Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([CH:20]=C)=[CH:15][CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:23].[Na+].O1CCCC1.O>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH:20]([C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]2)=[CH:16][CH:15]=1)=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCc2ccc(C=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.5% solution of osmium tetroxide in tertbutanol (2 ml) is added to a mixture of the compound obtained in step b) above (1.4 g, 0.0049 mol), sodium periodate (3.5 g), tetrahydrofuran (40 ml), and water (10 ml). The reaction mixture is stirred at room temperature under nitrogen atmosphere for 1 hour, poured into water and extracted with ethyl acetate. The organic solution is washed with water, dried over sodium sulfate and concentrated under vacuum. The dark oily product which is thus obtained is purified by chromatography eluting with a mixture cyclohexane:ethyl acetate 6:4.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:23]C1C=C(S(Cl)(=O)=O)C=CC=1>>[F:23][C:7]1[CH:2]=[C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1cccc(F)c1

Procedure:
Following the 14a synthetic method, using 3-fluorobenzenesulfonyl chloride (66.19 μL, 0.5 mmol) instead of 2-fluorobenzenesulfonyl chloride gave 15a as a colorless oil; (103.95 mg, 64.3%). [α]D25: −16.5 (c=0.31, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.49-7.32 (m, 3H), 7.25-7.20 (m, 4H), 7.10-7.08 (m, 2H), 5.45 (d, J=7.8 Hz, 1H), 4.25 (m, 1H), 3.19-2.91 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 163.89, 160.56, 141.51, 134.71, 130.88, 129.34, 128.68, 127.47, 122.75, 120.24, 119.96, 114.49, 114.17, 56.86 38.74; HRMS (ESI): calcd for: C15H14FNO4S [M−H]−=322.0555, obsd [M−H]−=322.0549.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:18]([C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:11][C:10]=1[O:27][CH3:28])C1C=CC=CC=1.Br.C(O)(=O)C>ClCCl>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:18]([C:23]([F:24])([F:25])[F:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:11][C:10]=1[O:27][CH3:28]
Reactant: COc1cc(C(=O)c2cccnc2C(F)(F)F)ccc1OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridin-3-yl)-methanone (0.913 g, 2.36 mmol) in dichloromethane cooled in an ice-water bath was added a 30% solution of hydrogen bromide in acetic acid (3.54 mL, 17.7 mmol) dropwise. The resulting solution was allowed to stir at room temperature overnight then poured onto ice-water (100 mL). The phases were separated and the aqueous phase extracted with dichloromethane (10 mL). The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 1:1) to give (4-hydroxy-3-methoxyphenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone as a colourless solid, 0.561 g (80%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH:19]2[CH3:22])=[C:15]([F:23])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:23][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:20]3[C:21]=2[C:16]=1[CH2:17][CH2:18][CH:19]3[CH3:22]
Reactant: CC1CCc2c(F)ccc3nc([C@H](C)NC(=O)OC(C)(C)C)n1c23
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1CCc2c(F)ccc3nc([C@H](C)N)n1c23
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To an ice-cooled solution of [(S)-1-(7-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethyl]carbamic acid tert-butyl ester (24.2 mg, 0.0726 mmol) in DCM (4 mL) was added TFA (0.8 mL) and the mixture was stirred at RT for 16 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a colourless gum (15.8 mg, 93%). LCMS (Method B): RT 1.98 min [M+H]+ 234
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@:12]2([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=O)=[N:6][CH:7]=1.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@:12]1([C:10]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][N:9]=1)[CH3:18]
Reactant: CN1CCC[C@@]1(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCC[C@@]1(C)c1nnc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a solution of Intermediate 47a (668 mg, 2.64 mmol), Et3N (1.5 mL, 11 mmol) and Ph3P (1.4 g, 5.3 mmol) in THF (20 mL) at 0° C. was added hexachloroethane (1.25 g, 5.29 mmol). The mixture was stirred at 0° C. for 10 min, then at RT for 1 h. The mixture was partitioned between EtOAc/water and the aqueous extracted with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by FCC, using 0-10% MeOH in EtOAc, gave the title compound as a pale brown solid (300 mg, 49%). LCMS (Method 4): Rt 0.39, m/z 235 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:14][C:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:6]([O:5][C:4]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:2]([CH3:1])[CH:3]=2)=[CH:7][C:8]=1[CH3:16])=[O:15]
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(Oc2cc(C)cc(C)c2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(C)cc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (6.30 g, 23.5 mmol) in acetonitrile (47.0 mL) was added tetrabutylammoniumtribromide (TBABr3, 11.9 g, 24.7 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (8.3 g), which was used directly for the next step without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH2:23]>CO>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:23])([CH3:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Solvent: CO
Product: COc1ccc(S(=O)C(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mol) in Example 1) was dissolved in methanol (100 ml) and 30% H2O (10 ml) was added. The reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to 0° C. and quenched with saturated Na2SO3 (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHCl3 and washed with H2O. The organic layer was dried over MgSO4, filtered and concentrated. The title compound isolated by silica gel column chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)+; 1H NMR (300 MHz, CDCl3): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:17]=[C:18]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:19]([NH:21][NH:22][C:23]([C:25]1[O:26][CH:27]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:24])=[O:20])=O)(C)(C)C.ClCCl>C(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:15][C:16]1[CH:17]=[C:18]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:19]([NH:21][NH:22][C:23]([C:25]1[O:26][CH:27]=[C:28]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:29]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])=[O:20]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1N
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (8.00 ml) was added dropwise to a mixture of the compound of Example 40 (4.81 g) and dichloromethane (10 ml) at 25° C., and the mixture was stirred overnight. The reaction solution was diluted with chloroform and neutralized with 1 M aqueous sodium hydroxide solution. The thus-precipitated crystals were collected by filtration, thereby giving 3.85 g of the desired compound. HPLC retention time: 3.36 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1n[nH]c2c1CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2ccccc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To a stirring solution of 2.0 g (10.30 mmol) of 4,5,6,7-Tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (Ainsworth, C. J. Am. Chem. Soc. 1957, 79, 5242) in 50 mL of DMF is added 1.85 g (13.838 mmol, 1.3 equiv) of K2CO3, followed by 1.35 mL (11.33 mmol, 1.1 equiv) of benzyl bromide. The reaction mixture is stirred 15 min at RT then heated at 60° C. for 16 h. The reaction is cooled to RT, poured into 100 mL 1N HCl, and extracted with Et2O (2×100 mL). The organic layers were washed with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 6/1 to 3/1 afforded 1.05 g of 4,5,6,7-Tetrahydro-1-Benzyl-1H-indazole-3-carboxylic acid ethyl ester as a yellow oil which later solidified: 1H NMR (CDCl3, 300 MHz) δ7.37-7.23 (m, 3H), 7.13 (m, 2H), 5.31 (s, 2H), 4.39 (q, 2H, J=7.2), 2.74 (m, 2H), 2.40 (m, 2H), 1.72 (m, 4H), 1.39 (t, 3H, J=7.2).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.CCCCCC>[OH:19][CH2:8][CH:7]([C:11]1[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=1[OH:9])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c(C(CO)c2ccccc2)c(O)c1C
Yield: 82 %

Procedure:
Using 3-phenyl-4,6,7-trimethyl-1-benzofuran-2 (3H)-one obtained in Reference Example 228, the title compound was synthesized in the same manner as in Reference Example 8. Yield 82%. Melting point: 103-104° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OCC6C=CC=CC=6)=O)=[N:36][CH:35]=5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])[C:66](O)=[O:67])=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>O.C(O)C.[Pd].C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C>[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])[C:66]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:19]4[CH:20]=[CH:21][C:15]5[N:14]=[C:13]([C@@H:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[NH:17][C:16]=5[CH:18]=4)=[CH:23][CH:24]=3)=[CH:29][CH:30]=2)=[CH:35][N:36]=1)=[O:67])=[O:63]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)cc4)cc3)cc2[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4ccc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)cc3)cc2)[nH]1)C(C)C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
To a solution of (S)-benzyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.65 g, 0.92 mmol), potassium carbonate (200 mg, 1.4 mmol) and water (2 drops) in ethanol (11.6 mL) was added 10% palladium on carbon (260 mg). The reaction flask was flushed with argon for 2 minutes. Hydrogen gas was bubbled through the reaction mixture for 10 minutes. The reaction was stirred under hydrogen gas for 18 hours, and then flushed with argon. The mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated and used without purification in the next step. The crude material was dissolved in dimethylformamide (7.4 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (156 mg, 0.9 mmol), HATU (340 mg, 0.9 mmol) and diisopropylethylamine (0.39 mL, 2.2 mmol). The reaction was stirred at room temperature for one hour, and then diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(6-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (368 mg, 68%). LCMS-ESI+: calculated for C42H49N7O5: 731.88; observed [M+1]+: 732.75.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([CH3:21])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([NH:19][CH3:20])=[CH:8][N:7]=1)=[O:4].CCN(C(C)C)C(C)C.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:38](Cl)=[O:39]>C1COCC1>[CH3:20][N:19]([C:9]1[CH:8]=[N:7][C:6]([N:5]([CH3:21])[C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])=[CH:11][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:38](=[O:39])[C:37]1[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:35]([C:34]([F:33])([F:48])[F:49])[CH:36]=1
Reactant: CNc1cnc(N(C)C(=O)C(F)(F)F)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N(C)C(=O)C(F)(F)F)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 60 h

Procedure:
2,2,2-Trifluoro-N-methyl-N-(5-(methylamino)-4-o-tolylpyridin-2-yl)acetamide (46 mg, 0.14 mmol) and DIPEA (61 μL, 0.35 mmol) in THF (1.5 mL) were treated with 3,5-bis-trifluoromethylbenzoyl chloride (51 μL, 0.28 mmol, CAS RN 1271-19-8). 3,5-Bis-trifluorobenzoyl chloride (25 μL, 0.14 mmol, CAS RN 1271-19-8) was added again at 90 min. and 4 hours. The reaction mixture was stirred for 60 hours and then evaporated to dryness. From the resulting residue, the product N-methyl-N-(4-o-tolyl-6-(2,2,2-trifluoro-N-methylacetamido)pyridin-3-yl)-3,5-bis(trifluoromethyl)benzamide was isolated by flash chromatography on silica gel (33-50% EtOAc in n-hexane) as a foam (70 mg, 87% over two steps). The compound was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][N:31]([CH2:42][CH3:43])[C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:9]([O:12]CC2C=CC=CC=2)=[CH:10][CH:11]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=2[CH2:30][N:31]([CH2:42][CH3:43])[C:32]([NH:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(O)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1
Reaction time: 8 h

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.580 g, 0.96 mmol) in EtOAc was treated with 10% palladium on carbon (catalytic) and stirred under a balloon of H2 overnight. Analytical tlc indicated that some starting material was still present, so fresh palladium on carbon was added, and the reaction was stirred under a balloon of H2 for an additional 24 hours. Once no starting material was seen by analytical tlc, the mixture was filtered over Celite, and the filtrate was concentrated and purified by silica gel chromatography to give the title compound. M+H is 515.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9])[CH:2]=[CH2:3].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C1COCC1>[CH2:1]([N:4]([C:5]1[CH:6]=[C:7]([C:8]([NH:10][CH:11]2[CH2:12][CH2:13]2)=[O:9])[CH:14]=[CH:15][C:16]=1[CH3:17])[C:27](=[O:28])[C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[Br:18])[CH:2]=[CH2:3]
Reactant: C=CCNc1cc(C(=O)NC2CC2)ccc1C
Reactant: COc1ccc(Br)c(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)c1cc(OC)ccc1Br)c1cc(C(=O)NC2CC2)ccc1C
Yield: 93.7 %

Procedure:
3-(Allylamino)-N-cyclopropyl-4-methylbenzamide (688 mg) was stirred with 2-bromo-5-methoxybenzene-1-carbonyl chloride (745 mg) and triethylamine (0.83 ml) in THF (10 ml) at room temperature for 2.5 hours and then concentrated. The residue was dissolved in ethyl acetate and washed with 1N HCl (×2), water, brine, dried (magnesium sulfate) and concentrated to yield N-allyl-2-bromo-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-methoxybenzamide as a pale orange solid (1.24 g); Mass Spectrum: M+H+ 443.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[N:4][CH:3]=1.C[CH:14](Br)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]2=[O:12])=[N:4][CH:3]=1
Reactant: CC(Br)c1ccc(F)cc1
Reactant: Oc1nncc2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)cnc2cnn1Cc1ccc(F)cc1

Procedure:
The alkylation of 7-bromo-1-hydroxy-3,5-diazaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-fluoro-benzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(4-fluorobenzyl)-7-3-phenylprop-1-ynyl-2H-3,5-diazaisoquinolin-1-one
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23]Cl)=[CH:20][C:14]=2[CH:13]=1)=[O:11].O>CN(C)C=O>[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:20][C:14]=2[CH:13]=1)=[O:11]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc2cc(OCCCl)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(OCCn3ccnc3)ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
Sodium hydride (0.22 g. of 50% dispersion in mineral oil) was added portionwise with stirring to a solution of imidazole (0.306 g.) in dry N,N-dimethylformamide (10 ml.) and the mixture was stirred at room temperature for 30 minutes and then warmed for a few minutes. 5-(2-Chloroethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester (1.22 g.) was then added and the mixture was heated on a steam bath for 5 hours, and then cooled and poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave first mineral oil and some impurity followed by pure product. The product containing fractions were evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-[2-(1-imidazolyl)ethoxy]benzo[b]thiophene-2-carboxylic acid methyl ester (0.45 g.), m.p. 127°-129° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:6]=1[CH3:16]>C(O)C.[Pd]>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:6]([CH3:16])=[C:5]([NH:4][CH2:3][CH2:2][OH:1])[CH:10]=1
Reactant: COc1cc(C)c(NCCO)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C)c(NCCO)cc1N

Procedure:
3 g (15 mmol) of 2-(2'-hydroxyethyl)amino-4-nitro-5-methoxytoluene were hydrogenated using a catalytic amount of Palladium/Carbon (5% Pd) in 100 ml absolute ethanol. After filtration of the catalyst the solvent was completely distilled away and the green crystals were recrystallized from methanol. 2.2 g (83% of the theoretical yield) of the 4-amino-2-(2'-hydroxyethyl)amino-5-methoxytoluene were obtained and melted at 148° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2([CH3:28])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].Cl>CO>[CH3:29][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2([CH3:28])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[O:14])[CH:7]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCNCC2)c1

Procedure:
tert-Butyl 4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)-4-methylpiperidine-1-carboxylate from step A (56 mgs, 0.138 mmol) was treated with HCl (4.0 N in dioxane, 0.17 mL, 0.69 mmol) in methanol (2.0 mL) at 40° C. for 3 hours. The mixture was concentrated to give the title compound as the hydrochloride salt in quantitative yield. MS (ES+) [M+H]+=306.