Azzindani/Open_Reaction_Data huggingface dataset:
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[N:24]([CH3:29])[N:25]=[C: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:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=1>CCOC(C)=O>[OH:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:38][CH:39]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CO)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 300 mg, 0.746 mmol) and THF (7.5 mL). To the resulting solution was added (4-amino-phenyl)-methanol (133 mg, 0.955 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and the resulting suspension was filtered. The solids collected were washed with 0° C. iPrOH (5 mL) and set aside. The filtrate was concentrated in vacuo and the residue obtained was dissolved in EtOAc (5 mL). The resulting solution was triturated with Hexanes (˜50 mL) to yield a precipitate. This precipitate was then filtered and washed with 0° C. iPrOH (5 mL). The solids collected were combined with those previously set aside to afford the title compound in 24% yield (0.091 g, 0.179 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:38][CH:39]1[CH2:44][CH:43]([CH3:45])[CH2:42][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC1CNCC(C)C1
Product: CC1CC(C)CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 3,5-dimethylpiperidine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.76-0.88 (m, 6 H), 1.33-3.22 (m, 8 H), 3.27 (m, 4 H), 3.77 (m, 4H), 6.17 (d, J=5.5 Hz, 1H), 7.02-7.06 (m, 1 H), 7.27 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1 H), 7.25-7.62 (m, 4H), 7.62-7.83 (m, 1 H), 7.99-8.01 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](O)(=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(=O)O
Reactant: NCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCC(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 2,4-difluorobenzylamine (0.47 g, 3.3 mmol) in methylene chloride (30 mL) were added nonanoic acid (0.52 g, 3.3 mmol) and DMAP (0.40 g, 3.3 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL), and brine (75 mL) and dried over anhydrous Na2SO4. Concentration in vacuo afforded 0.87 g (93%) of an oil, which solidified upon standing.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C1C(=O)N([Cl:21])C(=O)C1.O>CN(C=O)C>[Cl:21][C:13]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cc2c(OC)cccn2n1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn2cccc(OC)c2c1Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 92.1 %

Procedure:
The compound of Example 49 (2.07 g) was dissolved in DMF (60 mL). To this solution, NCS (1.88 g) was added and the mixture was stirred at room temperature for 5.5 hours. Subsequently, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=3:1) afforded the title compound as a gray powder (2.28 g).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][O:25][CH2:26][C:27]([CH3:31])([OH:30])[C:28]#[CH:29]>>[CH:19]1([C:13]2[N:8]3[CH:9]4[CH2:10][CH:11]([C:5]5[CH:4]=[C:3]([F:23])[C:2]([C:29]#[C:28][C:27]([OH:30])([CH3:31])[CH2:26][O:25][CH3:24])=[CH:22][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:12]4)[CH2:20][CH2:21]1
Reactant: C#CC(C)(O)COC
Reactant: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: COCC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C1CC1

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-cyclopropyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-methoxy-2-methylbut-3-yn-2-ol to give the titled compound. MS+410.2. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=7.5 Hz, 1H), 7.47 (br s, 1H), 7.25 (d, J=10.1 Hz, 1H), 6.98 (br s, 1H), 5.68 (s, 1H), 5.26 (m, 1H), 3.68 (m, 1H), 3.39 (m, 2H), 3.37 (s, 3H), 3.14 (m, 2H), 1.81-1.59 (overlapping m, 3H), 1.45 (s, 3H), 0.99 (m, 2H), 0.67 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][N:9]2[S:23]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])(=[O:25])=[O:24])=[O:5])C.[OH-].[Na+]>O1CCCC1.CO>[C:19]([O:18][C:16]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][CH:14]=2)[N:9]([S:23]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])(=[O:25])=[O:24])[CH2:10][CH2:11]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCN2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester (430 mg, 0.84 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was treated with 2N NaOH (5 mL). The mixture was stirred at room temperature for 1 hour. The organic solvents were then partially removed and the residue acidified with HCl 1N (10 mL). The precipitate which formed was filtered, washing with water, and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester was obtained as a light yellow gum, 386 mg (95%), MS (ISP): m/e=481.1 (M−H), which was used crude in the following reaction.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]1([Mg]Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([C:8]2([OH:11])[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: OC1(C2CCCCC2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (5.00 g, 24.0 mmol) in THF (100 mL) was dropwise added cyclohexylmagnesium chloride (2.0 M in diethyl ether, 24.0 mL, 48.0 mmol) at −78° C. over 10 min. The mixture was stirred at 0° C. for 1.5 h, and then quenched with aqueous NH4Cl (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give crude 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol as a colorless solid. To a solution of crude 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (<24.0 mmol) in THF (45 mL) was added 3 M HCl (15 mL). The mixture was stirred at room temperature for 4 h, and then poured into EtOAc (50 mL) and aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel hexane to 70:30 hexane/EtOAc) to give the title compound (2.34 g, 37%) as a colorless solid:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]2[C:19](=[O:20])[NH:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:8]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]2[C:19](=[O:20])[NH:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:8]1)=[O:4]
Reactant: O=c1[nH]cc(-c2ccncc2)cc1N[C@@H]1CCCNC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Chloroacetyl chloride (0.021 mL, 0.26 mmol) was added to a solution of (R)-5-(piperidin-3-ylamino)-[3,4′-bipyridin]-6(1H)-one hydrochloride (100 mg, 0.26 mmol) and triethylamine (0.17 mL, 1.2 mmol) in dichloromethane (5.0 mL) at 0° C. The solution was stirred at 0° C. for 30 min and was concentrated. The residue was diluted with water and extracted with 5% methanol in ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and concentrated. The residue was purified on silica gel eluting with 10% methanol in dichloromethane to provide 20 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) 11.80-11.95 (m, 1H), 8.45-8.60 (m, 2H), 7.60-7.70 (m, 2H), 7.20-7.35 (m, 1H), 6.70-6.95 (m, 1H), 5.50-5.80 (m, 1H), 4.20-4.50 m, 1H), 3.45-3.95 (m, 1H), 2.95-3.40 (m, 2H), 2.65-2.90 (m, 1H), 1.35-2.15 (m, 2H); MS (ES) m/z 347 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.P(Br)(Br)[Br:14].[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)ccc1CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 10 g of 4-chloro-2-nitrobenzyl alcohol in 200 mL of ether is added dropwise a solution of 17.7 g phosphorus tribromide in 100 mL of ether. The temperature of the reaction mixture is maintained at 15° or lower by means of cooling with an ice-water bath. On completion of the addition the reaction mixture is allowed to stir for an additional 1 hour at 15° and then at room temperature overnight. The reaction mixture is neutralized with 100 mL of 3N sodium hydroxide, and the layers are separated. The ethereal extracts are washed with 2×250 mL of brine, dried over anydrous sodium sulfate; the solvent is evaporated to dryness under reduced pressure to yield 4-chloro-2-nitrobenzyl bromide melting at 50°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH2:20][C:21]([O:23]C)=[O:22].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1CC(=O)O)CCC3
Temperature: 65 °C
Yield: 53 %

Procedure:
To a solution of methyl [2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.061 g; 0.181 mmol) in dioxane (4 mL) and water (1 mL) was added a 1N lithium oxide solution (1 mL; 1 mmol). The reaction mixture was heated at 65° C. for 2.5 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.031 g (54%) of the title compound as a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cccnc1
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a solution of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.2 g, 0.71 mmol) in N,N′-dimethylformamide is added 3-(aminomethyl)pyridine (0.073 mL, 0.71 mmol). The reaction mixture is heated at 60° C. under N2. After reaction is completed, diethyl ether is added, and the red precipitate is isolated and washed with methanol, ether, and hexane respectively to afford 0.16 g (63.2% yield) of orange solid: mp 299-300° C.; 1H NMR (DMSO-d6) δ 11.09 (s, 1H), 10.69 (m, 1H), 8.74 (d, J=9 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J=3 Hz, 1H), 8.10 (s, 1H), 7.84 (m, 2H), 7.42 (m, 1H), 7.31 (d, J=9 Hz, 1H), 3.40 (d, J=4.8 Hz, 2H); MS (ESI) m/z 355.7 and 357.7 (M−H)−1, Analysis for C16H12BrN3O2, Calcd: C, 53.70; H, 3.38; N, 11.70. Found: C, 53.45; H, 3.23; N, 11.74.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1.CCCCCC>[CH3:8][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([CH3:11])=[CH:3][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: COc1cc(C)c(Br)cc1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C)c(B(O)O)cc1C
Temperature: -62.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of 4-bromo-2,5-dimethylanisole (5, 172 g, 0.8 mol) in anhydrous THF (800 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 352 mL, 0.88 mol, 1.1 equiv) in hexane at −60-−65° C. under N2. The resulting reaction mixture was stired at −60-65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (165.44 g, 203.2 mL, 0.88 mol, 1.1 equiv) at −60 to −65° C. The reaction mixture was stirred at −60 to −65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (750 mL) at −60 to −65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 400 mL). The combined organic extracts were then washed with H2O (400 mL), and saturated NaCl solution (400 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (500 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×200 mL), dried in vacuo at 40-45° C. for overnight. The crude product (6, 116.7 g, 144.0 g theoretical, 81%) was obtained as a white powder.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[CH3:9][CH:10]([NH2:13])[C:11]#[CH:12].C(N(CC)CC)C>C(O)C>[CH3:9][CH:10]([NH:13][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[C:11]#[CH:12]
Reactant: O=C1NC(=S)CS1
Reactant: C#CC(C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CC(C)NC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (2 g) in ethanol (35 mL) were added but-3-yn-2-amine hydrochloride (2.38 g) and triethylamine (3.14 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.42 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O:25]CC)=[O:24])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)CO>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([OH:25])=[O:24])[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CC(=O)O
Product: Cc1ccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A mixture of 60.1 parts of ethyl 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylate, 27.6 parts of potassium hydroxide and 150 parts of 1,2-ethanediol is stirred and refluxed for 3 hours. The reaction mixture is cooled to room temperature and poured onto water. The whole is neutralized with acetic acid. The precipitated product is filtered off and crystallized from N,N-dimethylformamide. The product is filtered off and dried in vacuo, yielding 43.9 parts (79.2%) of 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid; mp. 264.6° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][N+:10]=1[O-].P(Cl)(Cl)([Cl:23])=O>ClC(Cl)C>[Cl:23][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1F
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)nc1-c1ccc(F)cc1F
Temperature: 72.5 °C

Procedure:
To a nitrogen purged 500 mL, 3-necked flask, fitted with a reflux condenser, heating mantle and a thermocouple was charged 2-(2,4-difluorophenyl)-3-(ethoxycarbonyl)pyridine 1-oxide, 4 (21 g, 75 mmoles, 1.0 eq), followed by 150 mL dichloroethane. Phosphorous oxychloride (75 mL) was added in one aliquate with stirring, causing an immediate rise in temperature from 21 to 23° C. followed by gradual warming. The solution was heated under nitrogen to 70-75° C. (completeness of reaction determined by HPLC). The reaction was then cooled to room temperature and concentrated under vacuum to remove most of the POCl3. The remainder was quenched by slowly pouring onto 450 g of ice. The mixture (after the ice melted) was then extracted into methylene chloride (2×200 mL). The combined organics were dried (MgSO4), filtered through silica, eluted with methylene chloride, and concentrated to give the title Compound, 5, as an orange solid. 1H NMR (500.0 MHz, CDCl3) d 8.15 (d, J=8.2 Hz, 1H), 7.54 (td, J=8.5, 5.0 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 6.96-6.92 (m, 1H), 6.79-6.74 (m, 1H), 4.16 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.1 Hz, H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:20][CH2:19][C@@H:18](O)[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:7]=2[CH:29]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P([N:77]=[N+:78]=[N-:79])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[N:77]([C@@H:18]1[CH2:17][N:16]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C@@H:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[CH2:20][CH2:19]1)=[N+:78]=[N-:79]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reaction time: 4 h
Yield: 36.5 %

Procedure:
To a solution of tert-butyl (2R,5R)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-5-hydroxypiperidine-1-carboxylate (Intermediate 185, crude, 0.8 g) in THF (20 mL) were successively added triphenylphosphine (1.30 g), diisopropylazodicarboxylate (1 mL) and diphenyl phosphoryl azide (0.90 g). After 4 hours, the reaction was diluted with ethyl acetate, washed with saturated solution of sodium hydrogen carbonate (NaHCO3) and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride gave 0.31 g of product.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([C:12](=O)[CH:13]=O)[CH:9]=[CH:10][CH:11]=1)([F:4])[F:3].I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:27]=[N:28][CH:13]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([S:5][C:2]([F:1])([F:3])[F:4])[CH:7]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=N)NN)cc1
Reactant: O=CC(=O)c1cccc(SC(F)(F)F)c1
Agent: I
Product: COc1ccc(-c2nncc(-c3cccc(SC(F)(F)F)c3)n2)cc1

Procedure:
(3-Trifluoromethylsulfanylphenyl)oxoacetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (1.11 g, 3.78 mmol) using the method described in Example 1 to give 3-(4-methoxyphenyl)-5-(3-trifluoromethylsulfanylphenyl)-[1,2,4]triazine as a yellow solid (820 g): δH (400 MHz, CDCl3) 3.92 (3H, s), 7.06-7.10 (2H, m), 7.67 (1H, t, J 7.8 Hz), 7.90 (1H, d, J 7.8 Hz), 8.35-8.39 (1H, m), 8.56 (1H, s), 8.60-8.64 (2H, m), 9.55 (1H, s); m/z (ES+) 364.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(OCC)C>[O:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:11][CH2:12]1
Reactant: C=C1CC(=O)O1
Reactant: NCCN1CCOCC1
Solvent: CCOCC
Product: CC(=O)CC(=O)NCCN1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diketene (23.0 ml) in diethyl ether (115 ml) was added dropwise a solution of N-(2aminoethyl)morpholine (34.7 g) in diethyl ether (300 ml) at -40° C. After stirring for 2 hours at the same condition, the resulting precipitates were collected by filtration and dried in vacuo to give N-(2morpholinoethyl)acetoacetamide (41.1 g).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])/[C:5](OC)=[O:6].[CH3:25][NH2:26]>>[CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])/[C:5]([NH:26][CH3:25])=[O:6]
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1COc1ccccc1C
Reactant: CN
Product: CNC(=O)/C(=N/OC)c1c(C)cccc1COc1ccccc1C

Procedure:
methyl E-2-((2-methylphenyl)oxymethyl)-6-methylphenylglyoxylate O-methyl oxime prepared in the step 1 is reacted with methylamine (NH2Me) to give N-methyl E-2-((2-methylphenyl)oxymethyl)-6-methylphenylglyoxylamide O-methyl oxime of the present invention (step 2).