Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][N:34]2[C:38](=[O:39])[CH2:37][CH2:36][C:35]2=[O:40])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: O=C1CCC(=O)N1O
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: N#CC(CCN1CCC(C(=O)ON2C(=O)CCC2=O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
24.5 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid are dissolved in 225 ml. of redistilled N,N-dimethylformamide by warming to about 60°C. To the warm solution were added, with stirring, 9.0 grams of recrystallized N-hydroxysuccinimide, followed by 12.4 grams of dicyclohexylcarbodiimide. A precipitate appears upon cooling to room temperature. The suspension is stirred at room temperature under anhydrous conditions for about 36 hours, then is cooled to approximately 5°C. and is filtered to remove the precipitate. The filtrate is diluted with approximately 400 ml. of ethyl acetate and 200 ml. of water. The organic layer is then separated and washed three times with water, solid sodium chloride being added as needed to break the emulsion formed. The solution is dried over anhydrous sodium sulfate and partially concentrated until a precipitate forms. Filtration and recrystallization of the precipitate from a mixture of tetrahydrofuran and isopropyl ether affords N-[1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carbonyloxy]succinimide, melting at about 156.5°-157.5°C. This product has the formula ##SPC3##
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N+](C1C=CC(C(NN)=O)=CC=1)([O-])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -50 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
(intermediate 1a)(8.3 g, 30.9 mmol), 4-nitrobenzohydrazide (6.16 g, 34.0 mmol) and anhydrous THF (200 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −50° C. 1-Hydroxybenzotriazole hydrate (4.2 g, 30.9 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (7.34 g, 38.3 mmol) at −50° C. followed by triethylamine (5.3 mL, 38.3 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 20 mL, whereupon ethyl acetate (200 mL) was added followed by water (100 mL). The phases were partitioned and the organic phase washed with water (150 mL), brine (150 mL), dried (Na2SO4) and concentrated to furnish a light yellow solid as the title compound (15.9 g, 80%) that was used without further purification. 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.88 (br s, 2H), 8.35 (d, J=6.7 Hz, 2H), 8.16 (d, J=6.7 Hz, 2H), 7.53 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.56 (d, J=6.6 Hz, 1H), 4.46-4.36 (m, 1H), 4.18-4.10 (m, 1H), 3.26 (s, 3H), 1.37 (d, J=7.4 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].[CH3:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>[Cu](I)I>[CH3:17][C:18]1[CH:22]=[CH:21][N:20]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]#[N:16])[N:19]=1
Reactant: N#CCc1ccccc1Br
Reactant: Cc1cc[nH]n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn(-c2ccccc2CC#N)n1
Temperature: 120 °C

Procedure:
A round bottom flask was charged under inert atmosphere with copper iodide (760 mg, 4 mmol), cesium carbonate (3.91 g, 12 mmol) then dimethylformamide (20 mL), previously degassed, was added followed by 2-Bromophenylacetonitrile (519 μL, 4 mmol), 3-Methylpyrazole (3.32 mL, 40 mmol) and N—N′-dimethylethylenediamine (425.86 μL, 4 mmol). The reaction mixture was heated to 120° C. for 2.5 hours. After cooling the reaction mixture was filtered through a Celite pad that was rinsed with dimethylformamide. The volume was reduced under reduced pressure, saturated ammonium chloride aqueous solution was added and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NH4Cl solution, brine then dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on SiO2 using cyclohexane/ethyl acetate mixture of increasing polarity (from 100% cyclohexane to 100% ethyl acetate) as eluent. The oil obtained was further purified by SPE Stratosphere “PL-THIOL MP” to completely remove copper salts. The title compound was obtained as a thick dark oil (300 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)(=O)C>CC#N.Cl[Pd]Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:12]=[C:13]([C:14]([CH3:21])([CH3:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:1]2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a mixture of ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 0.11 mol) and PdCl2 (10.4 g, 58.6 nmol) in CH3CN (350 mL) was heated to reflux for 1.5 hours. The reaction mixture was cooled down to room temperature. Ethyl acetate (300 mL) was added, the precipitate was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 40:1) to give ethyl 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutanoate (34.0 g, 98%) as a deep yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.11 (brs, 1H), 8.30 (d, J=7.2 Hz, 1H), 7.14 (d, J=11.7 Hz, 1H), 6.35 (d, J=1.5 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.69 (s, 2H), 1.51 (s, 6H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[N:13]=[N:12]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:31][C:32]1[C:33](=[O:46])[N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[N:35]([CH3:38])[C:36]=1[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([NH:31][C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])[N:35]([CH3:38])[C:36]=2[CH3:37])=[O:19])[N:13]=[N:12]1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-chloro-4-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Example 10, step 3) (95 mg, 0.342 mmol), oxalyl chloride (0.045 ml, 0.513 mmol) and DMF (0.053 ml, 0.684 mmol) in DCM (5 ml) was stirred at RT for 15 mins. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (83 mg, 0.376 mmol) was added to the mixture followed by triethylamine (0.143 ml, 1.026 mmol) and this was stirred at RT for 30 mins. The resulting mixture was diluted with DCM, washed with 0.1 M HCl(aq) and sat. NaHCO3(aq). The organic extracts were passed through a phase separating cartridge and concentrated under reduced pressure to give a brown oil. The oil was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined and concentrated under reduced pressure to give a yellow glassy solid. The solid was dissolved in 1:1 EtOAc:Et2O, washed with water (2×), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow glassy solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][N:7]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24].O>O1CCOCC1>[CH3:9][C:8]([C:5]1[CH2:4][S:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])=[N:7][N:6]=1)([CH3:11])[CH3:10]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(C)(C)C1=NN=C(N)SC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(OC)c1C(=O)NC1=NN=C(C(C)(C)C)CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
To a solution of 1.71 g of 2-amino-5-(1,1-dimethylethyl)-6H-1,3,4-thiadiazine and 1.01 g triethylamine in 18 ml dioxane was added 2.11 g of 2,6-dimethoxybenzoyl chloride. The reaction mixture was stirred at room temperature for 3 hours and poured into 100 ml water. The solid was collected and recrystallized from ethanol. The second crop of material provided 0.43 g of N-[5-(1,1-dimethylethyl)-6H-1,3,4-thiadiazin-2-yl]-2,6-dimethoxybenzamide. mp=175°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[SH:48][CH2:49][C:50]([OH:52])=[O:51]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([S:48][CH2:49][C:50]([OH:52])=[O:51])=[O:9])=[CH:5][C:4]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1OS(C)(=O)=O
Reactant: O=C(O)CS
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)SCC(=O)O)cc1OS(C)(=O)=O
Temperature: 50 °C
Yield: 32.3 %

Procedure:
To a solution of 4-methoxy-3-(methylsulfonyloxy)benzoic acid (prepared in an analogous manner to that described in Scheme 23, Step 2 and 3) (0.362 g, 1.470 mmol) in dry DMF (10.7 ml), HATU (0.559 g, 1.470 mmol) and N-methylmorpholine (0.162 ml, 1.470 mmol) were added. The resulting mixture was stirred at 50° C. under nitrogen until complete conversion of the starting acid into the activated specie (detected by UPLC-MS). Then the solution was allowed to warm to RT and 2-mercaptoacetic acid (0.102 ml, 1.470 mmol) was added drop wise; the resulting mixture was stirred overnight at RT. The solvent was removed under vacuum and the residue was partitioned between EtOAc and HCl 1N; the organic phase was dried over Na2SO4 and the solvent was removed. The crude was purified by preparative HPLC to afford 2-(4-methoxy-3-(methylsulfonyloxy)-benzoylthio)acetic acid (0.152 g, 0.474 mmol, 32.3% yield, MS/ESI+ 342.9 [MNa]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21]O)[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42]([O:46][C:47]([NH:49][O:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:42]([O:46][C:47]([N:49]([CH2:21]/[CH:20]=[CH:19]\[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][N:11]=2)[CH:14]=1)[O:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: OC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)ON(C/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of the product of Step 3, above (15, 1.8 g, 6 mmol), PPh3 (1.9 g, 7.2 mmol) and N,O-di-tert-butoxycarbonylhydroxylamine (1.85 g, 7.8 mmol) in THF (25 ml) was added dropwise a solution of diethylazodicarboxylate (1.2 ml, 7.2 mmol) in THF (5 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours and solvent was removed under reduced pressure. The resultant residue was purified by column chromatography on silica gel (eluent=ethyl acetate:n-hexane, 1:7) to afford 3.0 g (98% yield) of the title compound (16) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])[CH3:9].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>O1CCCC1>[CH2:8]([NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:31](=[O:32])[O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:24]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])[CH3:9]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 0 °C
Yield: 109.8 %

Procedure:
Tetrahydrofuran (20 ml) and triethylamine (2.70 ml, 19.4 mmol) were added to N1-ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.91 g, 6.45 mmol, Production example 27-1); phenyl chloroformate (1.79 ml, 14.2 mmol) was added thereto at 0° C. while stirred; and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated to yield a mixture (2.95 g) of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.454 g of the mixture was dissolved in N,N-dimethylformamide (5 ml); and 4-tetrahydro-1H-1-pyrrolylpiperidine (0.522 g, 3.39 mmol) was added; and the reaction mixture was stirred for 5 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated to yield a solid; the obtained solid was washed with hexane:diethyl ether=1:1 to yield the title compound as crystals (205 mg, 0.43 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+]>CN(C)C=O.O>[C:10]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:11]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCC(C#N)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Two grams of (3-methoxyphenyl)acetonitrile and 1.5 ml of ethyl 4-bromobutyrate are dissolved in 50 ml of dimethylformamide at 0° C. Six hundred milligrams of 60% sodium hydride (600 mg; 15 mmol) are progressively added to the solution. The reaction mixture is stirred at ambient temperature for 4 hours, taken up in 100 ml of acidic water and extracted with ether. The organic phase is then dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is purified on a column (eluant:ether/cyclohexane 4/6) to yield the title product in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 71 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 71%). 1H NMR (200 MHz, CDCl3): δ 3.68 (s, 4H), 3.96 (s, 3H), 4.12 (s, 4H), 6.23 (t, J=4.4 Hz, 1H), 7.02 (s, 1H), 6.89-7.00 (m, 1H), 7.36-7.43 (m, 1H), 7.67 (m, 1H), 8.32 (d, J=4.4 Hz, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][CH:26]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]1([C:24]2[N:23]=[CH:22][C:21]([C:38](=[O:40])[CH3:39])=[CH:26][N:25]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(-c2ccccc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
A stirring mixture consisting of palladium(II) acetate (215 mg, 0.32 mmol) and triphenylphosphine (335 mg, 1.28 mmol) in 1,4-dioxane (25 mL) was heated at 80° C. for 30 minutes. The dark reaction mixture was cooled to room temperature, and to this reaction mixture was added a solution consisting of 5-bromo-2-phenylpyrimidine (Example 1A, 3.0 g, 13 mmol) and tributyl(1-ethoxyvinyl)tin (4.74 mL, 14.0 mmol) in 1,4-dioxane (63 mL). The reaction mixture was stirred and heated at 75° C. overnight and was subsequently cooled to room temperature. The reaction progress was monitored by thin layer chromatography (95:5 v/v hexanes-ethyl acetate) until completion. The reaction mixture was treated with 1 N hydrochloric acid (19 mL) for one hour at room temperature and poured into a saturated aqueous sodium bicarbonate solution. The organic material was extracted two times with a mixture of ethyl acetate and hexanes, and the combined organic phase was washed sequentially with water and brine, and was dried over anhydrous magnesium sulfate, filtered through a well packed pad of magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and diluted with hexanes (30 mL). The resulting precipitate was filtered to give the title intermediate (872 mg). The filtrate was applied to a 80-g silica column eluted with 1:1:9 v/v/v ethyl acetate-dichloromethane-hexanes to afford 1.01 g of additional title intermediate (1.88 g total, 74%); Rf 0.23 with 9:1 v/v hexanes-ethyl acetate solvent system; 1H-NMR (400 MHz; DMSO-d6) δ 9.4 (s, 2H), 8.45-8.50 (m, 2H), 7.5-7.7 (m, 3H), 2.68 (s, 3H); MS (ESI+) m/z 199 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:6]=2[C:5](=[O:17])[CH:4](C(OC)=O)[CH2:3]1.O>CN1C(=O)CCC1>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:11]=[CH:12][C:6]2[C:5](=[O:17])[CH2:4][CH2:3][C:2](=[O:1])[NH:8][C:7]=2[CH:9]=1
Reactant: COC(=O)C1CC(=O)Nc2cc(C(F)(F)F)ccc2C1=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCC(=O)c2ccc(C(F)(F)F)cc2N1
Temperature: 135 °C
Reaction time: 15 h
Yield: 96.7 %

Procedure:
A 22 L reactor was charged with a solution of methyl 2,5-dioxo-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate [670 g, 2.22 mol] in NMP (4 L, 6 vol). Water (67 mL, 0.1 vol) was added and the resulting solution was slowly heated to 135° C. The reaction was continued for 15 h when HPLC analysis indicated >99% conversion. The reaction was cooled to ambient temperature. Water (8.7 L, 13 vol) was added slowly with vigorous stirring resulting in a suspension. The suspension was stirred at ambient temperature overnight. The solid was collected by filtration and the filter cake was washed with water (1.5 L). The solid was dried to a constant weight in a vacuum oven at 45° C. to obtain 8-(trifluoromethyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (522 g, 97% recovery) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm: 10.28 (s, 1H), 8.00 (d, 1H, J=8.0 Hz), 7.54 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 3.00-2.94 (m, 2H), 2.78-2.70 (m, 2H); ESI-MS m/z: 244 (M+H, 100%).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C(N(CC)CC)C.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](Cl)=O)[CH2:19][CH2:18]1)=[O:16]>O1CCCC1>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(N)=NO
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](c2nc(C)no2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of acetamide oxime (0.19 g, 2.6 mmol) and triethylamine (0.36 ml, 2.6 mmol) in tetrahydrofuran (24 ml) was added trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (0.50 g, 2.4 mmol) at 0-5° C. After completed addition the cooling bath was removed, and the mixture was stirred for 30 minutes. The precipitated ammonium salts were removed by filtration and washed with tetrahydrofuran. The filtrate was concentrated to dryness. The residue was redissolved in 1,4-dioxane (24 ml). The mixture was treated with a catalytic amount of toluene-4-sulfonic acid monohydrate and heated at reflux over night (16 h). The solvent was evaporated. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.48 g, 88%) as light brown oil. MS m/e: 225 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:21][S:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH2:24][CH2:23][S:22][CH3:21])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CSCCCl
Reactant: O=c1[nH]nc(-c2ccc(OCCCC(F)(F)F)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCn1nc(-c2ccc(OCCCC(F)(F)F)cc2)oc1=O
Temperature: 90 °C
Yield: 67.6 %

Procedure:
2 g of 5-[4-(4,4,4-trifluorobutoxy)phenyl]-1,3,4-oxadiazol-2(3H)-one, 1.14 g of 2-chloroethyl methyl sulphide, 2.4 g of potassium carbonate and 30 ml of dimethylformamide are introduced into a 50 ml three-necked round-bottomed flask. The reaction mixture is heated to 90° C. and is maintained at this temperature overnight, then poured into water. The precipitate formed is collected by filtration, washed with water and taken up in ethyl acetate. The solution is dried over sodium sulphate and the solvent is then evaporated off. After recrystallization in diisopropyl ether, 1.7 g of product are obtained.