Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17]C(C)C)=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:11]2>ClCCl>[Cl:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:11]2
Reactant: CC(C)Oc1c(Cl)cc(Cl)c2ccc(-c3ccccn3)nc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Oc1c(Cl)cc(Cl)c2ccc(-c3ccccn3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boron trichloride (27 mL of a 1 M solution in dichloromethane, 27.6 mmol) was added dropwise to a solution of 5,7-dichloro-8-isopropoxy-2-(2-pyridyl)quinoline 15 (1.83 g, 5.51 mmol) in dichloromethane (30 mL) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 1 h and then allowed to warm to RT. After 24 h, some starting material was still present (by TLC analysis). More boron trichloride (14 mL) was added and stirring resumed for a further 4 h. The reaction was quenched with methanol (10 mL) and the volatiles removed in vacuo. The process was repeated until the residue reached constant weight. This gave 5,7-dichloro-8-hydroxy-2-(2-pyridyl)quinoline as the hydrochloride salt. The hydrochloride salt (1.68 g) and water (20 mL) was then treated with saturated sodium bicarbonate until the pH of the solution was 8. The mixture was the extracted with ethyl acetate (30 mL×3) and dried. The residue obtained after solvent removal was washed with methanol. This provided 5,7-dichloro-8-hydroxy-2-(2-pyridyl)quinoline (PBT 1052) as an off-white solid (1.25 g, 78%), m.p.>230° C. 1H NMR (DMSO-d6, 200 MHz): δ 10.8 (br, 1 H), 9.21 (d, J=9, 1 H), 8.30-8.62 (m, 3 H), 8.12 (m, 1 H), 7.88 (s, 1 H), 7.62 (m, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22](B(O)O)=[CH:23][C:24]([F:27])=[N:25][CH:26]=1.C(Cl)Cl.COCCOC>CCOC(C)=O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:21]1[C:22]([C:2]2[CH:3]=[CH:4][C:5]([C:16]([F:19])([F:18])[F:17])=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:23][C:24]([F:27])=[N:25][CH:26]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: FC(F)(F)c1ccc(Cl)nc1NCC1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: Fc1cc(-c2ccc(C(F)(F)F)c(NCC3CCOCC3)n2)c(Cl)cn1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine (100 mg, 0.339 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (89 mg, 0.509 mmol), PdCl2(dppf).CH2Cl2 adduct (27.7 mg, 0.034 mmol), DME (1.5 mL) and 2M aqueous Na2CO2 (0.5 mL, 1 mmol) was stirred in a sealed glass vessel at about 100° C. for about 3 hours. After cooling to ambient temperature the mixture was diluted with EtOAc (25 mL) and MeOH (20 mL), filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography [silica gel, 12 g, EtOAc/hexane=5/100 to 50/50] to yield 5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)-2,4′-bipyridin-6-amine (Intermediate T, 102 mg, 77%). LCMS (m/z): 390.2 [M+H]+; Retention time=1.12 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[F-:13].[K+].[F-].[Ca+2].[F-]>C(#N)C>[F:13][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: [F-]
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Ca+2]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CF)cc1
Yield: 78.7 %

Procedure:
Dry acetonitrile (150 ml) was added to 25.00 g of methyl 4-(bromomethyl)benzoate, 19.02 g of potassium fluoride and 9.51 g of calcium fluoride, and the mixture was heated to reflux for 3 days. The reaction solution was concentrated. After addition of 200 ml of acetonitrile, insolubles were removed by filtration, and the filtrate was concentrated again. The residue was purified by silica gel column chromatography (YMC•GEL® SIL-60-230/70, n-hexane:ethyl acetate=10:1–4:1), followed by distillation under reduced pressure to provide 14.45 g of the objective compound as colorless oil. B.p. 118.5–119° C./18 mmHg.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].O1CCC[CH2:30]1.CCOCC.C[Mg]Br>C(OCC)(=O)C>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]([OH:27])[CH3:30])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: C1CCOC1
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCN(c1ccc(C)c2cc(-c3ncc(C(C)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 4 h
Yield: 65 %

Procedure:
To a mixed solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4-methyl-1H-indol-7-yl]thiophene-2-sulfonamide (0.30 g) and tetrahydrofuran (30 mL) was added ether solution (0.60 mL) of 3M-methylmagnesium bromide under ice-cooling, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed successively with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2-2:1), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (201 mg, yield 65%) as pale-yellow prism crystals. melting point 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.C(N(CC)CC)C.Cl.[CH3:39][N:40]([CH3:47])[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].S(Cl)(Cl)(=O)=O>C(Cl)Cl.O>[CH3:39][N:40]([CH3:47])[CH2:41][CH2:42][S:43]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2)(=[O:45])=[O:44]
Reactant: CN(C)CCS(=O)(=O)Cl
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN(C)C)ccc3[nH]2)CC1

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (VII, PREPARATION 56, 400 mg) in dry methylene chloride (5 ml) under nitrogen at 0° is added triethylamine (275 μl) and 2-(dimethylamino)ethanesulfonyl chloride hydrochloride (225 mg). The mixture is stirred at 0° for 1 hr and at 20°-250° for 23 hrs, during which additional sulfonyl chloride (20 mg) and triethylamine (14 μl) are added. The mixture is then diluted with 4 ml of water, the layers are separated, and the organic phase is washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give a solid which is chromatographed on silica gel (70-230 mesh, 46 g), eluting with a gradient of methanol/chloroform (2.5/97.5-6/94). Pooling of fractions having an Rf of 0.36 by TLC (methanol/chloroform, 10/90) and removal of solvent under reduced pressure gives an impure solid. Purification of this solid on two 2000 μ preparative silica gel plates, eluting with methanol/chloroform (10/90) and extracting the appropriate band, gives the title compound, NMR (CDCl3) 10.17, 7.71, 7.55, 7.35, 7.11, 6.94, 6.84, 6.69, 4.63, 4.50, 3.56, 3.45, 3.18, 3.30-3.00, 2.84, 2.63, 2.25, 1.93, 1.65 and 1.22 δ.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][CH:3]([C:2]([F:1])([F:18])[F:19])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11]2)(=[O:26])[CH3:25]
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(C(C)=O)ccc2OC1C(F)(F)F
Temperature: 0 °C

Procedure:
A 500 mL three neck round bottom flask was fitted with stir bar, thermocouple and heating mantle, condenser, and nitrogen inlet and charged with dichloromethane (150 mL), ethyl 2-trifluoromethyl-2H-chromene-3-carboxylate (14.94 g, 54.882 mmole), and AlCl3 (18.29 g, 137.21 mmole). With stirring, the reaction was chilled to 0° C. followed by addition of acetyl chloride (5.85 mL, 6.46 g, 82.32 mmole). The reaction was stirred at RT for three days and then at reflux for six days. The reaction was poured over ice and was extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield a solid. This solid was triturated with hexanes to provide a slurry. Vacuum filtration of the slurry yielded the title compound as a white solid. (11.78 g, 68.3%): mp 101-103° C. 1H NMR (acetone-d6/300 MHz) 8.14(s, 1H), 8.04 (d d, 1H, J=8.7, 2.2 Hz), 7.98(s, 1H), 7.13 (d, 1H, J=8.6 Hz), 5.95 (q, 1H, J=6.8 Hz), 4.38-4.23 (m, 2 H), 2.57(s, 3H), 1.33(t, 3H, J=7.0 Hz). GCMS m/z 314 (M+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C[Si]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(C)C.[Si:18]([O:25][C:26]1[C:27]([F:38])=[C:28]([C:32](=O)[CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:29]=[CH:30][CH:31]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][C:26]1[C:27]([F:38])=[C:28]([C:32]([CH2:33][CH:34]2[CH2:36][CH2:35]2)=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH:29]=[CH:30][CH:31]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CC2CC2)c1F
Reactant: COC(=O)C[Si](C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C=C(CC1CC1)c1cccc(O[Si](C)(C)C(C)(C)C)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
A 25 mL round bottom flask was cooled to −78° C. under N2 and charged with THF (2 mL) and lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene) (2.1 mL, 4.1 mmol) (available from Aldrich). To the cold, brown solution was added methyl (trimethylsilyl)acetate (0.61 mL, 3.7 mmol) (available from Aldrich) dropwise. The orange mixture was stirred for 15 minutes, and to it was added a solution of 84.C (0.46 g, 1.5 mmol) in THF (2 mL) dropwise. The mixture was stirred for 30 minutes at −78° C., the cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was washed with water, 1 N HCl and brine. The organic phase was then dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (0-2% EtOAc/hexane) to afford 84.D (mixture of geometric isomers) (0.44 g, 81% yield) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:16]=[CH:17][C:18]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[C:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:16]=[CH:17][C:18]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
4-(chloromethyl)benzoyl chloride (12 g, 63.5 mmol) was dissolved in THF (120 mL) and a solution of 1,1-dimethylethyl (3-aminobiphenyl-4-yl)carbamate (19.86 g, 69.8 mmol) and DIPEA (12.2 mL, 69.8 mmol) in THF (300 mL) was added dropwise at room temperature. After stirring for 1 hour, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in Et2O to give 1,1-dimethylethyl [3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.92 (s, 1H), 8.75 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.83 (s, 1H), 7.63 (m, 3H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (dd, J=8.4 and 1.8 Hz, 1H), 7.44 (t, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 1H), 4.84 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(C)=O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O.CC#N>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: C[C@H](CO)CBr
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](CO)CN1CCC(c2nsc3cc(F)ccc23)CC1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20 mmol), (R)-(-)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K2CO3 (2.7 g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH3CN (95 ml) and H2O (19 ml) was stirred and refluxed for 4.5 hours. After standing at ambient temperature for 16 hours, the reaction was poured into H2O, and subsequent extractive workup of the aqueous with EtOAc yielded 6.8 g of a partially solidified oil. The product was purified by flash chromatography on silica gel, eluting the column with CH2Cl2, then 2% MeOH-CH2Cl2 and finally 5% MeOH-CH2Cl2. Concentration of the appropriate fractions yielded 5.2 g of a waxy solid. The solid was dissolved in acetone and fumaric acid (1.9 g, 1.0 eq) was added and the reaction briefly heated at reflux. The resultant fumarate salt precipitated from solution yielding 4.8 g of white solid. The compound was recrystallized from acetonitrile to yield 3.1 g (36%) of the alcohol as a white solid, m.p.=151°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=1.C([O:17][C:18](=O)[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22])C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18](=[O:17])[NH:13][C:11]=2[N:10]([CH3:14])[N:9]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cn1nc(-c2ccccc2F)cc1N
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2F)c2c(C(F)(F)F)cc(=O)[nH]c21
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
A solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-amine (830 mg, 4.34 mmol) and 4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (960 mg, 5.21 mmol) in acetic acid (5 ml) was irradiated using a microwave at 150° C. for 1.5 h. After completion of the reaction, ice-cold water was added and the reaction mixture was stirred for 10 min. The precipitate was filtered, washed twice with pentane and dried under vacuum to yield 900 mg (67%) of the title compound. [1H-NMR (CDCl3, 300 MHz): δ 13.6 (s, 1H), 7.51-7.05 (m, 4H), 6.75 (s, 1H), 4.21 (s, 3H); LCMS RtA=1.459 min; [M+H]+=312.1]
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:20]4[CH2:22][CH2:21]4)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cc(C2CC2)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 100 °C
Yield: 92.5 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-iodophenyl)thiazolo[5,4-c]pyridine (0.20 g, 0.45 mmol), cyclopropyl boronic acid (0.051 g, 0.59 mmol), Pd(OAc)2 (0.005 g, 0.023 mmol), P(Cy)3 (tricyclohexylphosphine) (0.013 g, 0.045 mmol) and potassium phosphate tribasic (0.336 g, 1.58 mmol) in toluene (4 mL) and water (0.2 mL) was degassed with a stream of argon and then heated at 100° C. for 18 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, then dried (MgSO4) and concentrated under reduced pressure. The resultant residue was combined with the crude reaction mixture (79 mg) obtained by reacting 4-chloro-2-(2,6-dichloro-4-iodophenyl)-thiazolo[5,4-c]pyridine (0.10 g, 0.23 mmol) under the same reaction conditions and purified by column chromatography on silica gel eluting with 0-30% Et2O in petroleum ether (40-60° C.) to afford the title compound as a yellow/orange solid (148 mg, 61%). LCMS (Method D): RT=4.69 min, m/z: 355 [M+H+].
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>C(O)C>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH2:10])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)O
Reactant: Nc1ccccc1S
Solvent: CCO
Product: CC(=O)N[C@@H](CSc1ccccc1N)C(=O)O
Yield: 52.5 %

Procedure:
A mixture consisting of 8.6 g of α-acetylaminoacrylic acid, 20 g of 2-aminobenzenethiol and 50 ml of ethanol was heated for an hour. After the ethanol was distilled off, ether was added to the residue so as to cause crystallization. Upon recrystallization from ethanol, there was obtained 8.9 g of the desired product. Its melting point (m.p.) was 143°-144° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[S:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[O:14]1[C:9]2=[CH:8][CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[C:10]2[S:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1cccc2c1SCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2c1SCCO2
Yield: 87.1 %

Procedure:
1.6 g of the compound obtained in Step 4 are treated for 2 hours at room temperature with 8 ml of 2N sodium hydroxide solution and 8 ml of methanol. After treatment, 1.3 g of the expected acid are isolated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[NH4+]>C(#N)C>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1cc(O)c(C=O)cc1Cl
Temperature: 70 °C
Yield: 21.7 %

Procedure:
2-Hydroxy-4-methoxy-benzaldehyde (0.974 g, 6.40 mmol) was dissolved in 10 mL of acetonitrile and treated with N-chlorosuccinimide (0.983 g, 1.15 eq.) and ammonium nitrate (0.102 g, 0.20 eq.), and the mixture was warmed to 70° C. for roughly 5 h. Evaporation of the solvent, followed by flash chromatography (SiO2, heptane/AcOEt=85/15), and direct crystallization from heptane/AcOEt, produced then 0.259 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25](O)[CH3:26])=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:9]=1[C:28]([F:31])([F:30])[F:29].CCN(C(C)C)C(C)C.S(Cl)(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:52][C@@H:53]([CH:61]([CH3:63])[CH3:62])[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[CH3:62][CH:61]([CH3:63])[C@H:53]([NH:52][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[C:9]([C:28]([F:31])([F:29])[F:30])[CH:10]=3)[O:18][N:17]=2)=[CH:24][CH:23]=1)[C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(C)O)cc3)no2)cc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CCN[C@H](C(=O)OC(C)(C)C)C(C)C)cc3)no2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To (4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (84 mg; 0.2 mmol) in DCM (2 mL) was added DIEA (71 μL; 0.4 mmol) and mesyl chloride (17 μL; 0.22 mmol), at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes, allowed to warm to RT and stirred for 2 hours. The mixture was diluted with DCM (20 mL) and saturated aqueous NaHCO3 solution was added. The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was all used in the next step without further purification. It was dissolved in dioxan (2 mL). Potassium carbonate (165 mg, 1.2 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (104 mg; 0.60 mmol) were added. The mixture was heated at 130° C. for 72 hours, diluted with DCM (5 mL) and water (5 mL). The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with petrol containing increasing amounts of EtOAc to give the title compound as a colourless gum (86 mg; 72%). 1H NMR (CDCl3, 400 MHz) δ 8.63 (1H, s), 8.39 (1H, dd, J=8.0, 1.7 Hz), 8.12 (2H, d, J=8.1 Hz), 7.47 (1H, d, J=8.0 Hz), 7.43-7.21 (5H, m), 7.16 (1H, d, J=7.6 Hz), 2.99-2.68 (5H, m), 2.07 (3H, s), 1.94-1.79 (1H, m), 1.46 (9H, s), 0.94 (6H, dd, J=6.8, 3.7 Hz). LC/MS (Method B): 580 (M+H)+. HPLC (Method D) Rt 3.7 min (Purity: 94.9%).
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.[CH:14]([Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18])=[CH2:15].C(OOC(C)(C)C)(C)(C)C>C(O)(C)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14][Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C[Si](OC)(OC)OC
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CC(C)O
Product: CO[Si](CCP(c1ccccc1)c1ccccc1)(OC)OC
Reaction time: 100 h

Procedure:
A solution of 2-(diphenylphosphino)ethyltrimethoxysilane (DPETMS) in isopropanol comprising 12% DPETMS and 88% isopropanol and 2-4 drops titanium acetylacetonate dialkoxide in alcohol was prepared. The DPETMS was synthesized by combining diphenylphosphine and vinyltrimethoxysilane in a borosilicate flask and then exposing to sunlight for 100 hours, or by using t-butylperoxide or azodiisobutryonitrile as catalyst. Excess volatile material was removed in vacuo at 1-2 mmHg pressure and remaining material tested.