Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206-209° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1.[H-].[Na+]>CS(C)=O.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=3)=[C:2]([F:1])[CH:3]=2)=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 160 °C
Reaction time: 20 h
Yield: 28.8 %

Procedure:
To a suspension of N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.2 g, 6.4 mmol) and 4-chloropicolinamide (1 g, 6.39 mmol) in DMSO (12 mL) was added NaH (615 mg, 12.3 mmol, 50% dispersed in mineral oil). The reaction was stirred at 160° C. for 20 hours, then cooled to rt, and diluted with H2O (70 mL). The mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/4) to give the title compound as a white solid (0.85 g, 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>C(NCC)C.C(Cl)Cl.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.[Cu]I>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:18][C:6]=4[C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]=23)=[CH:22][CH:21]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: CN1Cc2c(C#Cc3ccc(Cl)cc3)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.6 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 16 hours with 1.5 g (11 mmol) of p-chlorophenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 35 ml of diethylamine. The reaction mixture was diluted with 175 ml of methylene chloride and washed three times with water. The organic phase was dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel and subsequent recrystallization from methylene chloride and ethyl acetate there was obtained 3-[(p-chlorophenyl)ethynyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 221°-222°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:23])[O:21][CH3:22].O>CN(C)C(=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:23])[O:21][CH3:22])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1cc(Cl)ccc1N
Agent: CN(C)c1ccccn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)Nc1ccc(Cl)cc1C#N
Temperature: 90 °C
Reaction time: 5 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (1.95 g) and dimethylaminopyridine (20.3 mg) in N,N-dimethylacetamide (15 ml) was added dropwise methyl chlorocarbonate (3.5 ml) at room temperature, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:20-1:4) to give methyl (4-chloro-2-cyanophenyl)carbamate (1.21 g) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C#N.[CH3:12][N:13](CC1C=CC=CC=1)C.[C-]#N.[Na+]>C(Cl)Cl.O>[C:1]([C:12]#[N:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)Cc1ccccc1
Agent: C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(=O)c1ccccc1
Reaction time: 2 h
Yield: 91 %

Procedure:
140.5 grams (1.0 mole) of benzoyl chloride were dissolved in 600 ml of methylene chloride. This solution was treated simultaneously with 27 grams (1.0 mole) of hydrogen cyanide and 1.83 grams (0.014 mole) of N,N-dimethyl benzyl amine. Then within 20 minutes there were fed in 171 grams of a 29.8 percent aqueous sodium cyanide solution (1.04 moles of sodium cyanide). The temperature of the reaction mixture meanwhile and for a further 2 hours was held at 15 to 35° C. Then there were added 60 grams of water and the phases separated. After removal of the hydrogen cyanide and the methylene chloride there were obtained by distillation 136 grams of crude, 91 percent benzoyl cyanide. In fractional distillation there were obtained 122 grams of pure benzoyl cyanide. This corresponds to a yield of 93% base on the benzoyl chloride employed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[CH:4][CH:3]=1.OP=O.[Si]([O:30][NH2:31])(C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:9]([CH2:13][CH3:14])[C:10]([NH:31][OH:30])=[O:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)ON
Reactant: CC[C@H](C(=O)O)[C@H](C(=O)N1CCOCC1)c1ccc(Cl)cc1
Agent: O=PO
Solvent: ClCCl
Product: CC[C@H](C(=O)NO)[C@H](C(=O)N1CCOCC1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
The crude acid 1b (310 mg, 0.95 mmol) was dissolved in 5 ml of dichloromethane. HOPO (111 mg, 1 mmol) and MEI (0.159 ml, 1.14 mmol) were added successively. The mixture was stirred for 30 minutes, then TMSONH2 (0.233 ml, 1.9 mmol) was added. After one hour another portion of TMSONH2 (0.233 ml, 1.9 mmol) was added and stirring continued over night. The reaction mixture was filtered (solid contained mostly HOPO) diluted with 20 ml of dichloromethane and extracted twice with 2N-HCl and brine, dried over anhydrous sodium sulfate and evaporated. The crude solid (237 mg, 73%) was purified by preparative HPLC (methanol/water=1/1). Yield: 100 mg (31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=O)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[NH4+:31].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:31])=[O:27])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cncc(Cl)c3)nc3c2CCC3)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3cncc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 48.7 %

Procedure:
A 10-mL vial was charged with ethyl 2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.060 g, 0.13 mmol) and ammonium chloride (0.022 g, 0.40 mmol) in methanol (3 mL). To this mixture was added NH3 (3.9 mL, 7N in methanol, 27.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 72 h. After this time, the mixture was concentrated under reduced pressure and the residue purified by preparative HPLC (water/acetonitrile with 0.05% TFA) followed by chromatography on silica using dichloromethane/(90:10:0.25 dichloromethane/methanol/aqueous NH4OH) (10:0 to 0:10) as eluent to afford 2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (0.024 g, 48%) as a white solid. MW=378.85. 1H NMR (CD3OD, 300 MHz) δ 8.77 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.20 (t, J=2.1 Hz, 1H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 2H), 7.15 (s, 1H), 3.52 (s, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.19 (quin, J=7.5 Hz, 2H). MS: ESI, m/z 379 [M+H]+. Treatment with 1.25 M HCl in methanol (0.25 mL, 0.31 mmol) afforded the title compound (0.026 g, 99%) as a yellow solid. MW=415.32. M.p. 193-195° C. 1H NMR (DMSO-d6, 500 MHz) δ 14.32 (br s, 1H), 9.85 (br s, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.43 (t, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.40-7.32 (m, 4H), 7.14 (s, 1H), 6.91 (s, 1H), 3.42 (s, 2H), 3.17 (t, J=7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.25 (quin, J=7.5 Hz, 2H); ESI MS m/z 379 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@H:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8][C:7]=2[CH:20]=1)=[O:2].CC(C)([O-])C.[K+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.O>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:10]2[CH2:9][CH2:8][C:7]3[CH:20]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3,4-dihydro-6-formyl-2-(4-hydroxybenzyl)-2H-benzopyran (1.8 g, 6.7 mmol) in DMF (10 ml) at 0° C. was added potassium tert-butoxide (0.83 g, 7.4 mmol). After 30 minutes m-fluorobenzyl bromide (0.91 ml), 7.4 mmol) was added and the resulting slurry was warmed to room temperature and stirred for 2 hours. Water was added and the precipitate was collected, washed with water and air dried (2.5 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[C:37](C)=[C:36]([CH:39]=O)[NH:35][C:34]=2[CH3:41])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:37]=[C:36]([CH3:39])[NH:35][C:34]=2[CH:41]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl) 1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (96.8 mg, 72%).
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:17].C(Cl)(Cl)Cl>ClCCl>[CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:17])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)OCc1ccccn1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)OCc1cccc[n+]1[O-]
Reaction time: 3 h

Procedure:
A stirred solution of 2-isopropoxymethylpyridine (18.4 g, 0.121 mol) in dichloromethane (200 mL) at room temperature was treated portionwise with meta-chloroperoxybenzoic acid (42.1 g, 0.121 mol), stirred for 3 h, poured into CHCl3 (450 mL) and washed with 2.5-M aqueous NaOH solution (2×250 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as a pale yellow oil; NMR δH (400 MHz, CDCl3), 1.19-1.21 (6H, d, J=6 Hz), 3.71-3.80 (1H, sept, J 6.5 Hz), 4.58 (2H, s), 7.37 (2H, m), 7.47-7.49 (1H, d, J 7 Hz) and 8.25-8.27 (1H, d, J 7.5 Hz)
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@@H](/C=C/CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude (4) (12.0 g, 24.3 mmol) in THF (200 mL) at 0° C. was added TBAF (1.0 M in THF, 1.25 eq, 30.4 mL, 30.4 mmol) and the reaction was warmed to RT and stirred for 2 h. The reaction was quenched with sat. aq. NH4Cl, organic layer washed with brine, dried (MgSO4), filtered and concentrated. The crude residue was purified by chromatography on SiO2 (3:7, EtOAc:hexanes) to yield 5.51 g (88%, 2 steps) as a colorless oil. [α]D −12.7 (c 1.0, CH2Cl2); 1H NMR δ 5.56 (dt, 1H, J=15.3, 6.9 Hz), 5.41 (dd, 1H, J=15.4, 6.4 Hz), 4.41 (bs, 1H), 4.06 (bm, 1H), 3.65 (appbq, 2H, J=5.7 Hz), 2.29 (q, 2H, J=6.3 Hz), 1.76 (bs, 1H), 1.68 (m, 1H), 1.44 (s, 9H), 1.33 (m, 2H), 0.92 (m, 6H); 13C NMR δ 155.4, 134.3, 126.9, 79.2, 61.5, 50.9, 44.5, 35.6, 28.3, 24.6, 22.5; EIMS m/z 257 ([M]+, 10), 227 (55), 171 (65); HRMS (EI) m/z calcd for C14H27NO3 257.1991, found 257.1994.
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Reactant: CN
Product: CN[C@H](C)C/C=C/c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (3.80 g, 11.97 mmol) and methylamine (20 mL, 2.0M solution in THF) was heated at 100–110° C. for 8 h in a sealed glass tube. The mixture was cooled to ambient temperature and concentrated under reduced pressure on a rotary evaporator. The resulting brown syrup was diluted with saturated NaHCO3 solution (25 mL) and extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, brown syrup (2.00 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-methanol (95:5, v/v). Selected fractions were combined, concentrated by rotary evaporation affording a 800 mg (37.9%) of a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([CH:48]([NH2:52])[CH:49]([CH3:51])[CH3:50])[CH3:47]>CN(C=O)C>[CH3:45][CH:46]([CH:48]([NH:52][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21])[CH:49]([CH3:51])[CH3:50])[CH3:47]
Reactant: CC(C)C(N)C(C)C
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C(C)C)C(C)C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2,4-dimethyl-3-pentylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(2,4-dimethyl-3-pentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[CH3:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:4][C:3]([F:6])([F:5])[C:10]([CH3:9])([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(C)=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)C(F)(F)F
Temperature: 48 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
24.9 g of trimethyl(trifluoromethyl)silane, 16.0 g of 2-heptanone, 38 g of tetrahydrofuran and 350 mg of tetrabutylammonium fluoride trihydrate were charged into a four-necked flask equipped with a nitrogen feeding tube, a reflux condenser, a dropping funnel and a thermometer, and a reaction was effected by a conventional method. Then, 17.5 g of hydrochloric acid was dropwise added to the reaction mixture at a temperature of 25 to 48° C. over 30 minutes, followed by stirring at about 48° C. for 2 hours. The reaction mixture was treated by a conventional method, and the resulting organic phase was washed with a saline solution, followed by drying with anhydrous magnesium sulfate. Thereafter, the resultant was concentrated under reduced pressure, thereby obtaining 26.4 g of 1,1,1-trifluoro-2-methyl-2-heptanol in the form of a pale brown oily matter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2.C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[CH3:30]>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:29][CH3:30]
Reactant: OCCCCCNCc1c2ccccc2cc2ccccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCCCO)Cc1c2ccccc2cc2ccccc12
Yield: 3.3 %

Procedure:
9-((5-hydroxypentyl)aminomethyl)anthracene (1.00 g, 3.41 mol) and K2CO3 (0.518 g, 3.75 mmol) were taken up in 25 mL acetonitrile. Ethyl bromide (11.14 g, 102 mmol) was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered on a sintered-glass frit and the solvent and excess ethyl bromide was removed under reduced pressure. Removal of the solvent afforded 1.07 g (98% yield) of 6 as a yellow solid; 1H NMR (300.13 MHz, CD3CN) δ1.15 (m, 2H), 1.38 (m, 5H), 1.81 (m, 2H), 3.05 (m, 4H), 3.49 (t, 2H), 5.21 (s, 2H), 7.45 (m, 2H), 7.62 (m, 2H), 8.05 (d, 2H), 8.44 (m, 3H); 13C-{1H} NMR (75.4 MHz, CDCl3) δ131.8, 131.3, 130.8, 129.6, 128.0, 125.6, 124.0, 61.7, 53.1, 49.4, 48.7, 31.4, 23.9, 23.3, 10.0.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:55])[C@H:10]([O:24][C:25]1[C:30]([Br:31])=[CH:29][C:28]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]4[CH:53]=[CH:52][CH:51]=[CH:50][C:40]=4[S:41][C:42]=3[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[Br:54])[CH2:11][CH2:12][N:13]1C(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].CO.Cl>O>[CH2:43]([C:42]1[S:41][C:40]2[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=2[C:38]=1[C:35]1[CH:36]=[CH:37][C:32]([C:28]2[CH:27]=[C:26]([Br:54])[C:25]([O:24][C@@H:10]([C:9]([O:8][CH3:7])=[O:55])[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]([OH:3])=[O:4])=[C:30]([Br:31])[CH:29]=2)=[CH:33][CH:34]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](CCNC(=O)c1ccccc1C(=O)O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 624.3 %

Procedure:
Potassium carbonate (0.01 g) was added into a mixture of (2R)-2-[4′-(2-benzyl-benzo[b]-thiophen-3-yl)-3,5-dibromo-biphenyl-4-yloxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (0.5, 0.063 mmol), methyl alcohol (10 mL), and water (0.5 mL). The reaction mixture was stirred at room temperature for 24 hours, poured into water, acidified with HCl (2 N), and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtAOc 4:1) gave white solid (0.32 g, 63% yield): mp 95-97° C; MS m/e 811 (M+);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH-:15].[Na+].Cl>CO>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[OH:15])([O-:14])=[O:13]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 0.17 h

Procedure:
45 g of 4-chloro-3-nitro-benzotrifluoride, dissolved in 150 ml of methanol, are initially introduced. 80 g of an ion exchanger resin containing quaternary ammonium groups are then introduced, the mixture is stirred for 10 minutes, 100 g of 50% strength sodium hydroxide solution are added dropwise, up to a maximum temperature of 70° C., and the mixture is stirred at 65° C. for 8 hours. After cooling the mixture, it is acidified with concentrated hydrochloric acid, the ion exchanger is filtered off and the crude product is distilled with steam. 27 g of 2-nitro-4-trifluoromethylphenol are obtained. nD20 : 1.5003.