Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10](OC(C)C)=[C:9](C(F)(F)F)[CH:8]=2)=[N:5][N:6]=1.[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[N:52]([CH3:55])C=O>O.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>[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26]([C:2]2[S:3][C:4]([C:7]3[CH:8]=[CH:9][C:10]([CH2:4][CH:7]([CH3:12])[CH3:8])=[C:11]([CH:12]=3)[C:55]#[N:52])=[N:5][N:6]=2)[CH:27]=1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Reactant: CN(C)C=O
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(CC(C)C)c(C#N)c3)s2)c1OC
Temperature: 120 °C

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D26) (400 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (459 mg) and tripotassium phosphate (659 mg) in N,N-dimethylformamide (DMF) (8 mL) and water (2 mL) under nitrogen was added Pd(Ph3P)4 (71.7 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 5-(5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D36) (140 mg) as a yellow solid. MS (ES): C23H22FN3O2S requires 423. found 424.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:4]
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)NCCN1CCOCC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
Chloroacetyl chloride (1.73 g, 15 mmol) was dissolved in 4 mL of dichloromethane and cooled to 5° C. in an ice-water bath. 4-(2-Aminoethyl)morpholine (2 g, 15 mmol) was dissolved in 4 mL of dichloromethane containing triethylamine (3.03 g, 30 mmol) which was then added to this cold solution at 5° C. A solid precipitate formed immediately after the triethylamine was added. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with 100 mL of dichloromethane and 20 mL of water. The organic solution was washed with 5% aqueous NaHCO3 (2×50 mL), brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was dried in vacuo to give 2.57 g (83.7%) of N-(2-chloroacetyl)-2-(4-morpholinyl)ethylamine as a yellow solid. 1H NMR (300 MHz / CDCl3): ∂ 2.48-2.55 (m, 6H), 3.38 (dd, 2H, J=5.63 Hz), 3.71 (t, 4H, J=4.53 Hz), 4.04 (s, 2H); mass spectrum, m/z=207.1 (M+H); HRMS calcd for C8H15N2O2Cl1 206.0822, found 206.0814.
Reaction SMILES: CO[C:3](=[S:11])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:12](C)[Na].CO.Cl>>[CH3:10][O:9][C:7]([CH:6]1[CH:5]([OH:12])[CH:4]=[CH:3][S:11]1)=[O:8]
Reactant: COC(=O)CCCC(=S)OC
Reactant: CO[Na]
Agent: Cl
Solvent: CO
Product: COC(=O)C1SC=CC1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
192 parts of 3-methoxycarbonylmethyl-thiopropionic acid methyl ester are added, in the course of 30 minutes, to a solution of 360 parts of a 30 percent strength by weight NaOCH3 /MeOH solution at 5° C. The resulting solution is stirred for one hour at 5° C. and then poured onto a mixture of 200 parts of concentrated hydrochloric acid and 1,000 parts of finely crushed ice. The oily layer which separates out is removed and the aqueous phase is extracted with three times 100 parts by volume of methylene chloride. The combined organic phases are extracted with three times 100 parts by volume of 5 percent strength by weight NaHCO3 solution, dried with sodium sulfate and evaporated. The residue is distilled under reduced pressure. 140 parts (88% of theory) of 3-hydroxy-dihydrothiophene-2-carboxylic acid methyl ester of boiling point 72°-73° C./0.14 mbar are obtained.
Reaction SMILES: [CH3:1][C:2]([CH2:5][CH3:6])=[CH:3][CH3:4].[CH2:7]([CH:9]([CH2:13][CH2:14][CH2:15]C)[C:10]([O-:12])=O)C.[C]=O.[H][H]>>[CH3:1][C:2]([CH2:5][CH3:6])=[CH:3][CH3:4].[CH3:7][CH:9]([CH:13]([CH3:1])[CH2:14][CH3:15])[CH:10]=[O:12]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: [H][H]
Agent: CC=C(C)CC
Agent: [C]=O
Product: CCC(C)C(C)C=O
Reaction time: 7 h

Procedure:
400 g of 3-methyl-2-pentene as well as 40 mg Rh (in the form of 2-ethylhexanoate) were introduced into a high pressure vessel (volume 2.1 liters) and were reacted with an equimolar mixture of carbon monoxide and hydrogen at 90° C. and 260-270 bar. The reaction was completed in 7 hours, after which the pressure was relieved and the reactor allowed to cool. The composition of the crude reaction product was determined by a vacuum distillation and a gas chromatographic analysis. With a 99.9% 3-methyl-2-pentene conversion, 81.3% of isomeric C7 aldehydes was obtained as 2,3-dimethylpentanal (cf. Table 1, Exp. 1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10](I)[CH2:9]1)[CH3:2].C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 71.8 %

Procedure:
5-Ethyl-3'-iodo-2',3'-dideoxyuridine (432 mg, 0.87 mmole) is dissolved in methanol (40 ml) and triethylamine (0.5 ml) is added along with 10% Pd/C (200 mg). The mixture is then stirred in an atmosphere of hydrogen at room temperature for 30 min. After filtration of catalyst, the filtrate is evaporated to dryness. Purification of the product was achieved on silica gel plates using chloroform-methanol (20:1) to obtain a solid (150 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:20][C@H:21]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)=[N:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[OH:19])=[N:9]2)=[CH:4][CH:3]=1.[OH:33][C:34]1C=CC=[CH:36][C:35]=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([OH:19])=[C:12]([C:8]2[N:7]=[C:6]([NH:20][C@H:21]3[CH2:25][CH2:24][NH:23][CH2:22]3)[C:5]3[C:10](=[CH:11][C:2]([CH2:36][CH2:35][CH2:34][OH:33])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(F)ccc3O)nc3cc(Br)ccc23)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Product: OCCCc1ccc2c(N[C@H]3CCNC3)nc(-c3cc(F)ccc3O)nc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59 and 60, replacing (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with (S)-tert-butyl 3-(7-bromo-2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: [C:1]1([O:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=2[N+:17]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N)c1Oc1ccccc1

Procedure:
A suspension of 2,6-dinitrophenyl phenyl ether (6.5g.) in ethanol (100ml.) was shaken with hydrogen at room temperature and atmospheric pressure in the presence of palladium-on-charcoal (0.5g. of 5% w/w) as catalyst. When the theoretical amount of hydrogen (3.4 l.) had been absorbed, the mixture was filtered and the filtrate evaporated to dryness under reduced pressure. The solid residue (4.9g.) was crystallised from cyclohexane to give 2,6-diaminophenyl phenyl ether, m.p. 110°-111°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](=[O:31])(=[O:30])[NH2:32])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cccc(C(=O)O)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCOc1cccc(C(=O)Nc2ccccc2S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
A benzene (30 ml) solution containing 3 g (12.5 mmol) of 3-heptyloxybenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.50 g (14.5 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from acetonitrile to obtain 3.00 g (yield: 60.0%) of the title compound. NMR (DMS-d6) δ: 0.87 (3 H, t, J=7 Hz), 1.22-1.50 (8 H, m), 1.70-1.80 (2 H, M), 4.41 (2 H, t, J=7 Hz), 7.17-7.23 (1 H, m), 7.33 (1 H, ddd, J=8 Hz, 8 Hz, 2 Hz), 7.77 (2 H, s), 7.90 (1 H, dd, J=8 Hz, 2 Hz), 8.48 (1 H, d, J=8 Hz), 10.38 (1 H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[O:17]=[C:16]1[C:15](=[O:20])[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[C:13]1[O:12][CH2:10][CH3:11]
Reactant: N#Cc1cccc(N)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc(C#N)c2)c(=O)c1=O

Procedure:
3-Aminobenzonitrile (2.06 g, 17.4 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.97 g, 17.5 mmol) in absolute ethanol (50 mL). The mixture was heated at reflux overnight. The mixture was cooled and the resulting yellow precipitate was collected by vacuum filtration. Yield: 3.40 g (81%): 1H NMR (DMSO-d6): δ 10.95 (s, 1H), 7.75-7.40 (m, 4H), 4.73 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1C=CC=CC=1>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:10]2[CH2:9][N:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:13][CH2:12][CH:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C2=CCCN(Cc3ccccc3)C2)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC=C(c2cccc(OC)c2)C1

Procedure:
A solution of 11.4 g of the product of Step B, 25 ml of benzene and 5.9 ml of ethyl chloroformate was refluxed for 3 hours and was then evaporated to dryness under reduced pressure. Excess ethyl chloroformate was entrained with benzene to obtain 11 g of ethyl 3-(3-methoxyphenyl)-1,2,5,6-tetrahydro-1-pyridine-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.060 g, 0.15 mmol, 1 eq), EtOH (2.6 mL) and DMF (0.35 mL), 4-(4-hydroxypiperidin-1-yl)benzaldehyde (0.034 g, 0.17 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aq NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.011 g, 13%); 1H-NMR (500 Mz, DMSO-d6): 1.40-1.50 (m, 2H), 1.77-1.87 (m, 2H), 2.60-2.92 (br s, 4H, piperazine N(CH2)2), 2.95-3.05 (m, 2H), 3.63-3.85 (m, 7H), 4.61-4.75 (br s, 1H, CHOH), 7.04 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.24-7.29 (m, 1H) and 7.50 (d, J=3.5 Hz, 1H) thiazole H-4, H-5), 8.01 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.07 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 3.69 min—514/516 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: ON=[C:3]([CH3:18])[C:4](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[C:19](=O)([O-])[O-].[K+].[K+].C.CI>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]2[N:13]=[N:14][C:15]([S:16][CH3:19])=[N:17][C:3]=2[CH3:18])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=NNC(N)=S)C(C)=NO)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(-c2nnc(SC)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of 2-hydroxyimino-4'-methoxypropiophenone thiosemicarbazone (5.32 g), potassium carbonate (6.35 g) and water (50 ml) was treated in a similar manner to that of Example 25-(2), and then treated with activated charcoal. To the filtrate was added methyl iodide (6 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, treated with silica gel, and filtered. The filtrate was concentrated to dryness to give a residue, which was crystallized from diisopropyl ether. The resultant crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-(4-methoxyphenyl)-5-methyl-3-methylthio-1,2,4,-triazine (2.42 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].N1C=CC=CC=1.[N+]1([O-])C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:4]2[C:3](=[O:17])[C:2]([Br:1])=[N:7][N:6]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[C:5]2=[O:8])=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
According to Scheme 2 Step 3: To a solution of 6-bromo-4-(4-chlorobenzyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.600 g, 1.9 mmol) in DCM (8 ml) were added 3-cyanophenylboronic acid (0.42 g, 2.8 mmol), copper(II) acetate (0.069 g, 0.38 mmol), pyridine (0.3 g, 3.8 mmol) and pyridine N-oxide (0.2 g, 2.1 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 30 g prepacked column, cycloexane/ethyl acetate 85/15 to afford 3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (300 mg, 38%) which was used in the next step without any purification
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][N:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1.CC(C)=O>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([C:29]([F:31])([F:32])[F:30])=[N:25][N:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C(F)(F)F)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cn(C)nc6C(F)(F)F)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47.5 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with 3 mL of acetone yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[C:6]([CH3:12])=[CH:5][N+:4]=1[O-:13].Cl.[CH2:15]([OH:17])[CH3:16]>C(OCC)(=O)C>[CH2:15]([O:17][C:7]1[C:6]([CH3:12])=[CH:5][N+:4]([O-:13])=[C:3]([CH3:2])[CH:8]=1)[CH3:16]
Reactant: CCO
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOc1cc(C)[n+]([O-])cc1C

Procedure:
13.5 g of sodium were dissolved in 2300 ml of ethanol under argon. 60 g of 2,5-dimethyl-4-nitropyridine 1-oxide were then added portionwise thereto and the solution was left to boil under reflux overnight. The pH was adjusted to 7 with 5N hydrogen chloride in ethyl acetate while cooling, whereupon the mixture was evaporated in vacuo. The residue was taken up in 1 l of methylene chloride, the solution was filtered through silica gel, which was rinsed with 500 ml of methylene chloride, and the combined filtrates were evaporated in vacuo. The product was chromatographed on 300 g of silica gel with methylene chloride/methanol (95:5). After crystallization from ether/petroleum ether there was obtained 4-ethoxy-2,5-dimethylpyridine 1-oxide of melting point 65°-67°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH2:14][Cl:18])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2cccc(Br)c2)[n+]([O-])c1C
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2cccc(Br)c2)nc1CCl
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A solution of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then stirred at reflux for 30 min. The reaction was then cooled to room temperature and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(3-bromophenyl)-4-(chloromethyl)-5-methyloxazole as a lime-green powder. 1H NMR (300 MHz, d6-DMSO) δ8.19 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, H), 7.35 (t, J=8.0 Hz, 1H), 4.45 (s, 2H), 2.41 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][OH:12])=[O:10])=[CH:5][CH:4]=1.[OH:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(N(C(C)C)C(C)C)C.C(OCC)C>CN(C)C=O.[I-].[K+]>[OH:12][NH:11][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NO)c1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(NO)c1ccc(CON2C(=O)c3ccccc3C2=O)cc1

Procedure:
α-Chloro-N-hydroxy-p-toluamide, 6.52 g (40 mmol) of N-hydroxyphthalimide (7.4 g) (40 mmol) and 0.28 g of potassium iodide are dissolved in 50 ml of absolute dimethylformamide and treated with 5.16 g (40 mmol) of N-ethyldiisopropylamine while stirring. After stirring at room temperature for 16 hours 50 ml of diethyl ether are added. The precipitated product is filtered off under suction and washed with diethyl ether. There are obtained 7.5 g of N-hydroxy-α-(phthalimidooxy)-p-toluamide as a white powder of m.p. 202° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:20][S:21]([NH2:24])(=[O:23])=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluorobenzoic acid (53 mg), methanesulfonamide (35 mg), HBTU (95 mg), and DIPEA (0.13 mL) in dichloromethane (0.83 mL) was stirred at rt for 4 hr. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine, and dried (Na2SO4). The crude was purified with HPLC. LCMS (Method D): RT=5.62 min, m/z: 362.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 5.69 (d, J=2.1 Hz, 2H), 4.06 (dd, J=6.5, 1.3 Hz, 2H), 2.28-1.97 (m, 4H), 1.98-1.76 (m, 2H), 1.50-1.29 (m, 1H).