Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]>>[F:1][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: [F-]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Product: N#Cc1cc([N+](=O)[O-])c(F)c([N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 5 %

Procedure:
A mixture of 7.0 parts of anhydrous potassium fluoride and 5.0 parts of 4-chloro-3,5-dinitrobenzonitrile was heated and maintained at about 150° C., with stirring, for a period of about 6 hours, under a positive pressure of nitrogen. The reaction mixture, a viscous, dark brown liquid was filtered and washed with methylene chloride. Analysis of the filtrate by gas chromatographic techniques indicated a 69% conversion and a 5% yield of 4-fluoro-3,5-dinitrobenzonitrile.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[NH2+:12].CC(C)([O-])C.[K+].[F:22][C:23]([F:31])([F:30])[C:24]([CH2:26][C:27](=O)[CH3:28])=O>O1CCCC1>[CH3:28][C:27]1[CH:26]=[C:24]([C:23]([F:31])([F:30])[F:22])[N:13]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([F:14])([F:15])[F:2])[N:12]=1
Reactant: NC(=[NH2+])Nc1ccccc1C(F)(F)F
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nc(Nc2ccccc2C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 24 g (0.1 mole) of 2-trifluoromethylphenyl-guanidinium hydrochloride in 80 ml of tetrahydrofuran is added to a solution of 12 g (0.1 mole) of potassium tert.-butoxide in 100 ml of tetrahydrofuran. When the exothermic reaction has subsided, 15.4 g (0.1 mole) of α,α,α-trifluoroacetylacetone in 20 ml of tetrahydrofuran are added. The reaction mixture is stirred for 2 hours at 60° C., then concentrated by evaporation in a rotary evaporator. The residue is chromatographed on silica gel with a mixture of ethyl acetate and hexane (ratio 1:2). 18.7 g (58 2% of the theoretical amount) of the title compound of formula ##STR16## are obtained in the form of crystals having a melting point of 65°-66° C. (Comp. No. 2.020).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[P:6](=[O:10])([OH:9])([OH:8])[OH:7].[U+4:11]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[U+4:11].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[U+4:11].[U+4:11]
Reactant: O=P(O)(O)O
Agent: [U+4]
Product: O=P([O-])([O-])[O-]
Temperature: 150 °C

Procedure:
The same procedure is followed as in Example 1. Thus, a uranium(IV) solution is first of all prepared by dissolution of 4 g of UCl4 in a 4M hydrochloric acid HCl solution in order to obtain a uranium concentration of 0.7M. This solution is mixed with a 5M phosphoric acid solution in the phosphoric acid/uranium(IV) molar ratio of 3/2 with an excess of 2% of phosphoric acid. The mixing is carried out in a container which is subsequently closed and which is heated, as in Example 1, at a temperature of 150° C. on a sand bath for 1 week. Under these conditions, the initial gel is converted by heating to a crystalline powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br-].[CH2:22]([Zn+])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Cc4ccccc4)n3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
N-(6-(2-Chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (59.0 mg, 194 μmol) was suspended in THF (1.8 mL) to which tetrakis(triphenylphosphine)palladium (25.6 mg, 22 μmol) and benzylzinc bromide, 0.5 m solution in THF (0.55 mL, 275 μmol) were added under argon, and the reaction solution was stirred at RT. After about 2 hours, the reaction was heated to 80° C., and stirring was continued under argon. After about 100 minutes, additional Pd(PPh3)4 (21 mg) and benzylzinc bromide (0.57 mL) were added, and the reaction was stirred. After another hour or so, additional benzylzinc bromide (0.73 mL) was added, and stirring was continued at 80° C. The reaction was stirred overnight and quenched with saturated ammonium chloride (1.5 mL) and 0.5 M EDTA (2.5 mL), extracted with 10:1 DCM/MeOH, and the organic phases were dried over sodium sulfate, filtered through Celite®(diatomaceous earth), and concentrated. The crude concentrate was purified on a silica gel column (20:1 to >5:1 DCM/MeOH), and the product-containing fractions were collected, concentrated, and washed with Et2O and MeOH and filtered. The solid was collected and purified on HPLC (10% to >95% MeCN/water with 0.1% TFA over 40 minutes), to provide N-(6-(2-benzylpyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (8 mg, 11% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C20H16N4OS: 360. 1H NMR (400 MHz, DMSO-d6): 12.50 (s, 1H), 8.85 (s, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.38 (m, 2H), 7.31 (m, 2H), 7.21 (m, 1H), 4.28 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6](=[O:17])[N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=1.Br[CH2:19][C:20](=[O:23])[CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([C:20]([CH2:19][N:5]1[C:4]([CH3:3])=[CH:8][N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:6]1=[O:17])=[O:23])[CH3:22]
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Reactant: CCC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)Cn1c(C)cn(N=Cc2cccnc2)c1=O
Reaction time: 0.5 h

Procedure:
0.72 g of sodium hydride are added to a suspension of 4.1 g of 2,3-dihydro-4-methyl-2-oxo-1-pyrid-3-ylmethyleneamino-1H-imidazole in 80 ml of N,N-dimethylformamide. The mixture is heated to 50°, treated with a solution of 3.78 g of 1-bromo-2-oxo-butane in 20 ml of N,N-dimethylformamide, and stirred for 30 minutes. The N,N-dimethylformamide is then removed on a rotary evaporator. In a mixer, the residue is mixed intimately with water. The crystals are filtered off, yielding the title compound melting at 183°-184°.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH:19]=[CH:20]C=2O)=[O:15])=[C:9]([F:31])[CH:8]=1.Cl>O1CCCC1.N1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14](=[O:15])[C:16]3[CH:17]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH:19]=[CH:20][C:5]=3[O:4][C:2]2=[O:3])=[C:9]([F:31])[CH:8]=1
Reactant: O=C(Nc1ccc(Cl)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 1 (1.5 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 2.5 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 13.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:45]=[C:46]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:47]=[CH:48][CH:49]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 58 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0298 g, 0.0646 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.388 mmol) and 3-trifluoromethylbenzenesulfonyl chloride (0.0310 mL, 0.194 mmol) to obtain 4-(3-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0251 g, yield 58%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(O)(=O)C.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[Cl:22])(=[O:12])[CH3:11]>O.C(O)C>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[CH:16][C:15]=1[Cl:22])(=[O:12])[CH3:11]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)cc1Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1Cl
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of 0.73 g (0.008 mole) of thiosemicarbazide (Aldrich T3,340-5) in 24 mL of water containing 1.6 mL of glacial acetic acid was added to a solution of 1.58 g of (0.008 mole) 4-acetamido-3-chlorobenzaldehyde (24) in 20 mL of ethanol at 70°. The mixture was stirred at this temperature for 45 minutes. A white precipitate developed in the reaction mixture, which was filtered after cooling to give 1.95 g (90%) of 25 as off white crystals, mp 235-2380°. Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3423, 3260, 3132, 1701 (C=O), 1594, 1508, 1303 cm−1. 1H nmr (90 MHz, DMSO-d6):δ 11.47 (1 H, s, thiosemicarbazone NH), 9.35 (1 H, s, amide NH), 8.15-7.91 (5H; m; H-2, H-5, imine H and thiosemicarbazone NH2), 7.6 (1H; dd, 3JH5-H6=8.1 Hz, 4JH2-H6=1.8 Hz; H-6) 2.18 (3H, s, CH3). Anal. Calcd. for C10H11CIN4OS (270.73): C, 44.36; H, 4.10; Cl, 13.10; N, 20.69; S, 11.84. Found: C, 44.51; H, 4.14; Cl, 12.91; N, 20.67; S, 12.27.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C>CN(C=O)C.CO>[CH:23]1([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[C:2]([F:1])=[CH:3][C:4]([C:16]4[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=4)=[CH:5][C:6]=3[F:15])[CH2:10][CH2:11]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCC1
Reactant: O=C1CCC(c2cc(F)c(OC3CCNCC3)c(F)c2)=NN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1CCC(c2cc(F)c(OC3CCN(C4CCC4)CC3)c(F)c2)=NN1
Yield: 27.5 %

Procedure:
A solution of 6-[3,5-difluoro-4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (350 mg, 1.1 mmol) in a mixture of DMF (2 mL) and MeOH (9 mL) was stirred under argon. Cyclobutanone (0.38 mL, 5 mmol), sodium cyanoborohydride (0.53 g, 8.45 mmol) and acetic acid (0.4 mL, 7 mmol) were added sequentially and stirred at 60° C. for 3 h. The reaction mixture was concentrated at reduced pressure and partitioned between aqueous 1M sodium carbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered and concentrated to provide a crude product. The crude product was purified by ISCO (40 g) chromatography using 2 to 5% methanol in methylene chloride to 10% methanol containing 0.2% ammonium hydroxide in methylene chloride. The recovered product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to furnish a pure product. The pure product was crystallized with a mixture of methylene chloride, ethanol, ether and hexane to obtain 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (110 mg, yield), mp 162-164° C.; MS m/z 364 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]([C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=O)[CH:7]=1.Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6](/[C:8](/[C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=[N:27]/[OH:28])[CH:7]=1
Reactant: NO
Reactant: COc1ccc(F)cc1C(=O)c1nccc(-c2cnccc2C)c1F
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1/C(=N/O)c1nccc(-c2cnccc2C)c1F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of (5-fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanone (0.024 g, 0.071 mmol) and hydroxylamine hydrochloride (0.033 g, 0.480 mmol) in pyridine (Volume: 0.353 ml) was refluxed for 3 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-95% EtOAc in hexanes over 15 min, tr=0.5, 1.5 2.5 min) gave the title compound (22 mg, 0.061 mmol, 87% yield) as a yellow residue. ESI MS (M+H)+=356.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([O:14][CH3:13])[CH:11]=1
Reactant: C[O-]
Reactant: Clc1cc(Cl)c2ccccc2n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c2ccccc2n1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of (2.5 g, 12.6 mmol) 2,4-dichloro-quinoline in anhydrous toluene (20 ml) was added a suspension of solid sodium methoxide (2.5 g, 46.3 mmol) in anhydrous toluene (20 ml). The mixture was stirred under reflux for 16 hours and then allowed to cool to room temperature. The solid that had formed was filtered off and washed with 50 ml toluene. The filtrate was evaporated to dryness under reduced pressure to yield a red solid (2.1 g, 10.8 mmol, 86%). MS (ES) m/z=193.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:13])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:13])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cccnc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cccnc2C1=O

Procedure:
The mixture of 2.83 g of N-(4-nitro-o-tolyl)-pyridine-2,3-dicarboximide, 200 ml of ethyl acetate and 1.6 g of prewashed Raney nickel is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, the residue taken up in chloroform, the solution treated with charcoal, filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-pyridine-2,3-dicarboximide of the formula ##SPC6##
Reaction SMILES: [CH:1]1[C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]([C:5]=23)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18]>CN(C)C=O>[CH2:18]([C:3]1[CH:2]=[CH:1][C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]=1[C:5]=23)[C:17]#[CH:16]
Reactant: C1=Nc2noc3cccc(c23)OC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCc1ccc2onc3c2c1OCC=N3
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A solution of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine of Example 7(b) (3.9 g; 22.1 mmoles) in 120 ml dimethylformamide was added to a suspension of sodium hydride (1.4 g; 27.7 mmoles). This was followed by a solution of propargyl bromide (2.7 ml of 80% solution; 24.4 mmoles). The reaction was heated at 80° C. for 1.5 hours and then quenched into water (400 ml). The resulting precipitate was filtered, rinsed and dried, then passed through a column of florisil (ethyl acetate/dichloromethane). This gave 3.5 g of a solid, mp 100°-104° C., which was recrystallized from isopropanol to give 2.5 g (53%) of 4,5-dihydro-3-(2-propynyl)isoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 104°-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:11]([O:18][C:19](=[O:20])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[NH2:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(NC(=O)CCCCCNC(=O)OCc2ccccc2)c1
Reaction time: 20 h
Yield: 65.9 %

Procedure:
The compound (510 mg) obtained in Example 46-1 was dissolved in DMF (20 ml). To this solution, a solution which was previously prepared by dissolving 6-benzyloxycarbonylamino-hexanoic acid (1.10 g) in DMF (10 ml), adding thereto WSCI hydrochloride (1.08 g) and HOBt (762 mg), and stirring the mixture for 30 minutes was dropped. The whole was stirred for 20 hours. The residue obtained by distilling the solvent off was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (961 mg) as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:17]1[CH:18]=[C:19]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][CH:30]([CH2:37][C:38]2([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:31]3O)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([C:17]1[CH:18]=[C:19]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30]([CH2:37][C:38]2([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31]3)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1(CC2Cc3c(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)cccc3C2O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(CC2=Cc3cccc(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)c3C2)CCCCC1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (0.88 g, 4.64 mmol, 0.2 equiv), compound 14 (10.0 g crude, 23.22 mmol, 1.0 equiv) and toluene (200 mL) was refluxed for 1 h. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an AnaLogix (65-200 g) column, eluting with heptanes to give compound 15 (7.8 g, 81% yield for 2 steps) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([Cl:20])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(CC(=O)Cl)cc1OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (3,4-diethoxy-phenyl)-acetic acid (2.0 g, 8.9 mmol) in DCM (6 ml) were successively added oxalylchloride (1.13 ml, 13.4 mmol) and a catalytic amount of DMF (0.069 ml, 0.89 mmol) at 0° C. (ice bath). The reaction mixture was stirred at 0° C. for 1 h then evaporated to dryness under vacuum to yield the crude (3,4-diethoxy-phenyl)-acetyl chloride (2.2 g, 8.9 mmol, quant.) as a brownish oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]([C:21](=[O:22])[CH2:20][Cl:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: Cc1ccc(Nc2c(F)cc(F)c(F)c2F)cc1
Reactant: O=C(Cl)CCl
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)c(F)c2F)cc1
Temperature: 90 °C
Reaction time: 1.3 h
Yield: 92.2 %

Procedure:
The mixture of N-(2′,3′,4′6′-tetrafluorophenyl)-4-methylanilin (0.82 g, 3.2 mmol) and chloro acetylchloride (1.6 g) is heated with stirring to 90° C. under nitrogen for 1.3 h. To destroy excess of the acid chloride, 2-propanol and water (2 ml each) is added and stirring is continued over night at room temperature. After adding toluene (20 ml), the mixture is extracted with sodium bicarbonate and the organic phase is dried with magnesium sulfate and evaporated to dryness. The residue is purified by flash chromatography (silica, toulene) to obtain N-(2′,3′,4′,6′-tetrafluorophenyl)-N-chloroacetyl-4-methylaniline (0.98 g, 2.95 mmol) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[CH:21][CH:20]=2)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:38]1([CH2:43]O)[CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:31][CH:32]=1)=[CH:21][CH:20]=2)=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:43][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2cn1
Reactant: OCC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCC2CCCC2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2cn1
Yield: 46.5 %

Procedure:
To a solution of 50 mg (0.1 mmol) of (2S)-{[6-(4-tert-butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid methyl ester (Example 298) in dry THF (1 mL) was added cyclopentanemethanol (1.5 eq., 0.15 mmol, 0.016 mL), triphenylphosphine (1.5 eq., 0.15 mmol, 39 mg) and DIAD (1.5 eq., 0.15 mmol, 0.030 mL) according to the procedure M. Chromatography on silica using 20-30% ethyl acetate in hexanes afforded 27 mg of the title compound.