Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:31])=[O:29])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)Cc1ccc(S(=O)(=O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(S(=O)(=O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A suspension of methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)sulfonyl)phenyl)acetate (0.109 g, 0.25 mmol) in 7N NH3 in MeOH was heated at 100° C. in a sealed tube. After 24 h, the mixture was concentrated and purified by silica gel chromatography eluting with 100% methylene chloride to 1:1 methylene chloride/89:9:1 (methylene chloride/methanol/concentrated ammonium hydroxide) to afford the title compound (0.055 g, 53%) as a white solid. MW=426.92. 1H NMR (DMSO-d6, 300 MHz) δ 8.20-8.18 (m, 2H), 8.10-8.08 (m, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.56-7.51 (m, 5H), 6.98 (s, 1H), 3.50 (s, 2H), 3.12 (t, J=7.6 Hz, 2H), 3.03 (t, J=7.8 Hz, 2H), 2.13-2.08 (m, 2H); APCI MS m/z 427 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:53][C:54]([F:64])([F:63])[C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH2:59]>CN(C=O)C>[F:53][C:54]([F:63])([F:64])[C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH:59][C:10]([C:5]1[C:4]2[CH:3]=[N:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:12]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc2[nH]ncc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cccc2[nH]ncc12
Reaction time: 0.25 h

Procedure:
To a stirred room temperature solution of indazole-4-carboxylic acid (1.0 g, 6.1 mmol) in DMF (15 mL) was added PyBOP (3.5 g, 6.5 mmol) and triethylamine (0.90 g, 7.5 mmol). After 15 minutes, 3-trifluoromethyl-benzylamine (1.2 g, 7.0 mmol) was added. After 4 hours, the mixture was quenched with water (30 mL) and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes to afford 1H-indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[C:9](I)[CH:10]=[C:11]([CH3:13])[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:9]1[CH:10]=[C:11]([CH3:13])[CH:12]=[C:7]([CH3:6])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)cc(I)c1
Reactant: CCCCO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCOc1cc(C)cc(C)c1
Temperature: 105 °C

Procedure:
A screw cap test tube was charged with n-butanol (573 μL, 6.26 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), Cs2CO3 (977 mg, 3.00 mmol), the ligand (0.500 mmol) and toluene (1 mL). The test tube was scaled with a screw cap. The reaction mixture was stirred magnetically and heated at 105° C. for 36 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from [6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetonitrile (0.2 g, 0.54 mmol), sodium azide (0.35 g, 5.4 mmol) and ammonium chloride (0.29 g, 5.4 mmol) in DMF (12 mL). The title compound was obtained as a white solid (0.085 g), mp 178-180° C. Mass spectrum (+APCl, [M+H]+) m/z 413. 1HNMR (400 MHz, DMSO-d6): δ8.27 (s, 1H), 8.03 (d, 1H, J=9.1 Hz), 7.97-7.87 (m, 2H), 7.68 (d, 1H, J=7.0 Hz), 7.61-7.56 (m, 2H), 7.36-7.25 (m, 3H), 5.63 (s, 2H), 2.96 (t, 2H, J=7.9 Hz), 1.72 (p, 2H, J=7.0 Hz), 1.41-1.29 (m, 4H), and 0.83 ppm (t, 3H, J=7.1 Hz). Elemental Analysis for C25H24N4O2.0.75H2O: Calculated: C, 70.49; H, 6.03; N, 13.15. Found: C, 70.18; H, 5.68; N, 13.3.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)=[CH:19][CH:20]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(NCc1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNC(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Yield: 73 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of N-(4-hydroxybenzyl)-4-nitrobenzamide INT-1 (647 mg, 2.38 mmol) in DCM (10 mL) at 0° C. was added TEA (1.03 mL, 7.13 mmol) followed by 4-(heptyloxy)benzoyl chloride (12.4 mL, 2.85 mmol). The suspension was sonicated until clear then diluted with DCM (50 mL) and washed with NaHCO3 (20 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to provide 857 mg (73%) of 4-((4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-2. LCMS-ESI (m/z) calculated for C28H30N2O6: 490; found 491 [M+H]+, tR=3.41 min (Method 5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24])[CH:7]2[CH2:25][C:26]([O:28][CH3:29])=[O:27].FC1C=CC=CC=1NC(NC1C=C(C(F)(F)F)C=CC=1OC)=O.C(OC)(=O)C=C>>[F:1][C:2]1[C:11]([NH:10][C:9]([NH:8][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[O:23][CH3:24])=[O:12])=[C:6](/[CH:7]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1c2cccc(F)c2NC(=O)N1c1cc(C(F)(F)F)ccc1OC
Agent: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccccc1F
Solvent: C=CC(=O)OC
Product: COC(=O)/C=C/c1cccc(F)c1NC(=O)Nc1cc(C(F)(F)F)ccc1OC

Procedure:
In addition, it has surprisingly been found that the structural unit methyl {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate can be synthesized efficiently by means of an ortho-palladization. Here, N-(2-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea is reacted with methyl acrylate and an oxidizing agent in the presence of an acid to give methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}-carbonyl)amino]phenyl}acrylate. The ring closure to the tetrahydroquinazoline then follows under basic reaction conditions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:15][N:16]([CH2:31][CH3:32])[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CNS(C)(=O)=O)c2ccccc2F)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To 4-[1-(2-Fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (408) (1.43 g, 3.56 mmol) in THF (30 mL) was added NaH (60% in oil) (0.16 g, 3.92 mmol) and the solution was allowed to stir for 1 h at room temperature. Iodoethane (0.31 mL, 3.92 mmol) was then added and the reaction was allowed to stir for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (100 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 10% MeOH in CHCl3) yielding 0.54 g (36%) pure product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([N-:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])#[N:14].N1CCCCC1.Cl>C(O)C.O>[CH2:19]([NH:18][C:16](/[C:15](=[CH:7]/[CH:6]=[CH:5]/[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1)/[C:13]#[N:14])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Reactant: O=CC=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#C/C(=C\C=C\c1ccc(O)c(O)c1)C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 68 %

Procedure:
To 3,4-dihydroxycinnamaldehyde A12 (example 59) (32 mg, 0.2 mmol) and amide A3 (Example 4) (32 mg, 0.2 mmol) in 8 mL of ethanol 40 μl of piperidine was added and the mixture was kept at room temperature for 1 h. 2N HCl and water were added and the precipitated solid was recrystallized from ethanol-water to give 44 mg (68%) of an orange solid. The analytical data were identical to the compound prepared as described in Example 8.
Reaction SMILES: [C:1]([O:9][C@@H:10]([CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[C:33](O)=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38].C(Cl)CCl>CN(C=O)C>[C:1]([O:9][C@@H:10]([CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C:11](=[O:13])[O:12][C:33]1[C:32]([F:35])=[C:31]([F:36])[C:30]([F:37])=[C:29]([F:38])[C:28]=1[F:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a stirring solution of (S)-2-(benzoyloxy)-4-(benzyloxycarbonylamino)butanoic acid (2, 196 g, 0.548 mol) and pentafluorophenol (111 g, 0.603 mol) in 1.3 L DMF at 0° C. was added EDC (126 g, 0.658 mol) and the reaction was stirred overnight. The reaction mixture was diluted with hexanes:EtOAc (1.5 L, 1:1) and with brine/water (1 L, 1:1), and the organic layer was separated and washed with 1 M citric acid (3×600 mL), followed by sat. NaHCO3:1M NaOH (3×500 mL, 1:1) and brine (500 mL). The organic layer was dried over MgSO4, filtered and concentrated under vacuum to yield (S)-4-(benzyloxycarbonylamino)-1-oxo-1-(perfluorophenoxy)butan-2-yl benzoate (3, 255 g, 88% yield) as a white waxy solid that was used in the next step without further purification.
Reaction SMILES: [Li]CCCC.N12CCN(CC1)CC2.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=1.CON(C)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[Cl:14][C:15]1[C:20]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CON(C)C(=O)c1ccccc1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(Cl)nc1Cl
Reaction time: 1 h
Yield: 14.4 %

Procedure:
n-BuLi (1.6 M in hexane, 13.94 mL, 22.298 mmol) was added dropwise to a cooled (−78° C.) solution of 1,4-diazabicyclo[2.2.2]octane (2.501 g, 22.298 mmol) in dry THF (40 mL) and stirred for 1 h. 2,6-Dichloropyridine (3.684 g, 20.272 mmol) was added portionwise to the reaction mixture while the color of the reaction mixture turned to pale pink. Stirring was continued for 1 h at −78° C. N-methoxy-N-methylbenzamide (3.0 g, 22.298 mmol) in dry THF (10 mL) was added to the reaction mixture dropwise (color changes to orange then slowly to yellow) and stirring was continued for 1 h. After completion of the reaction, the reaction mixture was concentrated and diluted with diethyl ether. The organic layer was washed with water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as a pale yellow oil. The crude compound was purified by column chromatography (3% EtOAc in hexane) to yield the title compound as a colorless solid (0.736 g, 16.1%). [1H-NMR (CDCl3, 300 MHz) δ 7.84-7.76 (m, 2H), 7.74-7.63 (m, 2H), 7.58-7.48 (m, 2H), 7.422 (d, 1H); HPLCA Rt=4.851 min. (94%); LCMS RtA=0.471 min; [M+H]+=251.9]
Reaction SMILES: [ClH:1].Cl.C([O:5][C:6]([C@@H:8]1[CH2:17][C@@H:16]2[C@@H:11]([CH2:12][CH2:13][C@H:14]([CH2:18][N:19]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=[CH:20]3)[CH2:15]2)[CH2:10][NH:9]1)=[O:7])C>Cl>[ClH:1].[ClH:1].[CH2:27]([O:26][C:24]([C:23]1[N:19]([CH2:18][C@H:14]2[CH2:13][CH2:12][C@@H:11]3[C@@H:16]([CH2:17][C@@H:8]([C:6]([OH:7])=[O:5])[NH:9][CH2:10]3)[CH2:15]2)[CH:20]=[N:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1cncn1C[C@H]1CC[C@H]2CN[C@H](C(=O)OCC)C[C@H]2C1
Agent: Cl
Product: CCOC(=O)c1cncn1C[C@H]1CC[C@H]2CN[C@H](C(=O)O)C[C@H]2C1
Reaction time: 18 h
Yield: 184.9 %

Procedure:
A solution of 0.20 g of [3S,4aR,6S,8aR]-ethyl-6-((5-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate dihydrochloride (prepared in example 5) in 10 mL of 5N HCl was heated at 50° C. for three hours and then at room temperature for 18 h. The solution was evaporated and vacuum dried at 50° C. to give 0.173 g of the title compound: MS m/z: 336.2 (m++1). Analysis calculated for C17H25N3O4.2HCl H2O: C, 47.9; H, 6.9; N, 9.85. Found: C, 48.11; H, 7.66; N, 9.99.
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.[CH3:20][Mg]Br>C1COCC1>[F:17][C:12]([F:16])([O:11][C:7]1[CH:6]=[C:5]([C:4](=[O:18])[CH3:20])[CH:10]=[CH:9][CH:8]=1)[CH:13]([F:14])[F:15]
Reactant: CON(C)C(=O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-methoxy-N-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzamide (7.5 g, 25.2 mmol) was dissolved in THF (84 mL) and cooled to −78° C. Methyl magnesium bromide (3N in diethyl ether, 21.03 mL, 63.1 mmol) was added dropwise and the resulting reaction mixture was stirred for 30 min. The reaction was warmed to 25° C. over 30 minutes and then was quenched by addition to an Erlenmeyer flask containing ice and saturated ammonium chloride solution. This mixture was extracted with EtOAc, the organic layers were collected and dried with anhydrous magnesium sulfate, then filtered and concentrated. Crude material obtained corresponds to 1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]ethanone. 1H NMR (400 MHz, CDCl3) δ 2.62 (s, 3H), 5.96 (t, t, J=53, 2.7 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.88 (d, J=7.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[C:6]=4[CH:18]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: COc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (34 mg, 27%), MS (ISP) m/z=385.5 [(M+H)+], mp 143° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methoxy-phenyl)-1H-benzo[d]imidazole (intermediate N) (100 mg, 330 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (81.6 mg, 396 μmol).
Reaction SMILES: [CH3:1]I.[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][S:19][C:7]=2[CH:6]=1)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][CH:12]=4.[H-].[Na+]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[N:10]([CH3:1])[C:11]4[C:16]([C:17]=3[CH2:18][S:19][C:7]=2[CH:6]=1)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][CH:12]=4
Reactant: CI
Reactant: COc1ccc2c(c1)SCc1c-2[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)SCc1c-2n(C)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CH3I (108 mg, 0.758 mmol, 1.5 eq.) was added to a mixture of 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (150 mg, 0.505 mmol) and NaH (61 mg, 60% in mineral oil, 1.515 mmol, 3.0 eq.) in DMF. The reaction mixture was then stirred at 25° C. for 2 hours. The reaction mixture was partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (Hexanes to EtOAc 4:1) to yield the title compound as a brown solid.
Reaction SMILES: CC1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[Na+].[CH3:17][C:18]([OH:20])=[O:19]>OS(O)(=O)=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:17]([C:18]([OH:20])=[O:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)([O-:14])=[O:13]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c2cccnc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])c2cccnc12
Temperature: 0 °C
Yield: 66 %

Procedure:
Compound 12A (1.0 g, 5.3 mmol) was dissolved in concentrated H2SO4 (7 mL), cooled to 0° C., and then CrO3 (2.12 g, 21.3 mmol) was added portionwise over 30 min. After the addition, the reaction mixture was warmed to rt and then heated to 80° C. for 1 h. After cooling to rt, the reaction was diluted with water, basified with 15% aqueous NaOH, then reacidified to pH=3 with AcOH, and extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound (760 mg, 66%) as a yellow solid. LC/MS m/z 219 [M+H]+.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[C:9]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](OCC)=[O:25])[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.Cl>O1CCCC1>[C:9]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC1CCN(C(=O)c2ccccc2)CC1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(CCO)CC1
Temperature: 0 °C

Procedure:
Lithium triethylborohydride (100 ml, 1M solution in tetrahydrofuran) was added dropwise to a solution of ethyl 1-benzoyl-4-piperidineacetate (13.8 g) in dry tetrahydrofuran (50 ml) at 0° C. under nitrogen over 20 minutes whilst maintaining the temperature at 0°-5° C. The mixture was stirred at 0° C. for a further hour, allowed to warm to 20° C. and then water (50 ml) was added slowly. The mixture was acidified with a slight excess of dilute hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts were washed (dilute hydrochloric acid, brine), dried and evaporated to give 1-benzoyl-4-(2-hydroxyethyl)piperidine as an oil.
Reaction SMILES: [OH-].[Na+].CO.[N:5]1([C:10]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6]1.Cl>C(OCC)(=O)C.O1CCCC1>[N:5]1([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=[CH:9]1
Reactant: COC(=O)c1ccnc(-n2cccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccnc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 mL of 2.0 mol/L aqueous sodium hydroxide was added to a mixed solution of 4.0 mL of methanol and 4.0 mL of tetrahydrofuran containing 0.47 g of methyl 2-(1H-pyrrol-1-yl)pyridine-4-carboxylate and stirred at room temperature for 1 hour. 5.0 mL of 1.0 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture sequentially. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated, under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was removed by filtration to obtain 0.39 g of 2-(1H-pyrrol-1-yl)pyridine-4-carboxylic acid as white solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[NH:8][N:7]=[CH:6][C:5]=1[CH3:9].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>C1COCC1>[I:3][C:4]1[N:8]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[N:7]=[CH:6][C:5]=1[CH3:9]
Reactant: Cc1cn[nH]c1I
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnn(COCC[Si](C)(C)C)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
NaH (0.48 g, 12.2 mmol, 60%) was added to a solution of 5-iodo-4-methyl-1H-pyrazole (compound 250.1, 2.3 g, 11.1 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then 2-(trimethylsilyl)ethoxymethyl chloride (2.15 mL, 12.2 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours, and then carefully quenched with a small amount of water and partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified with by silica gel column chromatography (hexanes:EtOAc, 10:1) to yield the title compound as a light yellow oil (3.15 g, 84%). m/z (ES+) 339 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[S:9])[NH:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[H-].[Na+].[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27]Cl)[CH3:23].C(O)(=O)/C=C\C(O)=O>CN(C=O)C.CC(C)=O.CCOCC>[CH3:1][N:2]1[C:8]([S:9][CH2:27][CH2:26][CH2:25][N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])=[N:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1
Reactant: CN1Cc2ccccc2C(c2ccccc2)NC1=S
Reactant: CCN(CC)CCCCl
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCCSC1=NC(c2ccccc2)c2ccccc2CN1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
A solution of 12 g (45 mmol) of 1,2,4,5-tetrahydro-4-methyl-1-phenyl-3H-2,4-benzodiazepin-3-thione of Example 152 in 100 mL of DMF was treated with 1.24 g (50 mmol) of sodium hydride at 70° and 7.5 g (50 mmol) of 3-diethylaminopropyl chloride was added dropwise at 70°. The reaction was stirred at 70° for five hours and then at room temperature for two days. The reaction was poured into 250 mL of ice water and extracted twice into ethyl acetate. The product was extracted into 150 mL of 2N HCl, washed with ethyl acetate, made basic, and extracted back into ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, stripped, and the residue was dissolved in acetone. Two equivalents of maleic acid in 40 mL of acetone was added, followed by a small amount of ether. The resulting precipitate was recrystallized from acetone/ether to provide 13.2 g of product as the dimaleate salt, mp 95-97.