Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24]C)=[O:15])=[C:12]([CH3:26])[C:11]2[C:6](=[CH:7][C:8]([C:27]([F:30])([F:29])[F:28])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].B(Br)(Br)Br.CCCCCC>C(Cl)Cl.O>[CH2:1]([S:3][C:4]1[C:13]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[O:15])=[C:12]([CH3:26])[C:11]2[C:6](=[CH:7][C:8]([C:27]([F:30])([F:28])[F:29])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1ccccc1OC
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
A solution of 350 mg (0.8 mmol) 2-ethylsulfanyl-N-[(2-methoxyphenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxamide (example 84) in DCM (10 ml) was cooled to 0° C. 500 μl (4.9 mmol) boron tribromide were added dropwise at this temperature. The mixture was then stirred for 90 min at room temperature. Then it was diluted with water and extracted with DCM. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) of the residue yielded 240 mg (0.57 mmol, 70%) 2-ethylsulfanyl-N-[(2-hydroxyphenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 421.1 [M+H]+.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:8][C:9]=2[CH:14]=1
Reactant: Cc1ccc(O)c(N=Cc2ccccc2)c1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 2-benzylideneamino-4-methylphenol 54 (1.34 g, 6.3 mmol) and manganese (III) acetate dihydrate (3.4 g, 12.7 mmol) in toluene (65 ml) was heated at reflux under an atmosphere of N2 for 1 hr and cooled to room temperature. The mixture was filtered to remove the insoluble manganese salts. The filtrate was evaporated under reduced pressure. The residue was taken up in methylene chloride and purified by filtration to yield 1.23 g 5-methyl-2-phenylbenzoxazole 55.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: OCCc1cccc(CCO)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)OCCc1cccc(CCO)c1
Yield: 41.6 %

Procedure:
2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol (2.49 g, 15.0 mmol) was dissolved in ACN (5 ml) and acetic anhydride (3.06 g, 30 mmol) added. The mixture was stirred under reflux for 1 h and then evaporated to dryness. Silica gel chromatography (HEP/EA gradient) of the residue yielded 1.30 g of the title compound (mono-acetylated product).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)CC>[Cu].C1(C)C=CC=CC=1>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[CH:2][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cccc1Cl
Agent: [Cu]
Solvent: CCC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1F
Temperature: 135 °C
Yield: 84.7 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with methyl 2-chloro-6-fluorobenzoate (5.11 g, 27.1 mmol) and copper powder (3.44 g, 54.2 mmol). Propionic acid (15 mL) was added, and the resulting mixture was heated to 135° C. Additional copper (0.34 g) was added after 7 hours in order to complete the dehalogenation. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (10.5 hours). Toluene (30 mL) was added as the reaction was cooled to room temperature. The resulting mixture was filtered, and the solids were washed with toluene. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting yellow organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum to give 3.54 g of methyl 2-fluorobenzoate as a pale yellow oil. Some of the product appeared to be lost during vacuum drying due to vaporization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][N:24]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:23]=2)[C:17]=1[F:39])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10].[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:36]1[CH2:35][CH2:34][CH:33]([N:24]2[CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:22]([C:18]3[C:17]([F:39])=[C:16]([N:12]([CH2:13][O:14][CH3:15])[S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:21]=[CH:20][CH:19]=3)=[N:23]2)[CH2:38][CH2:37]1)(=[O:42])[CH3:41]
Reactant: COCN(c1cccc(-c2nn(C3CCNCC3)cc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COCN(c1cccc(-c2nn(C3CCN(C(C)=O)CC3)cc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of 2,5-difluoro-N-[2-fluoro-3-(1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-N-methoxymethyl-benzenesulfonamide (135 mg, 0.242 mmol) (prepared as described in Example 2) in DCM (2 mL) triethylamine (0.040 mL, 0.290 mmol, 1.2 eq) was added, followed by acetylchloride (0.019 mL, 0.266 mmol, 1.1 eq) and the solution was stirred at r.t. for 2 h. The reaction mixture was then diluted with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH 97:3) affording 81 mg (56%) of N-{3-[1-(1-Acetyl-piperidin-4-yl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzene-sulfonamide. This intermediate was then treated with a 9:1 TFA/water mixture (1 mL) and stirred at 60° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, then taken up with AcOEt and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 95:5) affording 9 mg of the title compound. HPLC (254 nm): Rt: 5.22 min; 1H NMR (DMSO-d6) Shift: 10.66 (br. s., 1H), 8.48 (s, 1H), 8.38-8.43 (m, 2H), 7.51-7.60 (m, 1H), 7.40-7.49 (m, 2H), 7.29-7.38 (m, 2H), 7.21-7.27 (m, 1H), 7.11 (d, J=6.0 Hz, 2H), 4.44-4.55 (m, 2H), 3.90-3.96 (m, 1H), 3.17-3.28 (m, 1H), 2.69-2.78 (m, 1H), 2.07-2.18 (m, 2H), 2.04 (s, 3H), 1.91-1.99 (m, 1H), 1.74-1.84 (m, 1H); HRMS (ESI) calcd for C27H25F3N5O3S [M+H]+ 556.1625. found 556.1620.
Reaction SMILES: C[O-].[Na+].C([O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)(=O)C>CO>[OH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1
Reactant: CCCCCCCC(=O)c1ccc(CCOC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC(=O)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution (18.8 ml) of 28% sodium methylate in methanol was added to a solution of the material (280 g) which contains 2-(4-octanoyl phenyl)ethyl acetate obtained in the step A as a major component in methanol (200 ml), and the solution was stirred at room temperature for 1 hour. Suspension of Amberlite IR-120B in methanol (98 ml) was added to the solution, and the mixture was filtered. The filtrate was concentrated, and the residue was recrystallized from hexane-ethyl acetate (10:1) to obtain 4′-(2-hydroxy ethyl)octanophenone (138 g) in the form of colorless crystal.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH2:9][NH:8][CH:7]([C:14]([OH:16])=[O:15])[CH2:6]2.[CH3:17]O>>[ClH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH2:9][NH:8][CH:7]([C:14]([O:16][CH3:17])=[O:15])[CH2:6]2
Reactant: CO
Reactant: O=C(O)C1Cc2cc(O)c(O)cc2CN1
Agent: Cl
Product: COC(=O)C1Cc2cc(O)c(O)cc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 40° C., a steam of gaseous hydrogen chloride was bubbled through a solution of 1,2,3,4-tetrahydro-6,7-dihydroxy-3-isoquinolinecarboxylic acid (32.4 g, 155.0 mmol) in 1.5 l of methanol for 2 hours. After stirring overnight at room temperature, the solvent was distilled off in vacuo and the residue triturated with ether to furnish 38.95 g of the product. Melting point 204.8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>C(#N)C>[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[C:16]([NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])=[O:17]
Reactant: O=C=NC(=O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(C(=O)O)cc1N
Solvent: CC#N
Product: COc1ccc(C(=O)O)cc1NC(=O)NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
20 g (120 mmol) of 3-amino-4-methoxybenzoic acid were made to react with 36 g (168 mmol) of 2,4-dichlorobenzoyl isocyanate from step a in 400 ml of acetonitrile and left to react therewith at reflux for 2 hours. After the mixture has cooled down to room temperature, the precipitate is filtered off with suction, washed twice with in each case 20 ml of acetonitrile, sucked dry and dried under high vacuum. 44 g (96%) of the desired product are obtained.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]([CH2:21][S:22][CH3:23])([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O>[CH2:3]([C:10]([CH2:21][S:22][CH3:23])([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CSC)(Cc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCC(Cc1ccccc1)(C(=O)O)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
Powdered potassium hydroxide (4.8 g, 86 mmol, 5.0 equiv) was added to a stirred solution of diethyl 2-benzyl-2-(methylthiomethyl)malonate (5.3 g, 17 mmol, 1.0 equiv) in 3:1 methanol:water (28 mL) at 23° C. The resulting pale yellow suspension was heated to 100° C. and stirred for 4 h. The cooled reaction mixture was acidified to pH≈9 with concentrated hydrochloric acid and washed with diethyl ether (4×50 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with dichloromethane (4×60 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (3.1 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 7.13-7.34 (m, 5H), 3.15 (s, 2H), 2.73 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:15]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(F)c2C#N)CC1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2C#N)CC1
Temperature: 100 °C

Procedure:
To 655 mg (2.03 mmol) of 4-(2-cyano-3,6-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 10 mL DMF was added 560 mg (2 eq., 4.06 mmol) potassium carbonate and 243 μL (1.1 eq., 2.22 mmol) benzylamine. The mixture was heated to 100° C. for 5 days, cooled to room temperature and partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. 4-(3-Benzylamino-2-cyano-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (288 mg) was precipitated from dichloromethane/hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=3)=[O:10])=[CH:12]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 4ww was prepared following the procedure described in Step 3 of Example using 45 mg (0.16 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one 3d, 8 mg (0.21 mmol) of 60% sodium hydride and 53 mg (0.21 mmol) of 2-bromo-6-bromomethyl-pyridine in 0.7 mL N,N-dimethylformamide and stirring the reaction mixture at rt for 2 h. The product was purified using reverse phase HPLC (mobile phase with a gradient 10-50% acetonitrile in 50 min). The HPLC fractions containing pure product were combined, evaporated under vacuum and neutralized using methanolic ammonia and purified by flash chromatography (using 30-100% ethyl acetate in hexane) to give 18 mg of a pale yellow solid: LC-MSD, m/z for C23H18BrN3O2 [M+H]+: 448.4, 450.4; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.1 min; 1H NMR (400 MHz, CDCl3): δ 2.35 (s, 3H), 2.5 (s, 3H), 5.5 (s, 2H), 7.0-7.1 (m, 1H), 7.3-7.35 (m, 1H), 7.35-7.4 (m, 1H), 7.4-7.6 (m, 4H), 7.6-7.7 (m, 1H), 8.4-8.45 (m, 1H), 8.5 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:20][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccnc(Cl)c1C(=O)O
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
4-Amino-2-chloro-nicotinic acid (1 g, 5.795 mmol) was dissolved in DMF (30 mL) and dichloromethane (50 mL). Phenethylamine (0.87 mL, 6.954 mmol, 1.2 equiv.) was added followed by TEA (1.21 mL, 8.693 mmol, 1.5 equiv.) and HBTU (2.64 g, 6.954 mmol, 1.2 equiv.) and the reaction stirred at 20° C. for 12 hours. The reaction mixture was then diluted with dichloromethane and the aqueous layer was extracted with 20% isopropyl alcohol/dichloromethane. The combined organic portions were washed with 0.5N NaOH solution, NH4Cl solution, water, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography using 2:1 ethyl acetate:hexane to provide 1.23 g (77%) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[OH:12].[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15]>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:12][C:14](=[O:15])[NH:11][C:6]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:13]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)c1cc(Cl)cc(N)c1O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2[nH]c(=O)oc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
3-Amino-5-chloro-2-hydroxy-benzoic acid methyl ester 8 g (39.6 mmol) is dissolved in tetrahydrofuran 100 mL and carbonyl diimidazole (12.9 g, 79.3 mmol) is added. The reaction is heated to reflux for 2 hours and then cooled to room temperature. The reaction is evaporated in vacuo and then taken up in dichloromethane (200 mL) and then washed with HCl (2N, 50 mL 2×) and water (2×50 mL). The organic layer is dried (Na2SO4) filtered and evaporated in vacuo to give the title compound (8.2 g, 36 mmol, 91%). LCMS (ESMS): m/z 228.9 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.O[N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[O:31]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[N:21]1[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CON3C(=O)c4ccccc4C3=O)cc2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
N-(4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (250 mg), 2-hydroxy-1H-isoindole-1,3(2H)-dione (155 mg), triphenylphosphine (249 mg) and tetrahydrofuran (5 ml) were combined under nitrogen atmosphere, and then diethyl azodicarboxylate (0.15 ml) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 6 hours, poured into saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (20:1) as an eluent, and triturated with ethyl acetate to give N-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (218.2 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39]>>[CH3:41][O:40][C:38]([C:37]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:12])([F:13])[F:11])=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=2)=[CH:33][C:32]=1[F:31])=[O:39]
Reactant: CC(c1ccc(Br)cc1C(F)(F)F)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(C(F)(F)F)c2)cc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-trifluoromethyl-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 193, step 3) by Suzuki coupling with 3-fluoro-4-methoxycarbonyl-benzeneboronic acid [CAS Reg. No. 505083-04-5]. MS (m/e)=572.1 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([O-:20])(=[O:19])=[O:18].[Na+:21]>[Cl-].[Na+]>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[S:17]([O-:20])(=[O:19])=[O:18])[CH2:2][CH2:3]1.[Na+:21]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)[O-])c1
Temperature: 110 °C
Yield: 90 %

Procedure:
To 80 ml of morpholine, 82.5 g (0.3 mol) of sodium 2-chloro-5-nitrobenzenesulfonate was added with stirring. The reaction mixture was heated at about 110° C. on an oil bath with stirring for 30 minutes. After cooling, 100 ml of a saturated aqueous sodium chloride solution was added to the mixture. The crystals thus-precipitated were collected by filtration and washed with acetone to obtain 88 g (yield: 90%) of sodium 2-morpholino-5-nitrobenzenesulfonate. Melting Point: 208°-210° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.[Li]CCCC.[Cl:31][C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[CH:36]1[NH:37][C:32]([Cl:31])=[N:33][CH:34]=[CH:35]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(C(F)(F)F)cc2)nc(Br)c1Br
Reactant: Clc1ncccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(C(F)(F)F)cc2)nc(Br)c1C1C=CN=C(Cl)N1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
A solution of 4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.0 g, 2.0 mmol) in dry THF (10 mL) was cooled to −78° C. under Argon. n-BuLi (1.0 mL, 2.5 M in hexane, 2.5 mmol) was added dropwise, afterwards the reaction was maintained below −70° C. for an additional 45 minutes. A solution of 2-chloropyrimidine (0.29 g, 2.5 mmol) in dry THF (2 mL) was added dropwise at −78° C. After addition, the reaction was allowed to warm to −40° C. over 25 minutes and maintained at −40° C. for 20 minutes. The reaction was then warmed to −5° C. in a brine-ice bath, quenched with water (30 mL), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic phase was separated, dried (Na2SO4), and concentrated. The resulting residue was further purified by flash chromatography (SiO2, 0-20% EtOAc in hexanes) to afford 1.1 g (2.05 mmol, 82%) of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine. A solution of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine (410 mg, 0.8 mmol) in EtOAc (20 mL) was treated with MnO2 (920 mg, 10.6 mmol) and the resulting reaction mixture was heated to and maintained at reflux for 18 hours. The reaction was allowed to cool to room temperature and was then filtered through Celite. The filter cake was washed with EtOAc (2×20 mL) and the combined filtrates were concentrated to give 400 mg (0.75 mmol, 98%) of 4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=5.4 Hz, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 5.77 (s, 2H), 3.49 (t, J=7.5 Hz, 2H), 0.83 (t, J=7.5 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH:31](=O)[CH2:32][OH:33]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][N:22]([CH2:31][CH2:32][OH:33])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CNCC3)cc1
Reactant: O=CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CN(CCO)CC3)cc1
Yield: 11.3 %

Procedure:
2-(2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (20.00 mg, 11.3%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 61a) and glycol aldehyde according to the general procedure for reductive amination.