Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](Cl)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:41][CH2:42][CH2:43][N:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][NH2:47]>C1C=CC=CC=1>[CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([NH:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:42][OH:41])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCN(CCO)CCO
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)NCCN(CCO)CCO
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of N,N-dioctadecylcarbamyl chloride (2.9 g.), N,N-bis-(2-hydroxyethyl)-1,2-ethanediamine (4.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours. The mixture is then cooled, concentrated in vacuo and the residue taken up on chloroform (100 ml.). The chloroform solution is washed successively with water (2 × 50 ml.), aqueous sodium hydroxide (1 × 50 ml. of 1N) and water (2 × 50 ml.), then dried (Na2SO4). Removal of the chloroform in vacuo leaves the crude product as an oil (3.3 g.).
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+].O.[ClH:26]>C(O)C.CCOCC>[ClH:26].[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]2)[CH:17]=1
Reactant: Cc1cccc(C2CCN(C(=O)Oc3ccccc3)CC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Cc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 11.9 g of 1-phenoxycarbonyl-4-(3-toluyl)piperidine and 75 ml of an aqueous 50% potassium hydroxide solution in 300 ml of ethanol is heated at reflux for 24 hours and then stirred at ambient temperature for an additional 36 hours. 100 ml of water are added, the ethanol is partially removed, the resulting mixture is extracted with ether and the combined ether extracts are extracted with 1N HCl. The aqueous solution is basified with an aqueous sodium hydroxide solution, extracted with ether, the combined ether extracts are dried, and the ether is removed, leaving a dark oil. The oil is dissolved in ether and ethereal hydrogen chloride is added to produce the sale which is collected by filtration, dried and recrystallized thrice from an ethanol-water mixture to give 4-(3-toluyl)piperidine hydrochloride, mp 196°-197° C.,
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>O=S(Cl)Cl.CN(C=O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (0.5 g, 1.99 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) was added a few drops of DMF (0.05 mL). The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. This residue was dissolved in 2-propanol (30 mL), then 4-chloroaniline (0.25 g, 1.99 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:2:0.05) as eluent to give the desired (4-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 0.5 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[CH2:7][Br:8].[CH3:9][N:10]1C=NN=C1CO.Cl.NCCS>Br>[BrH:8].[BrH:8].[NH2:10][CH2:9][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[N:5][N:4]=1
Reactant: Cn1cnnc1CBr
Reactant: Cn1cnnc1CO
Agent: Br
Agent: Cl
Agent: NCCS
Product: Cn1cnnc1CCN

Procedure:
The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.), water (150 ml.) and sodium nitrite (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration, the residue was extracted with ethanolether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g.), b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours, concentrated to dryness and the residue obtained (a mixture of 4-methyl-3-bromomethyl-1,2,4-triazole and 4-methyl-3-hydroxymethyl-1,2,4-triazole) was used directly in the reaction with cysteamine hydrochloride and hydrobromic acid as described in Example 1 (i)(a) to give 3-(2-aminoethyl)-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175°-177°.
Reaction SMILES: C[N+](C1C=CC=C(O)C=1)(C)C.[I-].[CH3:13][C:14]1([CH3:23])[CH2:19][CH:18]([OH:20])[CH2:17][C:16]([CH3:22])([CH3:21])[NH:15]1.[C:24](OC)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].N#N.[ClH:42]>CN(C)C=O.CO>[CH3:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:20][CH:18]1[CH2:17][C:16]([CH3:22])([CH3:21])[NH:15][C:14]([CH3:23])([CH3:13])[CH2:19]1)=[O:31].[ClH:42]
Reactant: CCCCCCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: C[N+](C)(C)c1cccc(O)c1
Agent: Cl
Agent: N#N
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCC(=O)OC1CC(C)(C)NC(C)(C)C1
Yield: 41 %

Procedure:
TMPH Synthesis. To a mixture of 2,2,6,6-tetramethyl-4-piperidinol (472 mg, 3.0 mmol) and methyl heptanoate (476 mg, 3.3 mmol) in 3.0 mL of dimethyl formamide was added 250 mg of powdered potassium carbonate. The resulting mixture was heated at 145˜155° C. for 64 hours under a gentle stream of N2. After cooling, the reaction mixture was partitioned between water and hexanes. The organic layer was separated, washed with water (2×) and brine, then dried over anhydrous MgSO4 and evaporated to afford the crude product as an oil. The oil was dissolved in MeOH and was then treated with 2 equivalents of conc. HCl. The solvent was removed in vacuo, and the residue was then treated with diethyl ether. The resulting solids were removed by filtration. The ethereal filtrate was concentrated in vacuo and triturated with hexane to afford 380 mg (41%) of TMPH hydrochloride. It was recrystallized from boiling ethyl acetate/hexane to afford short colorless needles, mp 113-115° C. FAB-HRMS: calculated (C16H32NO2): 270.2433 found: 270.2435.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.Cl[C:35]1[N:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][N:36]=1>CN(C)C=O.O1CCOCC1>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:35]3[N:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][N:36]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrogen chloride salt (52 mg), ethyldiisopropylamine (59 mg), and 2-chloro-5-ethylpyrimidine (21 mg) in N,N-dimethylformamide (1.0 mL) and 1,4-dioxane (1.5 mL) is stirred over night at 120° C. After cooling to room temperature, the solvents are evaporated and the residue is purified by HPLC (H2O/MeOH/TFA) to give the title compound. LC (method 9): tR=1.74 min; Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:40][C:39]3[CH:41]=[CH:42][C:36]([F:35])=[CH:37][CH:38]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 77.2 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added 4-flouroaniline (0.003 mL, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (13 mg, 72%). LC-MS m/z 562 (M+H)+; 1H-NMR (MeOD) δ 2.81 (s, 6H), 3.21 (m, 2H), 3.59 (m, 2H), 4.53 (s, 2H), 7.17 (m, 4H), 7.53 (m, 1H), 7.72 (m, 3H), 7.80 (d, 1H), 8.10 (d, 1H), 8.16 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[S:9])[NH2:8].Cl[CH:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13]>C(O)C>[CH3:17][C:16]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:9][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccccn1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccn2)nc1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of pyridine-2-carbothioamide (5.00 g) and ethanol (15 mL) was heated at 50° C. Methyl 2-chloro-3-oxobutanoate (4.41 mL) was slowly added to this solution over 10 minutes. The solution was heated at 70° C. for 18 hours. The solution was cooled to room temperature and 50% ethanol (20 mL) was added. The solution was cooled to 0° C. and stirred for 1 hour. The solution was filtered and dried over vacuum to obtain the title compound (4.90 g) with the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]2)[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Br)ccc2F)nc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c2)CC1
Temperature: 85 °C
Yield: 76.8 %

Procedure:
2-(5-Bromo-2-fluoro-phenyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (2.52 g, 6.5 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.56 g, 8.40 mmol) and cesium carbonate (10.50 g, 32.20 mmol) were placed into a dry 500 mL round bottom flask under nitrogen and dry toluene (140 mL) was added. At the same time palladium acetate (0.29 g, 1.30 mmol) and BINAP (1.20 g, 1.93 mmol) were placed into a dry 250 mL round bottom flask under nitrogen and dry toluene (140 mL) was added. After 10 minutes the suspension containing BINAP and Palladium acetate was added to the 500 mL round bottom flask. The reaction mixture was heated at 85° C. overnight under nitrogen and cooled to room temperature. The mixture was filtered and the insoluble material was washed with EtOAC (3×20 mL). The organic solution was concentrated under reduced pressure and crude was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to cyclohexane 4:AcOEt 1) to afford 2.48 g of the title compound (76%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([C:18]2[C:19]3[CH:20]=[N:21][N:22]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:17])=[CH:10][N:9]=1)(C)(C)C.C(OC(=O)NC1C=CC(CN)=CN=1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([CH2:14][NH:15][C:16]([C:18]2[C:19]3[CH:20]=[N:21][N:22]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:17])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CC(C)(C)OC(=O)Nc1ccc(CN)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
[5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (0.200 g, 0.433 mmol) synthesized as described in Example 4, via the acid chloride and tert-butyl[5-(aminomethyl)pyridine-2-yl]carbamate) was treated with a solution of 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 6 hours at room temperature. A solid was obtained by filtration, and partitioned between saturated aqueous NaHCO3 (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with ethyl acetate (1 mL), filtered and air dried to afford the title compound as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.[BH3-]C#N.[Na+].O>C(O)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[N:15]1([C:20]2[CH:26]=[CH:25][C:23]([NH:24][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9]3)=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(CN2CCCC(Nc3ccc(-n4ccnc4)cc3)C2)cc1
Reaction time: 20 h
Yield: 17.1 %

Procedure:
1-Benzyl-3-piperidinone (2.07 g, 10 mmol), 4-(imidazol-1-yl)aniline (1.73 g, 1.0 eq.), and Ti(OiPr)4 (3.72 mL, 1.25 eq.) were stirred at ambient temperature for 1.25 hours. The mixture was then diluted with absolute ethanol (10 mL) and NaCNBH3 (0.44 g, 0.67 eq.) was added. The resulting mixture was stirred for 20 hours. Water (2 mL) was added to the mixture with stirring and the resulting precipitate was filtered. Flash column chromatography on silical gel with 1-5% methanol in methylene chloride gave a crude product. Further purification by HPLC afforded 3-[(4-(imidazol-1-yl)phenyl)amino]-1-benzylpiperidine (569 mg), which was dissolved in methanol (10 mL) and treated with 10% Pd/C (400 mg) and ammonium formate (800 mg). The resulting mixture was heated at reflux for 4 hours. After cooling to ambient temperature, the mixture was filtered. Evaporation of the solvent in vacuo gave 3-[(4-(imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:20]([O:24]C(C)(C)C)(=[O:23])[CH:21]=[CH2:22]>CN(C)C=O>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[O:1][CH2:22][C:21]([C:20]([OH:24])=[O:23])=[CH:4][C:3]=2[CH:6]=1
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)OCC(C(=O)O)=C2
Reaction time: 0.17 h

Procedure:
A well stirred mixture of 81.7 g of 2-hydroxy-4,5-dimethoxybenzaldehyde, 62 g of potassium carbonate, 100 ml of t-butyl acrylate and 320 ml of dimethyl formamide is heated at 140° for 5 hours. Most of the solvent is removed, the reaction mixture is diluted with water and the product is extracted with ethyl acetate/ether. After washing with 1N aqueous sodium hydroxide solution and drying over magnesium sulfate, the solvent is removed and the residue dissolved in 130 ml of trifluoroacetic acid. After 10 minutes, the solid mass is diluted with ice water and 70 ml of 20% aqueous sodium hydroxide solution. The precipitated product is collected by filtration and air-dried to yield 6,7-dimethoxy-2H-[1]-benzopyran-3-carboxylic acid, melting at 225°-228°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:41])C(=O)C1.[NH4+].[Cl-].CCOCC>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:30][CH3:31])([CH2:32][CH3:33])[CH2:28][CH3:29])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[C:10]([I:41])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)c(I)cn2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 1 g (2.1 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole in 7 mL DMF was treated portionwise at 0° C. with 1.94 g (8.6 mmol) of NIS and stirred for 2 hrs at 65° C. The mixture was poured into a mixture of a saturated aqueous solution of NH4Cl containing NaS2O3 and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.1 g (72%) of 1-benzyl-3-iodo-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole, of which 50 mg were dissolved in 1 mL of MeOH and treated with 0.2 mL of 2M NaOMe in MeOH. After stirring for 30 min at RT, the crude mixture was distributed between aqueous HCl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 30 mg of 2-(1-benzyl-3-iodo-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown solid, MS 498 (M−H)−.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:22][CH3:23])[C:10]([N:11]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[C:27]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[CH:19]1([CH2:18][N:11]([C:10]2[C:9]([CH2:22][CH3:23])=[N:8][N:7]3[C:2]([C:27]4[C:28]([CH3:34])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=4[O:25][CH3:24])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH2:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: COc1cc(C)c(OB(O)O)c(OC)c1
Reactant: CCc1nn2c(Br)cccc2c1N(CC1CC1)CC1CCOC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3c(C)cc(OC)cc3OC)cccc2c1N(CC1CC1)CC1CCOC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
After dissolving N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine (150 mg) in 1,2-dimethoxyethane (20 mL) and water (10 mL), 2,4-dimethoxy-6-methylphenylboric acid (155 mg), tetrakis(triphenylphosphine)palladium(0) complex (92 mg) and barium hydroxide octahydrate (250 mg) were added and the mixture was heated and stirred at 80° C. for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (88 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH:11]([CH3:13])[CH3:12])=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
60% NaH in oil (1.5:1, Sodium hydride:Mineral Oil, 5.20 g) was added in two portions to isopropyl alcohol (150 mL) at room temperature under N2. The mixture was stirred at 60° C. for 30 min. 5-bromo-2-chloropyridine (10.00 g, 51.96 mmol) was added in two portions and the mixture was stirred at reflux 4 h and then at 80° C. overnight. The solution was concentrated in vacuo. Water (50 mL) and EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was subjected to flash chromatography (silica, 0-50% EtOAc in heptanes) to give the title compound as a clear oil (8.74 g, 78%). 1H NMR (600 MHz, DMSO) δ 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H), 1.33 (s, 6H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](OC)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.CO.[BH4-].[Li+]>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][CH2:33][OH:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CCO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetate (400 mg), tetrahydrofuran (10 mL) and methanol (2 mL) was added lithium borohydride (85 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give the title compound as a crude product from a fraction eluted with hexane-ethyl acetate-methanol (1:4:0-0:95:5, volume ratio), the crude product was subjected to preparative HPLC to give the title compound (150 mg, yield 39%) as a pale-yellow amorphous solid. MS: 481 (MH+).