Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OCCC)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[OH-].[K+]>C(O)COCCO.O>[CH2:1]([C@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(NC(=O)OCCC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3.33 g of crude propyl p-[trans-4-(5-hexenyl)cyclohexyl]phenylcarbamate and 150 ml of a 10 percent solution of potassium hydroxide in diethylene glycol/water (vol. 4:1) was boiled at 120° C. for 2 hours, then cooled to room temperature and partitioned between 150 ml of methylene chloride and 150 ml of water. The aqueous phase was back-extracted twice with 150 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the brown, crystalline residue (3 g) on 70 g of silica gel with ethyl acetate/petroleum ether (vol. 20:80) gave 2.18 g (88%) of p-[trans-4-(5-hexenyl)cyclohexyl]aniline as light yellowish crystals (purity 98.1%); Rf value 0.20 (ethyl acetate/petroleum ether vol. 1:5).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.[Na].[CH3:14][CH2:15][OH:16]>>[CH2:15]([O:16][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(Br)cn1
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)c1ccc(OCC)cn1

Procedure:
To a solution of ethyl 5-bromopyridine-2-carboxylate 2 (1.5 g, 6.5 mmol) in 20 mL of EtOH was added a solution of sodium (0.18 g, 7.8 mmol) in 20 mL of EtOH. The mixture was stirred at reflux for 3 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give ethyl 5-ethoxypyridine-2-carboxylate 3 as an oil. Yield: 0.26 g, 20%. 1HNMR (CDCl3) δ (ppm): 8.38 (d, 1 H), 8.10 (d, 1 H), 8.23 (d, 1 H), 7.22 (dd, 1 H), 4.45 (m, 2 H), 4.25 (m, 1 H), 1.40 (m, 6 H).
Reaction SMILES: C1(COC2C(C3[N:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)[C:15]4[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:14]=4[N:13]=3)=CC=CN=2)CC1.[C:35]([C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42]C2C=CC=CC=2C(Cl)=O)=[CH:39][C:38]=1[F:54])#[N:36].FC1C=C(N)C(N)=CC=1F>>[F:33][C:31]1[C:30]([F:34])=[CH:29][C:15]2[NH:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:42][O:41][C:40]3[CH:52]=[CH:53][C:37]([C:35]#[N:36])=[C:38]([F:54])[CH:39]=3)=[N:13][C:14]=2[CH:32]=1
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)Cl)cc1F
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: Nc1cc(F)c(F)cc1N
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)cc1F

Procedure:
The title compound was prepared in analogy to Example 40, intermediate b, from 2-(4-cyano-3-fluoro-phenoxymethyl)-benzoyl chloride and 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3). Light yellow solid (15%). MS (Turbo Spray): m/z=380.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4].[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:21]([NH:20][CH3:19])=[O:22])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4]
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
The 2-pentafluoroethoxyphenylsulfonamide obtained in Example 4b is suspended in 400 ml of methylene chloride. Then 16.3 g of methyl isocyanate are added and 28.2 g of triethylamine are subsequently added dropwise over 15 minutes to form a clear solution. The solution is evaporated to dryness, and the residue is dissolved in 5% sodium carbonate solution. N-(2-pentafluoroethoxyphenylsulfonyl)-N'-methylurea with a melting point of 177°-179° C., is precipitated from the solution by acidification with 10% hydrochloric acid. Yield: 74.6 g.
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:10]1[CH:11]=[N:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=O)[CH3:8].Cl.[NH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7](=[N:18][O:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=2)[CH3:8])=[CH:11][N:12]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(O)nc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)nc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
124 μl of pyridine were added at room temperature to a suspension of 100 mg of 3-acetyl-6-hydroxypyridine and 232 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in step (e) above] in 10 ml of ethanol, and the resulting mixture was stirred and heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled to room temperature and the precipitate was collected by filtration to give 183 mg of the title compound as a crystalline powder, melting at 240-242° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(C(F)(F)F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CBr)nc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To (5-trifluoromethyl-pyridin-2-yl)-methanol (1.65 g) in dichloromethane (20 ml) at 0° C. (ice-bath) under nitrogen was added triphenylphosphine (3.66 g, 13.98 mmol) in portions, followed by addition of carbon tetrabromide (3.23 g) in portions. The ice-bath was removed and the flask was sealed with a glass stopper. The reaction mixture was gently stirred for 1 hour. The crude reaction mixture was loaded onto a silica gel column (120g), and eluted with methyl acetate/hexane to give 2-bromomethyl-5-trifluoromethyl-pyridine as a light orange oil (1.65 g, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CCOC(C)=O>[CH2:13]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])[CH:12]=[CH2:11]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C#N)cc1Br
Temperature: 25 °C

Procedure:
Mix 3-bromo-4-hydroxy-benzonitrile (1.520 g, 8.0 mmol), allyl bromide (1.161g, 9.6 mmol), potassium carbonate (3.317 g, 24 mmol) and potassium iodide (133 mg, 0.1 mmol) in acetone (80 mL). Heat the mixture to reflux for 12 h. Cool to ambient temperature, add EtOAc, wash the organic layer with water, and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to obtain the desired intermediate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[C:4]([Cl:19])[N:3]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:19][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:7]=[C:2]([N:24]2[CH2:25][CH2:26][C:22]([F:27])([F:21])[CH2:23]2)[N:3]=1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl 3-(2,6-dichloro-4-pyridyl)azetidine-1-carboxylate (1-a, 472 mg, 1.557 mmol), 3,3-difluoropyrrolidine hydrochloride (1.12 g, 5.0 equiv., 7.784 mmol) in NMP (3.0 mL, 31 mmol) in a microwave vial was added DIPEA (1.90 mL, 7.0 equiv., 10.90 mmol)), and the reaction was maintained at 140° C. for 30 min and then at 150° C. for 30 min in the microwave machine. LCMS showed more than 95% conversion. The crude was used without further treatment. LCMS: m/z 374 (M+H).
Reaction SMILES: [NH2-].[Na+].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].CO>O1CCCC1>[CH2:3]([NH:10][C:15]1[CH:16]=[C:17]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C)cc1Br
Reactant: NCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C)c(NCc2ccccc2)c1
Temperature: 60 °C

Procedure:
20.3 g (0.520 mol) of sodium amide was added to 140 g (1.31 mol) of benzylamine under an argon atmosphere. After stirring under cooling with ice for 20 minutes, a solution of 34.84 g (0.129 mol) of 3-bromo-4-methoxytoluene dissolved in 220 ml of tetrahydrofuran was added dropwise over 90 minutes. The reaction mixture was heated to 60° C. and stirred for 60 minutes. Methanol was added under cooling with ice, followed by further addition of ice water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized (chloroform-n-hexane) to obtain 26.96 g (yield, 68.4%) of colorless needles of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].[CH3:19][Mg]Br>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[CH3:19]
Reactant: C[Mg]Br
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Product: Cc1ccc(Cl)c(Nc2ccccc2C(C)O)c1Cl

Procedure:
The desired compound is prepared by reaction of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde, prepared as in step 1, with methylmagnesium bromide.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(=S)=S>[C:5]([C:17]1[CH:16]=[CH:15][C:14]2[O:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][O:12][C:13]=2[CH:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=COc2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Slowly add 8.1 g (60.7 mmol) of aluminium chloride to a solution of 2.85 g (36.3 mmol) of acetyl chloride and 5 g (24.7 mmol) of ethyl 1,4-benzodioxin-2-carboxylate in 120 cm3 of carbon disulfide at 0° C. Stir for 4 hours at room temperature and then, after acid hydrolysis with 20 cm3 of 2N hydrochloric acid, extract the reaction mixture with methylene chloride. After drying the methylene chloride phase over magnesium sulfate, concentrating to dryness and washing with ethanol, ethyl 6-acetyl-1,4-benzodioxin-2-carboxylate is obtained in a yield of 95%.
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32]2.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:33]2[CH2:34][C:35]3[C:31](=[CH:30][C:29]([O:28][CH3:27])=[C:37]([O:38][CH3:39])[CH:36]=3)[CH2:32]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(CCCCCCN2Cc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 61.1 %

Procedure:
A mixture of 1.79 g of 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 5,6-dimethoxyisoindoline, 25 mL of acetonitrile, and 1.74 mL of N,N-diisopropylethylamine is heated under reflux for 2 days. The reaction is concentrated in vacuo and the black residue partitioned between chloroform and aqueous ammonia. The organic layer is dried (sodium sulfate) and the solvent removed at reduced pressure. Chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol, twice, gives 1.34 g of the desired product as a brown gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCCCc1ccc(CCCCCCBr)c(CCC(=O)OCC)c1
Product: CCCc1c(OCCCCCCc2ccc(CCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 99 %

Procedure:
Starting with 0.505 g (1.08 mmol) of 4-(6-bromohexyl)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester from the preceding example, and 0.226 g (1.09 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, the title compound (0.636 g; 99.3%) was obtained as a colorless oil, using the procedure of example 214.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:23](O)[CH3:24].S(=O)(=O)(O)O>C(Cl)CCl>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:22])[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:23][CH3:24])=[O:7]
Reactant: CCO
Reactant: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCOC(=O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 8 h
Yield: 93 %

Procedure:
An 85.38 g. (0.25 mole) portion of 2,3-dichloro-4-(4'-hydroxybenzoyl)phenoxyacetic acid, 34.5 g. (0.75 mole) of ethanol, and 100 ml. of ethylene dichloride, using 3.5 ml. of sulfuric acid as the catalyst was mixed and refluxed with stirring overnight according to the procedure of Clinton and Laskowski, J.A.C.S. 70 3135, 1948. The acid gradually went into solution. The reaction layer was cooled, separated and the organic layer washed successively with water, twice with KHCO3 solution and finally with water. The dried ethylene dichloride was evaporated to dryness to give an oil which solidified to give 86 g. crude ester on trituration with pentane and filtering; m.p. 127°-9° (93% yield). This material was used without further purification in subsequent experiments.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[S:26][CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:29]=3)=[CH:22][C:21]=2[CH:34]=1.N1C(C)=CC=CC=1C>ClCCl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[S:26][CH:27]=[C:28]([C:30]([CH3:32])([CH3:31])[CH3:33])[N:29]=3)=[CH:22][C:21]=2[CH:34]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)c1csc(-c2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3o2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.74 ml) was added dropwise to an ice-cooled mixture of 2-(5-hydroxy-benzofuran-2-yl)-4-tert-butylthiazole (1.0 g), N,N-dimethylaminopyridine (67 mg) and 2,6-lutidine (0.52 ml, 4.39 mmol) in dry dichloromethane (10 ml) below 10° C. After being stirred at room temperature for 2 hours, the reaction mixture was washed with diluted hydrochloric acid, then dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane-ethyl acetate (4:1) as eluent to give 2-(4-tert-butylthiazol-2-yl)-benzofuran-5-yl trifluoromethanesulfonate as a colorless oil (1.39 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[Cl-].[NH4+:10].[OH-].[Na+]>CO.O>[N:10]1[CH:7]=[CH:8][C:3]([NH:4][CH2:5][CH3:6])=[CH:1][CH:2]=1
Reactant: C=Cc1ccccn1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1ccncc1

Procedure:
A slurry of vinyl pyridine (161.4 mL, 1.5 mol) and ammonium chloride (240.7 g, 4.5 mol) in 1:1 MeOH/H2O (1.2 L) was heated to reflux for 18 h. The resulting homogenous solution was basified to pH13 with 3N NaOH and extracted repeatedly with CH2Cl2. The organic extracts were combined and concentrated to give a green oil, which was fractionally distilled to give 2-1 as an amber liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:50])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][CH:48]=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.[CH3:51][Mg]Br>C1COCC1.S([O-])(O)(=O)=O.[K+]>[CH3:1][O:2][CH2:3][C@H:4]([CH3:50])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][CH:48]([OH:49])[CH3:51])[CH2:15]2)=[CH:12][CH:13]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.0 mmol of [(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetaldehyde in 10 ml of THF are added 2.0 mmol of methyl magnesium bromide (3M in THF) at 0° C. The reaction mixture is allowed to warm to RT and stirred for 1 h, diluted with an aqueous solution of 1N potassium hydrogen sulfate and extracted with TBME. The organic phases are combined and dried over Na2SO4. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as colourless oil. Rf=0.38 (EtOAc/heptane 2:1); Rt=5.35 (gradient I).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]=1)[C:7]([OH:9])=[O:8]>C(O)C>[S:1]([CH:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]=1)[C:7]([OH:9])=[O:8])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2cc(C(SC#N)C(=O)O)ccc2c1
Reaction time: 15 h

Procedure:
To a solution of 300 ml. of anhydrous ethanol and 0.15 moles of sodium thiocyanate is added 0.12 moles of α-chloro-6-methoxy-2-naphthylacetic acid and stirred for 15 hours. The reaction mixture is filtered and washed with absolute ethanol. The filtrate is evaporated to dryness, the residue is dissolved in 250 ml. of ether and washed several times with water. The ether is then dried and evaporated to dryness to obtain α-thiocyanato-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1

Procedure:
This compound was prepared from 1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (Description 1c) and α-bromo-m-tolunitrile according to the procedure described in Example 1d. 1H NMR (360 MHz, CDCl3) δ1.49 (9H,s, (CH3)3), 1.6-1.72 (2H, m), 1.87-1.99 (2H, m), 2.72 (1H, dt, J=13, 4 Hz, NCHH), 3.80-3.95 (2H, m, CHO+NCHH), 4.65 (2H, q, J=12 Hz, OCH2), 5.69 (1H, brs, CHPh), 7.1-7.5 (9H, m, ArH).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:7]=1[CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:5])=[O:4])[CH3:2]>CO.CCOC(C)=O.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([CH:18]=1)[CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 3A (2.2 g, 6.14 mmol) in MeOH (50 ml) and EtOAc (50.0 ml) was added 10% Pd on carbon (0.653 g, 0.614 mmol) and the mixture was stirred under a hydrogen balloon for 2 h. Pd/C was removed by filtration. The filtrate was concentrated to give 3B that was used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=8.35 Hz, 1H) 6.58-6.67 (m, 1H) 6.52 (s, 1H) 4.78 (s, 2H) 3.04-3.13 (m, 2H) 2.94 (s, 3H) 1.45 (d, J=39.11 Hz, 9H) 1.26 (t, J=7.47 Hz, 3H).
Reaction SMILES: C(C1C=CC([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[C:16]([C@@H:23]([OH:26])[CH2:24][OH:25])[N:15]=3)=[CH:10][CH:9]=2)=CC=1C(F)(F)F)#N.CC1(C)C(C)(C)OB(C2C=CC(O[C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=CC=2)O1>>[OH:26][C@H:23]([C:16]1[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:9][CH:10]=2)[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=1)[CH2:24][OH:25]
Reactant: N#Cc1ccc(Oc2ccc(-c3nc(C(N)=O)cc([C@@H](O)CO)n3)cc2)cc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)OC1(C)C
Product: NC(=O)c1cc([C@@H](O)CO)nc(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)n1

Procedure:
(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl) pyrimidine-4-carboxamide (Compound Example No. 18) was prepared a similarly to (R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl) pyrimidine-4-carboxamide (Compound Example No. 12) using 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6): 8.75-8.67 (2 H, m), 8.65-8.59 (1 H, m), 8.05-8.01 (1 H, m), 8.01-7.94 (1 H, m), 7.83-7.75 (2 H, m), 7.31-7.22 (4 H, m), 5.84-5.79 (1 H, m), 4.87-4.79 (1 H, m), 4.73-4.67 (1 H, m), 3.86-3.77 (1 H, m), 3.74-3.64 (1 H, m); LC/MS: m/z=420 [M+H]+.