Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.CSC.CO.[C:11](O)(C)(C)C.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>>[C:17]1([C:16]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CO
Product: c1ccc(C2(c3ccccc3)CO2)cc1
Reaction time: 2 h

Procedure:
Sulphuric acid (23.7 g at 98%, 0.237 moles) was added dropwise, with stirring, to dimethylsulphide (20.0 g at 98%, 0.316 moles) over 60 minutes, maintaining the temperature below 26° C. Methanol (5.0 g, 0.156 mole) was added slowly to the stirred mixture maintaining the temperature below 31° C. The reaction mixture was stirred for 41/2 hours and head overnight unagitated at room temperature. Tertiary butanol (3.6 g, 0.048 mole) and benzophenone (27.4 g, 0.15 mole) were added to the reaction mixture. Potassium hydroxide flake (43.4 g, 0.73 mole) was added in 10 equal aliquots over 3 hours while maintaining the temperature below 40° C. The reaction was monitored by GC and then stirred overnight at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([OH:21])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:21]
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 0.54 g, 2.8 mmol) and 3-bromo-5-trifluoromethyl benzoic acid (0.81 g, 3.0 mmol) in DMF (7 mL) were added TBTU (0.96 g, 3.0 mmol) and DIPEA (1.41 g, 10.9 mmol). The reaction mixture was stirred under nitrogen overnight at RT and then partitioned between ethyl acetate and an aqueous NaHCO3 solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic solutions were washed twice with water and then dried by a phase separator column. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (ethyl acetate-heptane 10% to 17%). There was obtained 0.86 g (68%) of 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide. 1H NMR (500 MHz, CDCl3): 2.1-3.8 (cm, 8H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.8-7.4 (cm, 6H), 7.8 (s, 1H). LCMS: m/z 445 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.[NH2-].[Na+].Br[CH:21](Br)[C:22]([O-:24])=[O:23].[K+].O>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH:21]([C:22]([OH:24])=[O:23])[O:9][C:8]([CH3:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: O=C([O-])C(Br)Br
Reactant: CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Agent: [K+]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 9.95 g of 5-chloro-2-hydroxy-α-methyl-α-phenyl-benzene-methanol in 150 ml of anhydrous toluene was added dropwise at room temperature to a mixture of 4 g of sodium amide and 50 ml of anhydrous toluene and the mixture was refluxed for 6 hours and cooled to room temperature. 10.25 g of potassium dibromoacetate were added thereto and the mixture was refluxed for another 6 hours and cooled. 200 ml of water were added thereto and the organic phase was decanted and extracted twice with 80 ml of water. The aqueous phase was washed twice with 80 ml of ether and was acidified with 40 ml of 2 N hydrochloric acid. The resulting precipitate was extracted 3 times with 100 ml of ether and the ether extracts were washed twice with 80 ml of water and extracted with 50% of an aqueous 5% sodium bicarbonate solution. The aqueous phase was washed 3 times with 80 ml of ether and acidified with 90 ml of 2 N hydrochloric acid solution. The mixture was extracted 4 times with 100 ml of ether and the combined ether extracts were washed with water, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness under reduced pressure to obtain 7.85 g of raw product. The latter was taken up in hexane and vacuum filtered and the recovered crystals were dried to obtain 6 g of 6-chloro-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers) melting at 144° C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=2)[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:39][C:40]1[C:45]([Cl:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:41]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:46][C:45]1[C:40]([OH:39])=[C:41]([S:48]([N:11]([CH2:10][C:9]2[CH:27]=[CH:28][CH:29]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=3)[CH:8]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=[O:50])=[O:49])[CH:42]=[C:43]([Cl:47])[CH:44]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CCCCCCCCc1ccc(CNCc2cccc(Oc3ccc(F)cc3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CN(Cc2cccc(Oc3ccc(F)cc3)c2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a mixture of N-(3-(4-fluorophenoxy)benzyl)-1-(4-octylphenyl)methanamine (100 mg, 0.238 mmol, 1.0 eq) in DCM (10 mL) was added triethylamine (72 mg, 0.72 mmol, 3.0 eq) followed by 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (62 mg, 0.238 mmol, 1.0 eq). After stirring at ambient temperature for 4 h, the reaction mixture was diluted with 100 mL DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title compound (25 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.64-7.63 (d, 1H), 7.55-7.54 (d, 1H), 7.21 (m, 1H), 7.19-7.11 (m, 2H), 7.09-7.02 (m, 4H), 6.95-6.91 (m, 2H), 6.88-6.86 (d, 1H), 6.80-6.78 (d, 1H), 6.68 (s, 1H), 4.43-4.40 (d, 4H), 3.35-3.30 (m, 6H), 2.55-2.51 (t, 2H), 1.57-1.56 (t, 3H), 1.3 (s, 10H), 0.87-0.91 (t, 3H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.S(O)(O)(=O)=O.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)=O.O.C(O)C>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]=[N:28][OH:29])[CH2:17][CH:18]=[CH2:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NO
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Solvent: O
Product: C=CC[C@H](COCc1ccccc1)OCC=NO
Reaction time: 0.5 h

Procedure:
A solution of ({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2) (234 g, 0.759 mol) in formic acid (400 mL) and water (100 mL) was stirred at room temperature for 2 hours. As LCMS analysis revealed a small amount of remaining starting material, formic acid (50 mL) was added and the reaction mixture was stirred for a further 30 minutes. The reaction mixture was diluted with ethanol (1 L) and water (400 mL). Hydroxylamine sulfate (435 g, 2.65 mol) and sodium acetate (217 g, 2.64 mol) were added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate (500 mL) and water (1 L), and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as an orange oil. By 1H NMR, this material consisted of a roughly 1:1 mixture of oxime isomers. Yield: 234 g, which was taken directly to the following step. LCMS m/z 250.1 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ [7.52 (t, J=5.5 Hz) and 6.96 (t, J=3.6 Hz), total 1H], 7.28-7.39 (m, 5H), 5.74-5.87 (m, 1H), 5.04-5.14 (m, 2H), 4.55 and 4.56 (2 s, total 2H), {4.45-4.55 (m) and [4.27 (dd, half of ABX pattern, J=13.2, 5.4 Hz) and 4.21 (dd, half of ABX pattern, J=13.2, 5.6 Hz)], total 2H}, 2.30-2.37 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A mixture of N-(1-(3-bromophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (1.25 g, 3.7 mmol), tert-butyl piperazine-1-carboxylate (0.7 g, 3.7 mmol), diisopropylethylamine (1.0 mL, 5.7 mmol) and acetonitrile (20 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10%-15% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.45 g, 24%). 1H NMR (400 MHz, CDCl3): δ 8.72 (d, 1 H), 8.10 (d, 1 H), 7.51 (s, 1 H), 7.40 (m, 1 H), 7.24 (m, 2 H), 6.17 (dd, 1 H), 5.60 (d, 1 H), 4.52 (m, 1 H), 3.48 (m, 4 H), 3.26 (m, 2 H), 3.13 (m, 2 H), 1.63 (d, 3H), 1.44 (s, 9 H). MS (ESI) m/z: Calculated: 504; Observed: 505 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].CO.C(Cl)(Cl)Cl>CN(C=O)C.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: Clc1cncc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1cc2cc(-c3cncc(N4CCOCC4)n3)cnc2[nH]1
Temperature: 100 °C
Yield: 22.2 %

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (147) (100 mg, 0.4 mmol) and 4-(6-chloropyrazin-2-yl)morpholine (103) (80 mg, 0.4 mmol) in DMF (5 mL) was degassed and purged with nitrogen for 10 min. To this reaction mixture was added Cs2CO3 (333 mg, 1.0 mmol, 2.5 eq) and the reaction mixture was purged again for another min followed by the addition of Pd(PPh3)4 (0.018 mg, 0.016 mmol, 0.04 eq). The resulting reaction mixture was heated to 100° C., overnight under sealed tube condition. After completion of the reaction the mass was diluted with chloroform and filtered through Celite and the solvents were removed to obtain the crude product. The crude was passed through neutral alumina eluting with 2-3% MeOH/CHCl3 provided a white coloured solid 25 mg of 4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)morpholine 148. 1H NMR (400 MHz, CDCl3) δ: 8.96 (s, 1H), 8.95 (s, 1H), 8.84 (s, 1H), 8.54 (d, J=1.95, 1H), 8.43 (s, 1H), 8.07 (s, H), 7.36 (m, 1H), 3.71 (t, 4H), 3.69 (bt, 4H); MS m/z 281.90 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:24][O:23]1)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)([OH:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CCCCC1(c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.3 g, 5 mmol) was dissolved in DMF (10 mL) and stirred for 5 min. Sodium hydride (709 mg, 17.7 mmol) was then added to it portionwise under nitrogen. This was followed by addition of 2-butyl-2-(4-fluorophenyl)oxirane (3.4 g, 17.7 mmol) at RT and the reaction mixture was stirred for 18 h. After completion of reaction, the reaction mixture was poured into ice water and the product extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by silica gel (#100-200 mesh) column chromatography using 1% methanol in DCM as eluent. The pure compound was converted into the oxalate salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][NH:12][CH2:11]3)[CH:8]=[CH:9][C:2]1=2.C([O:22][C:23]1([O:26][Si](C)(C)C)[CH2:25][CH2:24]1)C.[C:31]([OH:34])(=[O:33])C.C([BH3-])#N.[Na+]>O>[C:23]([OH:22])(=[O:26])/[CH:25]=[CH:24]/[C:31]([OH:34])=[O:33].[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][N:12]([CH:23]4[CH2:25][CH2:24]4)[CH2:11]3)[CH:8]=[CH:9][C:2]1=2
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: c1ccc2c(c1)CNCC2c1ccc2sccc2c1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: O=C(O)/C=C/C(=O)O
Product: c1ccc2c(c1)CN(C1CC1)CC2c1ccc2sccc2c1
Temperature: 25 °C
Yield: 30 %

Procedure:
A mixture of 4-benzo[b]thiophen-5-yl-1,2,3,4-tetrahydroisoquinoline (250 mg, 0.94 mmol, the preparation of which was described in Example 20), (1-ethoxycyclopropoxy)trimethylsilane (987 mg, 5.66 mmol), acetic acid (600 mg, 9.42 mmol), sodium cyanoborohydride (296 mg, 4.72 mmol), and molecular sieves (4 Å) was heated at reflux temperature for 16 hours, then cooled to room temperature. The mixture was treated with water, concentrated in vacuo, the residue dissolved in ethyl acetate and washed with 1N NaOH solution, then brine. The organic layer was dried over magnesium sulfate, concentrated and the residue purified by column chromatography (SiO2, 12 g, 85% to 0% hexanes/ethyl acetate) to provide the desired tetrahydroisoquinoline (87 mg, 30%). This material was dissolved in methanol and treated with a solution of fumaric acid in methanol (5 mL) at 0° C. The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether providing 4-benzo[b]thiophen-5-yl-2-cyclopropyl-1,2,3,4-tetrahydroisoquinoline, fumarate salt (100 mg, 95.5% AUC HPLC): 1H NMR (CD3OD, 300 MHz) δ 7.84 (d, J=8.3 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.56 (d, J=5.5 Hz, 1H), 7.32 (d, J=5.1 Hz, 1H), 7.20-7.07 (m, 4H), 6.84 (d, J=7.5 Hz, 1H), 6.73 (s, 2H), 4.48-4.43 (m, 1H), 4.23-4.10 (m, 2H), 3.57-3.47 (m, 2H), 3.13-3.06 (m, 1H), 2.21-2.18 (m, 1H), 0.71-0.64 (m, 4H); ESI-MS m/z=306 [+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11](C3C=CC=CC=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O.Cl>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([CH2:11][OH:12])[CH:19]=[CH:20][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
The method of synthesis presented in Ger.Pat. 2,461,406 uses 4-phenylbenzophenone as partition reactant, and has 2 or three steps, depending on the variation of synthesis to use. One of the variations comprises the dissolution of 4-phenylbenzophenone in ethanol, then adding sodium borohydride in a 1:2 molar relation to 4-phenyl benzophenone, for the reduction of ketone to alcohol. The system is heated to reflux during fifteen hours, it is let to cool down and the reaction mixture is hydrolyzed with water acidulated with HCl, the solid obtained is purified by recrystallization in ethanol. 89% of the theoretical yield of biphenyl-phenyl-carbinol is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]1[NH:38][C:37](=[O:39])[O:36][N:35]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][CH2:24][CH2:25]OS(C)(=O)=O.[NH:40]1[CH2:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:40]1([CH2:25][CH2:24][CH2:23][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH2:7][O:6][C:5]2[CH:31]=[CH:32][C:33]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: C1CNC1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCN2CCC2)ccc1-c1noc(=O)[nH]1
Temperature: 60 °C

Procedure:
To a suspension of 130 mg of methanesulfonic acid 3-[5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propyl ester in 7 mL of acetonitrile was added 25 μL of azetidine and 57 mg of diisopropylethyl amine. The resulting mixture was heated in a sealed tube to 60° C. under microwave irradiation for 30 minutes and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by a 2 g SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH and another column chromatography on silica gel (eluting with dichloromethane 90/methanol 10) to give 3.5 mg of 3-{4-[4-(3-azetidin-1-yl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([CH3:9])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(O)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(O)cc1C
Yield: 43.8 %

Procedure:
To a microwave vial containing 4-bromo-3-methylphenol (600 mg, 3.21 mmol) in anhydrous DMF (3.0 mL) was added ethyl acrylate (996 mg, 9.94 mmol), palladium (II) acetate (72.0 mg, 0.321 mmol), tri(o-tolyl)phosphine (146 mg, 0.481 mmol) and triethylamine (1.57 mL, 11.23 mmol). The resulting mixture was sealed and subjected to microwave irridation at 120° C. for 2 h after which time the reaction was diluted with EtOAc and filtered through Celite™. The filtrate was then washed with water, brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product as a brown oil which was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-ethyl 3-(4-hydroxy-2-methylphenyl)acrylate (289.8 mg, 1.405 mmol, 44% yield). LC/MS (m/z, MH+): 207.2.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([NH:8]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCC(F)(F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(4,4-difluorocyclohexyl)(t-butoxy)carboxamide (6.51 mmol) in CH2Cl2 (20 mL) was treated with TFA (10 mL) at room temperature. The reaction mixture was stirred for 2 hours, the solvent was removed in vacuo, and the crude product was dissolved in water and washed with chloroform. The acidic aqueous phase was cooled at 0° C. and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2Cl2, dried, and filtered yielding the title compound which was used without further purification as a 0.3 M solution in CH2Cl2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc(C#N)nc2)CC1
Temperature: 75 °C
Yield: 31 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (3.70 g, 23.5 mmol) and 5-bromo-pyridine-2-carbonitrile (3.66 g, 20 mmol) in toluene (50 mol) was added NaOtBu (2.31 g, 24.0 mol), BINAP (374 mg, 0.60 mmol) and tris(dibenilideneacetone)dipalladium(0) (366 mg, 0.40 mmol). The reaction mixture was heated at 75° C. for 1 hours, cooled down to RT, and diluted with AcOEt (500 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 1.61 g (31%) of 6′-cyano-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 260.3 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:18]([O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Reaction time: 5 h
Yield: 50.8 %

Procedure:
To a solution of 10.00 g (45.2 mmol) of methyl 3.5-dichloro-4-hydroxybenzoate dissolved in 100 mL of CH2Cl2 was added 11.06 g (90.2 mmol) of 4-dimethylaminopyridine and 8.18 g (54.2 mmol) of tertbutyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HCl, saturated NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 7.70 g (51%) of the title compound.