Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[SH:33][CH2:34][CH2:35][OH:36]>CN(C)C=O.C(OCC)(=O)C.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>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([C:10]3[NH:9][C:8]([C:5]4[N:6]=[CH:7][C:2]([S:33][CH2:34][CH2:35][OH:36])=[CH:3][CH:4]=4)=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: OCCS
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(SCCO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in N,N-dimethylformamide (1 mL) were added 2-sulfanylethanol (63 μL) and tetrakistriphenylphosphinepalladium(0) (230 mg), and the mixture was stirred using a microwave synthesis apparatus at 120° C. for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (114 mg, yield 57%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 513 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][OH:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][O:27][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-benzoyloxypyrrolidine (32.6 g) was dissolved in 64 ml of dry pyridine, and 28.02 g of p-toluenesulfonyl chloride was added thereto, followed by stirring at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with a mixture of diethyl ether and dichloromethane (4:1). The extract was washed successively with brine, dilute hydrochloric acid, brine, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-p-toluenesulfonyloxymethyl-4-benzoyloxypyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:14]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCCl>[F:15][C:3]1[C:2]([NH:1][C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:6]2[N:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: CC(C)n1c(=O)sc2cc(F)c(N)cc21
Reactant: COC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)Nc1cc2c(cc1F)sc(=O)n2C(C)C
Yield: 79.6 %

Procedure:
A mixture of 5-amino-6-fluoro-3-isopropyl-2(3H)-benzothiazolone (2.1 g), N,N-diethyianiline (1.5 g) and methyl chloroformate (1.0 g) was dissolved in 1,2-dichloroethane (10 g), and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water, and the organic layer was concentrated. The residue was washed with methanol to give 6-fluoro-5-methoxycarbonylamino -3-isopropyl-2(3H)-benzothiazolone (2.1 g).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:23][C:24]1[C:33]([F:34])=[C:32](F)[C:31]([O:36][CH3:37])=[C:30]2[C:25]=1[C:26](=[O:44])[C:27]([C:41]([OH:43])=[O:42])=[CH:28][N:29]2[CH:38]1[CH2:40][CH2:39]1>N1C=CC=CC=1>[NH2:23][C:24]1[C:33]([F:34])=[C:32]([N:9]2[CH2:10][CH2:11][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]2)[C:31]([O:36][CH3:37])=[C:30]2[C:25]=1[C:26](=[O:44])[C:27]([C:41]([OH:43])=[O:42])=[CH:28][N:29]2[CH:38]1[CH2:40][CH2:39]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(n3ccnn3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 120 °C

Procedure:
3-(1,2,3-triazol-1-yl)pyrrolidinehydrochloride (147 mg, 0.84 mmol) and DBU (128 mg, 0.84 mmol) were added to a suspension of 5-Amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.33 mmol) in pyridine (5 ml). The reaction mixture was heated at 120° C. for 30 hrs, concentrated and the residue was triturated with water. The separated solid was filtered, washed with water and recrystallized from chloroform-hexane. Yield 40 mg; m.p. 208° C.; 1H NMR (TFA) δ: 9.39 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 5.88 (s, 1H), 4.43-4.73 (m, 4H), 4.10 (m, 1H), 3.79 (s, 3H), 2.92 (m, 2H), 1.12-1.58 (m, 4H).
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[S:20][CH:21]=[C:22]([Br:28])[C:23]=3[C:24]([O:26][CH3:27])=[O:25])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl.N1CCOCC1>[NH2:18][C:19]1[S:20][CH:21]=[C:22]([Br:28])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(Br)csc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1COCCN1
Product: COC(=O)c1c(Br)csc1N

Procedure:
Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-bromothiophene-3-carboxylate (1 g) was stirred in DCM/morpholine (12 mL, 1:1) at rt until all the ester was consumed. The crude mixture was concentrated under reduced pressure. The residue was dissolved in ethyl ether. The white solid was removed. The mother liquid was concentrated under reduced pressure and a 1:1 mixture of ethyl ether/pentane (20 mL) was added. An additional white solid was removed. The organic layer was concentrated under reduced pressure and the crude mixture was placed under high vacumn to remove the excess of morpholine. The crude amine was taken directly to the next reaction step without further purification. Method[1], MS(ESI) 235.9 [M+H], Retention time=1.919 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
To a stirred solution of 4-azabenzimidazole (304 mg, 2.55 mmol) in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was allowed to warm to rt and stirred for a further 20 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of this Example in DMF (5 mL). The mixture was stirred at rt for 15 h. To the reaction mixture was added water and the mixture was extracted with DCM. The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (290 mg, 38%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.38 (dd, J=1.2, 4.6 Hz, 1H), 8.10 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.25-7.41 (m, 2H), 5.61 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:41])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH:39]=O)[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1.[NH:42]([CH3:44])[CH3:43].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:1][C:2]1([F:41])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH2:39][N:42]([CH3:44])[CH3:43])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:27])[F:28])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1
Reactant: O=Cc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CC(F)(F)C2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CC(F)(F)C2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of (R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.03 mmol) in MeOH (2 mL) was added NHMe2 (0.009 mL) and a drop of acetic acid. The reaction mixture was stirred at rt for 30 min, followed by addition of NaCNBH3 (2 mg, 0.03 mmol). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between sat. NaHCO3 and EtOAc. The organic phase was concentrated and purified by prep HPLC (Phemomenex Luna 5u C18 Axia column, 21×100 mm, 10%-90% H2O/ACN with 0.1% TFA/, monitoring at 220 nm) to yield (R)-1-(3,3-difluorocyclobutyl)-3-(1-(3-((dimethylamino)methyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (Example 328, 8 mg, 44% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (d, J=2.27 Hz, 1H), 7.09 (m, 7H), 6.88 (d, J=8.84 Hz, 1H), 6.63 (d, J=7.07 Hz, 2H), 6.51 (br. s., 1H), 5.88 (m, 1H), 4.34 (d, J=12.63 Hz, 1H), 4.10 (m, 2H), 3.87 (m, 1H), 3.31 (d, J=12.63 Hz, 2H), 2.92 (m, 3 H), 2.74 (d, J=2.78 Hz, 3H), 2.70 (d, J=3.28 Hz, 3H), 2.46 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]([O:8][Si](C)(C)C)([CH3:7])[C:5]#[N:6])[CH2:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:13]([O:8][C:4]([CH3:7])([CH:1]1[CH2:3][CH2:2]1)[C:5]#[N:6])(=[O:15])[CH3:14]
Reactant: CC(C#N)(O[Si](C)(C)C)C1CC1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CC(=O)OC(C)(C#N)C1CC1
Yield: 87.5 %

Procedure:
To a well stirred and ice-cooled solution of 2-cyclopropyl-2-trimethylsilanyloxy-propionitrile (188.5 g, 1.03 mol) in acetonitrile (1000 mL) was added acetic anhydride (194 mL, 2.06 mol) and scandium trifluoromethanesulfonate (5 g, 10.3 mmol). The temperature rose to ˜10° C. and stirring was continued for 15′ at room temperature. The solvent was evaporated in vacuo and the residue was distilled to yield 138 g of the title compound as colorless liquid, bp: 84-86° C./6 mbar.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.CCCCC>[CH2:33]([O:32][C:30](=[O:31])[N:8]([C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:34]
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Reactant: CCOC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine (57 gm 170 mmol) was dissolved in tetrahydrofuran (750 mL) and stirred under N2. Cooled in an ice/salt bath to −5° C. To this solution was added drop wise over a period of ˜30 minutes, a solution of potassium t-butoxide (21.2 gm, 189 mmol) in tetrahydrofuran (200 mL), maintaining the temperature between −5° and 0° C. to give a deep red reaction mixture. Stirred at this temperature for 15 minutes before the drop wise addition of a solution of ethyl chloroformate (21.4 gm, 198 mmol) in tetrahydrofuran (100 mL), keeping the temperature below 5° C. The cooling bath was removed and the reaction mixture was allowed to reach ambient temperature over 1 hour to give a light brown hazy solution. Evaporation of the solvent was followed by partition of the residue between saturated brine (50 mL) and t-butyl methyl ether (300 mL). The organic phase was washed with water (50 mL) followed by saturated brine (50 mL), dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was dissolved in n-pentane (250 mL) and stored at ambient temperature overnight. The n-pentane solution was decanted from a dark brown tar which had precipitated out. Evaporation of the solvent gave ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate as a pale brown viscous oil (63 gm, 91% yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[C:22](=[O:38])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37])=O)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:37][C:25]1[CH:26]=[C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:12][NH:8]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CN[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4S)-4-[(5-Chloro-thiophene-2-carbonyl)-amino]-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg) was dissolved in CH2Cl2 (1 ml) and TFA is added (1 ml). The mixture was stirred for 1 h at 25° C. and evaporated to dryness to yield (2S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide trifluoro-acetate (31 mg) as a colorless solid. MH+=461.3 (Cl-isotopes).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][C:24]=1[CH3:30])[CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:17]([O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([O:16][C:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:25][C:24]=1[CH3:30])[CH3:18]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1C
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C=Cc1ccc(Oc2cc(C)cc(OCc3ccccc3)c2)cc1C
Temperature: 130 °C
Reaction time: 20 h
Yield: 58.6 %

Procedure:
A mixture of 3-benzyloxy-5-methyl-phenol (3.24 g, 15.1 mmol), 3-(4-fluoro-2-methyl-phenyl)-acrylic acid ethyl ester (3.15 g, 15.1 mmol) and 325 mesh potassium carbonate (2.51 g, 18.2 mmol) in dry DMSO (40 mL) is heated to 130° C. and stirred for 20 hours under N2. The reaction is cooled and acidified with 1 N HCl (30 mL). The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.56 g (58%) of the title compound. Rf=0.39 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H26O4 402, found 403 (M+1, 100%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li]CCCC.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: CNC(=O)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of N-methyl-o-toluamide (4.47 g) in THF (100 ml) was added dropwise 1.6 M n-BuLi (40 ml, 2.2 equivalents) in nitrogen atmosphere at 0° C. After stirring for 2 hr, the resulting solution was cooled in a dry ice/acetone bath to −70° C., followed by the addition of anisole (4.0 g) at once. The reaction mixture was drawn out of dry ice/acetone bath, and then returned to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, which was stirred for further 1 hr. The resulting white precipitates were collected by filtration, and then washed with water, ether and n-hexane, in this order. The resulting precipitates were dried, to give the title compound (1.72 g, yield; 24%).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:18](=[O:20])=[O:19]>>[C:3]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:18]([OH:20])=[O:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C=O
Reactant: CC(C)(C)C(Cl)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)C(C(=O)O)c1ccc(OC(F)(F)F)cc1

Procedure:
The neopentyl chloride prepared in Example 25 is converted to the Grignard reagent and subsequent carbonation with carbon dioxide according to the procedure of Weinstein and Morse [Journal of the American Chemical Society 74, 1133 (1952)] gives the desired acid as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[CH3:17][Mg]Br>C1COCC1>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([OH:16])[CH3:17])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)c1noc(N2CCC(C=O)CC2)n1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(C(C)O)CC2)n1
Reaction time: 2 h
Yield: 33.1 %

Procedure:
A solution of 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde (1.1 g, 4.93 mmol) in THF (25 mL) at −10° C. was treated dropwise with methylmagnesium bromide (3M in Et2O, 3.94 mL, 11.8 mmol). The mixture was stirred at −10° C. to −5° C. over a 2 h period. The reaction was carefully quenched by the addition of saturated aqueous NH4Cl and the aqueous was extracted with ether (6 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by chromatography on a silica gel column eluted with 0 to 70% EtOAc/hexanes to give 0.39 g (33%) of (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol as a light yellow oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCOc1ccccc1
Yield: 83.1 %

Procedure:
2-Phenoxyethanol (2.76 g), 1,6-dibromohexane (14.6 g), TAB (1 g) and 50% sodium hydroxide (20 ml) were vigorously stirred for 21 h, added to water (100 ml) and extracted with diethyl ether (3×100 ml). The dried extract was evaporated and the residual colourless liquid (15 g) was purified by FCC eluting with cyclohexane followed by System A (1:1). Evaporation of the latter eluate gave the title compound (5.0 g) as a colourless liquid. T.l.c. (System A 1:1) Rf 0.6.
Reaction SMILES: CN(S(F)(F)[F:5])C.[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20]O)[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9].O>ClCCl>[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20][F:5])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]
Reactant: CN(C)S(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CO)c1SC(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1SC(F)(F)F
Reaction time: 3 h
Yield: 84 %

Procedure:
Dimethylaminosulfur trifluoride (2.27 mL) was added to a solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole (2.9 g) in dichloromethane. After stirring for 3 hours, water was added followed by dichloromethane. The organic phase was washed with an aqueous solution of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (2.45 g, 84%). 1H NMR: (400 MHz, CDCl3): 5.38 (d, J=47.5 Hz, 2H) and 7.83 (s, 2H). 19F NMR (376 MHz, CDCl3): −43.83 (s, 3F), −63.76 (s, 3F) and −84.12 (t, J=47.5 Hz, 1F).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].N[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].CC1ON=C(CCC(O)=O)C=1>>[OH:27][CH2:26][CH:25]1[O:28][C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([CH3:20])[CH:16]=3)=[CH:21][CH:22]=2)=[N:2][CH2:24]1
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Reactant: NCC(O)CO
Agent: Cc1cc(CCC(=O)O)no1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Yield: 60 %

Procedure:
5-{7-[4-(4,5-Dihydro-5-hydroxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R1, R2, R3, R4 and R5 =H, R6 =CH2OH, Y=(CH2)7, oxazole at 4-position] was prepared from the ethyl imino-ester hydrochloride of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole and 3-amino-1,2-propanediol according to the procedure of Example 1, part (c), and was obtained in about 60% yield in the form of a colorless solid, m.p. 75°-76° C., when recrystallized first from isopropyl acetate and then from acetonitrile.