Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20].O>C1COCC1>[CH3:20][O:19][CH:18]([O:21][CH3:22])[CH2:17][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: N#CC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CC1(C#N)CCCC1)OC
Reaction time: 0.08 h

Procedure:
0.1 mol of cyclopentanecarbonitrile in 50 ml of THF is added in a rapid dropwise manner to a solution, stirred at 78° C. under an argon atmosphere, of 0.1 mol of lithium diisopropylamide (prepared from 0.1 mol of diisopropylamine and 63 ml of 1.6M butyllithium in hexane) in 250 ml of anhydrous THF. The mixture is stirred for 5 minutes at this temperature before adding 0.11 mol of 1-bromo-2,2dimethoxyethane. The mixture is allowed to return to room temperature and is hydrolyzed using 150 ml of water. The medium is allowed to settle, and the aqueous phase is separated and extracted twice with 150 ml of ether. The combined organic phases are washed with 100 ml of aqueous saline solution and 100 ml of water and then dried over magnesium sulfate. The solvents are evaporated off under vacuum and the residual oil is distilled.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1[C:42]([O:44]CC)=[CH2:43].[ClH:57]>O1CCOCC1.O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:9]=1[C:42](=[O:44])[CH3:43].[ClH:57]
Reactant: C=C(OCC)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (11.5 g, 14.4 mmol) in dioxane (60 mL) was added 4M HCl in water (14.4 mL) at 0° C. After stirring for 30 min at 0° C., the reaction mixture was allowed to warm to rt in 1.5 hours. 4M HCl in dioxane (10 mL) was added. The reaction mixture was stirred at rt overnight. Solvent was removed in vacuo to get the desired product as an HCl salt (6.97 g).
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[N:18]1([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]3=[CH:4][CH:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1n[nH]c2nc(N3CCNCC3)ccc12
Yield: 36.1 %

Procedure:
t-Butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (3.00 g, 0.0126 mole) was dissolved in 100 mL of toluene containing 10.85 g of piperazine (0.126 mole) and refluxed overnight. The resultant precipitate was filtered off and distributed between an aqueous NaHCO3 solution and EtOAc and then the organic phase was dried and concentrated to give a product which was recrystallized from CH3CN to give 1.57 g, mp 190°-191° C. The toluene filtrate was washed with NaHCO3 solution and then concentrated and purified by flash chromatography (EtOAc:MeOH:Et3N/16:2:2) to give an additional 1.38 g of product (total yield 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>ClCCl>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([C:13](=[O:15])[CH3:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 205a (672 mg, 4.0 mmol) in dichloromethane (20 mL) was added acetyl chloride (936 mg, 12.0 mmol) and K2CO3 (1104 mg, 8.0 mmol). The mixture was stirred overnight. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 209a as white solid (500 mg, 60%). MS: [M+H]+ 211.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:13].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH:8][CH3:13])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ncc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-3-methylpyridin-2-amine (B-4-1) (3.7 g, 0.02 mol) in THF (50 mL) was added portionwise NaH (0.8 g, 0.02 mol) at 0° C. After the addition, the mixture was stirred at room temperature for about 0.5 hr, and cooled to 0° C. again. Iodomethane (2.8 g, 0.02 mol) was added slowly. The resulting mixture was allowed to rise to room temperature and stirred for 1 hr. TLC (EtOAc: Petroleum ether=1:4) showed that the reaction was complete. Saturated aqueous NaCl (10 mL) and EtOAc (10 mL) were added. The organic layer was concentrated and the residue was purified via a silica gel column eluted with EtOAc/Petroleum ether (1:8) to give 5-bromo-N,3-dimethylpyridin-2-amine (B-4-2) (2.3 g, 57.8%) as a white solid.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.ON1C2C=CC=CC=2N=N1.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:42][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)N
Reactant: O=C(O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 9.9 grams of Z-D-Glu-OBzl and 3.6 grams of 1-hydroxybenzotriazole in 50 ml of absolute tetrahydrofurane are added 1.96 grams of tert.-butylamine and at 0° C. 5.86 grams of DCC. The mixture is stirred for 2 hours at 0° C. and overnight at room temperature. The next day the precipitate is filtered off with suction and the filtrate is concentrated. The residue is dissolved in ethyl acetate and the solution is washed in succession with a saturated solution of sodium bicarbonate, 2n-HCl, a saturated solution of sodium bicarbonate and water, dried with sodium sulphate and concentrated. Yield: 4.6 gams of an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:31][NH:30][C:4](=[O:3])[CH:5]=2)=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: CCCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (28.08 mmol, 10.8 g) and hydrazine hydrate (15 mL) in acetic acid (45 mL) was stirred at 120° C. for 4 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water (200 mL). This was extracted with DCM (3×200 mL), and the combined organic layer was dried and concentrated under reduced pressure. The resultant residue was purified by flash silica gel column chromatography eluting with 50% ethyl acetate in hexanes to afford 5-(4-benzyloxy-phenyl)-6-butyl-2H-pyridazin-3-one.
Reaction SMILES: [I-].[K+].[CH2:3]([N:5]([CH2:30][CH3:31])[C:6]([C:8]1[N:12]=[C:11]([CH2:13]Cl)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=O)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4].[NH3:32]>O.O1CCOCC1>[CH2:30]([N:5]([CH2:3][CH3:4])[C:6]([C:8]1[N:12]=[C:11]2[CH2:13][N:32]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:10]2[N:9]=1)=[O:7])[CH3:31]
Reactant: N
Reactant: CCN(CC)C(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
An amount of 1.99 g (0.012 mole) of potassium iodide is dissolved in 6 ml of water. The obtained solution is diluted with 20 ml of dioxane; an addition is then made at 25°, with stirring, of a solution of 4.3 g (0.01 mole) of N,N-diethyl-1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide in 40 ml of dioxane, and the reaction solution heated for one hour at 50°. There is then added 35 ml of conc. aqueous ammonia solution, the mixture heated for a further 2 hours at 50°, and subsequently concentrated in vacuo. Water is added to the residue and extraction performed twice with methylene chloride. The organic phase is washed with water and saturated sodium chloride solution; it is then dried over sodium sulphate and concentrated in vacuo to dryness. The residue is recrystallized from benzene/cyclohexane to obtain pure N,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 175°-177°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:8][CH:9]=[CH:10][C:2]1=2.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC>C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7](/[CH:11]=[CH:12]/[C:13]([N:30]=[N+:31]=[N-:32])=[O:15])=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1cccc2c1OCCO2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc2c1OCCO2
Reaction time: 16 h
Yield: 84.5 %

Procedure:
(E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acrylic acid (5 g, 24.25 mmol), diphenylphosphoryl azide (4.96 mL, 23.04 mmol), and Et3N (6.76 mL, 48.5 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give 4.5 g of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acryloyl azide as a yellow solid, which was taken into PhCH2Ph (50 mL). The resulting solution was slowly heated to 80° C. for 1 h and then to reflux for 3 h. After cooling to rt, the solid was collected washing with benzene to give 3.5 g of the desired product 2,3-dihydro-[1,4]dioxino[2,3-f]isoquinolin-7-ol as a solid. 1H NMR (400 MHz, CD3OD) δ ppm 4.37 (m, 4H), 6.83 (d, J=7.09 Hz, 1H), 7.02 (d, J=8.80 Hz, 1H), 7.12 (d, J=7.34 Hz, 1H), 7.79 (d, J=8.80 Hz, 1H); MS: (M+H)+ 204.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:32])[CH2:11][NH:12][C:13](=[O:31])[C@@H:14]([NH:22][CH2:23]C(OC(C)(C)C)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:32])[CH2:11][NH:12][C:13](=[O:31])[C@@H:14]([NH:22][CH3:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.7 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (S)-N-(2-{N-[(1,1-dimethylethoxy)carbonyl]methylamino}-1-oxo-3-phenylpropyl)glycine methyl ester (Description 32, 2.28 g, 6.5 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 3.5 h. The solvent was evaporated under reduced pressure, then toluene was added and evaporated under reduced pressure. Aqueous sodium carbonate (10%, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (95:5), to give the title compound as a colorless oil (1.59 g, 98%). 1H NMR (250 MHz, CDCl3) δ7.71 (1H, br s), 7.61-7.21 (5H, m), 4.15 (1H, dd, J 18.3, 6.1 Hz), 4.02 (1H, dd, J 18.3, 5.5 Hz), 3.76 (3H, s), 3.25 (2H, m), 2.69 (1H, dd, J 14.7, 10.9 Hz), 2.31 (3H, s), and 1.30 (1H, br s). m/z (ES+) 251 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]3[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=23)=[CH:17][CH:16]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Solvent: CCO
Product: Cc1cc2c(c(Nc3ccc(F)cc3)n1)C(=O)OCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (200 mg, 1.012 mmol) was dissolved in 5 mL of ethanol and then added with 4-fluoroaniline (224.9 mg, 2.024 mmol) and stirred at 80° C. overnight. The mixture was concentrated under reduced pressure. A silica gel column chromatography (20% EtOAc/Hexane) was performed on the resulting residue and 250 mg (90%) of 8-(4-fluoro-phenylamino)-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in pale yellow solid.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[OH:24].O>CN(C)C=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[O:24][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH2:26][CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[C:13]([C@@H:15]([O:22]C(=O)C)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:14])=[CH:9][CH:10]=2)[C:5]([CH3:38])=[N:4]1)[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH2:26][CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=3)[C:13](=[O:14])[C@@H:15]([OH:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:9][CH:10]=2)[C:5]([CH3:38])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c2cc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](OC(C)=O)c3ccccc3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(C)c2cc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of acetic acid (S)-{(1-ethyl-3-methyl-1H-indazol-5-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-carbamoyl}-phenyl-methyl ester (150 mg, 0.286 mmol) in tetrahydrofuran (2.0 mL) were added 1.0 mL water and 20.0 mg (0.84 mmol) lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 89 mg (65%) of the title compound as a colourless oil. MS(m/e): 483.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].Br[C:34]1[S:35][CH:36]=[CH:37][N:38]=1>C(N(CC)CC)C.C(#N)C>[CH3:10][C:7]1[S:6][C:5]([C:4]#[C:3][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C#C[Si](C)(C)C)s1
Reactant: Brc1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2nccs2)s1
Yield: 41.8 %

Procedure:
In a manner similar to Step E of Example 3, the reaction of 7.96 gram (0.0410 mole) of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne, 1.23 gram (3.9×10-4 mole) of tetrabutylammonium fluoride, and 2.6 gram (0.045 mole) of potassium fluoride in 120 ml of triethylamine and 40 ml of acetonitrile with 6.39 grams (0.0390 mole) of 2-bromothiazole yielded 3.35 grams of 1-(5-methylthien-2-yl)-2-(thiazol-2-yl)ethyne as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][O:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:13]=1
Reactant: Cc1cc(O)cc(-c2ccc(F)cc2)n1
Reactant: ClCCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(OCCCCCl)cc(-c2ccc(F)cc2)n1
Yield: 40.1 %

Procedure:
A mixture of 2.5 g of 2-(4-fluorophenyl)-4-hydroxy-6-methylpyridine, 3.16 g of 1-bromo-4-chlorobutane, 1.7 g of silver carbonate, and 100 ml of toluene was refluxed for 40 hours. This reaction mixture was filtered to remove insolubles and the filtrate was concentrated. The residue was purified with silica gel column chromatography to provide 1.45 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[CH:6][C:5]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][C:5]=1[OH:12]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1O
Temperature: 70 °C
Yield: 45.5 %

Procedure:
To a solution of 5-Bromo-2,4-dihydroxy-benzoic acid methyl ester (1.0 g, 4.04 mmol) in DMF (7 mL) was added Cs2CO3 (1.58 g, 4.85 mmol) and benzylbromide (0.69 g, 4.04 mmol) and heated at 70° C. for 6 h. Reaction mixture was diluted with EtOAc (10 mL) and filtered, filtrate was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3) gave pure 4-benzyloxy-5-bromo-2-hydroxy-benzoic acid methyl ester (0.62 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Temperature: 100 °C

Procedure:
2.44 g (0.02 mol) of 4-hydroxybenzaldehyde, 2.73 g (0.02 mol) of 6-chlorohexanol, 1.66 g (0.012 mol) of potassium carbonate and 20 ml of N,N-dimethylformamide were put in a three-neck 50 ml-flask equipped with a stirrer and a thermometer and heated at 100° C. for 2 hours with stirring. The reaction mixture was cooled to room temperature, poured into water containing ice and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The oily residue was allowed to stand at room temperature, whereupon it gradually crystallized. By silica gel thin layer chromatography (using a developer of ethyl acetate), the purity of the crystals was high. The yield of the product was 4.4 g (99.0%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:33])[CH2:25][O:26]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(N=C=S)O[Sn](CCCC)(CCCC)N=C=S)CCC>CO>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:33])[CH2:25][OH:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCCC=C(F)COC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(N=C=S)O[Sn](CCCC)(CCCC)N=C=S
Solvent: CO
Product: CC(C)(C)[Si](OCCCCC=C(F)CO)(c1ccccc1)c1ccccc1
Yield: 88.9 %

Procedure:
The tetrahydropyranyl derivative prepared in 2C (2.26 g, 4.8 mmoles) was dissolved in methanol. Tetrabutyl-1,3-diisothiocyanatodistannoxane (30 mg) was added and the mixture was refluxed for 24 hrs. Methanol was evaporated under reduced pressure. The residue was dissolved in ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silicagel and elution with a 2:8 mixture of hexane and ethyl acetate afforded the alcohol as an oil (1.65 g, 92%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=O)[C:27](O)=[O:28])[CH:20]=1>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:27](=[O:28])[C:26]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[N:18][C:17]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: CC(=O)Nc1cccc(Nc2ncccc2N)c1
Solvent: CCO
Product: CC(=O)Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 67.8 %

Procedure:
A mixture of 2-(3-acetamidophenylamino)-3-aminopyridine (1.0 g) and 3-(3-pyridyl)pyruvic acid (0.82 g) in ethanol (50 ml) was stirred under reflux for 6 hours. After evaporation of the solvent, crude residue was chromatographed on silica gel and crystallized from ethyl acetate to give 4-(3-acetamidophenyl)-2-(3-pyridyl-methyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.04 g).