (ethyl-3-(3-dimethylamino)-propylcarbodiimide hydrochloride (EDAC) are placed in 150 ml dichloromethane, cooled to 0° C. and stirred for 0.75 hours at this temperature. Then 10.50 g (114.26 mmol) 1-amino-2-butanol are added, and the mixture is stirred for 2.5 hours at 0°-5° C. The reaction mixture is extracted with water and 1 molar sodium carbonate solution, the organic phase is dried and evaporated to dryness. The residue is extracted again with dichloromethane and sodium carbonate solution.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[C:5]([N+:11]([O-])=O)[CH:6]=[C:7]([F:10])[C:8]=1[Cl:9])#[N:2].[H][H]>[Pd].C(O)C>[C:1]([C:3]1[C:4]([Cl:14])=[C:5]([CH:6]=[C:7]([F:10])[C:8]=1[Cl:9])[NH2:11])#[N:2]
Reactant: [H][H]
Reactant: N#Cc1c(Cl)c(F)cc([N+](=O)[O-])c1Cl
Agent: [Pd]
Solvent: CCO
Product: N#Cc1c(Cl)c(N)cc(F)c1Cl
Temperature: 25 °C

Procedure:
27.0 g of 3-cyano-2,4-dichloro-5-fluoronitrobenzene (0.247 mol), 500 ml of ethanol and 2.18 g of Pd/C were heated to 60° C. and hydrogenated under 3 Mpa of hydrogen pressure for 3 hours. The reaction mixture was cooled to room temperature. The catalyst was filtered off. After removing the solvent, 48.0 g of 3-cyano-2,4-dichloro-5-fluoroaniline were given in 94.7 yield.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([O:17][CH:18]([CH3:20])[CH3:19])=[N:12][C:11]([NH:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1)=[CH:10]2)=[O:6])(C)C>[OH-].[K+].CO>[CH:18]([O:17][C:13]1[C:14]2[C:9](=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:16][CH:15]=2)[CH:10]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1)([CH3:20])[CH3:19]
Reactant: Cc1cc(Nc2cc3cc(C(=O)OC(C)C)ccc3c(OC(C)C)n2)n[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Yield: 90.3 %

Procedure:
Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid isopropyl ester (300 mg) was dissolved in KOH and MeOH (1:1, 10 ml), the mixture was stirred at room temperature for 20 hrs, the MeOH was evaporated and neutralized with concentrated HCl (PH=3). The solid was collected to give 240 mg of desired product (91% yield). LC-MS: m/e 325 (M−1).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:30][CH:31]1[CH2:34][N:33]([C:35]2[S:36][C:37]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:38]([CH:40]([CH3:42])[CH3:41])[N:39]=2)[CH2:32]1.[Cl:48][C:49]1[N:50]=[C:51]([C:56](O)=[O:57])[NH:52][C:53]=1[CH2:54][CH3:55]>CC(N(C)C)=O.ClCCl.C(OCC)(=O)C>[Cl:48][C:49]1[N:50]=[C:51]([C:56]([NH:30][CH:31]2[CH2:34][N:33]([C:35]3[S:36][C:37]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:38]([CH:40]([CH3:42])[CH3:41])[N:39]=3)[CH2:32]2)=[O:57])[NH:52][C:53]=1[CH2:54][CH3:55]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CC(N)C2)nc1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1sc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.9 %

Procedure:
WSC hydrochloride (203 mg, 1.06 mmol), 1-hydroxybenzotriazole (48 mg, 0.35 mmol) and N-methylmorpholine (0.08 mL, 0.71 mmol) were added to a mixed solution of ethyl 2-(3-aminoazetidin-1-yl)-4-isopropyl-1,3-thiazole-5-carboxylate obtained in Example (221b) (95 mg, 0.35 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (62 mg, 0.35 mmol) in DMA/dichloromethane (4 mL/2 mL), and the mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with 10% saline and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 61 mg of the title compound as a white solid (41%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:23][O:22]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1>[OH:22][CH:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)[CH2:23][NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(C2CO2)cc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 90 °C

Procedure:
Tosylamide (0.69 g, 4.0 mmol), 2-(4-nitrophenyl)oxirane (183) (0.33 g, 2.0 mmol), benzyltriethylammonium chloride (46 mg, 0.20 mmol) and potassium carbonate (28 mg, 0.20 mmol) were suspended in dioxane (1.0 mL) and the resulting mixture was stirred at 90° C. After four hours the mixture was cooled to room temperature and poured into DCM (15 mL). The resulting mixture was filtered and evaporated. The residue was chromatographed (Isolera, 40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I84) as an orange solid (363 mg, 38% yield); 1H NMR (400 MHz, d6-DMSO) δ 8.19-8.13 (m, 2H), 7.64-7.59 (m, 2H), 7.57-7.52 (m, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.27 (s, 1H), 5.82 (d, J=4.5 Hz, 1H), 4.71 (dd, J=10.7, 6.0 Hz, 1H), 2.92 (td, J=6.2, 1.7 Hz, 2H), 2.36 (s, 3H). LCMS Method C: rt 5.55 min, m/z 335.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([P:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19]C2C=CC=CC=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:26]1([P:18](=[O:19])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]([NH:11][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])[CH2:2][CH2:3][CH3:4])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)Nc1ccc(Cl)cc1
Reactant: c1ccc(OP(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCC(NC(=O)Nc1ccc(Cl)cc1)P(=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 0.15 mole each of p-chlorophenylurea, phenyl diphenylphosphinite, and n-butylraldehyde in 150g of toluene is warmed at reflux for 5.5 hr, giving a reaction mixture having a 31P nmr signal only at -36.8 ppm. When the toluene is removed at reduced pressure, the residue solidifies. Recrystallization of a portion from benzene gives a white solid: mp 275°-278° C.; 31P nmr -37.4 ppm; 1H nmr δ9.1 (s, 1, NHC6H4Cl), 6.4-8.1 (m, 15, aryl and CHNH), 5.1 (m, 1, PCH), 0.6-2.0 (m, 7, CH2CH2CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:14]=1[F:13]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(C(F)(F)F)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-trifluoromethylphenol (407 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([CH2:25][NH:26][CH3:27])[C:21]([CH3:28])=[N:20]1.O1CC1>CO>[Cl:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([CH2:25][N:26]([CH3:27])[CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:21]([CH3:28])=[N:20]1
Reactant: CNCc1c(C)nn(Cc2ccccc2Cl)c1C
Reactant: CCOc1ccc(OCC2CO2)cc1
Solvent: CO
Solvent: C1CO1
Product: CCOc1ccc(OCC(O)CN(C)Cc2c(C)nn(Cc3ccccc3Cl)c2C)cc1
Temperature: 68 °C
Yield: 61.4 %

Procedure:
2-((4-Ethoxyphenoxy)methyl)oxirane (0.06 g, 0.32 mmol) and 1-(1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (0.10 g, 0.38 mmol) were dissolved in methanol (0.32 ml), warmed to 68° C. and stirred until the oxirane was consumed as observed by TLC. The solution was cooled to room temperature and the solvent removed under reduced pressure. The resulting oil was purified using flash column chromatography with 1:2:0.01 ethyl acetate:hexanes:triethylamine as the eluting solvent to yield 0.09 g (63%) of 1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.35 (dd, J=7.8, 1.2, 1H), 7.17 (td, J=7.7, 1.3, 1H), 7.12 (td, J=7.5, 1.2, 1H), 6.85-6.79 (m, 4H), 6.48 (dd, J=7.6, 0.9, 1H), 5.28 (s, 2H), 4.12-4.04 (m, 1H), 3.97 (q, J=7.0, 2H), 3.90 (d, J=4.9, 2H), 3.47 (d, J=13.2, 1H), 3.34-3.29 (m, 1H), 2.60 (dd, J=12.2, 9.7, 1H), 2.48 (dq, J=12.2, 3.9, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H), 1.38 (t, J=9.1, 3H). 13C NMR (75 MHz, CDCl3) δ 153.47, 153.04, 148.04, 138.67, 135.31, 131.92, 129.43, 128.79, 127.58, 127.50, 115.63, 115.63, 115.53, 115.53, 113.71, 71.25, 66.37, 64.14, 59.51, 51.70, 50.28, 42.09, 15.13, 12.36, 9.82. HRMS (m/z): [MNa]+ calc for C25H32ClN3O3Na+, 480.20. found 480.2030.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1cncc(-c2cccs2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
A mixture of 3-bromopryidine (1.30 mL, 13.5 mmol) and tetrakis(triphenylphosphine) (0.468 g, 0.41 mmol) in 40 mL of dimethoxyethane is stirred under nitrogen at room temperature for 10 minutes. 2-Thiophene boronic acid (1.90 g, 14.8 mmol) and 20 mL of 1N sodium carbonate are added and the resulting mixture is refluxed overnight. The solution is cooled to room temperature and filtered through Celite. The filtrate is extracted with ether (2×30 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to afford the title compound (0.355 g, 2.20 mmol) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1.[OH-].[Li+].[ClH:38]>CO.C1COCC1>[ClH:38].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Temperature: 45 °C
Yield: 87 %

Procedure:
Methyl (1-{5-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)-amino]pyridin-2-yl}piperidin-4-yl)acetate (Example 319, 216 mg, 0.44 mmol) was suspended in a mixture of MeOH (4 ml) and THF (8 mL). Lithium hydroxide (4.4 mL of a 1M aqueous solution) was added. The resulting clear solution was heated at 45° C. for 15 minutes then cooled and acidified to pH ˜2 with dropwise addition of concentrated aqueous HCl. Volatile material was removed by evaporation and the residue was washed with water then dried to give the title compound (182 mg, 87%) as a solid; 1H NMR δ 1.16-1.45 (2H, m), 1.76-1.93 (2H, m), 1.98-2.13 (1H, m), 2.28 (2H, d), 3.12 (2H, t), 4.28 (2H, d), 7.25-7.41 (1H, m), 7.70-7.88 (1H, m), 8.13-8.32 (2H, m), 8.55 (1H, d), 11.16 (1H, s), 11.29 (1H, s); MS m/e MH+ 477.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:34]#[N:35])=[CH:20][N:21]2[C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=2)=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].CO>[NH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:34]#[N:35])=[CH:20][N:21]2[C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(OCCNC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(OCCN)ccc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of 4-[6-(2-benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-hydroxybenzoic acid (0.087 g) in a mixed solvent ethyl acetate (2 mL) and methanol (2 mL) was added palladium-carbon powder (0.016 g) under an argon atmosphere at 0° C., and this mixture was stirred at 40° C. under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. This obtained light yellow solid was washed with diethyl ether, dried to give the title compound (0.058 g).
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][CH:9]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])#[N:2].[CH3:18][CH:19]([CH3:42])[CH:20]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:27])[C:21]([O:23][CH3:24])=[O:22]>>[C:1]([C:3]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:30]3[S:29][C:28]([C:26]([NH:25][CH:20]([CH:19]([CH3:42])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])=[O:27])=[N:32][CH:31]=3)=[CH:34][CH:35]=2)=[O:14])=[CH:16][CH:17]=1)([CH2:4][CH3:5])[CH2:6][CH3:7])#[N:2]
Reactant: CCC(C#N)(CC)c1ccc(C(=O)OC)cc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: CCC(C#N)(CC)c1ccc(C(=O)Nc2ccc(-c3cnc(C(=O)NC(C(=O)OC)C(C)C)s3)cc2)cc1

Procedure:
The title compound was synthesized analogous to Example 85, using methyl 4-(3-cyanopentan-3-yl)benzoate (Intermediate 6) and intermediate 2. 1HNMR (DMSO-d6, 300 MHz) δ 10.52 (s, 1H), 8.78 (d, 1H), 8.41 (s, 1H), 8.03 (d, 2H), 7.93 (d, 2H), 7.81 (d, 2H), 7.62 (d, 2H), 4.33 (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 2.1-2.02 (m, 4H), 0.95 (t, 6H), 0.81 (t, 6H); MS (ES+): m/z 533.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6](C(C1C=CC=CC=1)=O)[CH:7]2[C:12]#N.BrC[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[H-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH2:12][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: N#CC1c2cccc(Br)c2C=CN1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(Br)cccc12
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
A dried round bottomed flask was charged with 5-bromo-2-(phenylcarbonyl)-1,2-dihydro-1-isoquinolinecarbonitrile (D10; 687 mg, 2.03 mmol) and dry, nitrogen purged N,N-dimethylformamide (DMF) (15 ml). The solution was cooled to −10° C. with stirring in an ice/methanol bath at which temperature the flask was evacuated. The flask was closed from the vacuum and allowed to warm to room temperature before the vacuum was re-introduced and the vessel then filled with nitrogen. (3-Bromopropoxy)-tert-butyldimethylsilane (available from Aldrich; 0.563 ml, 2.43 mmol) was added, the vessel purged with nitrogen three times and the solution cooled again to −10° C. To the solution was added sodium hydride (97 mg, 2.43 mmol) as a single portion. The mixture was held at −10° C. for 5 minutes before being allowed to warm to room temperature and stirred under nitrogen for 5 hours. To the mixture was added potassium carbonate (560 mg, 4.05 mmol). The slurry was warmed to 80° C. for 3 hours before being filtered through a plug of celite (ethyl acetate eluent). The organic layers were further diluted with ethyl acetate and partitioned with water (×3) then brine. The aqueous fractions were discarded and the organic layers passed through a hydrophobic frit before being concentrated in vacuo to give a tan oil. The oil was dissolved in DCM and purified by flash column chromatography on silica using 0% to 20% ethyl acetate in cyclohexane gradient elution. The relevant fractions were pooled and concentrated in vacuo to give the title compound as a yellow semi-solid (0.64 g).