Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (290 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (240 mg, 46%).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[CH:10][CH:9]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:12]1([C:11]2[CH:23]=[CH:24][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])=[CH:9][CH:10]=2)[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: C[Si](C)(C)CCOCOc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1ccc(C2(Cl)OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Distilled THF (10 mL) was added to 2-[4-(2-trimethylsilanylethoxymethoxy)-benzoyl]benzoic acid (1.86 g, 5 mmol) followed by thionyl chloride (0.43 mL, 6 mmol) and 3 drops of DMF. The system was stirred at room temperature under nitrogen for 2 h and monitored by TLC. The solvent was removed to give 3-chloro-3-[4-(2-trimethylsilanylethoxymethoxy)phenyl]-3H-isobenzofuran-1-one as a clear oil.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17]Br)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]3[CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(OC(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(OC(=O)c4ccccc4)cc3)cn2c1
Yield: 70.7 %

Procedure:
13.33 g (corresponding to 43.68 mmol) of 4′-benzoyloxy-2-bromoacetophenone and 5.67 g (corresponding to 45.67 mmol) of 2-amino-5-methoxypyridine were dissolved in 481 mL of ethanol. The resulting solution was refluxed for 2 hours. After the reaction solution was cooled, 6.64 g (corresponding to 79.09 mmol) of sodium hydrogencarbonate was added thereto. The resulting reaction mixture was further refluxed for 4 hours. After the completion of the reaction, the solvent was concentrated under reduced pressure. The resulting residue was dissolved in chloroform and then washed with water. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform/ethyl acetate=20/1), to obtain 10.20 g (corresponding to 30.87 mmol) of 2-(4′-benzoyloxyphenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 5, Step 5).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:35](O)([CH3:37])[CH3:36]>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([O:6][CH:35]([CH3:37])[CH3:36])=[O:5]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)OC(C)C)c1

Procedure:
A solution of the title product of Example 4 (6.2 mmole) and sulfuric acid (0.5 ml) in 120 ml of isopropyl alcohol (100 ml) was heated at 45° C. for 12 days, refluxed for 36 hours, and concentrated on a rotary evaporator to an oil. The oil was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound, m.p. 72°-73° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:15]=[C:14]2[C:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=1.C(O)CC.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][N:32]1[CH2:33][CH:34]=[C:29]([C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH:12]=3)[N:16]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:15]=2)[CH2:30][CH2:31]1
Reactant: OB(O)c1cccnc1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(-c4ccncc4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Into a 100 mL 3-necked round bottom flask was placed pyridin-3-ylboronic acid (200 mg, 1.63 mmol), 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole (470 mg, 1.08 mmol), and n-propanol (140 mL). The mixture was stirred at room temperature for 30 min during which time the solids dissolved. A solution of Na2CO3 (430 mg, 4.06 mmol) in water (5 mL) was then added, followed by the addition of Pd(PPh3)4 (130 mg, 0.108 mmol). The resulting solution was stirred at reflux temperature overnight, and then concentrated. The residue was dissolved in water (10 mL), and the resulting solution was extracted diethylether (2×50 mL). The organic layers were combined and the residue was purified by column chromatography using a 1:5 dichloromethane/methanol solvent system to afford 200 mg (42.5%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-(pyridin-4-yl)-1H-indole as a deep yellow solid. 1H NMR (CDCl3) δ 8.69 (d, 2H), 8.12 (d, 1H), 7.93 (t, 3H), 7.60 (d, 3H), 7.48 (d×d, 4H), 6.18 (s, 1H), 2.85 (2H), 1.52 (2H), 1.25 (3H), 0.87 (2H). LC/MS (EI) tR 2.18, m/z 430.0 (M++1)
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]([NH2:12])[CH:6]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[N:14]([C:6]1[C:7]([NH2:12])=[N:8][C:9]([NH2:11])=[N:10][C:5]=1[O:4][CH2:3][CH:2]([CH3:13])[CH3:1])=[O:15]
Reactant: O=N[O-]
Reactant: CC(C)COc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)COc1nc(N)nc(N)c1N=O
Temperature: 32 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a stirred solution of 18.2 g (0.100 mol) 6-(2-methylpropoxy)-2,4-diaminopyrimidine in 100 ml acetic acid (10% conc. in water) at 6° C. was added dropwise over 1 h a solution of 9.11 g (0.132 mol) sodium nitrite in 40 ml water, whereupon the temperature was allowed to increase to 32° C. Stirring was then continued for a further 2 h at room temperature. The resulting precipitate was filtered off with suction, washed with water and dried. 5-Nitroso-2,4-diamino-6-(2-methylpropoxy)-pyrimidine (18.3 g, 81%) was obtained as a violet solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11]C(OC(C)(C)C)=O)[CH2:7][CH:6]1[CH2:8][CH2:9][CH3:10])=[O:4].[ClH:19].O1CCOCC1>C1COCC1>[ClH:19].[CH3:1][O:2][C:3]([C:5]1([NH2:11])[CH2:7][CH:6]1[CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC1CC1(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCCC1CC1(N)C(=O)OC
Reaction time: 2 h

Procedure:
A solution of 1-tert-butoxycarbonylamino-2-propyl-cyclopropanecarboxylic acid methyl ester (0.27 mmol) in THF (0.5 mL) was treated with 4M HCl in dioxane (2.4 mmol HCl). After 2 h, the volatiles are removed in vacuo to afford 1-amino-2-propyl-cyclopropanecarboxylic acid methyl ester hydrochloride salt as an amorphous white solid that was used without further purification (0.053 g, quant). LCMS found 157.9 ([M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1
Reactant: OCc1ccc(C2CC2)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.61-0.65 (2H, m), 0.89-0.94 (2H, m), 1.91-1.84 (1H, m), 5.12 (2H, s), 5.67 (1H, d, J=1.6 Hz), 7.01-7.24 (4H, m), 7.32-7.33 (1H, m), 7.50 (1H, d, J=1.2 Hz), 7.95 (1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H16N4O, 317; Found, 317.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:23])[O:21][CH3:22].O>CN(C)C(=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:23])[O:21][CH3:22])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)Nc1ccc(Cl)cc1C#N
Temperature: 90 °C
Reaction time: 5 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (1.95 g) and dimethylaminopyridine (20.3 mg) in N,N-dimethylacetamide (15 ml) was added dropwise methyl chlorocarbonate (3.5 ml) at room temperature, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:20-1:4) to give methyl (4-chloro-2-cyanophenyl)carbamate (1.21 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:19]([F:31])=[CH:18][N:17]=1>>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([F:31])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[N:21]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine gave N4-(3,4-dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.70 (bs, 1H), 9.50 (bs, 1H), 8.20 (d, 1H, J=4.5 Hz), 8.09 (m, 1H), 7.80 (m, 3H), 7.62 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H), 3.88 (s, 3H); LCMS: purity: 94%; MS (m/e): 448 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dibromopyridine (1.0 eq, 5.0 g, 20.9 mmol) in TEA (100 ml) under an inert atmosphere of nitrogen is added copper(I) iodide (0.1 eq, 406 mg, 2.09 mmol) and PdCl2(PPh3)2 (0.1 eq, 1.5 g, 2.09 mmol). Trimethylsilylacetylene (1.2 eq, 3.6 ml, 25 mmol) is added and the resulting mixture is stirred at room temperature for 2 h. The solvent is removed in vacuo and the residue is partitioned between water and DCM. The organic portion is separated and washed with sat. aqueous NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (hexane/DCM) yields the title compound; [M+H]+=254/256.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][C:13]([OH:15])=[O:14])[N:8]=1)=[O:5])[CH3:2].[CH3:16]O>>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:9]1[N:8]=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:11][N:10]=1
Reactant: CCOC(=O)Nc1nc(CC(=O)O)ns1
Reactant: CO
Product: CCOC(=O)Nc1nc(CC(=O)OC)ns1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into a 3 L round bottom flask equipped with mechanical stirrer, thermometer and nitrogen purge was charged 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid (185 g, 0.80 mol, 1.0 eq.) followed by methanol (925 mL) and the resulting solution was cooled to 0° C. To the solution was bubbled in HCl gas for 30 minutes and the thinning slurry was allowed to stir overnight at 20° C. Proton NMR analysis shows complete conversion to the title compound. The solvent was removed by rotary evaporation to 400 mL and then cooled to 0° C. and seeded with pure title compound. The thickening reaction mixture was stirred at 0° C. for two hours and the white solid was collected by vacuum filtration. The solid was dried under high vacuum for 12 hours at 20° C. to give 172.2 grams of the title compound as an off white solid. 1H NMR (CD3OD): δ 1.47 (t, 3H); 3.83 (s, 3H); 3.97 (s, 2H); 4.45 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O)(=O)[CH3:12].C1(C)C(C)=CC=CC=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11]([CH3:12])=[C:14]3[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)C1CCCCC1=O
Reactant: NNc1ccc(Cl)cc1F
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Cc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2

Procedure:
A solution of 19.7 parts of 4-chloro-2-fluorophenylhydrazine and 14.0 parts of 2-acetylcyclohexanone in 50 parts of xylene and 1 part of glacial acetic acid were refluxed for 24 hours with a Dean Stark trap to collect the water formed. The xylene was distilled from the mixture. The residual oil was dissolved in arm hexane solution. On cooling, 6.2 parts of crude product was obtained. Recrystallization of this product yielded white crystals of 2-(4-chloro-2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole, melting point 84.5°-87.5° C; ir bands (1570 cm-1, 905 cm-1, 822 cm-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28].Cl>C(Cl)Cl>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[C:27](=[O:29])[CH3:28])=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2cc(Nc3ccc(O)cc3)ccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2cc(N(C(C)=O)c3ccc(O)cc3)ccc2c1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of 190 mg (0.72 mmol) of 4-[(6-methoxy-2-naphthyl)amino]phenol (prepared as described in Example 2) and 0.50 ml of pyridine (dried over KOH) in 4 ml of dry CH2Cl2 at 0° was added dropwise over 5 minutes 55 ul (0.77 mmol) of acetyl chloride. The reaction mixture was stirred for 30 minutes then added to 25 ml of 1N aqueous HCl solution and extracted with 25 ml of warm ethyl acetate. The organic extract was washed with an additional 25 ml of 1M aqueous HCl solution, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (silica gel, 10×3.0 cm, 1:1 EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 145 mg (66%) of title compound as white crystals, m.p. 187°-188°.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOCC>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: COc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1S(=O)(=O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of methoxybenzene while stirring. Then, while the stirring was continued, the temperature was raised at 45 to 55° C., reacting for 12 hours. After the reaction, 500 g of distillation water was added. Then, 200 g of ether was added. The lower phase (water phase) of the two separated phases was taken, into which a step of distillation for condensation and addition of water was repeated twice, so as to obtain methoxybenzenesulfonic acid. As a result of analysis, the methoxybenzenesulfonic acid included the para compound thereof at a concentration of 86 mole % in the total of the methoxybenzenesulfonic acid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15](Cl)=[O:16]>N1C=CC=CC=1.ClCCl>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=1[NH:7][C:15]([N:14]([CH3:13])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)Cl)C1CCCCC1c1ccccc1
Reactant: Cc1cccc(C(C)(C)C)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(C(C)(C)C)c1NC(=O)N(C)C1CCCCC1c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.82 g of 2-tert-butyl-6-methylaniline in pyridine is added a solution of 1.2 g of N-methyl-N-(2-phenylcyclohexyl)carbamoylchloride in dichloromethane dropwise. The mixture is stirred at room temperature until starting compounds disappear on TLC. The mixture is concentrated and the residue is dissolved in ethyl ether. The solution is washed with diluted hydrochloric acid, aqueous sodium hydrogencarbonate solution and brine. The organic layer is dried over sodium sulfate and filtered off. The filtrate is distilled away and the resuling residue is crystallized to give N-(2-tert-butyl-6-methylphenyl)-N'-methyl-N'-(2-phenylcyclohexyl)urea.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][OH:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][OH:26])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1)[C@@H]1Cc2ccccc2CN1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-(4-[2-(hydroxyethyl)phenyl]-piperidyl]-2-oxoethyl)carbamoyl]-(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step f) (323 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC (Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white solid (145 mg). MS (ESI, pos. ion) m/z: 546 (M+1); (ESI, neg. ion) m/z: 544 (M−1). Calc'd for C32H36ClN3O3: 545.24.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Sn](C)(C)C)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=2)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1

Procedure:
N-(3-Bromo-5-trifluoromethyl-phenyl)-methanesulfonamide (37 mg), 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium(II) (7 mg) in DMF (1 mL) were heated in a microwave to 180° C. for five minutes. The mixture was diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed with water (10 mL) and saturated sodium chloride solution (10 mL). Organics were separated, dried over sodium sulphate, filtered and solvent was removed under reduced pressure to yield crude product. Purification by HPLC afforded 4-(3-benzyloxy-propyl)-6-(3-methanesulfonylamino-5-trifluoromethylphenyl)-pyrimidine-2-carbonitrile.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC(Cl)=CC=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(Cl)cc1)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (164 mg, 6.86 mmol) in water (20.00 mL) was added dropwise to a stirred solution of (4-chlorophenyl)methyl 5-bromo-2-{[(4-chlorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 15; 320 mg, 0.69 mmol) in THF (20 ml) over 5 min. The reaction mixture was then stirred at 20° C. for 16 h. The organic phase was evaporated and the residual aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and was extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to give the title compound as a light yellow solid. 180 mg.