Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1.C(OC(=O)C)(=O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2ccc(OC)cc2)nc1
Reaction time: 12 h
Yield: 21.3 %

Procedure:
4-Methoxybenzaldehyde (210 mg, 1.52 mmol), methyl 6-methylnicotinate (230 mg, 1.52 mmol), acetic anhydride (310 mg, 3.04 mmol) and catalytic amount of zinc chloride were heated at 140° C. with stirring for 12 h. Ethyl acetate and brine were added to the cooled reaction mixture and the product was extracted. The organic layers were combined, dried (MgSO4) and the solvent removed under reduced pressure. The crude product was applied to a silica gel column and the product was eluted with ethyl acetate/n-hexane (1:1 RF=0.60 fluorescent under the UV lamp). Fractions containing the required product were collected and the solvents removed under reduced pressure to give the sub-title compound as a yellow solid (87 mg, 21%).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]([CH2:11][N+:12]([O-:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[C:5]([O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC>CN(C=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>[CH2:17]([O:16][C:5]1[C:6]2[B:7]([OH:15])[O:8][CH:9]([CH2:11][N+:12]([O-:14])=[O:13])[C:10]=2[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1)[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOc1ccc(Br)c2c1B(O)OC2C[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccccc2)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A mixture of 4-bromo-7-ethoxy-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (315 mg, 1 mmol), tributyl-phenyl-stannane (750 mg, 2 mmol) and Pd(Ph3P)4 (Cat.) in DMF (15 mL) was degassed for 15 min with N2 and then stirred at 100° C. for 30 min in microwave reactor (Biotage). After the reaction was quenched with ice-water, the resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and then concentrated to dryness. The residue was purified by column chromatography on silica gel to give the compound as white solid (60 mg, yield 20%). 1HNMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.46-7.49 (m, 5H), 7.34-7.48 (m, 2H), 6.17-6.20 (m, 1H), 4.88-4.92 (m, 1H), 4.21-4.25 (m, 1H), 4.05-4.16 (m, 2H), 1.34-1.37 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].Br[CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1c(I)cc(I)cc1I)C(=O)OCC
Temperature: 100 °C
Yield: 63.7 %

Procedure:
A stirred mixture of 70.8 g (0.15 mol) of 2,4,6-triiodophenol, 39.0 g (0.15 mol) of diethyl bromomalonate and 20.7 g (0.15 mol) of milled anhydrous potassium carbonate in 200 ml of dry dimethylformamide was heated at 100° C. under argon for 5 hours. The mixture was cooled and concentrated in vacuo. The resulting residue was combined with 300 ml of ice-cold water and the oily product was extracted with ethyl acetate (1×300 ml), 3×100 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to a dark oil. The oil was purified by chromatography (eluted by hexanes to 20% diethyl ether in hexanes) to yield 60.2 g (64%) of product as a light cream-colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:11]1[C:10]2[CH:9]=[CH:8][C:5]([CH:6]([C:14]3[CH:23]=[CH:22][C:17]([O:18][CH3:19])=[C:16]([O:21][CH3:20])[CH:15]=3)[OH:7])=[CH:4][C:3]=2[O:2][CH2:1][CH2:12]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: Brc1ccc2c(c1)OCCO2
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1ccc(C(O)c2ccc3c(c2)OCCO3)cc1OC
Yield: 89.4 %

Procedure:
3,4-dimethoxybenzaldehyde (2.21 g, 13.32 mmol), 6-Bromo-2,3-dihydrobenzo[1,4]dioxine (3.15 g, 14.65 mmol), and n-butyl lithium (5.86 ml, 14.65 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,4-dimethoxy-phenyl)-methanol as an oil (3.60 g, 89%): 1HNMR (CDCl3) 6.93-6.80 (m, 6H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.24 (s, 4H, CH2CH2), 3.86 (s, 6H, 2OCH3), 2.14 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O=S(Cl)Cl.[Cl-].[NH3:27]>C1(C)C=CC=CC=1.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:27])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Reactant: N
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(CC#N)cc2)cc1
Reaction time: 6 h

Procedure:
180 g of SOCl2 was added to a suspension of 281 g of 4'-pentylbiphenyl-4-ylacetamide [m.p. 185°; obtained by reaction of 4-acetyl-4'-pentylbiphenyl with morpholine/sulfur and subsequent hydrolysis to give 4'-pentylbiphenyl-4-ylacetic acid (m.p. 160°), reaction with SOCl2 to give the chloride and reaction with NH3 ] in 1 l of toluene at 80°. After stirring at 80° for 6 hours, cooling down and pouring into water, 4'-pentylbiphenyl-4-ylacetonitrile was obtained, m.p. 80°, c.p. -10°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>CN(C)C=O>[F:17][C:18]([F:20])([F:19])[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:8]
Reactant: COc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C(F)(F)F)cc1
Yield: 84.1 %

Procedure:
According to Reference Example 8-2, by use of 4-methoxybenzaldehyde (500 mg, 3.67 mmol) dissolved in N,N-dimethylformamide (7.5 mL), potassium carbonate (101 mg, 0.734 mmol) and (trifluoromethyl)trimethylsilane (1.09 mL, 7.34 mmol), the mixture was stirred and reacted at room temperature, at 80° C. for 7 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(4-methoxyphenyl)ethanol (Compound CJ) (636 mg, yield: 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.O>C1(C)C=CC=CC=1.C(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>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[CH:3][C:2]=1[C:29]1[CH:30]=[CH:31][S:27][CH:28]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1-c1ccsc1
Reaction time: 12 h
Yield: 49.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-bromo-4-methoxy-benzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added thiophene-3-boronic acid (0.09 g, 0.67 mmol) and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction was then poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, methylene chloride then 30-40% ethyl acetate/hexanes) afforded 0.1 g (50%) of 3-(4-methoxy-3-thiophen-3-ylbenzylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:29]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc5ccccc5c4)cc3c2C1
Yield: 71.4 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.2 μL (0.051 mMol) 2-naphthoyl chloride, 12.6 mg (72%) of the title compound were recovered as a dark brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22]CC4C=CC=CC=4)=[CH:19][CH:20]=3)[O:15][CH2:14][C@H:13]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][CH:7]=1>O1CCCC1CO.C(O)=O.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[O:15][CH2:14][C@H:13]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: OCC1CCCO1
Product: COC(=O)COc1ccc([C@H]2c3ccc(O)cc3OC[C@H]2c2ccccc2)cc1

Procedure:
(+,−) cis [4-(7-Benzyloxy-3-phenyl-chroman-4-yl)-phenoxy]-acetic acid methyl ester(100 mg, 0.21 mmol) was dissolved in a solvent mixture of tetrahydrofuran-methanol-formic acid (8+1+1, 10 ml). The solution was added to a 5% Palladium on carbon catalyst (20 mg), and hydrogenated (1 atm.) overnight. The reaction mixture was filtered and evaporated to give a dark oil, which was dissolved and evaporated from EtOH (×3), triturated with toluene, and recrystallised from toluene.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.C(O[CH2:21][CH3:22])(=O)C>CO.C(O)C>[N:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:21]=1[CH:22]=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1
Reactant: CCOC(C)=O
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Solvent: CCO
Solvent: CO
Product: FC(F)(F)c1cccc(N2CCC(N=Cc3ccccn3)=N2)c1
Reaction time: 8 h

Procedure:
3-Amino-1-(3-trifluoromethylphenyl)-2-pyrazoline in methanol (23 ml) was stirred together with 2-pyridylaldehyde at room temperature for 2 hours and then under reflux for a further 2 hours. Thin layer chromatography (SiO2, ethyl acetate) indicated that the reaction was substantially complete. After standing overnight, additional 2-pyridylaldehyde (0.5 g) was added and heating was continued for 2 hours. TLC again indicated that no further reaction had occurred. The reaction mixture was evaporated in vacuo to yield an orange-coloured solid which was stirred for 45 minutes in aqueous ethanol (3:1) and 3-(2-pyridylmethyleneamino)-1-(3-trifluoromethylphenyl)-2-pyrazoline was collected, m.p. 155.6°.
Reaction SMILES: CS(OC[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC(C(O)(C)C(F)(F)F)=CC=1)(=O)=O.C1(NC)CC1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].[CH:44]1([CH2:47][NH:48][CH2:49][C@H:50]2[CH2:55][N:54]([S:56]([C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)(=[O:58])=[O:57])[CH2:53][CH2:52][N:51]2[C:64]2[CH:69]=[CH:68][C:67]([C:70]([OH:76])([CH3:75])[C:71]([F:74])([F:73])[F:72])=[CH:66][CH:65]=2)[CH2:46][CH2:45]1>>[CH:44]1([CH2:47][N:48]([CH2:49][C@H:50]2[CH2:55][N:54]([S:56]([C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)(=[O:58])=[O:57])[CH2:53][CH2:52][N:51]2[C:64]2[CH:69]=[CH:68][C:67]([C:70]([OH:76])([CH3:75])[C:71]([F:72])([F:73])[F:74])=[CH:66][CH:65]=2)[S:40]([CH3:39])(=[O:42])=[O:41])[CH2:45][CH2:46]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNCC2CC2)cc1)C(F)(F)F
Agent: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: CNC1CC1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN(CC2CC2)S(C)(=O)=O)cc1)C(F)(F)F

Procedure:
This compound was synthesized following the scheme described for Example 195. The reaction of ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (Intermediate B) and cyclopropyl methylamine (Alfa Aesar, Ward Hill, Mass.), followed by sulfonamide formation (using MsCl) delivered 2-(4-((2S)-2-(((cyclopropylmethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of two isomers.
Reaction SMILES: [CH2:1]([C:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])(C(OC)=O)[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].O.[Cl-].[Li+].CCCCCC.C(OCC)(=O)C>CS(C)=O>[F:28][C:23]([F:29])([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OC
Temperature: 180 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
Dimethyl 2-hept-6-enyl-2-(7,7,8,8,8-pentafluorooctyl)propan- 1,3-dioate(9.31 g, 21.62 mmol) prepared in Step 4 was dissolved in anhydrous DMSO(100 ml), water(0.39 ml, 21.62 mmol) and lithium chloride(1.82 g, 43.25 mmol) were added, and the resulting mixture was stirred for 4 hours at 180° C. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, washed with distilled water, and dried over anhydrous magnesium sulfate. The solvent was removed by concentration under reduced pressure and the residue was purified by column chromatography(eluent:n-hexane/ethyl acetate=50/1, v/v) to give 4.46 g(Yield 55.4%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[N:16]=[CH:15][C:14]([O:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>CS(C)=O.C(OCC)(=O)C.[Cu]>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:16][CH:15]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc(Oc2ccc(Br)nc2)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(Oc2ccc(C#N)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A mixture of ethyl 2-bromo-2,2-difluoroacetate (22.13 mL, 109.05 mmol) and copper (13.85 g, 218.1 mmol) in dry dimethylsulfoxide (DMSO) (80 mL) was stirred at room temperature (rt) for 4 h. 4-((6-Bromopyridin-3-yl)oxy)benzonitrile (10 g, 36.35 mmol) was added and the mixture heated at 50° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with 200 mL of ethyl acetate (EtOAc) and stirred for 10 min. The mixture was filtered through a plug of Celite® and the filtrate was washed with saturated NH4Cl solution to remove any remaining copper. The solution was dried (Na2SO4) and solvent was removed under reduced pressure to give the title compound as brown oil (6.5 g, 56.5%): IR (thin film) 2229, 1767 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=2.7 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.73-7.64 (m, 2H), 7.49 (dd, J=8.6, 2.7 Hz, 1H), 7.16-7.07 (m, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); ESIMS m/z 319 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C1COCC1>[Br:25][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 1.5 h

Procedure:
The ketone from step 1 (0.32 g, 0.868 mmol) was dissolved in THF (9 ml), and phenyltrimethylammonium tribromide (PTT) (0.368 g, 0.868 mmol) was added as a solid leaving an orange solution which began to deposit a white solid immediately. Stirring for 1.5 hours leaves a colorless mixture to which water (5 ml) was added. THF was then evaporated and the resulting aqueous mixture was extracted with ethyl acetate. Drying over Na2SO4 and evaporation leaves a white crystalline solid (90% desired mono-brominated material by LC-MS, 5% starting material, 5% dibrominated) suitable for the next step. LC-MS (ES−): 436, 438 m/e.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([O:11]CC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1csc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 4-isopropylthiazole-2-carboxylate (9.1 g, 46 mmol) in THF (100 ml) and MeOH (30 ml) was added a solution of lithium hydroxide (1.16 g, 48.5 mmol) and the mixture was stirred for two days at room temperature. The mixture was acidified with 2M hydrochloric acid and extracted four times with diethyl ether. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 7.1 g, 90%.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(Cl)(Cl)[Cl:21].Cl>CO.[Pd]>[ClH:21].[NH2:1][C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1cc(-c2nnn[nH]2)oc2c([N+](=O)[O-])cccc12
Reactant: ClC(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12
Reaction time: 4 h

Procedure:
Following the process described in example 1 (point B), by hydrogenating for 4 h 8-nitro-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran (0.896 g, 3.46 mmol) with 5% palladium-on-charcoal (91 mg) in a mixture of methanol (65 ml), chloroform (20 ml) and concentrated hydrochloric acid (2 ml), the title compound was prepared as its corresponding hydrochloride (quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C[Si](C)(C)[C:11]#[C:12][CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>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.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC#Cc1ccc(Br)cc1
Yield: 72.5 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-iodobenzene (2.00 g, 7.07 mmol), PdCl2(PPh3)2 (99.2 mg, 0.14 mmol), CuI (26.8 mg, 0.14 mmol), trimethyl(prop-1-yn-1-yl)silane (2.08 mL, 14.1 mmol) and tetrahydrofuran/TEA (9:1) (100 mL). Stirring was initiated and tetrabutylammonium fluoride (3.69 g, 14.1 mmol) was added rapidly to the mixture. The resulting mixture was stirred for 18 h at room temperature, then concentrated under reduced pressure. The residue diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield the title compound as a light yellow oil (1.0 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[F:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][CH:38]=1)[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:21])=[CH:18][CH:17]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[C:6]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:26]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:25]2[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:14]2[CH:36]=[CH:37][CH:38]=[C:12]([F:11])[CH:13]=2)=[CH:35][CH:34]=1)#[N:7]
Reactant: CC[Si](C#CCCNC(=O)c1ccc(Cc2cccc(F)c2)cc1)(CC)CC
Reactant: N#Cc1ccc(N)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 26.7 %

Procedure:
4-Amino-3-iodobenzonitrile (0.10 g; 0.41 mmol), 4-(3-fluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)benzamide (0.162 g; 0.41 mmol) bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.017 g; 0.020 mmol), lithium chloride (0.017 mg; 0.410 mmol) and sodium carbonate (0.087 g; 0.820 mmol) were suspended in DMF (5 mL) and the mixture was stirred at 100° C. for 15 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane) to afford 0.056 g (27%) of the title compound as a white solid.