Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (0.71 ml, 10 mmol) in dry THF (20 ml) was added dropwise 1.6 M-BuLi in hexane (6.9 ml, 11 mmol) under argon at -78° C. The reaction mixture was stirred at -78° C. for 0.5 hr and Bu3SnCl (3.1 ml, 11 mmol) was added dropwise. After stirring for 1 hr at -78° C. and for 1 hr at room temperature, the mixture was concentrated, triturated with water (50 ml) and extracted with diethylether (100 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure to give (50) as a colorless oil. (3.7 g, quant.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Oc1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 99.9 %

Procedure:
To a solution of 3-hydroxyquinoline (1.00 g) and 3-chloro-4-fluoronitrobenzene (1.21 g) in acetone (20 mL), was added K2CO3 (2.86 g). The mixture was refluxed for 1 h. After cooling the reaction mixture was filtered through a short celite pad. The filtrate was concentrated to provide compound 51 (2.07 g, quant.) as a brown oil. 1H NMR (300 MHz/CDCl3) δ 7.02 (1H, d, J=9.1 Hz), 7.61 (1H, m), 7.72-7.80 (3H, m), 8.10-8.18 (2H, m), 8.45 (1H, d, J=2.7 Hz), 8.82 (1H, d, J=2.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.N.Cl>O.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc(C=CC(=O)O)cn1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
A mixture of 1-methylpyrazole-4-carboxaldehyde (made as in reference 15) (18.1 g), malonic acid (17.1 g), pyridine (15 ml) and piperidine (0.2 ml) was heated to 100° C. for 1 hour. After cooling, water was added, followed by aqueous ammonia to obtain a clear solution, which was acidified to pH5 with hydrochloric acid. The resulting solid was filtered off, washed with water and dried to obtain 3-(1-methylpyrazol-4-yl)acrylic acid (18.9 g). 1H-NMR (d6-DMSO) δ 3.83 (3H, s), 6.18 (1H, d), 7.44 (1H, d), 7.83 (1H, s), 8.07 (1H, s). (APCI) M+H=153. C7H8N2O2 requires 152.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:7]2[CH2:8][C:9]([F:12])([F:11])[CH2:10][CH:6]2[O:5][N:4]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>>[F:13][CH:2]([F:1])[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:7]2[CH2:8][C:9]([F:12])([F:11])[CH2:10][CH:6]2[O:5][NH:4]1
Reactant: Fc1ccccc1Br
Reactant: FC(F)C1=NOC2CC(F)(F)CC12
Product: Fc1ccccc1C1(C(F)F)NOC2CC(F)(F)CC21

Procedure:
Intermediate XXIX-1 was obtained following general procedure L: Starting from rac-(3aR,6aR)-3-difluoromethyl-5,5-difluoro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole, the reaction with 1-bromo-2-fluoro-benzene yielded the product rac-(3S,3aR,6aR)-3-difluoromethyl-5,5-difluoro-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole as a light brown oil. MS: m/z=294.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[NH:4][C:3]1=[O:12].[CH2:14](I)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH3:13])([CH3:1])[C:3](=[O:12])[NH:4]2)[CH:15]=[CH2:14]
Reactant: CC1(C)C(=O)Nc2cccc(O)c21
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1C(C)(C)C(=O)N2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.01 g (5.71 mmol) of 2,3-dihydro-3,3-dimethyl-4-hydroxy-1H-indol-2-one, 1.92 g (5.99 mmol) of allyl iodide, and 1.57 g (11.4 mmol) of potassium carbonate were added to 8.73 ml of N,N-dimethylformamide, and the mixture was stirred for one hour over a water bath at 70° C. After the reaction, the solvent was evaporated and chloroform was added to the residue. The residue was then washed with water, 2N aqueous solution of sodium hydroxide, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, chloroform) to obtain 914 mg (yield: 70.2%) of colorless prisms of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([OH:20])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([NH:29][CH2:30][CH2:31][NH:32][C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 1 g (2.54 mmol) of (3S)-7-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]heptanoic acid, 406 mg (2.54 mmol) of tert-butyl (2-aminoethyl)carbamate and 0.96 ml of triethylamine (6.85 mmol) are dissolved in 20 ml of dimethylformamide. Then, at 0° C. (ice bath), 826 mg (4.3 mmol) of EDC and 113 mg (0.84 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried under high vacuum.
Reaction SMILES: CON(C)[C:4](=[O:36])[C@@H:5]([NH:13][C:14]([CH2:16][N:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:20]([C:29](=[O:31])[CH3:30])[CH:19]([CH:32]([CH3:34])[CH3:33])[C:18]1=[O:35])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Li].O1CCC[CH2:41]1.C1(C(C)C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[C:29]([N:20]1[CH:21]=[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:17]([CH2:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:36])[CH3:41])=[O:15])[C:18](=[O:35])[CH:19]1[CH:32]([CH3:34])[CH3:33])(=[O:31])[CH3:30]
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CC(C)c1ccccc1
Product: CC(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of N1-methoxy-N1-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide (122 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (2 ml) is cooled to −78° C., a 1.0 M methyllithium/tetrahydrofuran/cumene solution (1.2 ml) is added thereto, and the mixture is stirred for 15 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the temperature is raised to 0° C. The whole is extracted with ethyl acetate, and the extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (53.8 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:23]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:4]([NH:27][CH:24]2[CH2:26][CH2:25]2)[N:3]=1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1nc(NC2CC2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 3000 ml three-mouth bottle, 2,6-dichloropurine (300 g), ethyl acetate (1500 ml), pyridinium salt of paratoluenesulfonic acid (3 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (360 ml) is added thereto within 30 min. The above mixture is reacted at 50˜60° C. for 5 h. The completion of reaction is checked with TCL analysis. Triethylamine (240 ml) is added to the bottle, and cyclopropylamine (204 ml) is added thereto under refluxing within 30 min. The above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid compound 2-choro-N-cyclopropyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine (364 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].Cl[C:12]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:18])[N:13]=1>>[Cl:18][C:14]1[N:13]=[C:12]([N:2]([CH3:1])[C@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:4])[CH:17]=[N:16][CH:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CN[C@@H](C)c1ccccc1
Product: C[C@@H](c1ccccc1)N(C)c1cncc(Cl)n1
Yield: 38.8 %

Procedure:
In an analogous fashion to example 1, N-methyl-N-[(1S)-1-phenylethyl]amine (0.27 g, 2.0 mmol) was condensed with 2,6-dichloropyrazine (0.36 g, 2.4 mmol), to furnish the desired product as a light brown solid (192 mg, 39%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([F:24])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)C>C(O)C.[Pd]>[F:24][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:25])[NH:16]2)=[CH:21][CH:20]=1
Reactant: O=C1Nc2cc(F)ccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: O=C1Nc2cc(F)ccc2CN1C1CCNCC1
Reaction time: 96 h
Yield: 86.8 %

Procedure:
3-(1-Benzylpiperidin-4-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (1.32 g, 3.89 mmol) was dissolved in ethanol (100 mL) at room temperature. To this was added palladium (10% on charcoal, 130 mg). The resulting mixture was stirred under a hydrogen balloon for 4 d. The reaction was filtered through a pad of celite, eluting with ethanol (50 mL), and concentrated in vacuo to afford a yellow residue. Upon addition of diethyl ether (20 mL), a solid precipitated from solution. Trituration and filtration with diethyl ether (2×5 mL) gave the title compound as a yellow solid (0.842 g, 87% yield). 1H-NMR (CD3OD, 400 MHz) δ 6.94-6.88 (m, 2H), 6.78 (dd, J=6.2, 4.0, 1H), 4.42 (s, 2H), 4.41-4.35 (m, 1H), 3.53-3.47 (m, 2H), 3.21-3.13 (m, 2H), 2.25-2.14 (m, 2H), 1.98-1.92 (m, 2H). Mass spec.: 250.10 (MH+).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)CC1

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate in 73% as a tan solid. 1H NMR (400 MHz, MeOD) δ 1.24 (qd, J=12.8, 4.4 Hz, 2H), 1.41 (s, 9H), 1.78 (br d, J=12.1 Hz, 2H), 2.02 (m, 2H), 2.77 (m, 2H), 4.00 (br d, J=13.1 Hz, 2H), 4.15 (d, J=6.3 Hz, 2H), 7.74 (dd, J=7.5, 1.5 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([Br:41])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Br:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(Br)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (5 g), 2-bromo-1-(3-bromo-4-methoxyphenyl)ethanone (4.4 g) and N,N-dimethylformamide (300 mL) was added 60% sodium hydride (0.57 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (3.4 g, 43%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].[CH3:13][NH2:14]>C(Cl)CCl>[CH3:13][NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CN
Solvent: ClCCCl
Product: CNC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Commercially available 3-nitrobenzoic acid is reacted with methylamine and EDC under standard conditions to afford N-methyl-3-nitrobenzamide, which is reduced with LAH under standard conditions to afford N-methyl(3-nitrophenyl)methanamine, which is protected with benzylchloroformate under standard conditions to yield t-butyl 3-nitrobenzylmethylcarbamate. This material is nitrosated and reduced to yield t-butyl 3-hydrzazinobenzylmethylcarbamate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH2:27][CH2:26]2>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:28](=[O:32])[CH2:27]1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(Br)CC2=O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then washed with CH2Cl2 (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C10H9BrO2+H: 241, observed: 241.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:18])=[O:17])[CH3:3].CO[C:21]([CH3:23])=[CH2:22]>C(O)(=O)C>[CH3:3][C:2]1([CH3:1])[N:4]([CH:21]([CH3:23])[CH3:22])[C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16](=[O:17])[NH:18]1
Reactant: C=C(C)OC
Reactant: CC(C)Nc1cc(-c2ccncc2)sc1C(N)=O
Solvent: CC(=O)O
Product: CC(C)N1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 35 °C
Yield: 52 %

Procedure:
A mixture of 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.225 g, 0.858 mmol), ammonium chloride (0.459 g, 8.58 mmol) and triethylamine (1.21 mL, 8.58 mmol) in DMF (5 mL) was stirred at room temperature for 15 min. To the resulting mixture was added 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (0.493 g, 2.57 mmol), and 1-hydroxybenzotriazole (0.347 g, 2.57 mmol) and the reaction was stirred at room temperature for 65 h. Then, the reaction mixture was diluted with sat. NaHCO3 (120 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated to give crude 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxamide (0.225 g) as an orange solid. A mixture of 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxamide (0.105 g) and 2-methoxypropene (1.53 mL, 16.0 mmol) in acetic acid (1.5 mL) was heated at 35° C. overnight. Then, the reaction mixture was cooled to room temperature and concentrated. The obtained residue was dissolved in methanol (10 mL), and the solution was concentrated with NaHCO3 (1 g) and silica gel (5 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 95:5 ethyl acetate /methanol) to give the title compound (0.063 g, 2 step yield 52%) as an orange solid:
Reaction SMILES: [CH:1]1([C:8](=O)[CH:9]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[C:10](OCC)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[N:30]=[CH:29][NH:28][N:27]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:1]1([C:8]2[N:27]3[N:28]=[CH:29][N:30]=[C:26]3[N:25]=[C:10]([OH:11])[C:9]=2[C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 62.1 %

Procedure:
A mixture of ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate (342 mg, 1.0 mmol), 3-amino-1,2,4-triazole (84 mg, 1.0 mmol), and tributylamine (185 mg, 1.0 mmol) is stirred under nitrogen atmosphere at 160° C. for 2.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acid and saturated sodium chloride, dried over magnesium sulfate, and concentrated to a solid. The solid thus obtained is washed with hexanes to give crude 7-cycloheptyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol as a light tan solid (225 mg). MS: m/z 363.2 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]([C@H:12]([OH:16])[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.[Cu](Cl)Cl>[CH3:20][C:19]1([CH3:21])[O:16][C@@H:12]([C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([OH:11])=[O:10])[C:13](=[O:15])[O:14]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@H]([C@@H](Cc2ccccc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of (2R,3S)-2-benzyl-3-hydroxysuccinic acid (1.70 g; 7.58 mmol; 1.0 eq.) in acetone (50.0 mL) was added 2,2-dimethoxypropane (1.86 g; 15.2 mmol; 2.0 eq.) and copper(II) chloride (102 mg; 0.76 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 2 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product as a greenish oil (1.46 g) used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].ClCCl.C([Zn][CH2:28][CH3:29])C>CCCCCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH:13]1[CH2:14][CH:15]1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:28][CH3:29]
Reactant: CC[Zn]CC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCC1CC1CC1CC1CCCCCCCC(=O)OC
Reaction time: 1 h

Procedure:
To a mixture of linoleic acid methyl ester (2.5 g) and dichloromethane (50 ml), a 0.99M solution of diethylzinc (103 ml) in n-hexane was added under a nitrogen atmosphere. The mixture was cooled in an ice-water bath (−5° C. to 0° C.) and stirred for 1 hour at this temperature. Diodomethane (16.4 ml) was added to the mixture, and the mixture was stirred at ambient temperature overnight. After evaporation in vacuo of the solvent, the reacting mixture was dissolved in a mixture of ethyl acetate (EA) and a saturated aqueous solution of ammonium chloride. The separated organic layer was washed with water and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (eluted with 1% EA in n-hexane). The fractions including 8-(2-((2-pentyl-cyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester were collected and concentrated in vacuo to give 8-(2-((2-pentylcyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester (2.81 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[NH2:17].N1C=CC=CC=1.CO[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1OC)[C:30](Cl)=[O:31].[CH2:38]([Cl:40])Cl>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[NH:17][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([CH2:38][Cl:40])[CH:28]=1
Reactant: CCCN(CCC)c1ccc(N)c(C(=O)OC)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: ClCCl
Solvent: c1ccncc1
Product: CCCN(CCC)c1ccc(NC(=O)c2cccc(CCl)c2)c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-5-dipropylamino-benzoic acid methyl ester (compound A) (243 mg) produced by the above reaction was dissolved in anhydrous methylene chloride (3.0 ml). Subsequently, pyridine (170 μl) and 3-(chloromethyl)benzoyl chloride (compound B) (166 μl) were added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3-chloromethyl-benzoylamino)-5-dipropylamino-benzoic acid methyl ester as a useful intermediate (280 mg, yield 64%).