Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.[CH2:14]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[N:20]=[C:19]([NH:29][CH3:30])[N:18]=1)[CH3:15].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[C:10]3[S:9][C:8]([NH:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:12][C:11]3=[O:13])[CH:25]=2)[N:20]=[C:19]([NH:29][CH3:30])[N:18]=1)[CH3:15]
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: O=C1CSC(NCc2cccs2)=N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4cccs4)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a brown solid: 48.6 mg (69.1%), MS: m/e 426 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Li+]>ClCCl>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
In accordance with the method of “Helvetica Chimica Acta”, 2002, vol. 85, no. 11, p. 3616-3623, triethylamine was added under ice-cooling to a mixture of trans-cinnamic acid chloride, (S)-4-benzyl-2-oxazolidinone, lithium chloride and dichloromethane, and then stirred at room temperature for 3Hours. Thereafter, (4S)-4-benzyl-3-[(2E)-3-phenylprop-2-enoyl]-1,3-oxazolidin-2-one was obtained by purifying it in the standard method. FP: 308.
Reaction SMILES: [ClH:1].[C:2]([NH:10][CH2:11][C:12]([OH:14])=O)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(Cl)Cl>[ClH:16].[C:2]([NH:10][CH2:11][C:12]([Cl:1])=[O:14])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N=C(NCC(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N=C(NCC(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To benzimidoylaminoacetic acid hydrochloride (2.2 g., 10 m moles) in 40 ml. of dry methylene chloride is added 2.5 g. (12 m moles) of phosphorous pentachloride, and the reaction mixture allowed to stir overnight at room temperature. The product is filtered, washed successively with methylene chloride (50 ml.), chloroform 2 × 75 ml.) and hexane (50 ml.) and dried in vacuo, 2.5 g. (99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:30][CH3:31])CC)C>ClCCl.C(OCC)(=O)C>[CH:19]1[C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:6](=[O:7])[C:5]4[CH:4]=[CH:3][CH:2]=[CH:24][C:30]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 130.8 %

Procedure:
A mixture of 0.10 g of 5-(4-aminobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine, 0.10 g of triethylamine in 1 ml of dichloromethane is stirred at room temperature for 6 hours. The mixture is diluted with 6 ml of ethyl acetate and the solution washed with 1N HCl, 1N NaOH, brine and dried (Na2SO4). The solvent is removed and the solid purified by chromatography on thick layer silica gel plates with the solvent ethyl acetate-hexane (1:1) to give 90 mg of a pale yellow solid.
Reaction SMILES: NC1C=C(Cl)C=C[C:3]=1[CH2:4][N:5]1[CH:9]=C[CH:7]=[C:6]1C#N.[NH2:17][C:18]1[CH:31]=[C:30]([Br:32])[C:29]([Br:33])=[CH:28][C:19]=1[CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]#[N:27]>>[Br:33][C:29]1[C:30]([Br:32])=[CH:31][C:18]2[N:17]=[C:26]([N:27]3[CH2:7][CH2:6][N:5]([CH3:9])[CH2:4][CH2:3]3)[C:22]3=[CH:23][CH:24]=[CH:25][N:21]3[CH2:20][C:19]=2[CH:28]=1
Reactant: N#Cc1cccn1Cc1ccc(Cl)cc1N
Reactant: N#Cc1cccn1Cc1cc(Br)c(Br)cc1N
Product: CN1CCN(C2=Nc3cc(Br)c(Br)cc3Cn3cccc32)CC1

Procedure:
The general procedure of Example 7 is repeated but replacing the 1-(2-amino-4-chlorobenzyl)-2-pyrrolecarbonitrile employed in that example with an equivalent amount of 1-(2-amino-4,5-dibromobenzyl)-2-pyrrolecarbonitrile whereby there is obtained the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH2:33])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH:33][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Yield: 33 %

Procedure:
To a solution of 5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (50 mg, 0.112 mmol) in DCM was added pyridine (26 mg, 0.33 mmol, 3.0 eq.) and ethanesulfonyl chloride (17 mg, 0.135 mmol, 1.2 eq.). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 33% yield (20 mg). 1H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 9.02-8.99 (m, 2H), 8.81 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.77-7.69 (m, 2H), 7.49-7.42 (m, 2H), 7.31-7.25 (d, 1H), 4.33 (d, 2H), 3.42-3.26 (m, 2H), 1.34-1.24 (t, 3H), 0.63-0.60 (t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI): Calculated mass: 535.5; Observed mass: 535.8 [M+H]+ (rt: 0.1.33 min).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)#[C:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>CN(C=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:2]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCC#Cc1ccccc1
Reactant: O=Cc1ccc(Br)c2cccnc12
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C#CCCCCc2ccccc2)c2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A solution of 5-bromo-8-quinolinecarboxaldehyde (987 mL, 418 mmol), 5-hexyn-1-yl-benzene [CAS 100848-88-2] (1.05 mL, 5.85 mmol), triethylamine (2 mL) and 1,3-bis(diphenylphosphino)propane (dppp, 59 mg) in DMF (10 mL) was heated to 90° C. with stirring for 2 h. After cooling to RT, the reaction mixture was extracted with ether and washed with water and brine, dried over magnesium sulfate and concentrated. Purification by MPLC (35% ethyl acetate in hexanes) gave rise to 1.04 g of Intermediate.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH:11](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:12]([CH3:14])=[O:13]>ClCCl>[O:13]=[C:12]([CH3:14])[CH:11]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)C=Cc1ccc(C#N)cc1
Yield: 80 %

Procedure:
By stirring 3.02 g of 4-cyanobenzaldehyde and 7.32 g of acetonylidene-triphenylphosphorane in 50 ml of dichloromethane and then recrystallizing from isopropanol, 3.15 g (80%) of 4-(3-oxobutenyl)-benzonitrile is obtained. 1.71 g of it is mixed in 20 ml of dichloromethane with 20 ml of a 0.5 M solution of bromine in dichloromethane. After decolorization, the solvent is drawn off in a vacuum. The remaining oil is refluxed with 0.95 g of imidazole and 7 ml of triethylamine in 40 ml of toluene for 2 hours. A precipitate is filtered off, the filtrate is distributed in ethyl acetate-2M hydrochloric acid, the hydrochloric acid phase is alkalized with potassium carbonate and extracted with ethyl acetate. 1.2 g of a crude product is obtained, which, after recrystallization from isopropanol, yields the Z-isomer with mp. 131°-135° C. After chromatography of the mother liquor on silica gel (eluant ethyl acetate), the E-isomer is obtained from ethyl acetate/ether as crystals of mp: 123°-126° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: COC(=O)Cl
Reactant: CNCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(C)CCCC(=O)O
Temperature: 25 °C
Yield: 170.4 %

Procedure:
4-(Methylamino)butyric acid hydrochloride (5 g, 32.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 4-[(methoxycarbonyl)(methyl)amino]butyric acid as a thick clear oil (9.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[CH2:20](S)[SH:21].[OH-].[K+]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:20](=[S:21])[NH:15][N:14]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: SCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc(I)ccc1Nc1cnccc1-c1n[nH]c(=S)o1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (744 mg, 2.ommol) in methanol (15 mL) were added dithiomethane (0.22 mL, 4.66 mmol), followed by potassium hydroxide (2.51 mL, 2.13 mmol). The reaction mixture was stirred at 60° C. for 7 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (50 mL), washed with Brine (15 mL×3), dried over anhydrous MgSO4, filtered, removed off solvent. Residue was subjected to silica gel column (EtOAc:Hexane=1:1) collected product 210 mg. LC-MS (Method A) [5.71 min; 415(M+1)]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[NH:19][C:23]1=[O:24])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[C@H](NC(=O)c1cc(OC)ccc1N)C(=O)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2ccc(OC)cc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 136 %

Procedure:
To a solution of (S)-2-(2-amino-5-methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 1.39 mmol) in THF (30 mL) is added trichloromethyl chloroformate (200 mg, 1.01 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give (S)-2-(6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (440 mg, 98%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[CH3:23][C:24]1([CH3:39])[CH2:29][N:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[C:27](=[O:38])[CH2:26][NH:25]1>C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[CH2:29][N:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[C:27](=[O:38])[CH2:26][N:25]1[CH2:9][C@H:7]([NH:8][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]1[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]1
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: Cc1ccc(F)cc1N1CC(C)(C)NCC1=O
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Yield: 95.4 %

Procedure:
A solution of 844 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (2.59 mmol) and 733 mg of 5,5-dimethyl-1-(5-fluoro-2-methylphenyl)piperazin-2-one obtained in Example (70d) (3.10 mmol) in toluene (26 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1-1/1) to obtain 1.39 g of the title compound (yield: 95%).
Reaction SMILES: [CH:1]([C:5]1[C:6](O)=[C:7]([CH:10]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:12]=1)C=O)([CH2:3][CH3:4])[CH3:2].C(C1C(O)=C(C=C(/C=C/C(=O)C2C=CC(C)=CC=2)C=1)C=O)(CC)C.[C:49]([O:56][CH3:57])(=[O:55])[CH2:50][C:51]([O:53][CH3:54])=[O:52].CN1CCOCC1>CO>[CH:1]([C:5]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:10]=[C:7]2[C:54]=1[O:53][C:51](=[O:52])[C:50]([C:49]([O:56][CH3:57])=[O:55])=[CH:6]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C=O)c1O
Reactant: COC(=O)CC(=O)OC
Agent: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Solvent: CO
Solvent: CN1CCOCC1
Product: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc2cc(C(=O)OC)c(=O)oc12

Procedure:
A solution of 3-sec-butyl-5-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-hydroxybenzaldehyde of formula III (0.5 g, 1.46 mmol), dimethyl malonate (0.19 g, 1.46 mmol) in methanol (30 mL) was treated with N-methyl morpholine (0.3 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (25 mL) was added and extracted 3-fold with 25 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane. Concentration provides methyl 8-sec-butyl-6-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (General Formula IV). (0.49 g, 80% yield). White solid, m. p. 145-146° C.; 1H NMR (CDCl3, 300 MHz); δ 8.59 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.84-7.75 (m, 3H), 7.58-7.47 (m, 3H), 4.0 (s, 3H), 3.45-3.36 (m, 1H), 1.78-1.69 (m, 2H), 1.32 (d, 3H, J=7.0 Hz), 0.89 (t, 3H, J=7.3 Hz): 13C NMR (CDCl3, 75 MHz); δ 188.6, 163.4, 156.1, 154.0, 149.1, 143.1, 139.5, 136.7, 136.2, 131.6, 131.4, 130.0, 129.0, 127.3, 122.3, 118.4, 118.2, 52.9, 33.5, 29.6, 20.4. 12.0; ESI-MS (m/z): 425 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[NH2:27])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]1[C:44](=[O:45])[CH2:43][S:42]/[C:41]/1=[N:46]\[C:47](=O)[O:48]C1C=CC([N+]([O-])=O)=CC=1)([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]1[C:44](=[O:45])[CH2:43][S:42]/[C:41]/1=[N:46]\[C:47]([NH:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:28])[F:29])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:48])([CH3:32])[CH3:31]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: NC1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2CCCCC2c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 5.9 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanamine (CB56) (0.200 g, 0.497 mmol) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50) (0.205 g, 0.497 mmol) were dissolved in acetonitrile (10 mL) in a vial. Cesium carbonate (0.162 g, 0.497 mmol) was added, and the reaction was stirred at room temperature for 25 hours. The solution was adsorbed onto silica. Purification by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent afforded the title compound as a red oil (0.020 g, 6%).
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>CN(C)C(=O)C>[CH:29]1([C:32]([NH:1][C:2]2[N:28]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 52.6 %

Procedure:
In the same manner as in Example 28-2 and using N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (303 mg, 0.803 mmol), cyclopropanecarbonyl chloride (74.0 μL, 0.815 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (188 mg, 53%) was obtained as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[O:13][CH2:14][C:15]([CH2:33][OH:34])([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[N:16]=1>C(Cl)Cl>[CH3:11][C:12]1[O:13][CH2:14][C:15]([CH:33]=[O:34])([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[N:16]=1
Reactant: CCCCCCCCc1ccc(CCC2(CO)COC(C)=N2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(CCC2(C=O)COC(C)=N2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
A solution of 0.059 mL (0.8 mmol) of oxalyl chloride in 1.5 mL of CH2Cl2 at −78° C. was treated with 0.12 mL (1.6 mmol) of DMSO. The resulting mixture was stirred cold for 10 min, 118 mg of (+/−)-2-methyl-4-hydroxymethyl-4-(2-(4-octylphenyl)ethyl)oxazoline (from EXAMPLE 2, Step A) was added and resulting mixture was stirred cold for 30 min. TEA (0.28 mL, 2.0 mmol) was added and the resulting mixture was warmed to rt. The mixture was partitioned between 30 mL of ether and 10 mL of water. The organic layer was separated, dried and concentrated to afford 118 mg (100%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cncc(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cncc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
To a mixture of 4-[(5-bromo-pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (33.8 g, 100 mmol) and Ytterbium(III) triflate hydrate (6.2 g, 10 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (9.2 mL, 100 mmol) and water (1.8 mL, 100 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (42.2 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H21BrN2O3 (M+H)+: 406.29, observed: 405.0 & 406.9.
Reaction SMILES: [C:1](N1C=CN=C1)#[N:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:16]1=2.O>CN(C)C(=O)C>[F:41][C:9]([F:8])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:13][N:14]([C:1]#[N:2])[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:16]1=2
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Reactant: N#Cn1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Temperature: 100 °C

Procedure:
Add a solution of 1-cyanoimidazole in N,N-dimethylacetamide to a solution of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in N,N-dimethylacetamide at room temperature under nitrogen and heat the mixture to 100° C. Pour the cooled mixture into water and extract with methylene chloride. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(OCc2ccccc2)ccn1
Yield: 43.8 %

Procedure:
A solution of 4-(benzyloxy)pyridin-2(1H)-one (9.92 g, 49.3 mmol), methyl iodide (4.60 mL, 74.0 mmol) and silver carbonate (13.6 g, 49.3 mmol) in chloroform (50 mL) was stirred with heating under reflux for four hours. After leaving to cool, the insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 2:1) to obtain the title compound (4.65 g, 44%) as a pale yellow oil.