Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na+].[Br-].CC1(C)N([O])C(C)(C)CCC1.C([O-])([O-])=O.[Na+].[Na+].[O-]Cl.[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following the method of Leanna et al. (M. Robert Leanna, Thomas J. Sowin, Howard E. Morton, Tetrahedron Lett., 1992, 33(35), 5029-5032), carbobenzyloxy-L-prolinol (9.23 g, 39 mmole) in toluene (100 mL) at 0° C. was added NaBr (Aldrich, 4.01 g, 40 mmole) in water (45 mL) followed by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO reagent, Aldrich, 0.05 g, 0.32 mmole). To this vigorously-stirred mixture was added a mixture of Na2CO3 (11.16 g, 132 mmole) in water (50 mL) and aqueous NaOCl (0.7M, 65 mL, 46 mmole) dropwise over 30 minutes. After stirring 30 minutes at 0° C. the mixture was extracted with ethyl acetate (2×250 mL). The combined organics were washed With KI in 5% KHSO4 (1×50 mL), then aqueous Na2S2O3 (1×100 mL), then pH 7 phosphate buffer (1×100 mL), then brine (1×100 mL) and dried (Na2SO4). Filtration and evaporation of solvents left carbobenzyloxy-L-prolinal (5.55 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26].O>O1CCCC1>[C:11]([C:10]1[C:14]([CH3:15])=[C:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[C:25](=[O:26])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:13])[CH3:12]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(=O)C(=NNc1cccc(Cl)c1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(-c2cccs2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Pentan-2,3,4-trione 3-(3-chlorophenylhydrazone) (2.39 g) was added to a suspension of 66% sodium hydride (0.77 g) in anhydrous tetrahydrofuran (40 ml) under ice cooling, followed by stirring at room temperature for 30 minutes. Then, a solution of 2-thiopheneacetyl chloride (1.77 g) in anhydrous tetrahydrofuran (10 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), and the resulting crude crystals were washed with hexane to obtain 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-(2-thienyl)-3(2H)-pyridazinone (2.19 g) (Compound No. 1-97).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccccc1Cl
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Clc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-chlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 335.0 (M+). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.43 (d, J=3.9 Hz, 1H); 8.02 (br s, 1H); 7.85 (m, 1H); 7.37 (m, 2H); 6.85 (d, J=5.5 Hz, 1H); 5.93 (br s, 1H); 4.85 (d, J=6.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCOCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1
Reactant: COc1cccc([Mg]Br)c1
Solvent: O
Solvent: CCOCC
Product: COc1cccc(C2(O)CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of 3-methoxyphenylmagnesium bromide (1M in THF, 61 ml, 61 mmol, 1 equiv) at 0° C. was slowly added cyclohexanone (6 g, 61 mmol, 1 equiv) in Et2O (30 ml). The resulting mixture was stirred at room temperature for 4 h then poured in H2O at 0° C. The two layers were separated and the aqueous phase was extracted three times with Et2O. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-[3-(methyloxy)phenyl]cyclohexanol (D314) (12.4 g, 100%) as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[CH2:14][CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH:10]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][C:7]=1[Cl:8].C1CCN2C(=NCCC2)CC1.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(OS(C)(=O)=O)CCCC1(C)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: COC(=O)C1=CCCCC1(C)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 101.4 %

Procedure:
A solution of methyl 2-(3,4-dichlorophenyl)-2-methyl-6-(methylsulfonyloxy)cyclohexanecarboxylate (185 mg) in benzene (5 mL) was stirred at rt and treated with DBU (131 μL). The mixture was heated to 60° C. and stirred for 36 h. The cooled mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to provide methyl 6-(3,4-dichlorophenyl)-6-methylcyclohex-1-enecarboxylate (142 mg). Mass spectrum m/z 321.12 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C([O-])(O)=O.[Na+].[Li+].[Cl-]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:18]1[CH:17]=[CH:16][C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]=1[F:12]
Reactant: Oc1cc2cn[nH]c2cc1Br
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
A mixture of 6-bromo-5-hydroxy-1H-indazole (7.0 g, 33.0 mmol), 3,4-difluoronitrobenzene (4.98 mg, 31.0 mmol), NaHCO3 (2.5 g, 31.0 mmol) in DMF (100 mL) is stirred at 80° C. for 4 hours. Then LiCl (10% aqueous solution) is added and the solution is extracted with EtOAc. The organic phase is dried over anhydrous MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with PE:DCM (1:1) to give the desired product (5.5 g, 46.6% yield). MS (m/z): 354.0 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[C:5]([F:13])=[C:4]([CH2:14][NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1.Br[C:24]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:14][C:4]2[CH:3]=[C:2]([F:1])[C:7]3[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=3[C:5]=2[F:13])[CH:24]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CSc1nc2c(F)cc(CNc3ncccc3N)c(F)c2s1
Product: CSc1nc2c(F)cc(Cn3cnc4cccnc43)c(F)c2s1

Procedure:
6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluoro-2-(methylthio)benzo[d]thiazole was synthesized as a orange solid (220 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N2-((4,7-difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 349 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:9]([CH3:11])[CH3:10])([CH2:7]O)[CH2:5][OH:6].[CH3:12][O:13][CH2:14][CH:15]=[O:16].C1CCCCC1>O>[CH3:12][O:13][CH2:14][CH:15]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH:9]([CH3:11])[CH3:10])[CH2:7][O:16]1
Reactant: COCC(CO)(CO)C(C)C
Reactant: COCC=O
Solvent: O
Solvent: C1CCCCC1
Product: COCC1OCC(COC)(C(C)C)CO1
Yield: 83 %

Procedure:
A mixture of 486 g (3 moles) of 2-methoxymethyl-2-isopropyl-1,3-propanediol, 287 g (3.3 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb AC 10 under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 543 g (83% yield) of 2,5-dimethoxymethyl-5-isopropyl-1,3-dioxane of boiling point 95° C./1 mbar obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:16]([OH:18])=O)=[O:13])[CH:9]=[CH:8][C:7]=2[C:23]([F:26])([F:25])[F:24])[CH2:3][CH2:2]1.Cl.[CH3:28][NH2:29]>>[CH2:21]([C:15]([NH:14][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:23]([F:24])([F:26])[F:25])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])([C:16](=[O:18])[NH:29][CH3:28])[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)O
Reactant: CN
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoic acid and methanamine hydrochloride as starting materials. MS (EI): m/e=388.0 [M+H]+.
Reaction SMILES: CC1C=CC([O:8][S:9]([C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([NH:32][C:33]([NH:35][C:36]5[CH:45]=[C:44]6[C:39]([CH:40]=[CH:41][C:42]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:43]6)=[CH:38][CH:37]=5)=[O:34])=[CH:29]4)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=CC=1.[OH-].[Na+:51].Cl>>[Na+:51].[Na+:51].[S:9]([C:12]1[CH:13]=[C:14]([NH:18][S:19]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][C:28]([NH:32][C:33]([NH:35][C:36]4[CH:45]=[C:44]5[C:39]([CH:40]=[CH:41][C:42]([S:46]([O-:49])(=[O:47])=[O:48])=[CH:43]5)=[CH:38][CH:37]=4)=[O:34])=[CH:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:15]=[CH:16][CH:17]=1)([OH:11])(=[O:10])=[O:8].[S:9]([C:12]1[CH:13]=[C:14]([NH:18][S:19]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][C:28]([NH:32][C:33]([NH:35][C:36]4[CH:45]=[C:44]5[C:39]([CH:40]=[CH:41][C:42]([S:46]([O-:49])(=[O:47])=[O:48])=[CH:43]5)=[CH:38][CH:37]=4)=[O:34])=[CH:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:15]=[CH:16][CH:17]=1)([OH:11])(=[O:10])=[O:8]
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(NS(=O)(=O)c3ccc4ccc(NC(=O)Nc5ccc6ccc(S(=O)(=O)O)cc6c5)cc4c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1)Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 8 mg (0.011 mmol) of compound 8 was added 2 mL of 5 N NaOH. The reaction was allowed to stir at ambient temperature for 6 hours. The reaction was acidified with 6 N HCl and the solution was added to a small reverse-phase (C18) solid phase extraction column. The column was washed with H2O followed by 50:50 (v:v) CH3CN:H2O to elute the product. This provided 5 mg of compound 12.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5]Cl.[Mg].C(Br)CBr.[CH2:13]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][C:21]1([OH:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: CN(C)CCCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2CCc2ccccc21
Yield: 72.6 %

Procedure:
3-(Dimethylamino)propyl chloride (110 g) is dissolved in 600 ml of tetrahydrofuran. About 10% of this solution is added to the reaction flask containing 26.4 g of magnesium and 50 ml of tetrahydrofuran. The mixture is heated to reflux and reaction is initiated with ethylene dibromide. The remaining halide is added slowly (over about 30 minutes) to control the rate of reflux. The mixture is then heated under reflux for an additional 30 minutes. After cooling in an ice bath, 100 g of dibenzosuberone in 200 ml of tetrahydrofuran is added slowly (over about 30 minutes). The mixture is heated under reflux for 1.5 hours. After cooling in an ice bath, the mixture is decomposed by dropwise addition of saturated ammonium chloride solution (1 liter added in 2 hours). The mixture is stirred for an additional hour, the layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The residue is dissolved in ether and extracted with 10% hydrochloric acid. The aqueous layer is basified with sodium hydroxide and extracted twice with ether. The ether extracts are dried, filtered, and the solvent is removed in vacuo leaving 103 g of a solid.
Reaction SMILES: SCCCS[C:6](=[O:28])[CH2:7][C:8]1([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][C:8]1([CH2:7][CH2:6][OH:28])[C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=2[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2
Reactant: CN(C)CCC1(CC(=O)SCCCS)c2ccccc2CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCC1(CCO)c2ccccc2CCc2ccccc21
Temperature: 0 °C

Procedure:
To a solution of [5-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]-thioacetic acid-S-(3 mercapto-propyl)ester (104), 3.1 g, 7.5 mmol) in 50 mL of THF, maintained under an argon atmosphere, was added lithium aluminum hydride (37.5 mL of a 1M solution in THF; 37.5 mmol) dropwise. The clear solution was refluxed for 5 hours and then cooled to 0° C. The mixture was diluted with ethyl acetate and quenched with 10% sodium hydroxide. The resulting slurry was filtered over celite and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried the over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by chromatography on silica gel (95:5:0.5 of methylene chloride:methanol:ammonium hydroxide). The product fractions were evaporated to dryness to yield the title product. as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:6]=1Br.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:6]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:13]#[N:14])[CH:20]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(Br)c(Br)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: CCOC(=O)c1cc(Br)c(-c2cccc(C#N)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 3.00 g (10.1 mmol) of the compound from Example 2A are provided in 96 ml of 1,2-dimethoxyethane, and 1.63 g (11.1 mmol) of 3-cyanophenylboronic acid, 9.84 g (30.2 mmol) of cesium carbonate, 0.14 g (0.30 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane and 0.16 g (0.71 mmol) of palladium(II) acetate are added. The mixture is stirred at RT overnight. 0.44 g (3.02 mmol) of 3-cyanophenylboronic acid are subsequently added, and the mixture is stirred at RT for a further 24 h. The mixture is concentrated and the crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 20:1). 1.15 g (36% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](F)[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2].CS(C1C=CC(C2SC(N)=NC=2C)=CC=1[C:47]([F:50])([F:49])[F:48])(=O)=O>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([C:47]([F:50])([F:49])[F:48])[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[C:27]([NH2:30])(=[O:29])[CH3:28]>>[C:27]([NH:30][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1)(=[O:29])[CH3:28]
Reactant: CC(N)=O
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CC(=O)Nc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and acetamide were reacted to give 121bp. 1H NMR (400 MHz, CDCl3) δ 6.84-7.31 (m, 6 H), 6.76 (s, 1 H), 5.05 (s, 2 H), 3.40 (s, 3 H), 2.16 (s, 3 H). LCMS (ESI) m/z: 414.9
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 69.1 %

Procedure:
tert-Butyl 3-(2-cyano-4-pyridyl)propionate (0.51 g, 2.2 mmol) and methyl thiosalicylate (0.55 g, 3.3 mmol) were dissolved in toluene (2 ml), and triethylamine (0.47 ml, 3.4 mmol) was added thereto. The mixture was refluxed for 8 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.56 g, 69%) as white crystals.
Reaction SMILES: [N+](C(=[C:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@:19]([OH:24])([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C:14]4(OCC[O:25]4)[CH2:15][CH2:16]2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)C)#[C-].Cl.O.[CH2:31]([O:33]CC)[CH3:32]>O1CCCC1.[OH-].[Na+]>[OH:24][C@:19]12[CH2:9][CH2:8][C@@:22]3([CH3:23])[C@@H:21]([CH2:7][CH2:6][C@@H:5]3[C:31](=[O:33])[CH3:32])[C@@H:20]1[CH2:10][CH2:11][C:12]1[C@:17]2([CH3:18])[CH2:16][CH2:15][C:14](=[O:25])[CH:13]=1
Reactant: CCOCC
Reactant: [C-]#[N+]C(C)=C1CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C

Procedure:
A solution of 20-isocyano-3,3-ethylenedioxypregna-5,17(20)-dien-9α-ol (2.30 g) in a mixture of tetrahydrofuran (60 ml) and aqueous 2N hydrochloric acid (20 ml) was refluxed for 1 hour. The reaction mixture was cooled to room temperature after which water (25 ml) and diethyl ether (100 ml) were added. The mixture was neutralised with IN sodium hydroxide solution. After separating the layers the aqueous phase was extracted twice with diethyl ether (50 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford 2.02 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[ClH:1].[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][N:11]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 100 °C
Yield: 57.4 %

Procedure:
Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 6-(trifluoromethyl)pyridin-3-yl boronic acid (5.01 g, 26.23 mmol), potassium carbonate (1.450 g, 10.49 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield an orange solid. The solid was diluted with MTBE, then HCl (4 M in dioxane) was added to give a suspension. The solids were collected by filtration to yield methyl 6′-(trifluoromethyl)-2,3′-bipyridine-4-carboxylate hydrochloride (3.2 g, 57%). MS m/z 283 (M+H)+
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:11]=[C:10]([C:9]2[O:19][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: COc1cc(C(=O)Nc2ccccc2O)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1C

Procedure:
A mixture of N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide (1.5 g, 5.8 mmol), toluene (30 mL), p-toluenesulfonic acid monohydrate (7.6 g, 40 mmol) and molecular sieves was refluxed overnight. After cooling reaction to rt, filtered washing with warm chloroform and concentrated filtrate in vacuo. The resulting brown oil was purified by flash chromatography on silica gel using 1:4 EtOAc:hexanes to give the desired intermediate, 2-(3-methoxy-4-methylphenyl)-1,3-benzoxazole, as a colorless solid.