Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:14][C:13]([NH:12][CH:10]([C:4]1[C:3]([O:20][CH3:21])=[C:2](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[CH3:11])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CC(=O)OC
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Temperature: 130 °C
Yield: 68.1 %

Procedure:
Into a sealed tube was placed a suspension of tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate [from Example 113, step 1, peak 2] (1.0 g, 2.6 mmol) in DMF (15 mL) that was degassed with nitrogen and treated with methyl acrylate (0.83 mL, 9.2 mmol), triphenylphosphine (97 mg, 0.37 mmol), and palladium acetate (59 mg, 0.26 mmol). Lastly, triethylamine (1.1 mL, 7.9 mmol) was added and the reaction mixture was heated at 130° C. for 16 hours. After cooling to room temperature, the mixture was filtered over Celite and the Celite was washed with EtOAc (100 mL). The EtOAc was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude foam. The crude material was dissolved in 2:1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.68 g, 68%) as a white foam. LCMS for C14H16ClO3 (M−NHBoc)+: m/z=267.1. Found: 266.9.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].Cl>CN(C=O)C.C1COCC1>[CH2:23]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:11]([S:10][C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:2])=[O:22])=[C:12]1[CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Sc2cncc(C(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 0 °C

Procedure:
5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester and benzyl bromide (0.0267 mL, 0.225 mmol) were dissolved in DMF:THF (1:1, 4 mL). The mixture was cooled to 0° C., sodium hydride (60% in mineral oil, 0.015 g, 0.375 mmol) was added, and the ice bath was removed. After warming to room temperature, the reaction was heated to 50° C. for 1 hour. Analytical LCMS indicated complete conversion and, furthermore, complete hydrolysis of the methyl ester. The reaction was neutralized with HCl (aq.), diluted with EtOAc/hexanes and washed with H2O/brine. The organic portion was dried and concentrated and the residue was purified via preparatory HPLC (10-100% ACN in H2O, 20 minute run, r.t.=13.1 minutes) to give the title compound. Mass spectrometric data: [M+H]+=409.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:17]([NH:53][CH2:54][C:55]2[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=2[CH3:61])=[O:19])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Br)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCOCC3)c2Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a stirred solution of 3-bromo-6-chloro-4-[methyl(oxan-4-yl)amino]pyridine-2-carboxylic acid (73 mg, 0.21 mmol) in DMF (2 ml) were added DIPEA (56 μl, 0.31 mmol) and HATU (95 mg, 0.25 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 52 mg, 0.31 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured onto 50 ml of water, the aqueous phase was extracted with EtOAc (3×50 ml), washed with brine (50 ml) dried (Na2SO4) and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 4% MeOH in DCM and evaporated to give a glassy solid which was triturated with diethyl ether and filtered and dried in a vacuum oven at 40° C. for 24 h to afford the title compound as a white powder (50 mg, 41%). LC-MS 99%, m/z=483.1/485.0/486.9, 1H NMR (500 MHz, CDCl3) δ 10.94 (br. s, 1H), 8.14-7.98 (m, 1H), 6.83 (s, 1H), 5.92 (s, 1H), 4.55 (d, J=6.1 Hz, 2H), 4.15-3.94 (m, 2H), 3.93-3.70 (m, 1H), 3.40 (t, J=11.0 Hz, 2H), 2.78 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.99-1.82 (m, 2H), 1.79-1.64 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N+:23]([O-])=O)=[C:11]([CH:26]=[CH:27]N(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.C(Cl)Cl.[Zn]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[NH:23][CH:27]=[CH:26][C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Cc1nc(OCc2ccccc2)nc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(COc2nc(OCc3ccccc3)c3[nH]ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a suspension of 2,4-Bis-O-Benzyl-5-nitro-6-β-dimethylaminovinyl pyrimidine 14 (2 g, 4.9 mmol) in AcOH (40 ml), Zn (4 g) was added in lot of 2 g with an interval of 4 hrs. The reaction mixture was stirred overnight at room temperature during which a dark yellow suspension became pale yellow suspension. The reaction mixture was filtered and the filtrate concentrated in vacuo to obtain syrup which was dissolved in CH2Cl2 then washed with saturated aq. NaHCO3 followed by brine. The organic phase was dried over MgSO4 and loaded on silica. The product 15 was purified using column chromatography eluting with 4:1 and 1:1 hexanes/EtOAc to obtain product as pale-yellow solid (1.45 g, 90%). Rf 0.3 in 1:3 hexanes/EtOAc. 1H NMR (400 MHz, CDCl3): δ 5.47 (s, 2H), 5.54 (s, 1H), 6.50-6.51 (dd, 1H, J=1.84, 2.28), 7.29-7.38 (m, 7H), 7.43-7.45 (m, 2H), 7.52-7.53 (m, 2H), 8.41 (br s, 1H, NH). 13C NMR (400 MHz, CDCl3): δ 68.3, 69.0, 102.6, 111.9, 127.8, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 136.1, 137.3, 151.8, 156.79, 159.7. FAB-MS for C20H17N3O2 calculated [M+H]+ 332.1394. found 332.1398.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:40]=[C:39](Br)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:40]=[C:39]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
46 mg of 4-(dimethylamino)phenylboronic acid, 49 mg of sodium carbonate and 5.7 mg of polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature 5.7 mg polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) was added and stirred at 110° C. for 24 hours, After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(4-(dimethylamino)phenyl)benzoate.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.[OH:24]O.[OH-].[Na+]>CO.O.ClCCl>[O:24]1[C:8]23[C@:3]([CH3:23])([CH2:4][CH2:5][C:6](=[O:22])[C@H:7]12)[C@:2]1([F:1])[C@H:11]([C@H:12]2[C@@:16]([CH2:18][C@@H:19]1[OH:20])([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]2)[CH2:10][CH2:9]3
Reactant: OO
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@]12CCC(=O)[C@@H]3OC31CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 10g of 9-fluoro-11β-hydroxyandrost-4-ene-3,17-dione in 1.5 liter of methanol is stirred at room temperature with 30ml of 30% hydrogen peroxide and 20ml of 4N sodium hydroxide solution. The resulting solution is diluted with 4 liters of water and extracted with dichloromethane. The dichloromethane solution is washed with 5% hydrochloric acid, 5% sodium bicarbonate solution, water, dried, and evaporated in vacuo to give 9.1g of crude product. This material is dissolved in dichloromethane and chromatographed on a 100g-silica gel column. Elution with the same solvent gives 3.39g of the title compound and some impure material which is rechromatographed to give a further 1.71g of the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:30][C:26]1[CH:25]=[C:24]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
(R)-N-(2-(3-(3-Chlorophenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (3.0 g, 7.0 mmol) dissolved in 96% ethanol (10 ml) and a 12 N sodium hydroxide solution (1.75 ml) was added. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo and dichloromethane was added (100 ml). A concentrated hydrochloric acid solution (2.9 ml) was added with cooling on an ice-bath. The phases were separated, and from the organic phase the solvent was evaporated in vacuo. Water (100 ml) was added to the residue and the aqueous solution was washed with small portions of ethyl acetate. The aqueous phase was reduced in vacuo to approx. 50 ml and dichloromethane (250 ml) was added. A 4 N sodium hydroxide solution was added until the pH was measured as 8.3. The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give 2.7 g (96%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22]CC3C=CC=CC=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(O)ccc21
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of 3-(5-benzyloxy-indol-1-yl)-3-phenyl-acrylic acid ethyl ester (1.94 g, 4.89 mmol) and palladium on carbon [10% w/w] (60 mg) in methanol (25 mL) was stirred under hydrogen atmosphere for 24 h. After removal of the catalyst by filtration, the crude product was purified by flash chromatography on silica gel with hexane/ethyl acetate (4:1) to give the title compound in 96% yield. 1H NMR (CDCl3) δ 7.10–7.30 (m, 7H), 6.99 (d, J=2.4 Hz, 1H), 6.69 (dd, J=2.4 and 8.7 Hz, 1H), 6.39 (d, J=3.2 Hz, 1H), 5.99 (t, J=7.6 Hz, 1H), 5.31 (br, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.26 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 170.4, 149.7, 139.8, 131.5, 129.3, 128.8, 127.9, 126.2, 125.8, 111.6, 110.6, 105.2, 101.4, 61.1, 56.2, 40.4, 13.9. Mass Spectrum (LCMS, ESI) calculated for C19H20NO3 310.1 (M+H); found 310.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7](OC)[N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[CH2:20]([Si](C)(C)C)[CH:21]=[CH2:22].B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:22][CH:21]=[CH2:20])[N:6]1[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:4]
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)C1CCCC(OC)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C=CCC1CCCC(C(=O)OC)N1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 6-methoxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 37, (5.0 g, 18.3 mmol) and allyltrimethylsilane (5.8 mL, 36.6 mmol) in CH2Cl2 (125 mL) at −78° C. is added dropwise boron trifluoride etherate (2.5 mL, 19.7 mmol). After 1 h, the solution is poured into water and extracted with EtOAc. The extracts are washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue is used in the next step without purification.
Reaction SMILES: ClC1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16](O)=[O:17])[CH:6]=[C:5]2[C:20]1[C:21](=[O:34])[NH:22][C:23](=[O:33])[C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].C1C=CC2N(O)N=[N:41]C=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.N.[CH2:61]([Cl:63])Cl>CN(C=O)C>[Cl:63][C:61]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH2:41])=[O:17])[CH:6]=[C:5]2[C:20]1[C:21](=[O:34])[NH:22][C:23](=[O:33])[C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: ClCCl
Reactant: COc1ccccc1C1=C(c2cn(-c3cncc(C(=O)O)c3)c3ccc(Cl)cc23)C(=O)NC1=O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CN(C)C=O
Product: COc1ccccc1C1=C(c2cn(-c3cncc(C(N)=O)c3)c3ccc(Cl)cc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirring solution of Compound 56 (80 mg, 0.17 mmol) in DCM (2 mL) and DMF (0.5 mL) was added HOBT (25.7 mg, 0.19 mmol) and DCC (37 mg, 0.18 mmol). The reaction was stirred at room temperature for 30 min, then 28% aqueous NH3 (15 mg, 0.36 mmol) was added. The reaction stirred at room temperature overnight. The reaction mixture was filtered and the filtered solid was washed with DCM (2 mL). The filtrate was diluted with ethyl acetate (6 mL), washed twice with NaHCO3 (2 mL), dried (Na2SO4) and evaporated in vacuo. The crude product was purified via flash column chromatography (DCM:MeOH:NH4OH 93:5:2) to give Compound 58 (36.7 mg, 46%). Compound 58 was dissolved in methanol and treated with 1N HCl/CH3CN (2:1) and lyophilized to give the HCl salt. 1HNMR (DMSO-d6) δ 11.2 (s, 1H), 9.11 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.32 (d, J=12.0, 2H), 7.80 (s, 1H), 7.58–7.47 (m, 3H), 7.34–7.01 (m, 3H), 6.42 (s, 1H), 3.34 (s, 3H). ES-MS m/z 473 (MH+).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:4]=[C:5]([S:14][CH3:15])[N:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[NH2:1][C:3]1[N:4]=[C:5]([S:14][CH3:15])[N:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: N
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Product: CCOC(=O)c1nnc(SC)nc1N

Procedure:
can be prepared if ammonia is used to displace the chloro group of 5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester to give 5-amino-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester. The aldehyde is obtained and reacted with a substituted phenyl acetonitrile as described above to provide the 6-amino-pyridotriazines. The methylthio group is displaced as described above, also, and the 6-amino group of the resulting 6-amino-7-substituted phenyl-3-substituted amino-pyrido-1,2,4-triazine is derivatized by standard methods, for example alkylation or acylation, to provide compounds of Formula III.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[C:20](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=O>[CH3:19][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:2]([CH3:20])[CH:3]=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: CCCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1sc(C(=O)OC)cc1-c1c(C)cnn1C
Yield: 84.5 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (242 mg, 0.71 mmol) PdCl2(dppf) (52 mg, 0.07 mmol), potassium carbonate (487 mg, 3.53 mmol) and trimethylboroxine (0.20 ml, 1.41 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (184 mg, 0.60 mmol, 84% yield) as a yellow oil: LCMS (ES) m/z=279 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:45]=[C:17]2[N:18]([CH:41]([CH3:44])[CH2:42][CH3:43])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:45]=[C:17]2[N:18]([CH:41]([CH3:44])[CH2:42][CH3:43])[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)CC)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.85 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-4-(1-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.064 g, 16%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3C=C[CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].C(N1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O)CCC>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Product: CCCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Yield: 94 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-butyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 94% yield: MS (ES+) m/z 284.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[S:5][CH:4]=1)=[O:2].[BH4-].[Na+].CC(C)=O>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[S:5][CH:4]=1
Reactant: COC(=O)c1cccc2c(C=O)csc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(C)=O
Product: COC(=O)c1cccc2c(CO)csc12
Reaction time: 1 h
Yield: 96.1 %

Procedure:
1.00 g of methyl 3-formyl-1-benzothiophene-7-carboxylate was dissolved in a mixed solution of 15 mL of ethanol and 15 mL of tetrahydrofuran, to which 86 mg of sodium borohydride was added at room temperature, and this solution was stirred for one hour at the same temperature. After acetone was added dropwise to the reaction mixture, from which the solvent was distilled out under reduced pressure, followed by addition of ethyl acetate and water, and this mixture was adjusted to pH 6 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.97 g of methyl 3-(hydroxymethyl)-1-benzothiophene-7-carboxylate as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[NH:10][N:9]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:23])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[N:12]=1
Reactant: CI
Reactant: FC(F)(F)c1ccccc1-c1nc(-c2ccccc2Cl)n[nH]1
Product: Cn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1Cl

Procedure:
starting from 3-(o-chlorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and methyl iodide there is obtained a mixture of isomeric N-methyltriazoles and therefrom there are obtained pure 5-(o-chlorophenyl)-1-methyl-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole as a resinous product, 1H-NMR(CDCl3): 3.86 (s, CH3); and pure 3-(o-chlorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 90°-92° C., 1H-NMR(CDCl3): 3.78 (s, CH3);