Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:39])([CH3:40])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[C:26]([NH2:46])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 2 h

Procedure:
3-Chloroperoxybenozic acid (mCPBA) (75% pure, 11.57 g, 50.27 mmol, 1.5 eq) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (15.00 g, 33.52 mmol, 1 eq) in dichloromethane (200 mL), and the reaction mixture was stirred for two hours. Analysis by thin layer chromatography indicated the reaction was incomplete and additional mCPBA (1.2 g) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane (300 mL), washed sequentially with 4% aqueous sodium carbonate solution (2×300 mL) and brine (300 mL), and concentrated under reduced pressure to afford a residue. Concentrated ammonium hydroxide (75 mL) was then added to a mixture of the residue in dichloromethane (200 mL) and cooled to 4° C. p-Toluenesulfonyl chloride (2.75 g, 14.44 mmol, 1.1 eq) was added in portions to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 4M aqueous sodium carbonate solution and separated. The aqueous layer was re-extracted with dichloromethane (200 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown solid. The crude material was purified by crystallization from diethyl ether to provide 9.8 g of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine as white plates of solid, mp 186-187° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.53-7.29 (m, 6H), 7.05 (dd, J=9.0, 2.6 Hz, 1H), 5.42 (br s, 2H), 5.18 (s, 2H), 4.94 (d, J=12.6 Hz, 1H), 4.83-4.69 (m, 3H), 4.68-4.58 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.86 (dd, J=8.6, 6.1 Hz, 1H), 3.62 (q, J=7.0 Hz, 2H), 1.45 (s, 3H), 1.29 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 158.3, 151.7, 149.0, 147.1, 136.8, 134.7, 128.6, 128.0, 127.6, 125.4, 120.9, 113.8, 110.2, 109.7, 108.9, 74.6, 70.0, 66.7, 66.3, 65.3, 48.2, 26.7, 25.1, 15.0; MS (APCI) m/z 463.1 (M+H)+; Anal. calcd for C26H30N4O4: C, 67.51; H, 6.54; N, 12.11. Found: C, 67.29; H, 6.33; N, 12.03.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=C[CH:38]=1.[C:43]1(C)[C:44]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:46]=[CH:47][CH:48]=1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:49]([C:44]2[CH:43]=[CH:48][C:47]([CH3:38])=[CH:46][CH:45]=2)(=[O:50])=[O:51])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 105 h
Yield: 84.7 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dichloromethane (9 parts) cooling at 0° C. are added pyridine (6 equivalents) and toluenesulfonyl chloride (6 equivalents). The mixture is let stand at 0° to 5° C. for 105 hours. The reaction mixture is diluted with ice-water, the organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from a mixture of ethyl acetate and hexane to give 3-p-toluenesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3d). Yield: 84.7%. mp. 133°-136° C. (decomposition).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:39]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[C:12]1([C:9](=[O:8])[C@H:10]([OH:39])[CH3:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](O)C(=O)c1ccccc1
Yield: 57.2 %

Procedure:
Compound 10b was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-phenprop-1-enyloxy)dimethylsilane (9b, 7.2 g, 0.029 mol), AD-mix-β (40.7 g), and CH3SO2NH2 (2.8 g, 0.0294 mol) in tert-butyl alcohol-water (110 mL:110 mL) The reaction was quenched with sodium sulfite (29.1 g). After purification, 2.49 g (80%) of the title product was isolated: [α]20D +84.9° (c 1.6, CHCl3); 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.66-7.58 (m, 1H), 7.54-7.47 (m, 2H), 5.23-5.12 (m, 1H), 3.84 (d, 1H, J=6.3 Hz), 1.45 (d, 3H, J=7.05 Hz); 13C NMR (CDCl3) δ 202.4, 134.0, 133.4, 128.9, 128.7, 69.3, 22.3. C9H10O2.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]=[O:41])[C:16]=12>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]([C:5]#[N:6])[OH:41])[C:16]=12
Reactant: COc1c(C)cnc(Cn2nc(CC=O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc(CC(O)C#N)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 16 h
Yield: 94 %

Procedure:
Trimethylsilyl cyanide (0.219 mL) and triethylamine (0.198 mL) were added to a mixture composed of the above di-tert-butyl {4-chloro-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (796 mg) and dichloromethane (10 mL) under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for 16 hours. Chloroform (80 mL) and a 0.5 N hydrochloric acid solution (100 mL) were added to the reaction mixture, followed by separation. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (20 mL). A 1 N hydrochloric acid solution (10 mL) was added and the mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate solution (80 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (788 mg, 94%). The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[CH2:2].Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:21]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:26]1[CH2:27][CH2:28][CH:23]([O:22][C:20]2[CH:21]=[C:16](/[CH:2]=[CH:1]/[C@H:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)[CH:17]=[N:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: Brc1cncc(OC2CCOCC2)c1
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](/C=C/c2cncc(OC3CCOCC3)c2)C1
Temperature: 130 °C
Reaction time: 17 h
Yield: 82.7 %

Procedure:
A mixture of tert-butyl(R)-3-vinylpyrrolidine-1-carboxylate 9 (7.00 g, 35.5 mmol), 3-bromo-5-(tetrahydro-2H-pyran-4-yloxy)pyridine 12 (10.0 g, 38.8 mmol), palladium acetate (0.40 g, 1.8 mmol), tricyclohexylphosphine (1.0 g, 3.57 mmol) and diisopropylethylamine (15 mL) in 1-methyl-2-pyrrolidinone (130 mL) was stirred at 130° C. for 17 h. The reaction was cooled to ambient temperature, diluted with water (800 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography using 60-100% ethyl acetate in hexanes. This product was further purified on reverse phase HPLC using 0.05% trifluoroacetic acid in acetonitrile and 0.05% trifluoroacetic acid in water to obtain tert-butyl(R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (11.0 g) as a gum. 1H-NMR (CDCl3, 400 MHz): δ 8.41 (s, 1 H), 8.37 (d, J=2.3 Hz, 1 H), 7.68 (s, 1 H), 6.48 (d, J=16.1 Hz, 1 H), 6.43 (dd, J=16.0, 6.4 Hz, 1 H), 4.71-4.66 (m, 1 H), 4.02-3.96 (m, 2 H), 3.68-3.52 (m, 4 H), 3.44-3.34 (m, 1 H), 3.28-3.15 (m, 1 H), 3.09-2.98 (m, 1 H), 2.18-2.04 (m, 3 H), 1.90-1.78 (m, 3 H), 1.48 (s, 9 H)
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.CCN(C(C)C)C(C)C.C1N=CN([C:27]([N:29]2[CH:33]=N[CH:31]=[CH:30]2)=[O:28])C=1.[Br:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:48]=1[C:42]1(CCNC[CH2:43]1)[CH2:41][C:40]2=[CH:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:48]=1[C:42]1([CH2:31][CH2:30][N:29]([C:27](=[O:28])[NH:2][CH:3]3[CH:4]4[CH2:12][CH:8]5[CH2:7][CH:6]([CH2:11][CH:10]3[CH2:9]5)[CH2:5]4)[CH2:33][CH2:43]1)[CH2:41][C:40]2=[CH:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]
Reactant: CCOC(=O)C=C1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a solution of 2-aminoadamantane hydrochloride (4.17 g, 22 mmol) and DIEA (28.7 g, 223 mmol) in anhydrous CH2Cl2 (40 mL) was added CDI (4.33 g, 27 mmol) at 0° C. and then stirred for 1 h at 0° C. under N2 atmosphere. Ethyl 2-(7-bromospiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate (7.77 g, 22 mmol) in CH2Cl2 anhydrous (40 mL) was added dropwise to the above mixture. The mixture was stirred for 8 h at rt under N2. The reaction mixture was washed with 1 N aq HCl. The organic layer was dried over Na2SO4, filtered and concentrated to leave a residue, which was purified by silica gel column chromatography to afford ethyl 2-(7-bromo-1′-(2-adamantylcarbamoyl)spiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate (4.1 g, 35%). Preparative SFC using a ChiralCel-OJ, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35° C. eluted with 75:25 supercritical CO2/MeOH at a flow rate of 70 mL min−1 and a nozzle pressure of 100 bar afforded two isomers.
Reaction SMILES: Br.BrCC(O[CH2:9][CH3:10])OCC.C(OCC)C.[Cl:16][C:17]1[N:22]=[N:21][C:20]([NH2:23])=[CH:19][CH:18]=1>O.C(O)CCC>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:9]=[CH:10][N:23]=2)[N:22]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1ccc(Cl)nn1
Agent: Br
Solvent: CCCCO
Solvent: CCOCC
Solvent: O
Product: Clc1ccc2nccn2n1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
Hydrobromic acid (48% solution in water, 1.8 mL, 15.47 mmol) was added to a solution of 2-bromo-1,1-diethoxyethane (11.6 mL, 77.11 mmol) in water (18 mL) at ambient temperature and the resulting mixture was heated at 110° C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and the solvent evaporated to obtain a colorless oil, which was added to a suspension at 0° C. of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130° C. overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85%) as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:6](=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH2:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](O)[CH2:23]CC>>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:6](=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH2:7])[CH2:2][CH2:22][CH3:23]
Reactant: CCCCO
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)c1cc([N+](=O)[O-])ccc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
210 parts of 5-nitroanthranilic acid ethyl ester, 210 parts of n-butanol and 10 parts of potassium carbonate are refluxed for half an hour. The thus formed ethanol is then distilled off over a column. Distillation is continued until the boiling point of n-butanol is reached. 450 parts of cyclohexane are then added, and after addition of 4 parts each of bleaching earth and active charcoal the hot mixture is filtered, followed by cooling to 0° C. The reaction lasts for about 4 hours. The precipitate is filtered off, washed with about 100 parts of cyclohexane and dried in vacuo at 60° C. There are obtained 222 parts of 5-nitroanthranilic acid-n-butyl ester, melting point 91°-93° C. The yield is approximately 93% of the theory.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[N:7][N:6]=[C:5]1[CH:19]([OH:21])[CH3:20].CN(C=O)C.Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)Cl.O>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:18])[F:17])=[N:7][N:6]=[C:5]1[CH:19]([O:21][C:28]1[N:29]=[CH:30][CH:31]=[CH:32][C:33]=1[C:34]#[N:35])[CH3:20]
Reactant: CC(O)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Oc1ncccc1C#N)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
Sodium hydride (53 mg) was added to a mixture of 1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethanol (300 mg) and DMF (10 ml) at room temperature, followed by stirring for 10 minutes, and 2-chloro-3-cyanopyridine (153 mg) was added thereto, followed by stirring at room temperature for 13 hours. Water and chloroform were added to the reaction solution, followed by separation operation, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain, as a light yellow amorphous product, 2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinonitrile (306 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18]C(=O)C.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>CC(O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([O:13][CH:24]([CH3:29])[CH3:25])[CH2:11][CH3:12])[C:7]([C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[NH2:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCC(OC(C)C)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 312 h
Yield: 38.5 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (394 mg, 1.23 mmol) in 2-propanol (2 mL) at room temperature was treated with p-toluenesulfonic acid monohydrate (75.3 mg, 0.39 mmol) and the reaction was stirred for 13 d at r.t. The reaction mixture was diluted with water and EtOAc and basified to pH 8 with sat. aq KHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20 g of silica gel, EtOAc/hexanes (0:1→3:7)) to give the title product (48 mg, 12%). as colorless crystals. m.p.: 54-56° C., ESI-MS: m/z 320 [M+H]+.
Reaction SMILES: [CH2:1]([Si:5](OC)([O:8][CH3:9])[O:6][CH3:7])[CH:2]([CH3:4])[CH3:3].[CH:12]1([Mg]Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CO>C(OCC)C>[CH2:1]([Si:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O:8][CH3:9])[O:6][CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CO[Si](CC(C)C)(OC)OC
Solvent: CO
Solvent: CCOCC
Product: CO[Si](CC(C)C)(OC)C1CCCCC1

Procedure:
Under an inert gas, 152.0 g isobutyltrimethoxy silane (0.85 mol) was dissolved in 50 ml diethylether. While stirring, 667 ml of a 1.5 molar solution of cyclohexylmagnesiumchloride in ether was added dropwise to the solution at a rate to maintain a moderate reflux. At the end of the addition, the reaction was continued under reflux for several hours. After cooling the reaction mixture, 4.8 g methanol (0.15 mol) was added, stirred for a few minutes and then the resulting precipitate was removed by filtration. The filter cake was washed with several portions of diethylether. The solvent was then evaporated from the combined filtrates using a water aspirator. The remaining residue consisted of 192.7 g (98.4% of the theoretical yield) isobutylcyclohexyldimethoxysilane, which had a purity of 98% according to gas chromatography (GC). Isobutyldicyclohexylmethoxysilane was not detected by GC.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16](O)[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9].[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>ClCCl.O>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ccc(C(COc2ccc(C=O)cc2)S(C)(=O)=O)nc1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
0.89 g (0.0088 mol) triethyl amine was added to a solution of 0.2 g (0.0007 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde and 0.098 g (0.0008 mol) mesyl chloride dissolved in 5 mL dichloromethane at 0-5° C. Reaction mixture was stirred at 0-5° C. for 4 hr. Progress of the reaction was monitored by TLC and after completion of reaction, substantial work-up in excess water yielded 0.18 g (70%) of the desired product. The product obtained was characterized by Mass and 1H NMR, which are as given below.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][N:30]=[C:31]([CH3:33])[CH3:32])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]([CH3:34])=[C:8]([CH3:35])[N:7]=1.C(O)(=O)C.CO>O1CCCC1>[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][NH:30][CH:31]([CH3:32])[CH3:33])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]([CH3:34])=[C:8]([CH3:35])[N:7]=1
Reactant: CC(C)=NOCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nc(N)c2nc(CONC(C)C)n(CCCCNC(=O)c3ccccc3)c2c1C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A solution of sodium cyanoborohydride in tetrahydrofuran (1 M, 6 mL) was added to a solution of N-{4-[4-amino-6,7-dimethyl-2-({[(1-methylethylidene)amino]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]butyl}benzamide (260 mg, 0.62 mmol) in 1:2 acetic acid/methanol (9 mL). The reaction mixture was stirred overnight, concentrated under reduced pressure, and partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (5 mL). After the bubbling subsided, the layers were separated and the aqueous phase was washed with chloroform (2×5 mL). The organic layers were combined and back-extracted with 1 M aqueous hydrochloric acid (2×5 mL). The aqueous layers were combined and adjusted to pH 10 with 1 M aqueous sodium hydroxide, then were extracted with chloroform (4×). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a foam. The foam was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 3-35% CMA in chloroform) followed by crystallization from acetonitrile. The crystals were isolated by filtration and dried under vacuum at 70° C. to yield 80 mg of N-[4-(4-amino-2-{[(isopropylamino)oxy]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]benzamide as a white powder, mp 161.0-162.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:15])[CH3:14].[CH3:16][O-:17].[Na+].O>O1CCOCC1.CO.Cl>[CH:13]([O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:17][CH3:16])([CH3:15])[CH3:14]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COc1nc(C(=O)O)ccc1OC(C)C
Temperature: 140 °C
Yield: 98.6 %

Procedure:
Methyl 6-chloro-5-isopropoxy-pyridine-2-carboxylate (330 mg, 1.44 mmol) was dissolved in dioxane (12 mL), and a solution of sodium methoxide (5.75 mL of 0.5 M, 2.87 mmol) in methanol was added. The reaction was heated under microwave irradiation at 140° C. for 1.5 hours. Water (52 μL, 2.9 mmol) was added, and the reaction mixture was heated by microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with 1 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 5-isopropoxy-6-methoxy-pyridine-2-carboxylic acid (300 mg, 98%) as a beige solid. ESI-MS m/z calc. 211.1, found 211.9 (M+1)+; Retention time: 0.97 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 4.72-4.61 (m, 1H), 4.06 (s, 3H), 1.45 (t, J=7.4 Hz, 7H).