Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[CH2:10])(C(C)(C)C)(C)C.C1C(=O)N([Br:28])C(=O)C1>C1COCC1.O>[Br:28][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cccnc12
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline (300 mg, 1.045 mmol) in THF (5 mL) and water (1 mL) was added NBS (203 mg, 1.149 mmol), and the resulting mixture was stirred at 25° C. for 30 min. The mixture was diluted with water (5 mL) and extracted in to EtOAc (2×5 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield crude 2-bromo-1-(quinolin-8-yl)ethanone (200 mg) (used without further purification in subsequent transformations): 1H NMR (400 MHz, DMSO-d6) δ 8.99-8.98 (1H, m), 8.27-8.23 (1H, m), 8.17-8.15 (1H, m), 7.67-7.63 (1H, m), 5.18 (1H, s), 5.02 (1H, s), 2.78 (2H, s). m/z (ESI, +ve) 249.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
1-(5-(4-(Trifluoromethyl)phenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 4-bromobenzotrifluoride according to general procedure A.
Reaction SMILES: C(N[C:6]([N:8]1[CH2:13]CC[C@@H](CNC2C(F)=CN=C(C3C4C(=NC=C(Cl)C=4)NC=3)N=2)[CH2:9]1)=[O:7])(C)(C)C.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:40][NH:41][C:42]1[C:47]([F:48])=[CH:46][N:45]=[C:44]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55]([Cl:58])[CH:56]=3)[N:51](S(C3C=CC(C)=CC=3)(=O)=O)[CH:50]=2)[N:43]=1.[Cl-]>>[Cl:58][C:55]1[CH:56]=[C:57]2[C:49]([C:44]3[N:43]=[C:42]([NH:41][CH2:40][C@@H:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]4[NH:33][C:6](=[O:7])[N:8]([CH3:13])[CH3:9])[C:47]([F:48])=[CH:46][N:45]=3)=[CH:50][NH:51][C:52]2=[N:53][CH:54]=1
Reactant: CC(C)(C)NC(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Product: CN(C)C(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
Urea 564 was prepared according to the procedure for compound 20 (Scheme 12A) using N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, and dimethylcarbomoyl chloride, afforded desired product, 564, as a racemic mixture of trans isomers.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:30]([S:33]([NH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:5][CH:4]=1)(=[O:35])=[O:34])[CH2:31][CH3:32]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1(c2ccccn2)CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(C1(c3ccccn3)CCC1)N(C(=O)OC(C)(C)C)CC2

Procedure:
tert-Butyl 7-(aminomethyl)-1-[1-(pyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (33 mg, 0.084 mmol) was dissolved in dichloromethane. 4-Dimethylaminopyridine (30.7 mg, 0.252 mmol) was added. After stirring for 5 min propane-1-sulfonyl chloride (12 mg, 0.084 mmol) was added and stirring was continued over night. The reaction mixture was diluted with dichloromethane (30 ml) and washed with aqueous ammonium chloride solution. The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 37 mg.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([CH2:23][OH:24])[O:16][CH:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]1[O:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:31]>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([C:23]([OH:31])=[O:24])[O:16][CH:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]1[O:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CC(=O)OC1O[C@H](C(=O)O)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Reaction time: 5 h
Yield: 54 %

Procedure:
A solution of crude 17 in the minimum amount of dichloromethane was stirred at room temperature with aqueous 80% acetic acid (100 mL) until TLC demonstrated the disappearance of 17. Water was then added with stirring; the solid was removed and the filtrate was concentrated. The crude 3-O-benzyl-1,2,4-tri-O-acetyl-D-glucopyranose (18) was thus obtained; 1H NMR data: 60:40 mixture of anomers 6.32 (d, 1 H, alpha-H), 5.64 (d, 1 H, beta-H). A solution of the crude residue 18 in acetone was cooled to -5° C. and a solution of chromium trioxide in 3.5M sulfuric acid was added dropwise with stirring. The mixture was allowed to attain room temperature, and, after 5 hours at room temperature, was poured into ice-cold water and extracted with chloroform. The extract was washed with water and concentrated, and a solution of the crude methyl ester of 3-O-benzyl-1,2,4-tri-O-acetyl-D-glucopyranosuronic acid (19) in ether was esterified with ethereal diazomethane. The product was eluted from a column of silica gel with chloroform-ethyl acetate (20:10) to give 19 (54%). 1H NMR date: mixture of anomers alpha:beta=60:40; 7.23-7.36 (m, 5 H, arom.), 6.38 (d, 1 H, alpha-H), 5.69 (d, 1 H, beta-H), 3.72 (s, 3 H, alpha-COOMe), 3.71 (s, 3 H, beta-COOMe), 1.96-2.16 (9 H, Ac).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14](NO)=O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:40][C:41](=[O:49])[CH2:42][CH2:43]CCCCN)C1C=CC=CC=1>>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:43][CH2:42][C:41]([OH:49])=[O:40])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Reactant: NCCCCCCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN(C)c1ccc(CNC(=O)NCCCCCCC(=O)O)cc1

Procedure:
Compound 5 was prepared using the methodology described for the preparation of compound 2, by substituting 4-amino-butyric acid benzyl ester toluene-4-sulfonic acid with 7-amino-heptanoic acid benzyl ester toluene-4-sulfonic acid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 10.33 (br, s, 1H), 8.66 (br s, 1H), 7.05 (d, J=8.7 Hz, 2H), 6.67 (d, J=8.7 Hz, 2H), 6.04 (t, J=5.7 Hz, 1H), 5.79 (t, J=5.7 Hz, 1H), 4.05 (d, J=6.0 Hz, 2H), 2.97 (dt, J=6.6, 6.6 Hz, 2H), 2.84 (s, 6H), 1.93 (t, J=7.5 Hz, 2H), 1.47 (m, 2H), 1.34 (m, 2H), 1.22 (m, 4H)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2cc(N)ccc21

Procedure:
A solution of 230.0 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-nitro-naphthalen-1(2H)-one (Compound D8) in 5.0 mL of EtOAc was stirred at room temperature with a catalytic amount of 10% Pd-C under 1 atm of H2 for 24 h. The catalyst was removed by filtration through a pad of Celite, and the filtrate concentrated under reduced pressure to give the title compound as a dark green oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=O.[N:7]1C=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:6]
Reactant: c1ccncc1
Reactant: CN(C)C(=O)Cl
Product: CN(C)c1ccccn1

Procedure:
In 5 ml of pyridine was dissolved 101 mg of DC-89B2 obtained in Reference Example 2 and 3 mg of dimethylaminopyridine and 0.1 ml of dimethylcarbamyl chloride were added to the solution. After stirring at room temperature overnight, the reaction mixture was poured into 2 N hydrochloric acid and extracted with chloroform. After washing successively with aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, the chloroform layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (50 ml; eluted with chloroform) to give 64 mg of Compound 13 (yield, 57%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1cccc(-c2ccc(C)cc2N)c1
Product: COc1cccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (0.065 g, 0.36 mmol) was reacted with the product from Example 217b (0.072 g, 0.34 mmol) for 96 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing a trifluoroacetic acid salt (0.102 gm, 64%). 1H NMR (300 MHz, DMSO-d6) ppm: 2.43 (s, 3 H) 2.72 (s, 3 H) 3.62 (s, 3 H) 6.29 (d, J=7.35 Hz, 1 H) 6.77 (dd, J=7.91, 2.02 Hz, 1 H) 6.87-7.00 (m, 2 H) 7.17 (t, J=7.91 Hz, 1 H) 7.36 (s, 1 H) 7.41-7.46 (m, 1 H) 7.51-7.56 (m, 1 H) 7.75 (d, J=8.46 Hz, 1 H) 8.32 (d, J=7.35 Hz, 1 H) 8.91 (d, J=8.82 Hz, 1 H) 11.99-12.22 (s, 1 H); MS (ESI+) m/z 356.0 (M+H)+; (ESI−) m/z 354.0 (M−H)−.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CC2CCC1C2
Product: O=C(Cl)CC1CC2CCC1C2
Yield: 99.8 %

Procedure:
2-Norbornaneacetic acid (Aldrich, Catalog #127264, CAS #1007-01-8, 2.01 g, 13.0 mmol) was dissolved in thionyl chloride (7 mL, 96 mmol). The reaction was heated to reflux for 5 hours. The reaction mixture was concentrated in vacuo to provide the title compound as a colorless oil (2.24 g, 100%) that was used without additional purification.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C([Li])CCC.[CH3:32][CH:33]([CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O>[CH3:48][C:47]([CH2:46][CH2:45][CH2:44][CH:43]([CH3:50])[CH2:42][CH2:41][CH2:40][CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:2])[CH3:38])=[CH2:49]
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A flask, equipped with a mechanical stirrer and placed under argon, was charged with 1.80 mol (642.6 g) of triphenylmethylphosphonium bromide and 2 L of THF. To this suspension 1.88 mol (1.175 L) of a solution of butyllithium (1.6 mol/L in hexane) were added dropwise during 3 hours at 0° C. The resulting mixture was stirred at 0° C. for an additional hour. Then 1.50 mol (402.7 g) of 6,10,14-trimethyl-2-pentadecanone were added dropwise at 0° C. during 1 hour and the mixture was allowed to warm up to 22 to 23° C. After 2 hours, 150 mL of water were added dropwise and the resulting white suspension was filtered off over decalite. The filtrate was washed thrice with 300 mL of water and dried over Na2SO4. After filtration and evaporation of the solvent in vacuo, the mixture was filtered off over decalite to remove white cristals and the filtrate was evaporated in vacuo. The resulting crude oil was purified by distillation under vacuum (145° C., 0.2 mbar) to give 1.20 mol (319.2 g) of 2,6,10,14-tetramethylpentadecene as a colorless oil (yield: 80% based on 6,10,14-trimethyl-2-pentadecanone; purity: 96.2%-GC area).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:13]=[C:14](/[CH:27]=[CH:28]/[CH3:29])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=2)=[N:16][CH:17]=1)([O:8]COC)[C:4]([F:7])([F:6])[F:5].[CH3:32][CH:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2([CH3:49])[NH:46][C:45](=[O:47])[NH:44][C:43]2=[O:48])=[CH:38][CH:37]=1)[CH3:34]>>[F:31][C:2]([F:1])([F:30])[C:3]([C:12]1[CH:13]=[C:14](/[CH:27]=[CH:28]/[CH3:29])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][N:44]2[C:43](=[O:48])[C:42]([C:39]3[CH:38]=[CH:37][C:36]([O:35][CH:33]([CH3:32])[CH3:34])=[CH:41][CH:40]=3)([CH3:49])[NH:46][C:45]2=[O:47])=[N:16][CH:17]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(CO)c1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Product: C/C=C/c1cc(C(O)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1

Procedure:
After reacting and treating (E)-(3-(5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-3-(prop-1-enyl)pyridin-2-yloxy)phenyl)methanol in a similar manner to Preparation example 3 b), 5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione was used in place of 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione in Example 1 for a similar reaction and treatment, and the title compound was obtained as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[N+:17]([CH:20]([CH3:22])[CH3:21])([O-:19])=[O:18].CC[O-].[Na+].[Na]>C(O)C>[CH3:21][C:20]([N+:17]([O-:19])=[O:18])([CH3:22])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(C=Cc1cccnc1)c1ccccc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)(C(CC(=O)c1ccccc1)c1cccnc1)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A solution of 51.8 g. of 3-(3-pyridyl)-acrylophenone and 44.2 g. of 2-nitropropane in 496 ml. of ethanol are heated at reflux with stirring in a nitrogen atmosphere. Then, a sodium ethylate solution manufactured from 2.54 g. of sodium and 49.6 ml. of ethanol is added dropwise within 1 hour. The reaction mixture is left standing for an additional half hour to react further and then evaporated under reduced pressure. The resulting residue is taken up in 1000 ml. of methylene chloride, washed three times with 300 ml. of water each time, dried over sodium sulfate, evaporated under reduced pressure and crystallized from methanol to yield 4-methyl-4-nitro-3-(3-pyridyl)-valerophenone with a melting point of 134°-135° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:25][CH:26]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Yield: 87.6 %

Procedure:
Methyl 4-[(2-phenyl-1H-indol-1-yl)methyl]benzoate (2.8 g, 8.20 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and the mixture was ice-cooled. A solution (13.5 mL, 20.3 mmol) of 1.5 mol/L diisobutylaluminum hydride in toluene was added dropwise to the solution. This solution was stirred under ice-cooling for 4 hr, and aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:4-1:2) to give the title compound (2.25 g, yield 88%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[CH:5][N:4]=1>C(O)C.[Pd]>[F:13][C:2]([F:1])([F:12])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[CH:5][N:4]=1
Reactant: FC(F)(F)c1ncc2cnccn12
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ncc2n1CCNC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
3-Trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, 64.2 mmol) was dissolved in 150 mL of anhydrous ethanol, then 10% Pd/C (500 mg) was added to the solution. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through a pad of coarse silica gel and the filtrate was concentrated under reduced pressure to obtain the title compound 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (12.2 g, yield 99%) as a brown solid. 1H NMR (400 MHz, CDCl3, ppm): δ 6.84 (s, 1H), 4.10 (m, 4H), 3.26 (m, 2H), 1.81 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]1.C([O-])(=O)C.[NH4+:19]>C(O)C>[NH2:19][C:11]1[CH2:12][CH:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: [NH4+]
Reactant: Cc1ccsc1C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccsc1C1CC(=O)C=C(N)C1
Yield: 90.4 %

Procedure:
A solution of 5-(3-methyl-2-thienyl)-1,3-cyclohexanedione (3.0 g) and ammonium acetate (3.3 g) in ethanol (60 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate and water to precipitate crystals, which were filtered, washed with water and dried to give pale yellow crystals of 1-amino-5-(3-methyl-2-thienyl)cyclohexen-3-one (2.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:33])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=2)[CH3:16])=[C:6]([CH:13]=1)[C:7]([NH:9][NH:10][CH:11]=O)=[O:8].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:16])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:32])[F:31])=[N:19][N:18]=2)[CH3:33])=[C:6]([C:7]2[O:8][CH:11]=[N:10][N:9]=2)[CH:13]=1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NNC=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nnco1
Temperature: -10 °C
Reaction time: 20 h
Yield: 13 %

Procedure:
5-chloro-N′-formyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl}-4H-1,2,4-triazol-3-yl)ethoxy)benzohydrazide (200 mg) was dissolved in dichloromethane (3 ml), pyridine (80 μl) was added thereto, followed by cooling to −10° C. Trifluoromethanesulfonic anhydride (140 μl) was added to the reaction solution, followed by stirring at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=98:2 to 90:10), the resulting light yellow solid was dissolved in ethyl acetate (3 ml), and 4M hydrogen chloride-ethyl acetate (100 μl) was added thereto. The precipitated solid was collected by filtration, followed by drying and then drying under reduced pressure. The resulting hydrochloride was suspended in chloroform and the suspension was neutralized with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate) and the resulting oily product was powdered with diisopropylether to obtain, as a colorless solid, 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3,4-oxadiazole (25 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([I:13])[C:5]=12.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:11]=[C:12]([I:13])[C:5]=12
Reactant: Clc1ccnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of protective gas (argon), 63.5 g (1.59 mol) of sodium hydride are suspended in 1000 ml of abs. THF. With cooling, at a temperature of 0-5° C., a solution of 402 g (1.44 mol) of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine in 3000 ml of abs. THF is added dropwise, and the reaction mixture is, after the end of the addition, allowed to stir for 15 minutes. 358 g (1.88 mol) of p-toluenesulfonyl chloride are added a little at a time to the reaction mixture, so that the temperature is kept between 5 and 10° C. After the end of the addition, the mixture is allowed to warm to 20° C. and stirred at this temperature for another hour. After complete conversion (the conversion is monitored by TLC), 20 l of saturated sodium bicarbonate solution and 10 l of ethyl acetate are added to the reaction mixture, the mixture is extracted and the organic phase is separated off. The aqueous phase is reextracted two more times with in each case 10 l of ethyl acetate and the organic phases are combined, dried and, under water pump vacuum, freed from volatile components. For purification of the crystalline crude product, the product is taken up in dichloromethane and chromatographed on silica gel (dichloromethane:petroleum ether=3:7). The solvents are removed under reduced pressure and the crystal slurry is triturated with diethyl ether, filtered off with suction and dried at 20° C. under high vacuum. 372 g (60% of theory) of the title compound are isolated as a solid.