Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15][CH2:14][N:13]1[C:21]([O:23][CH3:24])=[O:22].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:37]([O:39][C:40](=[O:45])[CH2:41]C([O-])=O)[CH3:38].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.O.CC(OC)(C)C>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:18]([C@H:16]1[CH2:15][CH2:14][N:13]([C:21]([O:23][CH3:24])=[O:22])[C@@H:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[F:1])[CH2:17]1)=[O:20])[CH3:38]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)cc1F
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.82 g, 13.80 mmol) was dissolved in methyl THF (120 mL), then di(1H-imidazol-1-yl)methanone (4.03 g, 24.84 mmol) was added. The mixture was stirred at room temperature under nitrogen for 5 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.23 g, 24.84 mmol) was suspended in methyl THF (120 mL), then magnesium chloride (2.365 g, 24.84 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 5 h using a large magnetic stirring bar (flask 2). The contents of flask 1 was transferred into flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (50 mL) and water (50 mL) was added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated leaving a slightly yellow oil. The residue was purified by chromatography on silica (Biotage (340 g) with a 1 CV EtOAc in heptane (20%) followed by a gradient of 20-60% EtOAc in n-heptane (8 CV). The column was conditioned at 20% EtOAc in -n-heptane (1 CV)). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl) piperidine-1-carboxylate (413 mg, 7%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)-phenyl)piperidine-1-carboxylate (2.83 g, 49%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.32 (m, 3H), 1.81-1.96 (m, 2H), 2.06-2.18 (m, 1H), 2.27-2.36 (m, 1H), 2.87-2.97 (m, 1H), 3.34-3.51 (m, 3H), 3.58-3.66 (m, 3H), 4.14-4.23 (m, 3H), 5.15 (dd, 1H), 7.25-7.40 (m, 3H). MS m/z 420 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.18-1.31 (m, 3H), 1.58-1.72 (m, 1H), 1.87-2.06 (m, 2H), 2.40-2.60 (m, 2H), 3.17 (dt, 1H), 3.45 (s, 2H), 3.73 (s, br., 3H), 4.08-4.23 (m, 2H), 4.34 (s, br., 1H), 5.75 (s, br., 1H), 7.22-7.43 (m, 3H). MS m/z 420 (M+H)+
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(O)(O)(=O)=O.[NH2:17]O.C(O)C.[OH-].[NH4+]>O.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:10][C:9]1[O:11][N:17]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(C)on1
Temperature: 40 °C
Reaction time: 4 h
Yield: 118.3 %

Procedure:
A mixture of 0.16 mole ethyl 2,4-dioxovalerate and 0.08 mole hydroxylamine sulfate, 50 ml ethanol and 70 ml toluene was stirred at 40° C. for four hours. The mixture was cooled to 15°-20° C., 1.8 g of concentrated ammonium hydroxide added and stirring continued at room temperature for 60 hours. The mixture was poured into water/toluene, the aqueous layer extracted with toluene, the organic layers combined, washed with brine and dried (Na2SO4). Evaporation of solvent in vacuo gave a yellow liquid which was distilled to afford 14.68 g of product, b.p. 120°-124° C. at 30 torr which crystallized upon standing.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1CC=Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(=Cc2cccc([N+](=O)[O-])c2)CCc2ccccc21

Procedure:
A mixture of 3,4-dihydro-1)(2H)-naphthalenone (21.9 g), 3-nitrobenzaldehyde (22.6 g) and p-toluenesulphonic acid monohydrate (50 mg) in toluene (250 ml) was stirred at reflux with separation of water for 4.5 hours. The brown solution was allowed to cool overnight. The resulting yellow-orange deposited solid was filtered off, washed well with toluene and dried in vacuo yielding 2-(3-nitrobenzylidene)-3,4-dihydro-1(2H)-naphthalenone as crisp yellow needles.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH:12]([O:14][CH2:15][CH2:16]Cl)=[CH2:13].O>CN(C)C(=O)C.C(OCC)(=O)C>[CH:12]([O:14][CH2:15][CH2:16][O:8][C:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:9])=[CH2:13]
Reactant: O=C(O)Cc1cccs1
Reactant: C=COCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C=COCCOC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 500 ml of N,N-dimethylacetamide (DMAc) was dissolved 100 g of thiophene-2-acetic acid, and to the resulting solution was added 31 g of sodium hydroxide, followed by stirring at room temperature for 10 minutes. Then, 112 g of 2-chloroethyl vinyl ether was added thereto and the mixture was stirred at 120° C. for 2 hours. The deposition of salt was observed. To the reaction solution were added water and ethyl acetate, and the mixture was subjected to separation procedure. The organic phase was washed three times with water, dried, concentrated and distilled under a reduced pressure to obtain the desired compound (X-1). The desired compound (X-1) was identified by NMR.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]C)=[C:31]([F:37])[CH:30]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:37])[CH:30]=1
Reactant: COc1ccc(Sc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Sc3ccc(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 18 %

Procedure:
(S)-2-(1-((6-Amino-5-((3-fluoro-4-methoxyphenyl)thio)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (233 mg, 0.45 mmol) was treated with boron tribromide (1M in dichloromethane, 1.35 ml, 1.35 mmol) with dichloromethane as a solvent according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 40 mg (18% yield) as a solid. Purity 99%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O.CO>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g (1.45 mmol) of 7-benzylxanthine from Example 6b) in 60 ml of dimethylformamide was heated to 50° C. and treated in portions with 0.35 g (1.45 mmol) of sodium hydride, diluted with 20 ml of dimethylformamide and stirred at 50° C. for one hour. 1.36 ml (1.45 mmol) of 2-bromopropane were added to this suspension and the temperature was increased to 80° C. In the course of the reaction, a total of 4.91 ml (52.3 mmol) of 2-bromopropane were additionally added. After a total of 16 hours at 80° C., 10 ml of water and 2 ml of methanol were added, and the mixture was stirred for 10 minutes, treated with a further 70 ml of water and extracted three times using 70 ml of methyl tert-butyl ether each time. The organic phases were washed with water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.4).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:24][CH2:23][C:15]2([N:19]=[C:18](SC)[NH:17][C:16]2=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[C:5]([O:9][C:10]([N:12]1[CH2:24][CH2:23][C:15]2([N:19]=[C:18]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:26]([F:25])([F:34])[F:35])[CH:28]=3)[NH:17][C:16]2=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CSC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(Nc1cccc(C(F)(F)F)c1)NC2=O
Yield: 50.5 %

Procedure:
Acetic acid (0.275 ml, 4.8 mmol) was added to a solution of 2-methylsulfanyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (72 mg, 0.24 mmol) and m-trifluoromethylaniline (0.150 ml, 1.2 mmol) in DMA (1.0 ml), and the mixture was irradiated with microwaves at 150° C. for 20 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 4-oxo-2-(3-trifluoromethyl-phenylamino)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (50 mg, 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH3:9][S:8][C:6]1[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]2=[C:2]([NH:18][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:7]=1
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Reactant: CCCCCN
Product: CCCCCNc1nc(SC)[nH]c2nccc1-2

Procedure:
To 200 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of n-pentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 71 mg (57%), m.p. 134°-137°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([Sn](CCCC)(CCCC)CCCC)[CH:44]=2)[C:39](=[O:59])[N:38]1[CH3:60]>O1CCOCC1.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.[Cu]I>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:43]4[CH:44]=[C:45]5[C:40]([C:39](=[O:59])[N:38]([CH3:60])[N:37]5[CH3:36])=[CH:41][CH:42]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(=O)n(C)n(C)c2c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(=O)n(C)n(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (32.0 mg, 0.061 mmol) and 1,2-dimethyl-6-(tributylstannyl)-1H-indazol-3(2H)-one (33.0 mg, 0.073 mmol) in dioxane (0.8 mL) was added Pd(PPh3)4 (4.0 mg, 0.003 mmol) and CuI (4.0 mg, 0.018 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. for 2 days. Concentrated in vacuo and then purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C36H36ClN4O4S: 655.2; found: 655.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CO[CH:11](OC)[CH2:12]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:11]=[CH:12][C:4]=2[CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: COC(CBr)OC
Product: Brc1ccc2sccc2c1

Procedure:
5-Bromobenzo[b]thiophene was prepared in quantitative yield for two steps from 4-bromobenzenethiol and bromoacetaldehyde dimethyl acetal as described in the preparation of 4- and 6-methoxybenzo[b]thiophene (see Example 92, Part A): mp 40-43.5° C.; FDMS 212.1 (M−1); Anal. Calcd for C8H5BrS·0.10C7H8OS: C, 46.01; H, 2.57; S, 15.53. Found: C, 46.19; H, 2.49; S, 15.79.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH:19]([OH:22])[CH2:20]O)=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:22][CH:19]([CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:24][CH:23]=2)[CH2:20][O:4]1
Reactant: OCC(O)COc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1ccc(OCC2COC(CBr)(c3ccc(Cl)cc3)O2)cc1

Procedure:
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 12.2 parts of 1-(p-chlorophenoxy)-2,3-propanediol, 3 parts of p-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed for 20 hours in a four-necked round-bottom flask equipped with a watertrap. The benzene solution is washed successively with a diluted sodium hydroxide solution and with water. The solvent is removed in vacuo. The residue is triturated in methanol. The precipitated product is filtered off (methanol filtrate is set aside) and crystallized from toluene, yielding A-2-(bromomethyl-4-(p-chlorophenoxymethyl)-2-(p-chlorophenyl)-1,3-dioxolane; m.p. 165°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:25])[CH2:12][C:13](=[O:24])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[Cl:23].CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](=[O:25])[CH2:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[Cl:23]
Reactant: O=C(/C=C/c1ccc(O)cc1Cl)CC(=O)/C=C/c1ccc(O)cc1Cl
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: O=C(CCc1ccc(O)cc1Cl)CC(=O)CCc1ccc(O)cc1Cl

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1,7-bis(2-chloro-4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (27 mg, 71 μmol, synthesized in Example 247) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=65/35 to 55/45. The product was obtained as a gum (15.1 mg, 56%) having the following characteristics.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.O.C(=O)(O)[O-:14].[Na+]>S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:11])=[O:14])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc2scnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccc2scnc2c1

Procedure:
A solution of 1,3-benzothiazole-5-carbonitrile (100 mg, 0.62 mmol, 1.00 equiv) in sulfuric acid (3.0 mL) was heated for 2 h at 45° C. After cooling down, the reaction mixture was poured into 15 mL of water. The pH value of the solution was adjusted to 7 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with of ethyl acetate (5×10.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under vacuum. This resulted in 60.0 mg of the title compound as a crude product, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 179.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:37][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Reaction time: 24 h

Procedure:
2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) was dissolved in CCl4 (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added. The reaction was heated to reflux and stirred for 24 h. The mix was diluted with CH2Cl2, washed with sat'd NaHCO2, dried over MgSO4 and concentrated to give the compound as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C)[C:5]2(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.N[OH:23]>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:23])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: COCCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 51.3 %

Procedure:
A stirred mixture of 2.89 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of 2-methoxyethanol (ethylene glycol monomethyl ether) was refluxed for 2 hours, and then cooled to 0°. The solid that formed was collected on a filter, washed with ethanol, and dried in air to give 1.40 g (51%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]2[C:20](=[CH:21][C:22]([NH2:30])=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]2[C:20](=[CH:21][C:22]([NH:30][C:4]([C:3]3[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[O:5])=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3Cl)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloronicotinoyl chloride (3.52 g, 20 mmol, 1.0 eq.) and 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (5.52 g, 20 mmol, 1.0 eq.) in CH2Cl2 (100 mL) was added NaHCO3 (6.4 g, 80 mmol, 4.0 eq.). The mixture was stirred for 1 h at RT, then filtered and concentrated, followed by drying on a vacuum pump for 3 hours. 7-[(2-Chloro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester was obtained as a white foamy solid. This title compound was used for next step without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].FC(F)(F)C(O)=O.[NH:45]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:46]([C:55](O)=[O:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1>CN(C=O)C>[NH:45]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:46]([C:55]([NH:1][C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:56])[CH2:47][C:48]1[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reaction time: 15 h

Procedure:
0.60 g of BOC-(D)-Gln-Gly-MePhe-NHNHCSNH2 is treated with trifluoroacetic acid and dissolved in 10 ml of DMF. The solution is neutralized with 0.19 ml of TEA, and 0.54 g of Z-Tyr ONB is added. The mixture is stirred for 15 hours. The DMF is distilled off and the residue is treated with ethyl acetate and filtered to obtain a powder, which is further reprecipitated from methanol-ether. Yield 0.54 g; m.p. 128°-133° C.; [α]D24 -72.4° (c=1.1, DMF); Rf1 0.13.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[K+].Cl.[NH2:18][CH:19]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:20]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)=[O:21]>C(OCC)(=O)C.CCCCCC.CN(C=O)C>[CH2:7]([NH:18][CH:19]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:20]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:23]1)=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc2c(cc1OC)CN(C(=O)C(N)C(C)(C)C)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)CN(C(=O)C(NCc1ccccc1)C(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
Anhydrous potassium carbonate (120 mg), benzyl chloride (20 μl, 0.174 mmol) and a catalytic amount of potassium iodide were added to a DMF (1 ml) solution of N(2-amino-3,3-dimethylbutyryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (43.2 mg, 0.141 mmol) obtained in Reference example 7, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with a 1:1 mixture (50 ml) of ethyl acetate and hexane, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate and hexane (2:1) as an eluent to obtain the captioned compound (33.5 mg, 59.6%) as a colorless foamy substance.