Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[NH2:15][C@@H:16]([CH3:31])[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>CO.C(O)(C)C>[NH2:15][C@@H:16]([CH3:31])[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CC1COc2cc(O)ccc21
Agent: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A racemate (0.05 g) of (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetic acid was charged, a mixed solvent of methanol/isopropyl alcohol (1/4) was added, and the racemate was dissolved. (S)-2-Amino-1,1-diphenylpropan-1-ol (0.059 g, 1 eq) was added thereto, and the mixture was stirred at room temperature for 12 hr. The precipitated crystals were collected by filtration to give the title compound (0.037 g). 87.8% de
Reaction SMILES: Cl[C:2]1([S:20]([CH2:22][CH3:23])=[O:21])[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[CH:3]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N12CCCCC1C=NCCC2>C(OC(=O)C)C>[CH2:22]([S:20]([C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:21])[CH3:23]
Reactant: CCS(=O)C1(Cl)CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: CCS(=O)C1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of benzyl 3-chloro-3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (54) (0.020 g) in ethylacetate (2 ml) was stirred at room temperature under argon and treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.009 g). After a period of 15 minutes the reaction mixture was washed with brine and dried over sodium sulphate. It was concentrated to give a single diastereoisomer of benzyl 3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (55) (0.017 g) as a gum; νmax (CHCl3) 2980, 1795 and 1730 cm-1 ; τ(d6 -acetone) 2.5-2.8 (5H, m, phenyl), 4.78 (2H, s, benzyl CH2), 5.71 (1H,tdd J9,5 and 3 Hz, C5-H), 6.49 (1H, dd J17 and 5 Hz, C6-H), 6.82 (2H, d J 9 Hz, C4-H2), 6.84 (1H, dd J17 and 3 Hz, C6-H), 7.13 and 7.15 (2H, 2q J71/2 Hz, SCH2) and 8.80 (3H, t J71/2 Hz, CH3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:12]=[C:13]5[C:17](=[CH:18][CH:19]=4)[NH:16][CH:15]=[CH:14]5)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2[nH]ccc2c1
Product: Fc1cnc(Nc2ccc3[nH]ccc3c2)nc1Nc1ccc2[nH]ccc2c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted to yield N2,N4-bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.26 min.; purity: 99%; MS (m/e): 359 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:40]3([F:39])[CH2:42][CH2:41]3)=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1(F)CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(F)CC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, 1-fluorocyclopropanecarbonyl chloride (20 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions, and the mixture was stirred for 12 h. The reaction mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.5 mg, 89% of theory).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.373 g, 4.11 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMSO (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)COC1C(Br)=[N:33]C(C)=CC=1)(C)(C)C>>[CH3:19][Si:18]([C:17]#[C:16][C:10]1[C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[CH:14][CH:13]=[C:12]([CH3:11])[N:33]=1)([CH3:21])[CH3:20]
Reactant: Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)n1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Product: Cc1ccc(OCC(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n1

Procedure:
Following the general method as outlined in Intermediate 2, starting from tert-butyl[(2-bromo-6-methylpyridin-3-yl)oxy]acetate (Intermediate 84), the title compound was obtained as a brown oil after purification by flash column chromatography (silica), eluting with petroleum ether and ethyl acetate (98:2).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:9][CH:10]=1
Reactant: COCCCOc1ccccc1CCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.200 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.113 g of 1-chloromethyl-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.44 (1:2 EtOAc-heptane); Rt=6.25.
Reaction SMILES: [S:1]1[C:5]2[C:6]([SH:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:11]([N:18]([CH3:29])[CH2:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)CC)(C)C>C(#N)CC>[S:1]1[C:5]2[C:6]([S:10][CH:19]([N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:29])[CH2:20][CH2:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CN(CCC(O)c1ccccc1)Cc1ccccc1
Reactant: Sc1cccc2ccsc12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1ccccc1)C(CCc1ccccc1)Sc1cccc2ccsc12
Temperature: 25 °C

Procedure:
A solution of 1-benzothiophene-7-thiol (0.32 g, 1.96 mmol), 3-[benzyl(methyl)amino]-1-phenyl-1-propanol (0.5 g, 1.96 mmol), (cyanomethyl) trimethylphosphonium iodide (Ref Tetrahedron, 2001, 57, 5451–5454) (0.714 g, 2.94 mmol), diisopropylethylamine (0.379 g, 2.94 mmol) in propionitrile (5 mL) was stirred at 90° C. in a reacti-vial for 72 h. After this time the reaction was allowed to cool to room temperature. The reaction mixture was purified by an SCX-2 column eluting with methanol followed by ammonia:methanol solution (7 N). The organics were then evaporated and the compound taken directly onto the next step without any further purification LCMS determined successful product formation (M+H+1 [404]).
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:23][NH2:24]>CCO>[CH3:6][CH:5]1[N:7]2[C:8]([CH2:9][O:10][C:11]3[C:12]2=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)=[N:24][NH:23][C:4]1=[O:21]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of 2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (133.0 g, 450 mmol) in EtOH (1.5 L) was added hydrazine hydrate (45.0 g, 900 mmol, 98%) and the mixture was heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was washed with cold EtOH (3×50 mL) to give 4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (80.0 g, 68%). 1H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.86 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.99 (q, J=6.4 Hz, 1H), 4.78 (d, J=12.8 Hz, 2H), 1.36 (d, =6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH2:12]([Sn](CCCC)(CCCC)CC=C)[CH2:13][CH2:14]C.CN(C)C=O.[F-].[K+]>C(N(CC)CC)C>[CH2:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCc2c(Br)cccc21
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1CCC2=O
Temperature: 20 °C

Procedure:
15 g of 4-bromo-1-indanone, 24 ml of tributyl allyl stannane, 150 ml of dimethylformamide, 0.82 g of tetrakis triphenyl phosphine palladium and 7.89 g of triethylamine are taken to 120° C. for one hour. After cooling to 20° C., the reaction mixture is poured over 300 ml of an aqueous solution of potassium fluoride, agitated, and filtered on celite; the filtrate is extracted with isopropyl ether. The insoluble part is taken up with ethyl acetate and filtered on celite. The reunited organic phases are washed with water saturated with sodium chloride, dried and brought to dryness under reduced pressure. The residue is chromatographed on silica with hexane-ethyl acetate (9-1) and 11.84 g of expected product is recovered.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:11][Br:1])[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16][CH3:17])[O:18]2)=[CH:8][CH:9]=1
Reactant: C=C(CCC(O)CCC)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A solution of bromine (1.28 g) in dichloromethane (25 ml) was added dropwise over 15 minutes to a stirred solution of 2-(4-chlorophenyl)-5-hydroxyoct-1-ene (1.9 g) and pyridine (0.63 g) in dichloromethane (25 ml) at 0° to 5° C. (decolourisation of bromine and mild exotherm). The cooling bath was removed and the mixture was stirred for a further 30 minutes, then washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate, and water, then dried over magnesium sulphate and concentrated under reduced pressure to give 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (2.6 g) as a red oil, 1H nmr (CDCl3): δ3.9 (2H, singlet, CH2Br).
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].[CH3:15]I>O>[CH3:15][S:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=c1[nH]c(S)nc2ccccc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 2-mercaptoquinazolin-4(3H)-one (4.45 g, 25 mmol) and NaOH (1.1 g, 27.5 mmol) in water (125 mL) was added methyl iodide (1.72 mL, 27.5 mmol) and the mixture was stirred at 25° C. for 3 h. The precipitate was collected by filtration, washed with water (3×20 mL) and dried in vacuum desiccator over silica gel for 24 h to give 3.66 g (73%) of the title compound as colorless solid: mp 224-225° C. An analytical sample was recrystallized from methanol-water: mp 225° C.; 1H NMR (CDCl3) δ 11.25 (br s, 1H, NH), 8.27 (dd, 1H, J=1.25, 6.3 Hz, ArH), 7.62 (d, 1H, J=7.3 Hz), 7.44-7.38 (m, 1H, ArH), 2.70 (s, 3H, SCH3); 13C NMR (CDCl3) δ 163.73, 155.76, 149.77, 135.50, 127.30, 126.96, 126.40, 120.37, 13.97.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(O[C:10]([O:12][CH:13]([O:15][C:16](=[O:32])[CH2:17][CH:18]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:14])=[O:11])C.IC(O[C:37](=O)[CH:38](C)[CH3:39])C>CO.CC#N>[C:10]([O:12][CH:13]([O:15][C:16](=[O:32])[CH2:17][CH:18]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:14])(=[O:11])[CH:38]([CH3:39])[CH3:37]
Reactant: CC(I)OC(=O)C(C)C
Reactant: CCOC(=O)OC(C)OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
Cesium carbonate (0.365 g, 1.12 mmol) was dissolved in methanol (5 mL) and S-form of compound 4 (0.500 g, 1.28 mmol) was added. The solution was stirred for 4 hours at room temperature and concentrated to dryness. The residue was diluted with CH3CN (7.5 mL), and compound 14 (0.945 g, 3.56 mmol) and CH3CN (5 mL) were then added. After stirring overnight at room temperature, the reaction solution was filtered and concentrated to give 1 g of the crude product, which was then purified by chromatography on a column of silica gel (70-230 mesh, elution: EA/Hexane=1:4). Compound 3-(tert-butoxycarbonylamino-methyl)-5-methyl-hexanoic acid 1-isobutyryloxy-ethyl ester 15 (0.13 g) was obtained with 27% yield. 1HNMR (CDCl3, 500 MHz) δ0.87-0.92 (m, 6H), 1.10-1.21 (m, 2H), 1.55 (d, J=5 Hz, 6H), 1.44 (s, 9H), 1.48 (d, J=5.5 Hz, 3H), 1.52-1.59 (m, 2H), 2.06-2.12 (m, 1H), 2.28-2.35 (m, 2H), 2.49-2.57 (m, 1H), 2.93-3.06 (m, 1H), 3.12-3.22 (m, 1H), 4.62-4.73 (m, 1H), 6.84 (q, J=5.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3cccc(F)c3)ccc2sc1=O

Procedure:
6-(3-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3-fluorophenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.549 (s, 1H), 7.814-7.664 (m, 2H), 7.463-7.249 (m, 3H), 7.132-7.042 (m, 1H), 4.028 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15][C:16]1([F:24])[CH2:20][NH:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.O.C(O)C>[F:15][C:16]1([F:24])[CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[C@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 88.2 %

Procedure:
To 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (416 mg, 2 mmol), (S)-4,4-difluoropyrrolidine-2-carboxylic acid (301 mg, 2 mmol), and sodium carbonate (633 mg, 574 μL, 6.0 mmol) was added 1:1 water/Ethanol (8 mL) and the reaction mixture was heated at 90° C. for 72 h. The reaction mixture was diluted with water (50 mL) then acidified with 1 N HCl and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield (S)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylic acid as a brown oil (600 mg, 89%), which was used directly in the next reaction. LC/MS: m/z 341.00 (M+H)+ at 1.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[F:16][C:17]([F:27])([F:26])[CH2:18][I+]C1C=CC=CC=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(Cl)Cl>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[CH3:28][N+:29]1[CH:33]=[CH:32][N:31]([CH2:18][C:17]([F:16])([F:26])[F:27])[CH:30]=1
Reactant: FC(F)(F)C[I+]c1ccccc1
Reactant: Cn1ccnc1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(CC(F)(F)F)c1

Procedure:
(2,2,2-Trifluoroethyl)(phenyl)iodonium bis(trifluoromethanesulfonyl)imide (compound 7) (3.4 g, 6 mmol) and methylene chloride (12 ml) were placed in a reaction vessel to convert the inside of the reaction vessel to a nitrogen atmosphere. While stirring and cooling in an ice bath, 1-methylimidazole (0.49 g, 6 mmol) was added dropwise thereto over the course of 1 minute. After the dropwise addition thereof, the ice bath was removed, and the mixture was allowed to react at room temperature for 3 hours. After the completion of the reaction, the solvent was removed by distillation. The resulting liquid product was washed with water and then with hexane in order to remove a side product, iodobenzene. Subsequently, this liquid product was dissolved in a small amount of ethyl acetate, and a large amount of ether was added thereto to separate the liquid product. The liquid product was separated from the solvent and then dried at 110° C. under reduced pressure using a vacuum pump. Thus, pure 1-methyl-3-(2′,2′,2′-trifluoroethyl)imidazolium bis(trifluoromethanesulfonyl)imide (compound 9) was obtained as a liquid substance (yield 1.94 g, 73%). When the product is colored, it may be subjected to decolorization with active carbon. Physical property, elemental analysis and spectral data of the compound 9 are shown in Table 8.
Reaction SMILES: [CH2:1](OCC)C.C[Mg]Br.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH:28]=[O:29])[C:23]=2[O:24][CH2:25][O:26][CH3:27])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>C1COCC1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH:28]([OH:29])[CH3:1])[C:23]=2[O:24][CH2:25][O:26][CH3:27])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1c(C(C)O)csc1-c1ccc(C(C)(C)C)cc1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
3.0 M Ethyl ether solution (2.0 mL, 6.0 mmol) of methylmagnesium bromide was added dropwise to 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-formylthiophene (0.77 g, 2.5 mmol) in THF (2.5 mL) under cooling with ice, and the reaction solution was stirred for 1 hour under cooling with ice. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1) to give the desired product as a pale yellow oil (0.64 g, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)=[O:12])=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[O:12][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[OH:30])=[O:5]
Reactant: Cn1nccc1O
Reactant: CC(C)(CCl)NC(=O)c1c(S(C)(=O)=O)ccc(C(=O)Cl)c1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NC(C)(C)CO3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
At 15° C., 1.65 g (4.3 mmol) of 2-chloro-3-(1-chloro-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoyl chloride in 25 ml of dioxane and 0.45 g (4.5 mmol) of triethylamine in 10 ml of dioxane were added dropwise to a mixture of 0.42 g (4.3 mmol) of 5-hydroxy-1-methylpyrazole in 10 ml of dioxane. The mixture was stirred at room temperature for 4 hours and then filtered off through silica gel, which was rinsed with dioxane. The combined filtrates were concentrated to 60 ml and admixed with 1.24 g (9 mmol) of finely powdered potassium carbonate. The mixture was heated under reflux for 5 hours and cooled, the solvent was removed under reduced pressure, the residue was taken up in water, insoluble components were filtered off and the solution was acidified using 10% strength hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were subsequently washed with water, dried and concentrated. 1.2 g (68% of theory) of 4-[2-chloro-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:21])[C:17]#[C:18][CH2:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:21][CH2:16][C:17]#[C:18][CH2:19][CH3:20])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
In 9 ml of N,N-dimethylformamide were dissolved 202 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 112 mg of 2-pentyn-1-ol, to which 54 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 211 mg of 4-(2,3-difluorophenyl)-6-(2-pentynyloxy)pyrimidine (the present compound (117)).