Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH3:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
Subsequently, 4-imidazo[1,2-a]pyridin-2-ylbenzaldehyde g) was dissolved in tetrahydrofuran (100 mL), followed by stirring under ice cooling. Methyl magnesium bromide (3.0M diethyl ether solution, 4.4 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform, followed by drying over magnesium sulfate. The solvent was evaporated, and the solid was recovered through filtration by use of dichloromethane-methanol (30:1) mixture. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography. Fractions eluted by dichloromethane-methanol (30:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of diethyl ether. Through the above procedure, 1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-ethanol (2.43 g) was yielded.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[N+:14]=[N-:15]>>[ClH:1].[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][N:13]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=2)[N:15]=[N:14]1
Reactant: [N-]=[N+]=NCc1ccco1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 50 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.093 g, 0.500 mmol) was reacted with 2-azidomethyl-furan (0.074 g, 0.601 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidazol-2-ylamine hydrochloride (0.075, 50%) as a pale yellow solid. 1H NMR (300 MHz, DMSO) δ 7.85 (s, 1H), δ 7.65 (s, 1H), δ 6.70 (s, 2H), δ 6.64 (s, 1H), δ 6.52 (t, 1H), δ 6.46 (s, 1H), δ 5.58 (s, 2H), δ 2.61 (t, 2H), δ 2.41 (t, 2H), δ 1.82 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.6, 149.4, 147.9, 147.4, 144.3, 128.5, 122.6, 111.5, 110.3, 109.9, 46.3, 28.4, 24.9 ppm; HRMS (ESI) calcd for C13H16N6O (M+) 272.1458. Found 272.1460.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[O:18][CH2:19][CH2:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)OCCC1
Agent: O=C[O-]
Agent: [NH4+]
Product: c1cc2c(cc1C1CCCCO1)CNC2

Procedure:
Prepared in analogy to Example A49(b) from 2-benzyl-5-(5,6-dihydro-4H-pyran-2-yl)-2,3-dihydro-1H-isoindole and ammonium formate. Light brown solid. MS (m/e): 204.4 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Br:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:12][C:4]1[C:5]([CH3:11])=[C:6]([CH:10]=[C:2]([F:1])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 5-fluoro-2-methyl-benzoic acid (20 g, 130 mmol) in conc. sulfuric acid (200 mL) was added N-bromosuccinimide (24.3 g, 136 mmol) portionwise. The resulting mixture was stirred at 0° C. for 3 hrs, then warmed to room temperature and stirred for 16 hrs. Then the mixture was poured slowly into ice water (2 L), and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated to provide 3-bromo-5-fluoro-2-methyl-benzoic acid, which was used directly in the next step.
Reaction SMILES: Br.[NH:2]=[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]1[CH2:10][C:11](OCC)=O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[N:2]=[C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]2[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1cc(F)ccc1=N
Agent: Br
Product: Fc1ccc2nc(Cl)cn2c1
Temperature: 105 °C

Procedure:
A mixture of ethyl 2-imino-5-fluoro-1,2-dihydropyridine-1-yl-acetate hydrobromide (4.12 g, 14.76 mmol) in phosphorus oxychloride (68.8 mL, 738 mmol) was heated at 105° C. for 2 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. To the resulting residue were added ice water and ammonium hydroxide until the pH of the solution was 8. The solution was then extracted with dichloromethane. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 170.96 [M+H]+, 172.79 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.53-7.50 (m, 2H), 7.18-7.13 (m, 1H).
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].[CH3:8][OH:9]>>[Si:3]([O:9][CH3:8])([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1]
Reactant: CO[SiH](OC)OC
Reactant: CO
Product: CO[Si](OC)(OC)OC

Procedure:
1642 gm of crude product prepared in Example 3 was added to the distilling flask and heated slowly. Distillation fractions were collected at the head temperatures shown in Table 4 . From the composition of the fractions, the 1642 gm of crude product afforded 660 gm trimethoxysilane, which is more than that calculable from the composition of the starting material (first row of Table 4). The additional tri-methoxysilane was formed via the disproportionation of the mixed dimethylaminomethoxysilanes, e.g., HSi(OCH3)2 [N(CH3)2 ]. The vapor phase methanolysis consumed 2521 gm tris(dimethylamino)silane and 1005 gm methanol and produced a total of 1166 gm trimethoxysilane. The stoichiometric amount of trimethoxysilane obtainable from 1005 gm (31.4 moles) methanol is 1277 gm. So the yield of trimethoxysilane was 91.3 wt. % based on methanol converted. Note, however, that the methanol not converted to trimethoxysilane in this pass through the reactor was converted mainly to the mixed dimethylaminomethoxysilanes, e.g., HSi[N(CH3)2 ]2 (OCH3), and mixed methoxydimethylcarbamatosilanes, e.g., HSi[OOCN(CH3)2 ]x (OCH3)3-x (x=1,2,3), which are recyclable. Only negligible quantities of Si(OCH3)4 were formed.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH2:21][CH2:20][CH2:19][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N(CCCO)c1cccc[n+]1[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN(C(=O)OCc1ccccc1)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)-amino] propanol (3 g, 9.92 mmol) and triethylamine (1.2 g, 11.91 mmol) in anhydrous dichloromethane, kept at 0° C. under nitrogen atmosphere, methanesulfonyl chloride (1.36 g, 11.91 mmol) was added, the reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was washed with ice-water, dried with sodium sulfate, filtered and concentrated to give 2.17 g (61%) of 3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]-propyl methanesulfonate which, when required, was purified by flash chromatography (dichloromethane/methanol 95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CCl
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccc(F)cc1F
Reaction time: 3 h

Procedure:
To a mixture of 2,4-difluorothiophenol (4.95 g) and chloroacetone (2.8 ml) in DMF (30 ml) was added potassium carbonate (9.67 g) at 0° C. The mixture was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid, water, and brine, dried over MgSO4, and concentrated to give 1-(2,4-difluorophenylthio)propan-2-one (6.80 g). This compound was dissolved in toluene and heated at reflux for 30 hours with polyphosphoric acid (24 g). The solvent was evaporated, and the mixture was heated at 150° C. for 1 hour, carefully neutralized with aqueous potassium carbonate with ice-cooling, and extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel using hexane as an eluent to give the titled compound as colorless crystals (2.00 g).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].O>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:25]/[C:22]1[S:21][C:20]([CH:17]([CH3:19])[CH3:18])=[N:24][CH:23]=1
Reactant: CC(C)c1ncc(C=O)s1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of 12G (1.5 g, 5.2 mmol), 2-isopropyl-thiazole-5-carbaldehyde (1.2 g, 7.7 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (1.5 g), then stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 14A (1.4 g, 62.9% yield).
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:16](Cl)(=O)[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:16]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and butyryl chloride (880 mg) was added. To this reaction system was added portionwise aluminium chloride (4.6 g) under ice-cooling. The mixture was stirred at room temperature for 45 minutes. Insoluble matter was filtrated and the filtrate was poured into ice water, and chloroform was added. The organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and water-ethanol was added. The precipitated crystals were collected by filtration. The obtained crystals were washed with chloroform-diisopropyl ether to give 2-butylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:36]=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cncc(B(O)O)c1
Product: COc1cncc(C2=COCCN2C(=O)OC(C)(C)C)c1
Yield: 45 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 5-methoxypyridin-3-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (45% yield); 1H-NMR (d6-DMSO) 1.07 (9H, s), 3.70 (2H, t), 3.81 (3H, s), 4.12 (2H, t), 6.57 (1H, s), 7.14 (1H, m), 8.02 (1H, d), 8.11 (1H, d); MS ES(+) 293.3 (M++1); HRMS m/z calcd for C15H20N20O4+H+ 293.1501 [M+H+]. Found 293.1519. IR λmax=1701 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19].S([O-])(O)(=O)=O.[K+]>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:19]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cccc(C=O)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: O=Cc1cccc(NC(=O)Nc2ccccc2F)c1
Yield: 83.7 %

Procedure:
The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 548 mg of 2-fluorophenyl isocyanate in 4 ml of DCE. After cooling, the mixture is poured into 100 ml of saturated potassium hydrogen sulfate solution and extracted with twice 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. 864 mg of the expected aldehyde are isolated in the form of a gum, in an LC/MS purity of 77%. A crystallized fraction is obtained after trituration from ethyl ether. 165 mg of solid are isolated ([M+H]+): 259. RT=4.28 min (acetonitrile/water gradient from 5% to 85%—Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=O)=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1.[F:34][CH:35]([F:43])[C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:39][C:38]3[CH:40]=[CH:41][CH:42]=[C:36]([CH:35]([F:43])[F:34])[CH:37]=3)=[O:28])=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-5 of Intermediate-26, 0.100 g, 0.20 mmol), 3-(difluoromethyl)aniline (Intermediate-29, 0.045 g, 0.30 mmol), trimethyl aluminium (2M solution in toluene) (1.0 mL) and dry toluene (5.0 mL) to afford 0.080 g of crude product which was triturated with methanol:DCM:ether to afford 0.080 g of pure product. 1H NMR (300 MHz, DMSO do): δ 3.95 (s, 3H), 4.47 (d, J=5.7 Hz, 2H), 7.05 (m, 1H), 7.30 (m, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.70 (m, 3H), 7.80 (d, J=6.3 Hz, 3H), 8.08 (s, 1H), 10.11 (br s, 1H), 10.28 (s, 1H), 12.72 (br s, 1H); MS (m/z): 596.12 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:6](=[N:11][C:12]3[C:17]([C:8]=2[Cl:25])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1ccc2nc3c([N+](=O)[O-])ccc(Cl)c3c(Cl)c2c1

Procedure:
A stirred mixture of 12.9 of 6-chloro-2[(4methoxyphenyl)amino]-3-nitrobenzoic acid, 25 ml of chlorobenzene and 50 ml of phosphorus oxychloride is heated to reflux temperature over a period of one hour, and held under reflux for 4.5 hours. The mixture is allowed to cool, the precipitate collected, providing the yellow title compound, mp 243-246 degrees after recrystallization from toluene.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:8]([CH3:26])=[N:9][C:10]2[N:11]([N:23]=[CH:24][CH:25]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=[O:6].O>CO>[CH3:3][O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])[N:11]2[N:23]=[CH:24][CH:25]=[C:10]2[NH:9][C:8]=1[CH3:26])=[O:6]
Reactant: COC(=O)c1c(C)nc2ccnn2c1-c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)Nc2ccnn2C1c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
16 mg of sodium borohydride is added gradually to a solution of 17 mg of 6-methoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine in 1 ml of methanol with stirring and heating at 60° C. The reaction mixture is poured into water, extracted with ethyl acetate and dried. The solvent is removed and the residue is recrystallized from methanol to give 6-methoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine, melting at 209°-210° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[C:20]2[NH:19][C:18](=[O:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[C:20]2[N:19]([CH3:32])[C:18](=[O:21])[N:17]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CN(CCOc1cccc2c1[nH]c(=O)n2Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCOc1cccc2c1n(C)c(=O)n2Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of [2-(1-benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (0.100 g, 0.252 mmol) in 2 mL of anhydrous N,N-dimethylformamide was added sodium hydride (11 mg of a 60% dispersion in mineral oil) under nitrogen. The suspension was stirred at room temperature for ten minutes and then methyl iodide (0.018 mL, 0.277 mmol) was added in one portion. Stirring was continued for one hour and the reaction mixture was added to 150 mL water, and extracted twice with 75 mL ethyl acetate. The combined organic fraction was washed with 100 mL brine, dried over sodium sulfated and concentrated in vacuo. The residue was purified by flash chromatography (18% to 28% ethyl acetate in hexane) to afford 92 mg (0.223 mmol, 88.5%) of [2-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester as a clear oil. MS: 412 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
4-hydroxy-2-methyl indole 1 (50 g, 0.339 mole) was dissolved in anhydrous DMF (1 L). To the mixture sodium hydride 60% in mineral oil (27.9 g, 0.697 mole) was added. The mixture was left to stir at rt. for 1 h. To the mixture benzyl bromide (82.7 mL, 0.697 mole) was added drop-wise. The mixture was left to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (4 L) and washed with water (5×500 mL) then brine (1 L). The organic layer was separated and dried with magnesium sulphate and concentrated. The orange oily residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 86 g (72%) of 2 as an yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 79.2 %

Procedure:
1-t-Butoxycarbonyl-4-(2-methoxyphenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.52 mmol) and 10% palladium-carbon (30 mg) were stirred in methanol for two nights in an atmosphere of hydrogen. The reaction solution was filtered and the thus obtained residue was thoroughly washed with methanol. Then the filtrate and washed solution were combined and evaporated under a reduced pressure to obtain 120 mg of the aforementioned compound of interest (0.42 mmol, 81% in yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:21]4[N:22]=[C:23]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[N:24]=[C:20]4[N:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:21]4[N:22]=[C:23]([C:25]5[CH:26]=[N+:27]([O-:36])[CH:28]=[CH:29][CH:30]=5)[N:24]=[C:20]4[N:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: FC(F)Oc1ccc(-c2ccnc3nc(-c4cccnc4)nn23)cc1OCC1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
In CH2Cl2, dissolved was 7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 101) (3.3 g, 8.06 mmol), and m-chloroperoxybenzoic acid (3.0 g, 12.09 mmol) was slowly added thereto. The mixture was stirred at room temperature. To the reaction mixture, NaHCO3 (aq) was added, and the resultant mixture was extracted three times with CH2Cl2. The extract was washed twice with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to remove solvent. The mixture was purified via silica gel column chromatography (CH2Cl2/MeOH, 50/1) to obtain 3-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyri midine-2-yl]-pyridine-N-oxide (Compound 102) (2.7 g, 79%).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH:3]=[C:4](Br)Br.[Li][CH2:17]CCC.CI>C1COCC1>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]#[C:4][CH3:17]
Reactant: [Li]CCCC
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CC#CC(C)(C)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a stirred solution of Compound 53 (335 mg, 1.00 mmol) in THF (10 ml) was added n-BuLi (1.69M in hexane, 1.19 ml, 2.01 mmol) at -78° C. under N2, then warmed up to 0° C., and stirred for 1.5 h. MeI (213 mg, 1.50 mmol) was added, and stirred for 1.5 h at 0° C. The mixture was quenched by the addition of NH4Cl aq., and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 54 (162 mg, 86%) as a colorless oil.