Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:19])CC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][F:19])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)c1ccc(Br)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(CF)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-bromophenyl)-2-methylpropan-1-ol (500 mg, 2.182 mmol) was dissolved in Dichloromethane (7.2 mL) in a 20 mL vial. DAST (0.433 mL, 3.27 mmol) was then slowly added to the solution. Stirred at ambient temperature overnight. TLC showed presence of starting material. Another 0.5 eq. of DAST was added and stirred for 4 hours. TLC then showed consumption of starting material. The reaction was loaded directly on a silica column and the column was then dried out. Purified with a Teledyne Isco Combiflash Rf purification system using a gradient of 5% EtOAc/hexanes. Isolated 1-bromo-4-(1-fluoro-2-methylpropan-2-yl)benzene as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (d, 2H), 7.10-7.09 (d, 2H), 2.88 (s, 1H), 2.83 (s, 1H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:15][S:16](O)(=[O:18])=[O:17].C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 1.84 g (10.0 mmol) of 4-methyldiphenyl ether (J. Chem. Soc., Perkin Trans. 1; 1992, 407-408) with 2 mL of dichloromethane in an ice-bath was added a solution of chlorosulfonic acid (0.73 mL, 11.0 mmol) in 2 mL of dichloromethane dropwise. The resulting mixture was stirred at 0° C. to room temperature for 2 hours, and then oxalyl chloride (11.14 mL, 13.0 mmol) was added dropwise, followed by 0.15 mL of DMF. The resulting mixture was heated to 40° C. for 1 hour and then allowed to cool to room tempereature over a 2 hour period. The reaction mixture was poured into ice-pH 7 phosphate buffer (50 mL), then extracted with EtOAc:Hexane (4:3) (3×150 mL). The combined organic layers were washed with brine (75 mL). The aqueous layer was extracted with EtOAc/Hexane(4:3) (150 mL). The organic layer was dried over Na2SO4, then evaporated by vacuum to give crude product as white solid. This solid was triturated with hexane and collected by filtration, then dried under high vacuum to give 1.555 g (57%) of 4-(4-methylphenoxy)benzenesulfonyl chloride as white solid: mp 295-300° C.; 1H--NMR (DMSO-d6) δ 2.34 (s, 3H), 6.91-6.99 (dd, J=7.7,8.4 Hz, 4H), 7.24-7.27 (d, J=8.4 Hz, 2H), 7.61-7.63 (d, J=8.1 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[O:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:11]=1)=[O:6].C(N(CC)CC)C.N1C=CC=CC=1S(O)(=O)=O>CS(C)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH:2]=[O:1])[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc(C(=O)CCCO)oc2-c2ccc(C)cc2)cc1
Agent: O=S(=O)(O)c1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc(C(=O)CCC=O)oc2-c2ccc(C)cc2)cc1
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of 4-hydroxy-1-[4,5-bis(4-methylphenyl)oxazol-2-yl)butan-1-one (0.78 g) and triethylamine (2 ml) in DMSO (10 ml) was added a solution of pyridinesulfonic acid (1.16 g) in DMSO (4 ml) at room temperature. After being stirred for 20 minutes at the same temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1M-HCl, water and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[4,5-bis(4-methylphenyl)oxazol-2-yl)butan-1,4-dione (0.22 g). MS (m/z): 334 (M+ +1) IR (Nujol): 1735, 1690 cm-1NMR (CDCl3, δ): 2.38 (3H, s), 2.40 (3H, s), 2.97 (2H, t, J=6.4 Hz), 3.47 (2H, t, J=6.4 Hz), 7.17-7.26 (4H, m), 7.53-7.59 (4H, m), 9.88 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:42][C:43]([F:50])([F:49])[CH2:44][NH:45][CH2:46][CH2:47][NH2:48]>CN(C=O)C>[F:42][C:43]([F:50])([F:49])[CH2:44][NH:45][CH2:46][CH2:47][NH:48][C:24]([C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:16]=[CH:15][CH:14]=2)=[O:25]
Reactant: NCCNCC(F)(F)F
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)NCCNCC(F)(F)F)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
A mixture of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (53 mg, 0.15 mmol), HOBt (28 mg), EDC (36 mg), TEA (0.042 mL) and N1-(2,2,2-trifluoro-ethyl)-ethane-1,2-diamine (0.036 mL) in DMF (1 mL) was stirred at rt for 48 hours. The solvent was removed and diluted with sat. NaHCO3. It was then extracted with DCM, dried and concentrated. The residue was purified on a silica gel column to give 52 mg (71%) of the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][NH:6][C:5](=O)[C:4]=1[F:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]([F:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc[nH]c(=O)c1F
Product: CCc1ncnc(Cl)c1F
Yield: 66 %

Procedure:
A mixture of the product of part (i) (6.4 g, 45 mmol) and phosphoryl chloride (30 ml) was heated under reflux for 3 hours. The excess phosphoryl chloride was removed by distillation under reduced pressure and the residue was poured into ice-water. The resulting mixture was extracted with methylene chloride (3×50 ml) and the combined organic extracts were washed with water and dried over magnesium sulphate. The solvent was removed under reduced pressure and the resulting oil was distilled under reduced pressure to provide the title compound (4.81 g, 66%), b.p. 74° C. at 22 mm Hg, which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone (55 mg, 0.13 mmol) was dissolved in ethanol (5 mL). Sodium borohydride (24 mg, 0.63 mmol) was added and the mixture was stirred at rt for 10 min. Acetone (2 mL) was added and the mixture was stirred for 20 min. The solvent were evaporated. The residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound as a solid, 40 mg (72%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 12.2 %

Procedure:
Compound A (1.53 g, 6.25 mmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (1.79 g) and sodium hydrogencarbonate (5.25 g) were added to DMSO (30 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography. This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (308 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[C:7]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:6]=2.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][C:44](Cl)=O>ClCCl>[CH2:26]([O:25][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:44]([CH2:43][CH2:42][O:41][CH3:40])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (28.62 g, 65.5 mmol) in dichloromethane (1 L) was cooled to ˜0° C.; triethylamine (10.0 mL, 72.1 mmol) was added. Methoxypropionyl chloride (8.57 mL, 78.6 mmol) was added dropwise, and the reaction was stirred at ambient temperature for two hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (840 mL). Triethylamine (33 mL) was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to provide 30.77 g of tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a brown oil, which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.FC(F)(F)C(O)=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:54]CI>O1CCOCC1>[Cl:54][CH2:1][O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCCl
Reaction time: 18 h

Procedure:
4-(N-CBz-L-valyloxy) butyric acid t-butyl ester (20 g, 50.8 mmole) was treated with trifluoroacetic acid (30 ml) at 0° C. for 3 h and then evaporated. The residue was coevaporated with toluene several time. The intermediate acid (2.56 g, 7.6 mmole) was dissolved in dioxane (10 ml) and to the solution was added tetrabutylammonium hydroxide (40%, 4.66 ml. 7.2 mmole). The solution was dried and dissolved in dichloromethane (20 ml) and then chloroiodomethane (10 ml, 144 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. Yield 2.1 g.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:16](=C)[C:17]([NH2:19])=[O:18])CCCCCCCCC.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])=[CH2:22].O>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:30]([NH:19][C:17](=[O:18])[CH:16]=[CH2:6])[CH2:29][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH2:21][CH3:22]
Reactant: C=C(CCCCCCCCCC)C(N)=O
Reactant: C=Cc1ccccc1C=C
Agent: C=CC(N)=O
Solvent: CCO
Solvent: O
Product: C=CC(=O)NCCCCCCCCCC

Procedure:
Polystyrenesulfonate (22.5 mmoles, 3.918 g), acrylamide (3.45 mmoles, 0.245 g), n-decylacrylamide (3.45 mmoles, 0.729 g) and divinylbenzene (0.6 mmoles, 85.5 microL) were dissolved in 15 mL ethanol and 5 mL water in a 40 mL vial fitted with a septa cap. The solution was degassed by bubbling nitrogen through and 1 mole % AIBN was added as a solution. The polymerization solution was further degassed and the placed in a heated reaction block at 60° C. for 18 h. A creamy yellow gel formed.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CS(C)=O>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Clc1cnccn1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.150 g, 0.50 mmol), 2-chloropyrazine (0.57 g, 1.67 mmol), triethylamine (0.1 ml, 0.72 mmol), and DMSO (50 ml) was stirred for three hours at 100° C. The crude reaction mixture was purified directly by reverse phase HPLC to give the product as a purple solid (0.014 g, 0.7%) MP=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.41 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.81 (m, 3H), 7.76-7.70 (m, 1H), 7.58-7.52 (m, 1H), 4.28-4.22 (m, 2H), 3.39-3.28 (m, 2H), 3.12 (s, 2H), 2.11-2.04 (m, 2H), 1.88-1.79 (m, 2H); LCMS: 380 [M+H].
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:15]Br>Br>[Br:15][CH:4]([C:3](=[O:12])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)C(=O)CCc1cccnc1
Reactant: BrBr
Agent: Br
Product: CC(C)(C)C(=O)C(Br)Cc1cccnc1
Yield: 100.9 %

Procedure:
320.5 g (1.676 mol) of 4,4-dimethyl-1-pyridin-3-yl-pentan-3-one were dissolved in 320 ml of aqueous 48% strength hydrobromic acid, and 267.8 g (85.3 ml; 1.65 mol) of bromine were added dropwise at 80° to 95° C. in the course of 2 hours. When the addition had ended, the solution was cooled and concentrated. The solid which remained was comminuted well, stirred with about 1.5 liters of ethanol, filtered off, washed with ethanol and dried. 450 g (78% of theory) of 2-bromo-4,4-dimethyl-1-pyridin-3-yl-pentan-3-one of melting point 163°-64° C. were obtained. ##STR119##
Reaction SMILES: C(N(S(F)(F)F)CC)C.[Cl:10][C:11]1[C:12]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26](O)([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[N:13][CH:14]=[N:15][C:16]=1[CH2:17][CH3:18].O>ClCCl>[Cl:10][C:11]1[C:12]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26]([CH3:28])=[CH2:27])[CH2:22][CH2:21]2)=[N:13][CH:14]=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)O)CC2)c1Cl
Agent: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C=C(C)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.8 g (11 mmol) of diethylaminosulfur trifluoride (DAST) were added to 3.0 g (10 mmol) of the alcohol from Example 1 in 50 ml of dichloromethane at -50° C., and the mixture was stirred at room temperature for 1 hour. It was poured into water and the organic phase was washed with aqueous sodium hydrogen carbonate solution, dried and concentrated. The crude product was chromatographed on silica gel with petroleum ether/ethyl acetate 7:3 to give, first of all, 0.8 g (28.6% of theory) of the product indicated above as a colorless oil, and then 1.5 g (50.5% of theory) of the fluorination product described in Example 6, as a colorless oil (see Example 6).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CC(C)=O.C(OCC)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])[S:3][CH:4]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1)OCC(Cl)(Cl)Cl
Yield: 68.5 %

Procedure:
Into 300 ml of acetone, were added 2.2 g of 2-amino-4-p-nitrophenylthiazole and 3.0 g of sodium hydrogen carbonate. To the resulting mixture, 6.3 g of 2,2,2-trichloroethyl chloroformate in 20 ml of acetone was added dropwise, followed by a stirring for 10 hours at the reflux temperature. Inorganic substances were filtered off and the filtrate was concentrated. Any substances, which were insoluble in diethyl ether, were removed from the concentrate. A crude reaction product resulting from the remaining portion, which was soluble in diethyl ether, was subjected to silica gel column chromatography. It was then eluted with a mixed solvent of chloroform-acetone (10:1) and thereafter recrystallized from chloroform to obtain 2.7 g of 2,2,2-trichloroethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CS([Cl:42])(=O)=O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Cl:42])=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CO)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-methanol and 1.84 ml triethylamine were dissolved in 150 ml dichloromethane. To this ice cooled solution were added 0.82 ml methanesulfonylchloride. The cooling bath was removed and the reaction mixture was stirred at room temperature additional three hours. The reaction mixture was washed three times with 50 ml saturated NaHCO3 solution dried over MgSO4 and the solvent was removed in vacuo to provide 3.1 g 4-Butyl-5-(3-chloro-4-chloromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole as crude material. This material was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[CH:19](Br)([CH3:21])[CH3:20].O>CS(C)=O>[CH:19]([O:7][N:8]1[C:9](=[O:18])[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:13])([CH3:21])[CH3:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Solid potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) in dimethyl sulfoxide (37 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture, isopropyl bromide (3.41 mL, 37.5 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-isopropyloxy-isoindole-1,3-dione (4.44 g, 86.6%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:14][NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:14][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a solution of 4-(trifluoromethyl)benzoic acid (115 mg, 605 μmol, CAS RN 328-90-5) in CH2Cl2 (2 mL) were added N-methyl-4-o-tolylpyridin-3-amine (0.1 g, 504 μmol, example 1, intermediate a), 2-bromo-1-ethylpyridinium tetrafluoroborate (166 mg, 605 μmol, CAS RN 878-23-9) and DIPEA (130 mg, 176 μL, 1.01 mmol). The reaction mixture was stirred at room temperature for 66 h. The red solution was poured on 10% aqueous citric acid and dichloromethane and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with 10% aqueous citric acid solution and brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with EtOAc (isocratic). The compound-containing fractions were evaporated and the residue was dissolved in dichloromethane and the solution washed twice with 2M aqueous Na2CO3 solution, twice with 1M aqueous HCl and once with brine, dried over MgSO4, filtered and evaporated. Brown solid (16%). MS (ESI): m/z=371.14 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)=[N:4][C:3]=1[C:20]#[N:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(C)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)=[N:4][C:3]([C:20]#[N:21])=[C:2]2[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2c(-n3cnc(C)c3)nc(C#N)c(Cl)c2c1
Reactant: C1CCNC1
Solvent: CC(C)O
Product: COc1ccc2c(-n3cnc(C)c3)nc(C#N)c(N3CCCC3)c2c1
Temperature: 160 °C

Procedure:
4-chloro-6-methoxy-1-(4-methyl-1H-imidazol-1-yl)isoquinoline-3-carbonitrile (0.010 g, 0.033 mmol) and pyrrolidine (0.048 g, 0.067 mmol) were combined in isopropanol (1 mL) in a sealed tube and heated at 160° C. in a microwave reactor for 1.5 h. Cooled to rt and partitioned between aqueous saturated NaHCO3 and EtOAc. The organic layer was washed with brine (1×), dried over Na2SO4 and concentrated. Purified by r.p. HPLC. The titled compound was obtained as a tan solid (free base, 0.0065 g, 58%). 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J=9.0 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.36 (dd, J=9.3, 2.7 Hz, 1H), 7.18(s, 1 H), 4.00 (s, 3H), 3.71-3.69 (m, 4H), 2.19-2.14 (m, 4H). HRMS 334.1666 (M+H)+.