Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of (3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)methanol (4.50 g), activated manganese dioxide (14.11 g) and tetrahydrofuran (100 mL) was stirred overnight at room temperature. Manganese dioxide was removed by filtration, and the filtrate was concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbaldehyde (4.01 g, yield 90%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 119-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](N)=[O:5].N([O-])=[O:14].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:14])=[O:5]
Reactant: Cc1cc(Cl)c(C(N)=O)c(Cl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A stirred 0° C. solution of 2,6-dichloro-4-methylbenzamide (8.6 g, 42. mmol) in 2:1 (v/v) acetic acid-concentrated hydrochloric acid (165 ml) was treated dropwise with a solution of sodium nitrite (19.0 g, 275 mmol) in water (42 ml). The mixture was stirred 30 minutes at 5° C., slowly warmed to 85° C., and kept 1 hour. The mixture was cooled, concentrated under vacuum, and treated with cold water (50 ml). The product was filtered, washed twice with cold water, and dried 16 hours at 50° C. over phosphorus pentoxide under vacuum to provide 7.15 g (83%) of 2,6-dichloro-4-methylbenzoic acid, m.p. 139°-145° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([C:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[SH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:52][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76]O)=[O:57])[CH3:54]>C1COCC1>[CH3:54][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76][S:39][C:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:57])[CH3:52]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1-c1cn2c(n1)C(CCO)N(C(=O)OC(C)(C)C)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 12 h
Yield: 111 %

Procedure:
Triphenylphosphine (4.08 g, 15.5 mmol) was dissolved in THF (25 ml), cooled to about 0° C. under N2 and Diethylazodicarboxylate (2.45 ml, 15.54 mmol) was added at a dropwise rate so that the reaction temperature was maintained at about <3° C. Stirring was continued for about 12 hour at 0° C. A mixture of the triphenylmethanethiol (4.30 g, 15.54 mmol) and the product from Step 13.e. (2.90 g, 7.77 mmol) in THF (25 ml) was added at a dropwise rate. The resulting mixture was stirred for about 1 hour at about 0° C. and then allowed to warm to room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in ether (40 ml) and allowed to stand overnight. The solid was filtered off and the filtrate was concentrated then purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc and then 4:1/hexanes:EtOAc as eluants. The product fractions were combined and concentrated under reduced pressure to obtain a pale yellow foam (5.49 g, 111%) which was used without further purification. Mass spec. 632.4 MH+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]3[CH2:54][CH2:55]3)[CH:42]=2)[CH2:38][C:37]2[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=2[Cl:31])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:29][CH2:30]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)acetic acid (1.7 g, 3.83 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.611 g, 3.83 mmol), EDC (2.205 g, 11.50 mmol), and DMAP (0.702 g, 5.75 mmol) were dissolved in DCM (60 ml); the mixture was stirred at RT for 2 days. Then it was concentrated to about half volume, diluted with EtOAc (about 200 ml) and washed with HCl 1N and NaHCO3 sat. sol. The organic layer was dried over Na2SO4, and the solvent was evaporated to dryness. The crude (3.35 g) was purified by flash chromatography on silica gel (eluent: Et20/EtOAc 2/1); (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained as a white amorphous solid (2.52 g, 2.98 mmol, 78% yield, MS/ESI+ 846.0 [MH]+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH2:22][OH:23].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22][O:23][S:45]([CH3:44])(=[O:47])=[O:46]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)OC)cc3)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCOS(C)(=O)=O)Cc3ccc(CC(=O)OC)cc3)c2n1
Reaction time: 5 h

Procedure:
The product from step (iii) (0.39 g) was dissolved in DCM (20 mL) and triethylamine (0.15 g) added, followed by addition of methanesulfonyl chloride (0.3 mL) and the mixture stirred for 5 hrs. The mixture was concentrated in vacuo to afford the subtitle compound as a crude product (0.45 g); MS multimode (+) 579.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14](O)=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:17]=1.C(Cl)(=O)C(Cl)=O.C[N:25](C=O)C>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([NH2:25])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:17]=1
Reactant: O=C(O)C1CCc2sc3ccc(F)cc3c2C1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1CCc2sc3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of 8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylic acid (1.2 g, 4.8 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.55 mL, 6.24 mmol) and a drop of DMF. The reaction was stirred at room temperature for 30 min, then was concentrated in vacuo. The resulting residue was dissolved in acetone (30 mL) and cooled to −5° C. Conc. NH4OH (10 mL) was added quickly, resulting in a white precipitate. The suspension was stirred for 30 min, then diluted with water and filtered to afford 1.14 g (95%) of the title compound as a white solid: mp 201-202° C.; MS (−) 248 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:37].O>CN(C=O)C.Cl>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH3:37])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3n2C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (400 mg, 0.85 mmol) was slowly added to an ice-cooled slurry of NaH (68 mg, 60% dispersion on mineral oil, 1.7 mmol) in DMF (10 ml). After 0.5 h iodomethane (0.90 mmol) was added. The reaction mixture was stirred at room temperature, under argon for 16 h. 2N HCl (9 drops) then water (100 ml) were added. The aqueous phase was extracted with EtOAc(2×) and the combined organics washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 50-100% pentane-ethyl acetate). Residual DMF was removed by dissolving in ethyl acetate/diethyl ether and washing with water (2×). Drying (Na2SO4) and removal of the solvent in vacuo afforded the title compound as a pale yellow solid (142 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]Br>CO.C(O)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(C)c1N
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(Br)cc(C)c1N
Reaction time: 2 h
Yield: 43.6 %

Procedure:
2-Methoxy-6-methyl phenylamine (10 g, 72.9 mmol) was set stirring in methanol (30 mL) and acetic acid (10 mL) at 0° C. Bromine (3.73 mL, 72.9 mmol) was dissolved in acetic acid (15 mL) and added dropwise to the reaction. The reaction was stirred for 2 hours and the solvent was removed under reduced pressure. The resulting residue was basified with 1N NaOH and partitioned with EtOAc. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (20% EtOAc/Hexanes) to afford a red-brown solid (6.86 g, 87%). 1H NMR (300 MHz, CDCl3): δ 6.87 (d, 1H), 6.81 (d, 1H), 3.85 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C(O)C>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([F:3])=[CH:5][CH:6]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(Cc2ccc(F)cc2)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 111.8 %

Procedure:
To a solution of (4-fluorobenzyl)hydrazine dihydrochloride (1.0 g, 4.7 mmol, Matrix) in ethyl alcohol (2 mL) was added 4,4-dimethyl-3-oxopentanenitrile (0.6 g, 4.7 mmol, Aldrich). After stirring at 85° C. for 2 h, the reaction mixture was cooled, concentrated, diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 1.3 g (99%) of the title compound. MS (ESI+) m/z 248 (M+H)+.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].[Br:17][CH2:18][C:19](Cl)=[O:20]>>[Br:17][CH2:18][C:19]([NH:1][C@@:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[C:3]([F:6])([F:7])[CH2:4][OH:5])=[O:20]
Reactant: C[C@@](N)(c1cc(Br)ccc1F)C(F)(F)CO
Reactant: O=C(Cl)CBr
Product: C[C@@](NC(=O)CBr)(c1cc(Br)ccc1F)C(F)(F)CO

Procedure:
Prepared in an analogous manner as described for intermediate A15A from (R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-butan-1-ol (intermediate A14B) (2.96 g, 9.93 mmol) and bromoacetyl chloride (1.72 g, 914 μl, 10.9 mmol). Obtained was the title compound as an off-white solid. MS (ISP): m/z=418.0 [(M+H)+], 420.0 [(M+2+H)+] and 422.0 [(M+4+H)+].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7]O)=[CH:5][N:6]=1.[NH2:9][C@H:10]([C:19]([OH:21])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.FC(F)(F)S(O)(=O)=O>[N+](C)([O-])=O>[NH2:9][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([CH2:7][C:4]2[S:3][C:2]([NH2:1])=[N:6][CH:5]=2)[CH:17]=1)[C:19]([OH:21])=[O:20]
Reactant: Nc1ncc(CO)s1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: Nc1ncc(Cc2cc(C[C@H](N)C(=O)O)ccc2O)s1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
To a suspension of (2-aminothiazol-5-yl)methanol (35 mg, 0.269 mmol) and L-Tyrosine (199.6 mg, 1.102 mmol) in nitromethane (3.00 mL) is added trifluoromethanesulfonic acid (170 μL, 1.914 mmol). The resulting solution is sonicated for 15 sec, then heated at 80° C. for 18 h. The reaction is evaporated to dryness and the residue is purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 0% Solvent B to 60% Solvent B over 12 min, ret. T=5.14 min. The product fractions are poured thru a washed WATERS OASIS® MCX 20 cc (1 g) LP extraction cartridge and washed with additional MeOH (50 mL). Elution with Aldrich 2.0M NH3/MeOH (20 mL) followed by evaporation gives 48.7 mg (55.6%) of the title compound as a light tan solid. LC/MS (Condition A): ret. T=0.63 min, (M+H)+ 294.05. Analytical HPLC: (Condition C): >95%, ret. T=3.26 min, (Condition D): >90%, ret. T=3.00 min. 1H NMR (500 MHz, DMSO-d6+D2O) δ ppm 6.86-7.04 (2 H, m), 6.67-6.76 (1 H, m), 6.58-6.67 (1 H, m), 3.74 (2 H, br. s.), 3.33 (1 H, br. s.), 3.02 (1 H, d, f=10.07 Hz), 2.68 (1 H, br. s.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]=2[CH:16]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][CH2:19][C:20]([N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][CH2:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]1=2)=[O:21]
Reactant: Clc1ccc2c(c1)Nc1ccccc1CC2
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2CCc2ccc(Cl)cc21
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepine (3.82 g, 16.6 mmol) was dissolved in toluene (20 ml). A solution of 3-chloropropionylchloride (2.53 g, 19.9 mmol) in toluene was added dropwise, and the resulting mixture was heated to 95° C. and stirred at that temperature for 30 minutes. The mixture was stirred overnight at room temperature. Further 3-chloropropionylchloride (2.53 g, 19.9 mmol) was added and the mixture was stirred at 95° C. for 1.5 h. After cooling, 0.2 M sodium hydroxide (10 ml) was added, and the phases were separated. The organic phase was diluted with more toluene (50 ml): and washed with first 0.2 M sodium hydroxide (6×10 ml) and then with more 0.2 M sodium hydroxide (3×20 ml) until the aqueous phase was alkaline. The organic phase was washed with water (3×15 ml), brine (25 ml), and dried (MgSO4). Evaporation in vacuo afforded 5.23 g (98%) of crude 3-chloro-1-(3-chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone as an oil. This was further purified by addition of a mixture of heptane and ethyl acetate (1:1). This afforded 3.14 g (59%) of the product as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1)=[O:11].[CH2:18]([N:25]([CH2:31]OC)[CH2:26][Si](C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:8][O:9][C:10]([C@@:12]12[CH2:31][N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C@@H:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11]
Reactant: COC(=O)C1=CCCCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)[C@]12CCCC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclohexene-1-carboxylic acid methyl ester (25.0 g, 178 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (46.6 g, 196 mmol) in 1,2-dichloroethane (178 mL) at room temperature, and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution (200 mL) was added to the reaction solution, followed by extraction with chloroform (150 mL×1, 100 mL×1). The organic layer was washed with brine (450 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→85:15→75:25) to give 21.3 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:25][C:26]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([CH3:36])[C:26]=4[OH:25])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 21 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 41 (21% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.13 and 2.17 (2s, 3H), 2.65 and 2.93 (2t, 2H), 3.51 and 4.06 (2t, 2H), 4.42 and 4.94 (2s, 2H), 6.29 and 6.75 (2d, 1H), 6.80 and 7.00 (2dm, 1H), 7.75-7.85 (m, 1H), 7.91-8.03 (m, 3H), 8.11-8.24 (m, 2H), 8.36 and 8.45 (2s, 1H), 8.69-8.74 (m, 2H); MS (ESI) m/z 464 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8]>ClCCl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[O:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC(c1ccc(F)c(Br)c1)c1ccc(F)cc1OC(F)(F)C(F)F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Br)c1)c1ccc(F)cc1OC(F)(F)C(F)F
Reaction time: 6 h
Yield: 60 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.0 g, 17 mmol) in ether (40 mL) at −78° C. was added a solution of n-butyllithium (6.9 mL, 2.5 M, 17 mmol). The reaction mixture was stirred for 15 minutes and was added a solution of 3-bromo-4-fluorobenzaldehyde (3.5 g, 17 mmol) in ether (10 mL). The reaction was stirred at −78° C. for 2 h, then quenched with sat. NH4Cl and warmed to room temperature. The ether layer was separated and dried over magnesium sulfate, filtered and concentrated to yield (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol as an amber oil (6.5 g, 92% yield). The product was used in the next step without further purification. To a solution of (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (29.5 g, 71.3 mmol) in dichloromethane (600 mL) was added MnO2 (30 g, 345 mmol). The reaction mixture was stirred for 6 h, then another 30 g of MnO2 was added and the reaction continued to stir overnight. The MnO2 addition was repeated twice and the reaction was stirred for a total of 48 h when the reaction was complete. The suspension was filtered through a pad of celite, the filtrate vas concentrated and the residue was purified by ISCO flash chromatography to yield (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone as a yellow oil (60% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, d, J=6.59 Hz), 7.76 (1H, ddd, J=6.48, 4.50, 2.20 Hz), 7.38-7.44 (2H, m), 7.21-7.29 (2H, m), 6.09-5.83 (1H, t).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[N:36]=2)[CH:30]=1)=O)(C)(C)C>>[CH3:41][C:37]1[N:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (138 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (46 mg).