Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:10]3=[C:9]([C:24]([O:26]CC)=[O:25])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO>[C:20]([O:19][C:17]([N:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]([C:24]([OH:26])=[O:25])=[C:10]2[CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Temperature: 65 °C
Yield: 94.6 %

Procedure:
A mixture of Intermediate 39A (0.81 g, 2.10 mmol) and lithium hydroxide monohydrate (706 mg, 16.8 mmol) in methanol (20 mL) was heated at 65° C. for 5 hours. After evaporation of methanol, the residue was dissolved in brine. Concentrated HCl (2.5 mL) was added carefully to acidify and the mixture was extracted twice with DCM. The combined organic extracts were dried and evaporated to give Intermediate 39B as white solid (0.71 g 95% yield). LCMS (+ESI) m/z 357.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:27]=[CH:28][C:23]([C:20](=[O:22])[CH3:21])=[CH:24][CH:25]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(C(C)=O)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-acetyl-phenylboronic acid to give 1-{4-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 359(MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH2:12][CH2:13][OH:14].[N+:15]([CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])([O-:17])=[O:16]>ClCCl.C(Cl)Cl.C1COCC1.CCN(CC)CC>[F:11][CH2:12][CH:13]([OH:14])[CH:18]([N+:15]([O-:17])=[O:16])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: OCCF
Reactant: NC(=O)CCC[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)CCC(C(O)CF)[N+](=O)[O-]
Temperature: 0 °C
Yield: 41.2 %

Procedure:
To a solution of oxalyl chloride (5.29 g, 41.4 mmol) in anhydrous dichloromethane (30 mL) at −78° C. was added anhydrous DMSO (6.2 mL, 87.4 mmol) dropwise with stirring in such a rate that the temperature was kept at −50 to −60° C. The solution was stirred for 15 min, then 2-fluoroethanol (1.62 mL, 27.6 mmol) was added dropwise and it was stirred for 15 min, diluted with dichloromethane (100 mL), followed by addition of dry Et3N (13.5 mL). The reaction mixture was stirred for 15 min, then allowed to warm to 0° C. and stirred at 0° C. for 2 h. To the reaction mixture was added a solution of 4-nitro-butyramide (3.04 g, 23 mmol) in CH2Cl2/THF (50 mL, 1:1). The reaction mixture was stirred at 0° C. for 3 h and then stirred at room temperature overnight. The mixture was concentrated to approximate 20 mL and poured into water (180 mL). It was extracted with ethyl acetate (12×40 mL), and the combined organic layers were dried and evaporated and the residue was purified by silica gel (CH2Cl2/EtOAc) to give 1.84 g (41%) of the titled product as a colorless viscous oil. 1H NMR (acetone-d6): 6.88 (bs, NH, 1H), 6.31 (bs, NH, 1H), 5.20-4.20 (m, 5H), 2.40-2.15 (m, 4H).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11](O)[C@@H:10]2O)[C@H](O)[C@@H](O)[C@@H]1O.Cl>O>[CH:18]([C:9]1[O:13][C:12]([CH2:14][O:15][CH:18]([O:15][CH2:14][C:12]2[O:13][C:9]([CH:18]=[O:19])=[CH:10][CH:11]=2)[C:9]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:11][CH:10]=1)=[O:19]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: O=Cc1ccc(COC(OCc2ccc(C=O)o2)c2ccc(CO)o2)o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
120 g of water was added to 46.8 g of sucrose, then 0.8 g of hydrochloric acid was added, and the resultant substance was heated to be refluxed at 100° C. for 4 hours. After the substance was cooled down, extraction with 120 mL of ethyl acetate was repeated 3 times, and the obtained extract solution was washed with 50 mL of water. An appropriate amount of magnesium sulfate anhydride was added to perform dehydrating overnight. Then, magnesium sulfate was filtered out by a paper filter, and the filtrate was concentrated under reduced pressure using an evaporator to obtain 3.15 g of a flavor improving agent. From this flavor improving agent, 5-hydroxymethyl-2-furaldehyde bis(5-formylfurfuryl)acetal was obtained at a yield of 4.6% by weight by substantially the same refining means as that in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([NH2:1])[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1cccc(N)c1
Solvent: C1CCOC1
Product: Nc1cccc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 3-aminobenzylamine (610 mg, 5 mmol) and TEA (1.01 g, 10 mmol) in 10 mL of THF at 0° C., was added benzyl chloroformate (936 mg, 5.5 mmol) dropwise. The mixture was stirred at rt for 30 min. The reaction was quenched with water and extracted with EtOAc (3×20 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0 to 50% EtOAc in hexanes) gives 66A (911 mg, 71%). MS (ESI) m/z 257.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([C:63]([O:65][CH2:66][C:67]([C:70]([OH:72])=O)([CH3:69])[CH3:68])=[O:64])[CH:60]2[CH2:62][CH2:61]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN.C(N(CC)CC)C>CC#N>[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([CH:60]2[CH2:61][CH2:62]2)[C:63]([O:65][CH2:66][C:67]([CH3:69])([C:70](=[O:72])[NH:2][CH3:1])[CH3:68])=[O:64])[CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)O)C2CC2)C(C)C)ccc1OC
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)C(C)(C)COC(=O)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HBTU (161 mg, 0.43 mmol) is added to a solution of (3S*,4R*)-3-{[(2-carboxy-2-methyl-propoxycarbonyl)-cyclopropyl-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 0.35 mmol) in CH3CN (10 mL) at 0° C. After 5 min a solution of methylamine (44 μL, 0.35 mmol, 8M in EtOH) and triethylamine (493 μL, 3.54 mmol) in CH3CN (10 mL) is added at 0° C. and the reaction solution is stirred at RT for 5 h. Another portion of methylamine (0.22 mL, 1.75 mmol) is added and stirring is continued for another 16 h. Then, triethylamine (247 μL, 1.77 mmol) and HBTU (268 mg, 1.02 mmol) are added and the reaction mixture is stirred at 50° C. for another 16 h. The solvent is evaporated and the crude product purified by HPLC (Interchrom C18 ODB 10 μm, 28×250 mm, eluent: CH3CN/H2O 5%/2.5 min, CH3CN/H2O 5-100%/23 min, 100% CH3CN/4.5 min, flow 40 mL/min) to give the title compound. MS (LC-MS): 691.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.38 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1I.[NH2:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[N+:30]([O-:32])=[O:31].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[C:18]1[CH:19]=[CH:20][C:15]([NH2:14])=[C:16]([N+:30]([O-:32])=[O:31])[CH:17]=1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: Fc1cccc(OC(F)(F)F)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2c(F)cccc2OC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
2-Fluoro-1-iodo-6-trifluoromethoxybenzene (612 mg, 2.00 mmol, prepared as described in WO2005/097136), 4-amino-3-nitrophenylboronic acid pinacol ester (1.3 eq., 687 mg, 2.60 mmol), and (dppf)PdCl2.DCM (0.05 eq., 81.6 mg, 0.100 mmol) were placed in a 40 mL vial equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (10 mL) and 2M aq Na2 CO3 (4 mL) were added via syringe. The vial was capped tightly and placed in a heating block where the reaction was stirred at 90° C. for 24 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed sequentially with water and brine. The organic extract was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:3, v/v over 30 min, yielding 548 mg (87%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 8.21 (s, 1H), 7.30-7.47 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 7.14 (t, J=8.6 Hz, 1H), 6.91 (d, J=6.6 Hz, 1H), 5.37 (br. s., 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:8][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH:18]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 12 mL solution of methyl 2-amino-4-bromobenzoate 1.2 g were added 1-fluoro-4-iodobenzene 1.5 mL, cesium carbonate 3.4 g, palladium acetate 12 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 32 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 12 hours. After the reaction mixture was cooled to room temperature, palladium acetate 12 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 32 mg were added to it, and it was heated and refluxed under nitrogen atmosphere for 12 hours. After the reaction mixture was cooled to room temperature, water was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B (spherical type), eluent; hexane:ethyl acetate=10:1] to give methyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g of pale yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[NH:15]C(=O)N[C:12]1=[O:17].[OH-:18].[Na+]>>[NH2:15][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:17])=[O:18]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(c2ccc3ccccc3c2)N1
Agent: [Na+]
Product: NC(C(=O)O)c1ccc2ccccc2c1

Procedure:
A solution of 5-(2-naphthyl) hydantoin (10g., 44.5 mmole) in 10% sodium hydroxide solution (50 ml.) was heated under reflux for 18 hours. The solution was cooled, filtered, diluted and treated with concentrated hydrochloric acid to bring the pH to 5.0. The resulting solid was filtered off washed with water and added to 5N-hydrochloric acid (2 L.). Insoluble material was filtered off and the filtrate was taken to pH 5.0 with 40% sodium hydroxide solution. On standing, the amino-acid crystallised out as platelets (3.92 g.) m.p. 238°-240°, λλmax. (pH 6.0 phosphate) 225 (ε 51,700), 276 (ε 3,520), 268 nm. (ε 3,420).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](F)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].ClCCl.[CH3:16][N:17](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:16]#[N:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(F)cc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc(C#N)c1
Temperature: 25 °C

Procedure:
A mixture of the methyl 3-chloro-5-fluorobenzoate, zinc cyanide (8.46 g, 72.3 mmol) zinc (dust, 235 mg, 3.6 mmol), [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.5 g, 1.8 mmol) in N,N-dimethylformamide (70 ml) was heated at reflux for 1 hour. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was extracted with water and brine and concentrated in vacuo, to afford crude methyl 3-chloro-5-cyanobenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(CC)[NH:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[S:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[N:10]([C:22](=[S:23])[NH:21][C:16]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC)NCCS1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SCCN1C(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 100.1 %

Procedure:
A mixture of 1.61 g of ethyl thiazolidine-2-carboxylic acid ethyl ester thus obtained, 2.04 g of 3,5-dichlorophenylisothiocyanate and 20 ml of toluene was heated at 90° C. for 1 hour. Then the reaction mixture was cooled and the precipitate was separated by filtration to give 3.11 g (yield 85.1%) of 3-(3,5-dichlorophenylthiocarbamoyl)thiazolidine-2-carboxylic ethyl ester. The melting point was 170.5°-171.5° C. and the results of elementary analysis were as follows: Found (calculated in parentheses): C 42.68% (42.74%), H 3.93% (3.86%), N 7.70% (7.67%), Cl 19.32% (19.41%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].CO.O.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-acetyl-5-(methyl(propyl)carbamoyl)benzoate (107 mg, 0.386 mmol) in a mixture of THF (0.4 mL), MeOH (0.8 mL) and H2O (2.0 mL), was added LiOH (28 mg, 1.159 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound which was ready for next step without further purification: HPLC retention time: 1.412 min (method A). MS (ESI) (M+H)+ 264.18.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2CCC#N)=[CH:4][C:3]=1[F:22].C(OC([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C>C(#N)C>[NH2:30][C@H:31]1[CH2:35][CH2:34][N:33]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][NH:9]3)=[CH:4][C:3]=2[F:22])[CH2:32]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC#N
Product: N[C@H]1CCN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of Example 7C (32.4 mg) and (3S)-3-(tert-butoxycarbonylamino)pyrrolidine (55.8 mg) in acetonitrile (1 mL) in a sealed vial was heated for 24 hours then cooled and concentrated. The concentrate was dissolved in 1:1 DMSO/methanol (1 mL) and chromatographed by reverse phase HPLC. The product was suspended in 2-propanol (1 mL), treated with 1M LiOH (1.2 mL), heated at 80° C. for 18 hours in a sealed vial for 24 hours, and concentrated. The concentrate was treated with 10% citric acid to pH 4-6 and filtered. The filtrant was dissolved in 4M HCl/dioxane (1.5 mL), and this solution was stirred for 2 hours and concentrated. NMR (500 MHz DMSO-d6) δ 13.4 (m, 1H), 8.50 (m, 1H), 8.45 (s, 2H), 8.00 (m, 1H), 4.00-3.40 (m, 5H), 2.38 (m, 1H), 2.18 (m, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([S:10][C:11]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=2[CH2:13]Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CS(C)=O>[C:4]1([S:10][C:11]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=2[CH2:13][C:1]#[N:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1ccc(Sc2ccccc2)c(CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Temperature: 40 °C
Reaction time: 9 h

Procedure:
11.2 g of sodium cyanide in 135 ml of dimethyl sulphoxide are warmed to 40° c and treated dropwise over a period of 10 minutes with a solution of 87 g of 2-(phenylthio)-5-trifluoromethyl-benzyl chloride in 72 ml of dimethyl sulphoxide. The mixture is stirred at 40° C for 9 hours, cooled to room temperature, treated with 200 ml of water and extracted with 200 ml of ether. The aqueous phase is then extracted twice with 100 ml of ether each time. The combined organic phases are now washed twice with 200 ml of water each time, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 2-(phenylthio)-5-trifluoromethyl-phenylacetonitrile as a dark-red oil.
Reaction SMILES: [NH2:1][C:2]1([C:13]([OH:15])=[O:14])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].O.[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>O1CCOCC1>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:23]([NH:1][C:2]3([C:13]([OH:15])=[O:14])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:3]3)=[O:39])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(N)(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottomed flask was charged with 3-amino-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (prepared according the procedure described in Synthesis 1991, 783-784.) (2.464 mmol), sodium carbonate (1.3 g, 12.32 mmol), a stir bar and water (70 mL). (9H-fluoren-9-yl)methyl carbonochloridate (1.9 g, 7.39 mmol) in 1,4-dioxane (50 mL) was added and the milky solution was stirred overnight at rt. The next day the reaction was poured into a separatory funnel and the aqueous solution washed with diethyl ether (repeated twice) (organic phases were discarded at this stage). The aqueous phase was acidified to pH 2-3 with 1 M HCl (a precipitate was formed) and the product was extracted with EtOAc (repeated 3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The solid was used without purification in the next step. LRMS (M+Na)+: 461 m/z.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([O:16][CH3:17])[C:9]=1[Cl:18])(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:18][C:9]1[C:10]([O:16][CH3:17])=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=1[CH:7]=[CH2:6]
Reactant: COc1c(C#N)ccc(CCOS(C)(=O)=O)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1ccc(C#N)c(OC)c1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-chloro-4-cyano-3-methoxyphenyl)ethyl methanesulfonate (207 mg, 0.714 mmol) in DCM (4 mL) was treated with DBU (0.538 mL, 3.57 mmol) and stirred overnight at 40° C. TLC (50% ethyl acetate/hexanes) showed complete conversion to a faster intense UV band for product. The reaction was then diluted with DCM and aq. citric acid and the mixture was extracted twice with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (5-20% ethyl acetate/hexanes) afforded the title intermediate.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7](=[O:13])[C:6]=2[CH:14]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=1)[C:20]([NH:22][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[C:19]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=2)[C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7](=[O:13])[C:6]=2[CH:14]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN1CCOc2cc(F)c(F)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)C(=O)N(C)CCO3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 6.6 %

Procedure:
A mixture of 7,8-difluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (725 mg, 2.0 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (600 mg, 1.97 mmol) and potassium carbonate (550 mg, 3.88 mmol) in DMA (10 mL) was heated to 160° C. for 5 hours. Water (20 mL) was added to the reaction and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (2×30 mL) and brine (2×30 mL), dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by column chromatography on silica, eluting with 20-100% ethyl acetate in isohexane, to give the desired compound as a foam (65 mg).