Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].[O:44]1[C:48]2([CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)[O:47][CH2:46][CH2:45]1>C(O)C>[O:44]1[C:48]2([CH2:53][CH2:52][CH2:51][N:50]([C:15](=[O:17])[C@@H:14]([NH:13][C:11]([C:9]3[NH:8][C:5]4=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:49]2)[O:47][CH2:46][CH2:45]1
Reactant: C1CNCC2(C1)OCCO2
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCCC2(C1)OCCO2)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.08 h

Procedure:
To a suspension of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 80 mg, 0.22 mmol) in ethanol (6 mL) was added DMTMM (78 mg, 0.27 mmol) and the reaction stirred for 5 min. To the mixture was added 1,4-dioxa-7-aza-spiro[4.5]decane (Preparation 94, 35 mg, 0.24 mmol) and stirring continued for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate and water. The organic layer was washed with NaHCO3 solution (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as a pale yellow powder. m/z (ES+)=487.21 [M+H]+; RT=3.50 min.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[F:14])[CH:2]=C.[O:15]=[O+][O-].CSC>CO>[F:14][C:5]1[C:6]2[CH2:10][O:9][C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][C:4]=1[CH2:1][CH:2]=[O:15]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1F)COC2=O
Solvent: CSC
Solvent: CO
Product: O=CCc1ccc2c(c1F)COC2=O
Temperature: 25 °C

Procedure:
To a solution of 5-allyl-4-fluoro-2-benzofuran-1(3H)-one (30 mg, 0.16 mmol) in MeOH at −78° C. was bubbled ozone through until it turned light blue. After excess ozone was removed by bubbling nitrogen through the solution, dimethyl sulfide (0.1 mL, 1.1 mmol) was added into the reaction. The solution was allowed to warm to RT. The crude material was purified by MPLC to deliver (4-fluoro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 195 [M+1]+.
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][C:25]3[O:28][CH2:29][O:30][C:24]=3[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][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13](Br)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:24]#[N:25]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:24]#[N:25])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (990.0 mg, 2.54 mmol) and copper(I) cyanide (273.3 m g, 3.05 mmol) in dry N,N-dimethylformamide (2.5 mL) was heated under reflux for 4 h. The reaction was allowed to cool to 25° C., and the crude reaction mixture was directly purified without further chemical work-up. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanes then 3/1 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (646.5 mg, 76%) as a very light yellow oil: EI-HRMS m/e calcd for C17H21NO4S (M+) 335.1191, found 335.1185.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11](I)=[CH:10]3)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27]([CH:29]=[O:30])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>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:29]([NH2:27])=[O:30])=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 13-bromo-4-iodo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (5.0 g, 0.013 mol) in DMF (50 mL) was added hexamethyldisilazane (16 mL, 0.077 mol) and Pd(PPh3)2Cl2 (0.45 g, 0.639 mmol). After being purged with CO three times, the mixture was heated at 70° C. for 3 h. After removal of the solvent, water (100 mL) was added. The solid was collected by filtration, washed with water, and dried in vacuo to afford the title compound (3.8 g, 95% yield) as a yellow solid. LCMS m/z [M+H]+ 309.1.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[N:13]([C:14]2[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[CH:18]=2)[C:12]2[N:11]=[C:10]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:39])[C:5]1=[O:40])[CH3:3]>O1CCOCC1.CO>[CH2:2]([CH:4]1[N:13]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[C:12]2[N:11]=[C:10]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:39])[C:5]1=[O:40])[CH3:3]
Reactant: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cnn(COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cn[nH]c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
HCl (2 mL of a 4 N solution in dioxane) was added to a solution of 7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one (Example 342, 49 mg, 0.0893 mmol) in 2 mL of methanol and the resulting solution was stirred at 60° C. for 2 hours. The mixture was concentrated under vacuum and purified by HPLC to give the title compound. 1H-NMR (CDCl3, 400 MHz): δ: 7.90 (s, 1H), 7.75 (s, 1H), 7.50-7.54 (m, 3H), 7.35 (s, 2H), 7.03-7.07 (m, 2H), 4.59-4.61 (m, 1H), 3.46 (s, 3H), 1.98-2.03 (m, 1H), 1.77-1.84 (m, 1H), 0.84 (t, 3H, J=7.4 Hz); LCMS: 418.9 m/z (M+H)+; ret. Time: 3.98 min (Analytical Method C).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:17])[C:8]([CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]1=O)=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]=2[NH:3][N:2]=1)=[O:17])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCC(C)C1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCC2C
Yield: 50.3 %

Procedure:
Hydrazine hydrate (0.101 mL, 2.05 mmol) was added to a stirring room temperature solution of 4 (0.4055 g, 2.05 mmol) in EtOH (2.0 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.2003 g (50.4%) of 5. 1H (CDCl3, 400 MHz): δ 9.55 (1H, broad s), 4.35 (2H, q, J=7.1 Hz), 3.26-3.16 (1H, m), 2.89-2.63 (3H, m), 2.09-1.98 (1H, m), 1.37 (3H, t, J=7.2 Hz), 1.30 (3H, d, J=6.9 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 128.67, 61.32, 39.73, 32.64, 22.94, 19.62, 14.52 ppm. HPLC: 8.901 min.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1
Reactant: Cc1nc2cc(F)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2sc(CBr)nc2c1
Yield: 6.6 %

Procedure:
127 mg of dibenzoyl peroxide were added to a solution of 8.79 g of 2-methyl-5-fluorobenzothiazole and 20.6 g of N-bromosuccinimide in 88 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 6 hours. At the end of this time, the reaction mixture was filtered and the resulting filtrate was concentrated by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate to give 850 mg (yield 7%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[BH4-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Product: OC(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
(5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanone 6f (4.35 g, 11.5 mmol) was dissolved in 40 mL of mixed solution (THF and MeOH, v:v=1:1) and cooled to 0° C., followed by addition of sodium borohydride (0.87 g, 23.0 mmol) in batch. The reaction mixture was stirred for 30 minutes at 0° C. Thereafter, the reaction mixture was concentrated under reduced pressure after 10 mL acetone were added. The reaction mixture was partitioned after 100 mL ethyl acetate and 50 mL water were added and the organic extract was washed with saturated sodium chloride solution (50 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanol 6g (4.4 g, pale yellow grease), which was used directly in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 1H), 7.43-7.40 (m, 2H), 7.36 (dd, 1H), 7.20 (t, 3H), 6.16 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]1=[O:20].N12CCCN=C1CCCCC2.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][O:19][C:15]1[CH:16]=[C:17]([CH3:18])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[F:1])[C:6]([O:8][CH3:9])=[O:7])[C:13](=[O:20])[CH:14]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(O)cc2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 18 h

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (14.4 g, 51.9 mmol) and N,N-dimethyl formamide (40 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (10.9 mL, 72.8 mmol) was added followed by 2,4-difluorobenzyl bromide (9.3 mL, 72.8 mmol). The reaction mixture was stirred at 65 C for 18 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title product, as an orange oil (21.59), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.20 (dddd, J=2.2, 4.8, 7.2 and 8.8 Hz, 1H), 8.00 (dd, J=2.2 and 7.2 Hz, 1H), 7.56 (td, J=2.4, 6.4 and 9.2 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J=0.8 and 2.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 1.98 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.34 (1F), −116.00 (1F), −117.35 (1F) ppm. ES-HRMS m/z 404.1104 (M+H calcd for C21H17F3NO4 requires 404.1104).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:18][C:19]1[C:20]([CH3:48])=[C:21]([C:25]2[N:26]=[C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:41])=[CH:36][CH:35]=3)[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CCO>[C:14]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([CH2:2][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[N:26]=[C:27]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[O:41])=[CH:38][CH:39]=4)[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=3)[C:20]=2[CH3:48])[CH:13]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1CBr
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1CNc1cccc(-c2cn(C)c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with bromide 101c (120 mg, 0.4 mmol), aniline 101g (168 mg, 0.4 mmol), diisopropyethylamine (0.08 mL, 0.48 mmol) in EtOH (3 mL). After the mixture was stirred at 100° C. for 16 h, aqueous Na2CO3 (5 mL) was added. The aqueous phase was extracted with EtOAc (2×5 mL), and the combined organic extracts were washed with brine (5 mL), dried with Na2SO4 and concentrated. The residue was chromatographed with (gradient, 50%-100% EtOAc/hexanes) to afford 100 mg (42%) of 101h.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>>[CH3:38][C:39]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH:42][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: Cc1ccc(CN)c(C)c1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(C)cc4C)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2,4-dimethyl benzylamine, m.p. 161-162° C. MS [(+)ESI, m/z]: 570 [M+H]+ Anal. Calcd for C37H35N3O3: C, 78.01; H, 6.19; N, 7.38. Found: C, 77.86; H, 6.40; N, 7.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1.[N+:19]([O-])([OH:21])=[O:20].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: Cc1sc2ncnc(N)c2c1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1sc2ncnc(N)c2c1-c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 0° C. suspension of Example 143A (2.13 g, 7.74 mmol) in concentrated H2SO4 (15 mL) was treated dropwise over 3 minutes with a solution of fuming nitric acid (0.38 mL) in concentrated H2SO4 (5 mL). The mixture was stirred for 30 minutes while warming to room temperature, poured onto ice, adjusted to pH 7 with solid Na2CO3, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide 2.31 g (93% yield) of the desired product. MS(ESI(+)) m/e 321 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:27]([C:26]([F:25])([F:41])[F:40])[CH:28]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3,5-bis-trifluoromethyl-phenyl boronic acid to give the title compound as colorless solid. MS: 529.2 (MH+).
Reaction SMILES: C(OC(=O)C[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[N:14]=1)(C)(C)C.F[C:22](F)(F)[C:23]([OH:25])=[O:24]>ClCCl>[F:19][C:15]1([CH2:22][C:23]([OH:25])=[O:24])[CH:16]=[CH:17][CH:18]=[C:13]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[NH:14]1
Reactant: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1(F)C=CC=C(c2ncc[nH]2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [2-(6-fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester (630 mg; 2.27 mmol) and trifluoroacetic acid (4 mL) in dichloromethane (4 mL) is stirred at room temperature for 5 hr. The reaction mixture is concentrated. The residue is treated with 3M HCl in ethyl acetate (10 mL) and the suspension stirred at room temperature for 1 hr. The precipitate is collected, washed with ethyl acetate, and dried to give 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine acetic acid as a tan solid (581 mg), 1H NMR (d6DMSO) δ 8.35-8.26(m,2H), 7.83(s,1H), 7.76(s,1H), 7.44-7.41(m.1H), 5.40(s,2H). LCMS: 222.1(MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=O)C.O.[NH2:31][NH2:32]>CO>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)(=[O:3])[NH:31][NH2:32]
Reactant: NN
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A solution of 2-ethoxycarbonyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 5) (1.0 g, 2.5 mmol) in methanol (50 ml) was added hydrazine hydrate (500 μl, 10.3 mmol) in methanol (20 ml). The reaction mixture was stirred at 60° C. for 16 h and then concentrated in vacuo. The residue was added ether and the solid isolated by filtration to yield 860 mg (88%) of the title compound. M.p. >250° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>O.[Cu]I>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc(C#Cc2ccccc2)nc1
Yield: 36 %

Procedure:
A mixture of 2,5 dichloropyridine (3.7 g, 25 mmol), phenylacetylene (3.02 ml, 1.1 eq), bis triphenylphosphine palladium dichloride (II) (Aldrich, 500 mg), copper (I) iodide (250 mg) and triethylamine (50 ml) was heated to reflux under N2 for 18 h. The cooled reaction mixture was diluted with water, extracted with diethyl ether, dried and concentrated to a black oil which was partially purified by SPE Si chromatography with gradient elution cyclohexane:ethyl acetate (100:0 to 10:1) gave the title compound as a brown solid (1.94 g, 36%). MH+ 213; 1H NMR (CDCl3) δ 7.37 (3H, m); 7.48 (1H, d, J 8 Hz); 7.59 (2H, m); 7.67 (1H, dd, J 8 & 2 Hz); 8.57 (1H, d, J 2 Hz); TLC SiO2 Cyclohexane: ethyl acetate (15:1) Rf 0.36.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](=O)[CH:18]([CH3:42])[CH2:19][C:20](=O)[CH:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:15][CH:16]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:48]>C(O)(=O)C.C(OCC)(=O)C>[Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:48][C:20]([CH:21]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:19][C:18]=2[CH3:42])=[N:15][CH:16]=1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccc(C(C)O[Si](C)(C)C(C)(C)C)cn1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccc(C(C)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 1-[5-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridin-2-yl]-5-[4-(cyclopropylsulfonyl)phenyl]-2-methyl-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (180 mg) in acetic acid (5 mL) was added ammonium acetate (354 mg), and the mixture was stirred at 90° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (130 mg, yield 74%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 609 (MH+).
Reaction SMILES: [CH2:1]([NH:6][S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[NH2:16])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH2:1]([N:6]1[CH2:17][NH:16][C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[S:7]1(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=O
Reactant: CCCCCNS(=O)(=O)c1cnccc1N
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCCCN1CNc2ccncc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.5 g of N-pentyl-4-aminopyridine-3- sulfonamide (Preparation 9) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 48 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is suspended in 20 cm3 of 0.1N NaOH. After stirring for 1 hour at ambient temperature, the insoluble material is collected on a filter, washed with water and recrystallized twice from a methanol/water (1/2) mixture and then once from CHCl3 /petroleum ether (40°-60° C.) (1/1).