Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:32]([CH2:33][CH3:34])=[N:31][NH:30][C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>C(O)(C)C.O1CCOCC1>[CH2:33]([C:32]1[C:17]2[C:18](=[N:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=3)=[CH:21][C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[NH:30][N:31]=1)[CH3:34]
Reactant: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)N3CCNCC3)c12
Yield: 102.9 %

Procedure:
To a solution of 4-[3-ethyl-6-(3-fluoro-4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 0.50 mmol) in iso-propanol (7 ml) was added 4N HCl in dioxane (1.3 ml). The reaction mixture was heated for 4 hours, diethyl ether was then added, the resulting precipitate was filtered off and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.19 g, 97%) as a yellow solid.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12]([C:27]#[C:28][Si](C)(C)C)=[CH:11]2)[O:7][C@@H:6]1[CH2:33][O:34][S:35]([NH2:38])(=[O:37])=[O:36])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[S:35](=[O:36])(=[O:37])([O:34][CH2:33][C@@H:6]1[C@@H:5]([OH:4])[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12]([C:27]#[CH:28])=[CH:11]2)[O:7]1)[NH2:38]
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(C#C[Si](C)(C)C)c3c(CCc4ccccc4)ncnc32)O[C@@H]1COS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)O2)c2ncnc(CCc3ccccc3)c12
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of (2R,3S,5R)-2-{[(aminosulfonyl)oxy]methyl}-5-{4-(2-phenylethyl)-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydrofuran-3-yl acetate (0.254 g, 0.457 mmol) in MeOH (5 mL) at r.t. was added K2CO3 (0.168 g, 1.22 mmol) and the mixture was stirred for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3 dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound (0.126 g, 62%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16]2)[O:12][C@@H:11]2[C@:5]3([CH:6]=[CH:7][C:8]([CH2:10]2)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C[C@H](N(C)C)[C@H](O)C1C=CC=CC=1.C(N1C=CC=CC1N)C.[OH-].[Na+].CN1CC2=C3C(=C(OC)C=C2)OC2C3(C=CC(O)C2)CC1>CCOCC>[CH3:1][N:2]1[CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16]2)[O:12][C@@H:11]2[C@:5]3([CH:6]=[CH:7][C@H:8]([OH:9])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Agent: CCN1C=CC=CC1N
Agent: COc1ccc2c3c1OC1CC(O)C=CC31CCN(C)C2
Agent: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Solvent: CCOCC
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Reaction time: 4 h
Yield: 85 %

Procedure:
(-)-Narwedine (>98% ee, 0.1 g) was added to a mixture of lithium aluminium hydride (1.2 ml of a 1.0 M solution in ether), (-)-N-methylephedrine (0.23 g) and N-ethyl-2-aminopyridine (0.31 g) in ether at 0° C., and the resulting mixture was stirred at that temperature for 4 h. Sodium hydroxide solution (10 ml of a 1.0 M solution) was added and the product extracted with dichloromethane. Evaporation of the organic phase gave (-)-galanthamine (>98% ee, 85% yield) free of epigalanthamine by GC/MS analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][O:29][C:28]1=[O:32]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)Cc1cc(Cl)ccc1O2
Reactant: O=C1OCCN1CCCl
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccc(F)cc32)CC1

Procedure:
1-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine is reacted with 3-(2-chloro-ethyl)-2-oxazolidinone in the manner described in Example 1, and there is obtained 3-[2-{4-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone as an oil. The maleate, prepared in acetone, melts at 180°-182° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:26])[CH3:25])[N:3]=1.C1(C)C=CC=CC=1.[CH3:34][O-:35].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]([O:35][CH3:34])[C:11]([C:12]#[N:13])=[C:10]([F:17])[CH:9]=2)[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH:24]([CH3:25])[CH3:26])[N:3]=1
Reactant: CC(C)[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(N)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(N3CCOC[C@H]3C(C)C)nc(N)n2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile (380 mg, 1.06 mmol) was azeotroped with toluene (2×12 mL). The residue was dissolved in 5 mL of DMF as a clear yellow solution, to which was added NaOMe (2.30 mL of a stock solution with concentration of 0.52 mmol/mL, 1.19 mmol, 1.12 equiv) at room temperature in one portion. The resulting mixture was stirred at room temperature for 18 hours. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, providing the title compound (276 mg) as a light yellow oily residue. LC-MS (ES) m/z=372 [M+H]+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]=1)[NH2:8].Cl>CCOCC>[CH:1](=[N:8][NH:7][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC1=NCCc2ccccc21
Reactant: CCCCC=O
Agent: Cl
Solvent: CCOCC
Product: CCCCC=NNC1=NCCc2ccccc21

Procedure:
Valeraldehyde (5.14 g.) was added to a refluxing solution of 1-hydrazino-3,4-dihydroisoquinoline (8 g.) in ether (300 ml.). The mixture was allowed to stand (for 45 min.) at room temperature. Ethereal hydrochloric acid was added. Recrystallization of the resulting solid from ethanol-ether gave 1-(2-pentylidenehydrazino)-3,4-dihydroisoquinoline (I: X=CH3 (CH2)3, X'=Y=Y'=Z=Z'=H) hydrochloride in two crops (11.6 g. and 0.2 g., m.p. 147°-148° C.).
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:10]([F:27])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[N+:28]([O-])([OH:30])=[O:29]>S(=O)(=O)(O)O>[Cl:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]([F:27])[C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:12][C:13]=1[N+:28]([O-:30])=[O:29])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)C(Cl)Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
A mixture of 10.4 grams (0.025 mole) of methyl 2-chloro-3-[3-fluoro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate in 100 mL of concentrated sulfuric acid was stirred for two hours until the methyl propanoate was completely dissolved. The mixture was then cooled to 10° C., and 2.7 grams (0.030 mole) of 70% nitric acid was added dropwise while the temperature of the reaction mixture was held at 10° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for one hour. The reaction mixture was then poured into ice-water and stirred until the ice melted. The mixture was extracted with diethyl ether. The extract was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.2 grams of methyl 2-chloro-3-[5-fluoro-2-nitro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate, mp 60°-65° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:19][OH:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:19][O:20][CH2:33][C:34]([F:37])([F:36])[F:35])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=NO)c1ncc(Cl)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To 5.0 g of tert-butyl N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]carbamate in 16.0 ml of N,N-dimethylformamide, 4.3 g of potassium carbonate and 5.4 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of water and extracted with ethyl acetate (100 ml×2), the resulting organic layers were combined, washed with water (50 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 4.8 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[OH:31])=[CH:26][C:25](=[O:30])[CH2:24][CH2:23]4)[CH3:12]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[O:31][C:8](=[O:9])[CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:26][C:25](=[O:30])[CH2:24][CH2:23]4)[CH3:12]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCC1CCCC1

Procedure:
Add 3-cyclopentylpropionyl chloride (2 g.) in benzene (6 cc.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (6 cc.) at -15°. Keep the mixture at -10° for 17 hours, work up and recrystallize the product from methanol to give the title compound, m.p. 88°- 89°; ultraviolet absorption peak at 241 mμ (ε17,000); infrared absorption peaks at 5.80, 6.00, 6.18 μ.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>CC(C)=O.CCCCC.O.C(OCC)(=O)C>[I:1][CH2:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [I-]
Reactant: CCOC(=O)CC(=O)CCl
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)CI
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium iodide (228 g) was dissolved in acetone (135 mL) and cooled to 0° C. 4-chloro-3-oxobutanoic acid, ethyl ester (5.0 g) was added to the sodium iodide solution and the mixture was stirred at 0° C. for 20 minutes It was diluted with pentane (135 mL) and water (135 mL). The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried over anhydrous sodium sulfate to give an intermediate (4-Iodo-3-oxobutanoic acid, ethyl ester; 6.2 g yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](Br)[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:24]1([C:2]2[CH:10]=[C:9]([C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=3)[CH:8]=[C:7]3[C:3]=2[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)cc(Br)c12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
Ethyl 4,6-dibromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.244 g, 0.5 mmol), phenylboronic acid (0.147 g, 1.2 mmol, 2.4 equiv.) and potassium phosphate trihydrate (0.400 g, 1.5 mmol, 3.0 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.021, 0.03 mmol, 6 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 60-70%. 1H-NMR (DMSO-d6) δ 1.09, 1.32 (each t, 3H, 3J=7.1 Hz, CH3); 2.11 (m, 2H, 2′-H); 2.84 (m, 2H, 1′-H); 3.89, 4.33 (each q, 2H, 4J=7.1 Hz, CH2); 7.12 (d, 1H, 2J=1.6 Hz, 7-H); 7.35 (t, 1H, 3J=7.4 Hz, Ph-ring); 7.43 (m, 7H, Ph-ring); 7.67 (d, 1H, 2J=0.9 Hz, 5-H); 7.68 (d, 1H, 2J=1.6 Hz, Phenyl-ring); 11.84 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.2, 14.3 (2CH3, each C═OOCH2CH3); 20.5 (C-2′); 34.8 (C-1′); 59.5, 60.5 (2CH2, each C═OOCH2CH3); 109.6 (C-5); 121.1 (C-7); 121.8 (C-3); 123.6 (C-2); 124.7 (C-3a); 127.0 (C-2″, C-6″); 127.4 (C-4″′); 127.5 (C-4″); 128.0 (C-3″′, C-5″′); 129.0 (C-3″, C-5″); 129.1 (C-2″′, C-6″′); 136.7 (C-7a); 137.4 (C-4), 137.6 (C-6); 140.7 (C-1″); 140.8 (C-1″′); 161.5 (2′-CO2Et); 171.7 (2-CO2Et). LC-MS (m/z): 442 [M]+, 440 [M]−. Purity (LC-MS): 96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH3:10])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].I[CH2:18][CH3:19].[Cl-].[NH4+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][CH3:19])[CH2:9][CH3:10])=[C:4]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:3]=1
Reactant: CCNc1ccc(Br)cc1C(C)(C)C
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCN(CC)c1ccc(Br)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
5 g (20 mmol) of (4-bromo-2-tert-butylphenyl)-ethylamine are dissolved, under a stream of nitrogen, in 200 ml of DMSO. After cooling to 0° C., 1.7 g (43 mmol) of sodium hydride are added slowly. After 30 minutes, 3.4 ml (43 mmol) of iodoethane are added and the mixture is then brought back to ambient temperature and stirred for an entire weekend. It is then poured into a saturated solution of ammonium chloride and extracted twice with diethyl ether. The organic phase is washed with water and then dried and concentrated to dryness. The residue is purified by flash chromatography (95/5 heptane/EtOAc). 3.6 g of (4-bromo-2-tert-butylphenyl)diethylamine are obtained in the form of a yellow oil (yield=63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][Cl:43])[CH:36]=[CH:35][C:31]=2[C:32](=[O:34])[CH:33]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl>C(#N)C.CCOCC.CC(O)C>[ClH:43].[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][N:13]3[CH2:12][CH2:11][CH:10]([C:8]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[OH:9])[CH2:15][CH2:14]3)[CH:36]=[CH:35][C:31]=2[C:32](=[O:34])[CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cc(=O)c2ccc(OCCCCl)cc2o1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(OCCCN3CCC(C(O)(c4ccc(F)cc4)c4ccc(F)cc4)CC3)cc2o1
Yield: 30.9 %

Procedure:
A ixture of 3.0 g (0.01 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol, 3.1 g (0.01 mole) of 7-(3-chloropropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of acetonitrile heated at reflux for 48 hr gave a gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. The desired fractions eluted with 10% acetone in benzene were combined and concentrated under reduced pressure to give a glass as residue. The glass was dissolved in ether/2-propanol and treated with ethereal hydrogen chloride. The solid which precipitated was collected by filtration and recrystallized from absolute ethanol to give 1.9 g (31%) of white solid, m.p. 191° C. with decomposition.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.[OH-].[Na+]>CO.O>[CH:15]1([NH:21][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CNC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (9.6 g, 152 mmol) to a solution of 4-cyanobenzaldehyde (5 g, 38 mmol), cyclohexylamine (3.8 g, 38 mmol) and acetic acid (0.46 g, 7.6 mmol) in methanol (100 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (100 mL) and adjust the pH to 10 with 3N aqueous NaOH. Extract with DCM and wash the organic phase with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (500 g) eluting with hexane/EtOAc (1:0 to 1:1 gradient) to obtain the desired intermediate (6.9 g, 86%). MS (APCI+) m/z: 215 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].I[CH3:13]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:13]
Reactant: Oc1cc(F)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride (0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) was heated to 60° C., stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[N:7]1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: COC(=O)c1cc(-c2cn[nH]c2)cc2c1c(C)nn2C(C)C
Temperature: 115 °C

Procedure:
The title compound was prepared in the same manner as described for example 80 (step a) from methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (0.5 g, 1.60 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.37 g, 1.92 mmol) wherein the reaction mixture was heated at 115° C. for 3 h. The crude compound was purified silica gel chromatography (eluent: 50% ethyl acetate\pet ether) to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 1.470 (d, J=6.4 Hz, 6H), 2.543 (s, 3H), 3.928 (s, 3H), 5.000-5.063 (m, 1H), 7.822 (s, 1H), 8.102 (d, J=9.6 Hz, 2H), 8.374 (s, 1H), 13.030 (brs, 1H). LCMS (ES+) m/z: 299.25.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.CO>O1CCCC1.ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Yield: 63 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) (280 mg, 0.45 mmol) in tetrahydrofuran (30.0 mL) was added 1N HCl (6.0 mL) at room temperature and the reaction mixture was stirred for 1 h at the same temperature (silica TLC, 5% methanol in dichloromethane, Rf=0.5). The tetrahydrofuran was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate (2×25 mL). The organic layer was washed with NaHCO3 solution (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried and concentrated in vacuum to get a crude mass which was purified by CombiFlash using gradient eluent of ethyl acetate and hexane mixture to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) (145 mg, 63%) as a white solid.