Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=O)C.[C:18]([CH:23]=[C:24]1[CH2:28]C[CH2:26][NH:25]1)([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:21]([O:20][C:18]([C:23]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]2[N:25]([CH2:26][CH2:4][CH2:5]2)[C:24]=1[CH3:28])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)C=Cc1ccccc1C
Reactant: CCOC(=O)C=C1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCCC2=C(C(=O)OCC)C1c1ccccc1C
Yield: 62 %

Procedure:
Upon boiling a solution of 7.7 g of 2-methylbenzylideneacetoacetic acid ethyl ester and 5.6 g of carbethoxymethylidenepyrrolidine in 50 ml of ethanol for 8 hours, 5-methyl-7-(2-methylphenyl)-1,2,3,7-tetrahydroindolizine-6,8-dicarboxylic acid diethyl ester of melting point 148° (alcohol) is obtained.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:28])[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27].[C:29]([O:33][C:34]([NH:36][C@H:37]([C:51](O)=[O:52])[CH:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:28])[CH2:17][N:18]([C:51](=[O:52])[C@@H:37]([NH:36][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[CH:38]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CNCc1ccccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccccc1OC)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g) was added over 5 minutes to a mixture of N-(2-methoxybenzyl)glycine methyl ester hydrochloride (1.72 g), N-(tert-butoxycarbonyl)-3,3-diphenyl-L-alanine (1.71 g), 1-hydroxybenzotriazole (0.81 g) and N,N-diisopropylethylamine (1.22 ml) in dichloromethane (40 ml). After being stirred for 3 hours at room temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1) to give N-[(2S)-2-(tert-butoxycarbonylamino)-3,3-diphenylpropionyl]-N-(2-methoxybenzyl)glycine methyl ester (2.34 g) as a colorless powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[C:9]([C:10]#[N:11])=[CH:8][NH:7][N:6]=1.Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].O>CN(C=O)C>[C:10]([C:9]1[C:5]([C:4]([F:3])([F:12])[F:13])=[N:6][N:7]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[CH:8]=1)#[N:11]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: N#Cc1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
NaH (60% [w/w] suspension in oil, 130 mg, 3.25 mmol) was added to a solution of 3-(trifluoromethyl)-4-cyanopyrazole (520 mg, 3.23 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 1 h before adding 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.023 g, 3.23 mmol). The reaction mixture was heated at 65° C. for 4 h then allowed to cool to RT. Water (20 mL) was added and the reaction mixture extracted with EtOAc (3×20 mL). The combined EtOAc layers were washed with water (5×20 mL), brine (20 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the crude reaction mixture as a cream solid. Purification by flash chromatography (eluent 1:1 EtOAc:heptane) gave desired product (626 mg, 1.58 mmol, 49%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:2]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27]Cl.[I-].[Na+].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O>[N:31]([CH2:24][CH2:25][CH2:26][CH2:27][C:10]([CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCCCBr
Reactant: CCOC(=O)C(CCCc1cccnc1)C(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCN=[N+]=[N-])(CCCc1cccnc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 63.34g (0.23 mole) of diethyl [3-(3-pyridyl)-propyl]malonate in 1.1L dimethylformamide is in small portions 9.91 g (0.25 mole) of sodium hydride as a 60% dispension in oil. After stirring at room temperature for 0.5 hours, 28 mL (0.23 mole) of 1-bromo-4-chlorobutane is added and then heated to 60° for 10 hours. Then 68.26 g (0.46 mole) sodium iodide is added followed by 44.44 g (0.68 mole) sodium azide and 9.0 g crown ether 18-Crown-6. The reaction mixture is heated for 15 hours at 60°, is then cooled and poured on ice. The mixture is then extracted with ether (4×500 mL). Combined organic extracts are extracted with 1N aqueous hydrochloric acid (1×200, 2×100 mL). Combined aqueous extract is adjusted to pH 8 by addition of solid sodium bicarbonate and then extracted with ether (3×300 mL). Combined organic extracts are washed with water (3×100 mL), brine (1×300 mL), dried (MgSO4), filtered and then evaporated to dryness to give diethyl [4-azidobutyl][3-(3-pyridyl)-propyl]-malonate as an oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.Cl[CH2:10][CH:11]=O.S(=O)(=O)(O)O.COC1C=CC(OC)=CC=1>C(OCC)(=O)C.O>[O:7]=[C:3]1[C:2]2[CH:10]=[CH:11][O:8][C:1]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=CCCl
Agent: COc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 ml of water were added 1.12 g (10 mmoles) of 1,3-cyclohexanedione and the each base shown in Table 1, and then 2 ml of 40% aqueous solution of chloroacetaldehyde was added thereto. The resulting mixture was stirred at a room temperature for 2 hours. To the reaction mixture was added about 10 ml of ethyl acetate, and then the reaction mixture was acidified with 0.5 to 1 ml of sulfuric acid and stirred for 30 minutes. The resulting ethyl acetate layer was analyzed by gas-liquid chromatography (hereinafter referred to as "GLC") (SE30 10%, 1.2 m×3 mmφ glass column, 130° C.) using p-dimethoxybenzene as an internal standard. The obtained each result is shown in Table 1. It was proved from the results of the GLC that 4-oxo-4,5,6,7-tetrahydrobenzofuran was produced in a yield shown in Table 1, in each Example. Comparative Example 1 was carried out in the absence of a base.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH2:13]([O:15][P:16]([CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(O)C>[C:31]([O:30][C:28](=[O:29])[NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][CH2:21][P:16]([O:15][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:20])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOP(=O)(CCNCCCNC(=O)OC(C)(C)C)OCC
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N(CCCNC(=O)OC(C)(C)C)CCP(=O)(OCC)OCC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (45 g, 0.265 mole; Aldrich 31,077-8) in absolute ethanol (1.2 L) under nitrogen was added dropwise a solution of N-[3-(t-butyloxycarbonylamino)propyl]-2-aminoethylphosphonic acid diethyl ester (80 g, 0.24 mole) in absolute ethanol (600 mL) and the reaction mixture was stirred at ambient temperature 15 hr. The reaction mixture was concentrated in vacuo and the residue was put on a pad of silica gel (6"×4") and eluted first with a mixture of methylene chloride/hexane 1:1 to remove excessive 3,4-diethoxy-3-cyclobutene-1,2-dione and finally with 10% methanol/methylene chloride to yield the title compound after evaporation as a viscous oil (107 g, 96%). NMR: (CDCl3, 400 MHz): 1.34 (t, 6H), 1.43 (s, 9H), 1.46 (t, 3H), 1.80 (m, 2H), 2.12 (m, 2H), 3.14 (m, 2H), 3.49 (t, 1H), 3.66 (m, 1H), 3.73 (t, 1H), 3.90 (m, 1H), 4.10 (m, 4H), 4.74 (m, 4H), 5.05 (br, H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26]C(=O)C(F)(F)F)[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH2:17][CH2:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO>[C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH2:17][CH2:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 72.1 %

Procedure:
2.0 g of 21-acetoxy-6α-methyl-17-propionyloxy-11β-trifluoroacetoxy-4-pregnene-3,20-dione is agitated in 50 ml of methanol and 2.5 ml of triethylamine for 4 hours at room temperature. The crude product is purified on 300 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone), thus isolating 1.2 g of 21-acetoxy-11β-hydroxy-6α-methyl-17-propionyloxy-4-pregnene-3,20-dione.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18]([OH:20])=[O:19].CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[C:8]([NH:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)CC(=O)O

Procedure:
Triethylamine (1.8 mL, 12.8 mmol), acetic anhydride (1.2 mL, 12.8 mL) and DMAP (10 mg, 0.09 mmol) are subsequentially added to a suspension of 3-amino-3-methyl-butyric acid (1.00 g, 8.5 mmol) in THF (100 mL). After heating at 60° C. for 3 h AcOEt is added and the organic phase is washed with 1N HCl. Drying (Na2SO4), filtration and evaporation of the solvent yields the desired product. MS (LC-MS): [M+H]+=160.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.40 min.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:28][CH:29]=1>CN(C=O)C.O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[N:26][CH:25]=3)=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1cnc(OCCN2CCCC2)nc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccc(C#Cc3cnc(OCCN4CCCC4)nc3)nc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere 0.11 mL (0.79 mmol) triethylamine, 7 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium and 1.3 mg (0.01 mmol) CuI are added successively to a solution of 56 mg (0.26 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 71 mg (0.26 mmol) 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidine in 3.0 mL DMF. The mixture is stirred for 20 min at 100° C. and at 300 Watt in the microwave. The reaction solution is diluted with 10 mL water and the aqueous phase is extracted with 20 mL EtOAc. The organic phase is extracted with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography with HPLC-MS.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH:28][CH3:29])C>O.Cl>[CH:1]1([CH2:7][CH2:8][N:9]2[C:11]3[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:25]([CH2:26][CH2:27][NH:28][CH3:29])=[CH:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(N(N)CCC2CCCCC2)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCCc1cn(CCC2CCCCC2)c2ccc(C)cc12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
The title compound was prepared by General Method 3. A solution of 1-(2-cyclohexylethyl)-1-p-tolylhydrazine (0.15 g) in water (1 mL) and conc. HCl (0.18 mL) was heated to 60° C. EtOH (1 mL) was added followed by 4,4-diethoxy-N-methylbutan-1-amine (0.12 g) and the temperature was raised to 90° C. Conc. HCl (0.1 mL) was added and the heating was continued for an additional 6 h after which the reaction mixture was cooled and stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 9/1/0.1) to obtain 79 mg of product.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1.[C:9](OC)(=[O:13])[C:10]([CH3:12])=[CH2:11].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:9]([O:8][CH2:7][CH:1]1[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1)(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: OCC1C=CCC=C1
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCC1C=CCC=C1
Yield: 87 %

Procedure:
The method of Example 1 was substantially repeated with 2,5-cyclohexadienylmethanol (40.86 g, 0.37 mol, containing ca. 13% 2-cyclohexenylmethanol), methyl methacrylate (159 mL, 1.5 mol), phenothiazine (0.1 g), and tetraisopropyl titanate (2.0 mL). The excess methyl methacrylate was distilled at 70 mm and the product was distilled to give 57.5 g (87% yield) of clear, colorless liquid 2,5-cyclohexadienylmethyl methacrylate, bp 58° C./0.15 mm to 54° C./0.12 mm. IR (film): ν 3030, 2941, 1709, 1629, 1445, 1309, 1287, 1152, 1009, 979, 934, 873, 810 cm-1. 220 MHz 1H NMR: δ 6.07 (1H, m, methacrylate vinyl), 5.8 (2H, m, vinyl), 5.6 (2H, m, vinyl), 5.50 (1H, m, methacrylate vinyl), 4.04 (2H, d, J=6), 3.1 (1H, m, allylic methine), 2.6 (2H, M, allylic methylene), and 1.93 (3H, m, allylic CH3); the minor impurity of cyclohexenylmethyl methacrylate showed a broad envelope of signals from δ 2.0 to 1.3 and a 6 Hz doublet (--CH2O) at 4.02 which showed it to be 13% of the mixture. 22.63 MHz 13C NMR: δ 167.1, 137.7, 126.3, 125.4, 125.2, 68.0, 35.7, 26.5, 18.3.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:19][I:20]>CC(C)=O>[I-:20].[CH3:19][N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1](=[O:8])[NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: O=C(NCCc1ccc(O)cc1)c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(C(=O)NCCc2ccc(O)cc2)c1
Product: [I-]
Reaction time: 6 h

Procedure:
To a solution of 1.21 g (5 mmol) of nicotinoyltyramine in 10 ml of acetone, 1.41 g (10 mmol) of methyl iodide were added and the mixture was refluxed while stirring for 6 hrs. The fine, yellow solid which separated was filtered and crystallized from methanol ether. Yield 1.78 g (93%), m.p. 208°-210° C. PMR (DMSO-d6 /D2O) δ 9.23-8.26 (m, 4H, C5H4N+), 7.33-6.83 (m, 4H, C6H4), 4.50 (s, 3H, ##STR1548## 3.70 (t, J=7 Hz, 2H, ##STR1549## 2.93 (t, J=7 Hz, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=1)[C:6](/[N:8]=[CH:9]/[N:10](C)C)=O.[CH3:19][NH:20]N>C(O)(=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6]1[N:20]([CH3:19])[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)c1cc(F)ccc1C(=O)/N=C/N(C)C
Reactant: CNN
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)ccc1-c1ncnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[1-dimethylamino-meth-(E)-ylidene]-5-fluoro-phthalamic acid methyl ester plus regioiosmer (2.9 g, 11.50 mmol) in acetic acid (10 mL) is added methyl hydrazine (6.0 mL, 113.95 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc (250 mL) and the organic layer is washed with H2O (150 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is triturated with 1:1 EtOAc:hexanes (200 mL), and filtered to remove the white solid. The mother liquor is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 7.5% MeOH in CH2Cl2 as the eluent to afford 5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-benzoic acid methyl ester plus regioisomer (1.5 g, 55%).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[CH3:18])=O.[NH3:20]>>[CH3:18][C:17]1[N:20]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: N
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(C)=O)c1C
Product: CCOC(=O)c1c(C)cc2cnc(C)nc2c1C
Yield: 40 %

Procedure:
Instead of the compound of formula (II) used in Example 1, ethyl 4-formyl-2,6-dimethyl-3-acetylaminobenzoate was used and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column in the same way as in Example 1. The solvent was evaporated, and the residue was recrystallized from ethanol/water to give 2-methyl-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 84° to 86° C. in a yield of 40%.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]5[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:47][CH:46]=5)[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)c3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and 4-(methylsulfonyl)benzoic acid (56.7 mg, 0.283 mmol) using a similar method to that employed for Example 14 (3%).
Reaction SMILES: Br[C:2]1[CH:3]([CH2:7][CH:8]=[O:9])[CH2:4][CH2:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)C>C1C=CC=CC=1.CCO.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>[C:16]1([C:2]2[CH:3]([CH2:7][CH:8]=[O:9])[CH2:4][CH2:5][CH:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: O=CCC1CCC=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCO
Product: O=CCC1CCC=C1c1ccccc1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) (1.85 g, 9.32 mmol) in benzene (70 mL) was treated with Na2CO3 (14.0 mL, 2M in H2O.) and phenylboronic acid (2.27 g, 18.6 mmol) in EtOH (40 mL). Tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4 catalyst (1.61 g, 1.40 mmol) was added and the mixture was heated to 80° C. for 3.5 h. until no starting material remained. The benzene was replaced with diethyl ether and the mixture was filtered through celite. The filtrate was washed with sat. K2CO3, brine and dried over MgSO4. Pure (2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) 1.07 g (62%) was isolated by chromatography on silica gel. Use of (2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) in Method A (without formation of the fumarate) produced 4-[(2-phenylcyclopent-2-en-1-yl)methyl]-1,3-dihydro-2H-imidazole-2-thione (Compound 112).
Reaction SMILES: [C:1]([O-:4])(=S)[CH3:2].[K+].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-])=O.CN(C=O)C>[Cl-].[Na+].O>[C:1]([NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Generally, the procedure is as follows: under nitrogen gas, a stirred mixture of potassium thioacetate (e.g., about 3.71 g, 32.5 mmol), nitrobenzene (e.g., about 1 g, 8.1 mmol) and DMF (e.g., about 2.0 ml) is heated at about 130° C. After two hours, the reaction mixture is cooled to room temperature, brine (e.g., about 2 ml) is added and the resulting mixture is extracted with tert-butyl methyl ether (e.g., about 2×15 ml). The combined organic layer is washed with brine (e.g., about 2×4 ml) to remove residual DMF and filtered through a pad of charcoal and Celite to remove any residual sulfur. Evaporation of the solvent produced about 0.9 g of acetanilide (about 83%).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH:7][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH2:9][C:10]([NH2:12])=[O:11])=[O:6])([CH3:4])[CH3:3].CO>N.C(O)CO.CCOC(C)=O>[CH3:4][C:2]([S:5]([NH:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=1)[CH2:9][C:10]([NH2:12])=[O:11])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[S@@](=O)NC(CC(N)=O)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: OCCO
Product: CC(C)(C)S(=O)NC(CC(N)=O)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 120 °C
Yield: 76.3 %

Procedure:
(R)-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanamide (prepared as described for Procedure 11, 0.70 g, 1.33 mmol) was dissolved in 8N NH3 in ethylene glycol (6 mL) at room temperature in a microwave vial. The reaction mixture was heated at 120° C. for 1200 sec, and then at 130° C. for 1200 sec under microwave irradiation. After cooling, the cap was removed, and H2O was added. The mixture was extracted with EtOAc (3×), washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, then 10% MeOH in EtOAc) to give 3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)-propanamide as white solid (0.52 g, yield: 76%) LCMS: 3.88 min [M+1]513.28 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.29 (m, 3H), 7.22-7.12 (m, 3H), 7.11-7.02 (m, 2H), 6.29 (m, 2H), 5.40 (s, br, 1H), 3.78 (d, J=14.50 Hz, 1H), 3.71 (s, 2H), 3.35 (d, J=14.50 Hz, 1H), 1.21-1.28 (m, 9H).