Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH3:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.[Cu]I.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>[CH3:12][O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: COC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and anhydrous tetrahydrofuiran (4 mL) was treated with copper(I)iodide (93.0 mg, 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.39 g, 14.2 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The resulting reaction mixture was heated to 70° C. for 60 h. The title compound (286.0 mg, 90%) was isolated by chromatography (0-3% EtOAc-hexanes).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH2:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[CH3:14][O:15][CH2:16][N:17]=[C:18]=[O:19]>>[CH3:14][O:15][CH2:16][NH:17][C:18]([NH:1][CH:2]1[CH2:3][C:4]([CH3:12])([CH3:13])[N:5]([CH2:10][CH3:11])[C:6]([CH3:8])([CH3:9])[CH2:7]1)=[O:19]
Reactant: CCN1C(C)(C)CC(N)CC1(C)C
Reactant: COCN=C=O
Product: CCN1C(C)(C)CC(NC(=O)NCOC)CC1(C)C

Procedure:
46 parts of N-methoxymethyl-N'-1-ethyl-2,2,6,6-tetramethylpiperidine-4-yl urea are obtained by reacting 36.6 parts of 4-amino-1-ethyl-2,2,6,6-tetramethylpiperidine with methoxymethyl isocyanate in the same way as described in Example 22(b)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[2-(4-Trifluoromethyl-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01063, 1.0 g, 2.16 mmol) was dissolved in DCM (20 ml), and cooled to 0° C., and to this was added TFA (5 ml). Allowed to warm to room temperature and stirred for 1 h. The solution was poured over solid potassium carbonate (12 g), and extracted with DCM and water. Organic layers dried over MgSO4 and evaporated to dryness, to afford a cream coloured solid. 0.85 g, 100%, R.f. 0.4 (5% MeOH in DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.65 (2H, m, CHCH2), 1.79 (2H, m, CHCH2), 2.30 (1H, m, CH), 2.64 (2H, td, J=12.4, 2.7 Hz, NCH2), 3.10 (2H, m, NCH2), 6.97 (1H, dd, J=6.4, 30.5 Hz, Ar HD), 7.05 (2H, m, Ar HF), 7.06 (1H, m, Ar HB), 7.17 (1H, t, J=7.2 Hz, Ar HC), 7.58, D, J=8.6 Hz, Ar HE), 8.39 (1H, d, J=7.9 Hz, Ar HA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].[CH:17](OCC)=[O:18]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:17][OH:18])[C:5]2=[O:16]
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Reactant: CCOC=O
Solvent: O
Product: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Temperature: 55 °C
Reaction time: 7 h
Yield: 75.1 %

Procedure:
A mixture of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline(200.5 g) and 1,5-diazabicyclo[5,4, 0] undecene-5(384.9 g) in ethyl formate(400.9 g) was heated at 55° C. with stirring for 7 hours and then diluted with cold water(450 ml). The mixture was washed successively with diisopropyl ether and ethyl acetate and then the aqueous layer was acidified with hydrochloric acid under ice cooling. The resultant precipitate was collected by filtration and dried to give 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline(168.29 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[C:16](OC)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=1.[Li].C[CH2:30][O:31]CC>O>[CH3:30][O:31][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][C:11]=1[CH2:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CCOCC
Reactant: Cc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: O
Product: COc1ccncc1CC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 3 moles of lithium diisopropylamide in 3 liters ether is added 3 moles of β-picoline. After 1/2 hour, a solution of 1 mole methyl anisate in ether is added dropwise. After 1 hour under reflux, the mixture is cooled and decomposed with water. After all the lithium has dissolved, the layers are separated. The organics are washed with water, dried (magnesium sulfate) and distilled. The product is collected at 155°-165°C at 0.3 mm Hg and recrystallized from benzene-pet ether to yield 88 g (39%) 4-methoxy-α-(3-pyridyl)-acetophenone. [Miller, Osuch, Goldberg, and Levine, JACS, 78, 674 (1956) and Raynolds and Levine, JACS, 82, 472 (1960)].
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C@H:18]1([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH2:38])[CH:34]=3)[N:29]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH:15]1([CH2:14][NH:13][C:1]([NH:38][C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[N:29]=[C:28]([NH:27][C@H:18]2[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19]2)[CH:37]=[CH:36]3)=[O:12])[CH2:17][CH2:16]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, aminomethyl cyclopropane and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=373.5 (M+H+).
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)=[O:29]>CCOC(C)=O>[Br-:26].[CH2:37]([O:36][C:34]([C:33]1[CH:39]=[CH:40][C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)=[CH:31][CH:32]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.1 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (75 mg, 0.22 mmol) in EtOAc (5 ml), was added ethyl 4-(2-bromoacetyl)benzoate (I12) (66.5 mg, 0.24 mmol), and the reaction was stirred at room temperature for 15 hours. The solvent was evaporated and the crude was triturated with i-Pr2O-EtOAc (1/1) to obtain (R)-1-(2-(4-(ethoxycarbonyl)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (128.5 mg, 95% yield).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@H:4]([OH:41])[CH2:5][NH:6][C:7](=[O:40])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:16]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])=[CH:10][CH:9]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@@H:4]([OH:41])[C:3]([OH:42])=[O:2])=[O:40])=[CH:13][CH:12]=2)[C:28]2[CH:29]=[CH:30][C:31]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:32][CH:33]=2)[CH3:20])=[CH:26][CH:25]=1
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)N(Cc1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-{4-[3-[1(S)-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)-hydroxypropionic acid methyl ester (280 mg, 0.473 mmol) was dissolved in a mixture of THF (2.5 mL) and methanol (2.5 mL) and 4 N aqueous sodium hydroxide (0.355 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH was adjusted to 3.0 by addition of 1 N hydrochloric acid. Solvent was removed by rotary evaporation in vacuo and the residue re-dissolved in ethyl acetate (10 mL). The organic phase was washed twice with water and once with brine, and then concentrated to dryness in vacuo leaving the title compound as a powder. Yield: 168 mg (89%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[S:22][C:21]([CH3:29])([CH3:28])[C:20]2=[O:30])=[C:15]([CH2:31][CH3:32])[CH:14]=1>ClCCl.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:24](=[O:25])[C:23]([CH3:26])([CH3:27])[S:22](=[O:9])[C:21]([CH3:29])([CH3:28])[C:20]2=[O:30])=[C:15]([CH2:31][CH3:32])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cc(Br)ccc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Solvent: O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)S(=O)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
A solution of 3-chloroperbenzoic acid (2.45 g, 0.0142 mol) in dichloromethane (40 ml) is added to a pre-cooled solution (0° C.) of 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-thiopyran-3,5-dione (3.5 g, 0.0095 mol) in dichloromethane (100 ml). The reaction mixture is stirred at 0° C. for one hour and then allowed to come to room temperature. The reaction mixture is stirred at room temperature for one hour, diluted with water (100 ml) and separated. The organic phase is collected, and the aqueous layer is extracted with dichloromethane (2×50 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-1-oxo-dihydrothiopyran-3,5-dione as a white solid (2.0 g).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH:9](=[O:13])C(C)C>>[CH3:1][CH2:2][CH2:3][CH:9]([OH:13])[CH:5]([CH:4]=[O:8])[CH2:6][CH3:7]
Reactant: CC(C)C=O
Reactant: CCCC=O
Reactant: C=CC
Product: CCCC(O)C(C=O)CC

Procedure:
This compound is usually prepared by the hydroformylation of propene yielding a reaction mixture which contains n-butanal, as well as i-butanal and other reaction products. The pure n-butanal is separated from the reaction mixture by distillation and is subsequently subjected to aldolisation to form the corresponding butyraldol. This product is heated, water splits off, and 2-ethyl-hexenal is formed. This compound is then hydrogenated in the presence of appropriate catalysts to form the desired 2-ethyl-hexanol which is then purified in a multi-step distillation process.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10](O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[N:40]=[C:39]([SH:45])[N:38]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[O:8]([C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([S:45][C:39]1[N:38]=[C:37]([O:36][CH3:35])[CH:42]=[C:41]([O:43][CH3:44])[N:40]=1)[C:11]([O:13][CH3:14])=[O:12])[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
7.2 g (25 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (Compound 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in 100 mo of DMF and added dropwise to a suspension 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) sodium bicarbonate in 100 ml of DMF at 0° C. After stirring at room temperature for 2 hours and at 60° C. for further 2 hours, the mixture is poured into 1 liter of ice-water, and the precipitate is filtered off with suction. Drying results in 4.2 g of a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41]O)=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1>C1(C)C=CC=CC=1.O>[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2cc(Cl)cc(Br)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of triphenylphoshine (1.44 g, 5.48 mmol) in toluene (50 mL) cooled to 0° C. was added the diisopropylazadicarboxylate (1.11 g, 5.48 mmol) followed by the phthalimide (0.81 g, 5.48 mmol) and the reaction mixture allowed to stir for 10 min. The (7-bromo-5-chloro-1-benzofuran-2-yl)methanol (1.37 g, 5.22 mmol) was then added and the reaction was allowed to stir at 0° C. an additional 1 h. The reaction mixture was then quenched with water (1 mL) and the solvent was removed in vacuo to provide a crude solid. The solid was suspended in water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL), the combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5) provided 1.73 g (85%) of 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 194-198° C.; HRMS-ESI (m/z). [M+H]+ calcd for C17H9BrClNO3, 388.94545; found, 389.9553.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[S:24][CH2:25][CH2:26][C:27]([NH:29][C@H:30]([C:63]([OH:65])=[O:64])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:62])[CH2:36][CH2:37][S:38][C@H:39]1[O:56][C@H:55]([CH2:57][O:58]C(=O)C)[C@@H:50]([O:51]C(=O)C)[C@H:45]([O:46]C(=O)C)[C@@H:40]1[O:41]C(=O)C)=[O:28])(=O)C>CO.O.CCN(CC)CC>[C@H:6]1([S:24][CH2:25][CH2:26][C:27]([NH:29][C@H:30]([C:63]([OH:65])=[O:64])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:62])[CH2:36][CH2:37][S:38][C@H:39]2[O:56][C@H:55]([CH2:57][OH:58])[C@@H:50]([OH:51])[C@H:45]([OH:46])[C@@H:40]2[OH:41])=[O:28])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCC(=O)NCCC[C@H](NC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NCCC[C@H](NC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(=O)O
Yield: 99.5 %

Procedure:
A solution of 36 (100 mg) in MeOH-H2O-Et3N 5:4:1 (v/v/v, 3 ml) is kept for 3 hours at room temperature, and evaporated to a residue which is put on a Sephadex G-25 column and eluted with water. The desired fractions are combined and lyophilized to give the title compound (65 mg, 100%): NMR (D2O)δ: 5.38 (d, J1,2 =15 Hz), 5.35 (d,J1,2 =1.5 Hz) (H-1), 2.70 (t), 2.63 (t) (SCH2CH2).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][C:10]([CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:12]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: OCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C(=O)OCCCCBr)CC1
Temperature: 25 °C

Procedure:
4-Propyl-cyclohexanecarboxylic acid (10.0 g, 58.0 mmol), 4-bromobutan-1-ol (9.2 g, 60.0 mmol) and a catalytic amount of para-toluene sulphonic acid are stirred under reflux in toluene (300 ml) in a flask equipped with Dean-Stark apparatus over night. The solution is allowed to cool to room temperature, is washed with aqueous sodium carbonate and water, dried and evaporated to dryness. Purification is achieved by flash column chromatography using petrol as eluant. Evaporation of the appropriate fractions gives 4-propyl-cyclohexanecarboxylic acid 4-bromo-butyl ester as the product. The structure is confirmed by 1H NMR spectroscopy and GCMS.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[F:12][C:13]1[CH:14]=[C:15]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[OH:36])[CH:16]=[CH:17][C:18]=1[C:19]([O:21]CC1C=CC=CC=1)=[O:20]>>[F:12][C:13]1[CH:14]=[C:15]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[O:36][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: BrCCCOC1CCCCO1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Product: O=C(O)c1ccc(-c2cc(F)ccc2OCCCOC2CCCCO2)cc1F

Procedure:
In accordance with the methods of Examples 11-2 and 1-5, 2-(3-bromopropoxy)tetrahydro-2H-pyran was used instead of the compound of Example 11-1, and the compound of Example 13-1 was used instead of the compound of Example 1-3 to afford 3,5′-difluoro-2′-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]biphenyl-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1C=C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[F:17])[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: C=Cc1ccccc1F
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC(c2ccccc2F)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 27 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 2-fluorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[CH:8]=1.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.O>[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: Fc1cc(F)c(F)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)cc(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.7M solution in n-hexane, 148 cm3) was added dropwise over a period of one hour to a stirred solution of 2,3,5,6-tetrafluorobenzene (60 g) in dry tetrahydrofuran (200 cm3) maintained at -70° C. under a nitrogen atmosphere, after which the mixture was stirred at -70° C. for a further one hour. Carbon dioxide gas was passed into the mixture over a period of 4 hours during which time the temperature was allowed to warm up to the ambient value (ca. 22° C.). After adding water and acidifying with dilute hydrochloric acid, the mixture was extracted with diethyl ether and the extracts dried over anhydrous magnesium sulphate. The product was obtained by removal of the solvent by evaporation under reduced pressure to give 2,3,5,6-tetrafluorobenzoic acid (42.5 g), mp. 152°-154° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc3ccccc3o2)ccc1Oc1ncccc1-c1ccncn1
Temperature: 100 °C

Procedure:
To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (30 mg, 0.11 mmol) in toluene (2.0 mL) was added 2-chlorobenzo[d]oxazole (0.014 mL, 0.12 mmol). The resulting mixture was heated to 100° C. for 47 h. The mixture was diluted with DMSO and purified by Gilson reverse-phase HPLC. The product-containing fractions were combined, diluted with methylene chloride, and extracted with saturated sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound as a tan solid. MS m/z=396 [M+H]+. Calc'd for C23H17N6O2: 395.42.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([F:22])([F:21])[F:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(I)cc2)CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (0.60 g, ˜1.9 mmol) in CH3CN (6 mL) was added (3,3,3-trifluoro)-propyl bromide (1.02 mL, 9.6 mmol, 5 eq.) and K2CO3 (1.33 g, 9.6 mmol, 5 eq.) and the resulting mixture was stirred and heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with H2O (25 mL) and saturated brine (2×25 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonitrile as a red solid (0.761 g, 1.86 mmol, 98%). 1H NMR (300 MHz, CDCl3): δ 7.83 (dd, 2H), 7.33 (dd, 2H), 3.09 (d, 2H), 2.82 (dd, 2H), 2.66 (td, 2H), 2.45 (m, 2H), 2.18 (m, 4H); MS (ESI): 409.1/410.2 (M +1).