Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH:37]([F:39])[F:38])[C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=3[N:33]=2)[C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:18]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH:37]([F:38])[F:39])[C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=3[N:33]=2)[C:24]=1[C:25]([OH:27])=[O:26])=[O:18]
Reactant: CC(C)(C)OC(=O)c1c(-c2nc3ccccc3n2C(F)F)csc1NC(=O)c1cc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1scc(-c2nc3ccccc3n2C(F)F)c1C(=O)O)c1cc2ccccc2o1
Reaction time: 6 h
Yield: 88.9 %

Procedure:
Under an atmosphere of argon, trifluoroacetic acid (0.75 mL) was added to a stirred solution of 43 (33 mg, 65 μmol) in dichloromethane (0.75 mL) at room temperature. The reaction was stirred for 6 hours then concentrated under reduced pressure. Flash chromatography (silica, 5% methanol in dichloromethane) provided 44 (26.2 mg, 90%) as a solid: 1H NMR (500 MHz, d6-DMSO) δ 13.70 (bs, 1H), 12.46 (s, 1H), 7.92 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.81-7.72, (m, 3H), 7.65-7.54 (m, 2H), 7.44-7.38 (m, 4H); LRESIMS m/z 454 [M+H]+, calcd. for C22H13F2N3O4S1 454.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH3:15]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH2:15])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-hydroxy-2-nitrobenzoate (48 g) in 340 ml methanol was heated 30 hours at 107° in a pressure vessel with 140 ml NH3. The mixture was cooled and concentrated to dryness on the rotovap. Water was added (200 ml) and the solid filtered and dried to give 12 g product, m.135-8.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(OC)cc2)CC1
Product: COc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methoxyphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-methoxyphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C@H:14]1[C@@H:19]([NH2:20])[C@H:18]2[CH2:21][C@@H:15]1[CH2:16][CH2:17]2)=[O:13])[CH3:10].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:9]([O:11][C:12]([C@H:14]1[C@@H:19]([NH:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:18]2[CH2:21][C@@H:15]1[CH2:16][CH2:17]2)=[O:13])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Benzaldehyde (0.454 mL, 4.47 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.82 g, 4.47 mmol) in methanol (15 mL) at 25° C. Sodium cyanoborohydride (0.703 g, 11.2 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 35% ethyl acetate in hexanes) to afford the desired product, (1S,2R,3S,4R)-3-benzylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.875 g, 3.22 mmol, 72%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.06-1.16 (2H, m), 1.20-1.23 (2H, m), 1.28 (3H, t, J=7.0 Hz), 1.46-1.61 (2H, m), 1.93-1.97 (1H, m), 2.33-2.34 (1H, m), 2.43-2.44 (1H, m), 2.59-2.62 (1H, m), 2.98-3.00 (1H, m), 3.71 (1H, d, J=14.0 Hz), 3.85 (1H, d, J=13.3 Hz), 4.14 (2H, q, J=7.3 Hz), 7.20-7.24 (1H, m), 7.27-7.33 (4H, m).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:35])[C@H:16]([CH2:25][C:26]1[CH:31]=[C:30]([I:32])[C:29]([OH:33])=[C:28]([I:34])[CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Br:36][CH2:37][CH2:38][CH2:39]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:35])[C@H:16]([CH2:25][C:26]1[CH:31]=[C:30]([I:32])[C:29]([O:33][CH2:39][CH2:38][CH2:37][Br:36])=[C:28]([I:34])[CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19]
Reactant: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)OC(C)(C)C
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(I)c(OCCCBr)c(I)c1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Diethylazodicarboxylate (197 μ1, 1.25 mmol) was added dropwise to a solution of N-t-butoxycarbonyl-3,5-diiodo-L-tyrosine methyl ester (274 mg, 0.5 mmol), 3-bromo-1-propanol (76 mg, 0.55 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in tetrahydrofuran (5 ml) under argon atmosphere at −15° C. and the mixture was stirred at the same temperature for 0.5 hrs., at 0-5° C. for 0.5 hrs., and then at room temperature for 23 hrs. The solvent of the reaction mixture was distilled off at room temperature under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=9) to give O-(3-bromopropyl)-N-t-butoxycarbonyl-3,5-diiodo-L-tyrosine methyl ester (145 mg, 43%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: NCCCN
Reactant: Brc1nsc2cccnc12
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCCNc1nsc2cccnc12
Temperature: 25 °C

Procedure:
3-Bromoisothiazolo[4,5-b]pyridine (1.90 g, 8.8 mmol) and 1,3-diaminopropane (6.70 g, 90 mmol) in methanol (15 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water yielded N1-(isothiazolo[4,5-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.55 (d, 1H), 8.05 (d, 1H), 7.32 (dd, 1H), 6.25 (br s, 1H), 3.65 (m, 2H), 2.85 (t, 2H), 1.85 (t, 2H), 1.45 ppm (br s, 2H). MW=208 confirmed by LC-MS, tr=5.91 min (Method Y) MH+=209.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][O:23][C:24]([CH:26]1[CH2:30][C:29](=O)[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25].CC(C)([O-])C.[K+].O>C1COCC1>[CH3:22][O:23][C:24]([CH:26]1[CH2:30][C:29](=[CH2:2])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of methyltriphenylphosphonium iodide (1.25 g, 3.08 mmol) in THF (20 ml) at 0° C., 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (500 mg, 2.05 mmol) and potassium ter-butoxide (460 mg, 4.11 mmol) was added. It was stirred for overnight at room temperature. Water was added and the compound was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography offered 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil (0.23 g, 46%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23]([NH:25][CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:18]([O:22][C:23](=[O:24])[NH:25][CH:26]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:35][CH:36]=1)[C:27](=[O:28])[N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: c1ccc(-c2cnc(C3CCCCN3)o2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N1CCCCC1c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.20 g (0.88 mmol) of 2-(5-phenyl-oxazol-2-yl)-piperidine, 0.36 g (1.05 mmol) of 2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.49 g (1.05 mmol) of PyBrop and 0.287 mL of diisopropylethylamine was added 1 ml of dimethylformamide. The resulting mixture was allowed to stir under argon at room temperature overnight. The following morning, LC analysis indicated that about 20% of starting material remained. An additional 0.09 g (0.26 mmol) of 2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.12 g (0.26 mmol) of PyBrop and 0.072 ml (0.45 mmol) of diisopropylethylamine was added. After stirring for 3 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The product was taken to the next step as is without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C1C(=O)N([Br:47])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:47])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 1-(4-benzyloxy-3-methyl-phenyl)-ethanone (12.89 g; 53.1 mmol) in CH2Cl2 was added, dropwise, at 0° C., DIPEA (10.9 mL; 63.7 mmol) and trimethylsilyl trifluoromethanesulfonate (11.1 mL; 61.1 mmol). The resulting mixture was stirred at 0° C. for 1 hour, and subsequently, NBS (10.87 g; 61.1 mmol) was added in one portion. The mixture was allowed to warm to RT stirred overnight. Then the mixture was concentrated in vacuo, the residue dissolved in EtOAc, washed with water twice, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 1-(4-benzyloxy-3-methyl-phenyl)-2-bromo-ethanone (11.90 g).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].[CH3:20][N:21]1C(=O)CCC1>>[C:20]([C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19])#[N:21]
Reactant: CN1CCCC1=O
Reactant: O=C(N1CCc2ccc(Br)c(O)c2CC1)C(F)(F)F
Product: N#Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Temperature: 150 °C
Yield: 86 %

Procedure:
Add copper nitrile (2.6 g, 28 mmol) to a solution of 7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.4 g, 7.0 mmol) in anhydrous NMP (45 mL), degas and purge with nitrogen and heat to 150° C. for 18 h. Allow the reaction mixture to cool to ambient temperature and then dilute with EtOAc/heptane (2:1) and filter through a silica pad. Dilute the filtrate with water, and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/heptane (1:4 to 1:1) to obtain the desired intermediate as an orange oil (1.7 g, 86%). MS (ES−) m/z: 283 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([C:16]1([NH2:39])[C:22](=[O:23])[N:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]1=[O:38])=O)C>>[CH:1]1([CH2:6][C:7]([NH:39][C@H:16]([C:22]([NH:39][CH:16]2[C:17](=[O:38])[N:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[N:21]([CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:22]2=[O:23])=[O:23])[CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white amorphous solid. Purification was by flash chromatography eluting with CH2C2/EtOAc (2:1 gradient to 3:2). Rf=0.29 (CH2Cl2/EtOAc, 2:1).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]([CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:10]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(CCC(C)C)c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of N-(3-methylbutyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (1.20 g, 3.82 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.229 g, 5.73 mmol). The mixture was stirred for 30 min, and methyl 4-(bromomethyl)benzoate (1.05 g, 4.58 mmol) was added. The mixture was stirred at 60° C. for 1.5 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-40:60) to give the title compound (1.34 g, yield 76%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:3]=[CH:2]1.[Cl:14][C:15]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]SC1SCC(=O)N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:3]=[CH:2]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(CCCCCCOc2ccc(OC)cc2Cl)c1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Stir for 24 hours at room temperature 3.7 gm. dimethyl 4,5-imidazole dicarboxylate, 3.7 gm. of the iodide prepared in Examples 2 and 3, 25 ml. DMF and 2.8 gm potassium carbonate. Remove the solvent, extract the residue with methylene chloride, filter, wash methylene chloride fractions with water, elute on a silica column with 100% methylene chloride then 10% methanol/methylene chloride to recover the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=2)=[C:4]([O:31][CH3:32])[CH:3]=1.[CH3:33]B1OB(C)OB(C)O1>>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([CH3:33])[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:29][CH:30]=1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CB1OB(C)OB(C)O1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 95.4 %

Procedure:
Following General Procedure J, tert-butyl 4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (52 mg, 0.10 mmol) was reacted with trimethylboroxine (13 mg, 0.10 mmol) to afford the desired product (43 mg, 95%) as a grey solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[Cl:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[Cl:11]
Reactant: C1=COCCC1
Reactant: Clc1c(Br)ccc2[nH]cnc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Product: Clc1c(Br)ccc2c1ncn2C1CCCCO1
Yield: 90.1 %

Procedure:
To a solution of 128 (22 g, 0.095 mol) in dry THF (660 mL) was added 3,4-dihydro-2H-pyran (24 g, 0.286 mol) and camphorsulfonic acid (2.2 g, 0.00948 mol) and the solution was heated to reflux for 16 h. The resulting mixture was concentrated, and the residue obtained was purified by SiO2 chromatography eluting with 20% EtOAc/petroleum ether to afford 27 g (90%) of 5-bromo-4-chloro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (130) as pale yellow solid.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C[O-].[Na+].[NH2:26][NH:27][C:28](=O)[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>C(O)C.CO>[CH2:31]([N:30]([CH2:33][CH3:34])[CH2:29][C:28]1[NH:27][N:26]=[C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)[CH3:32]
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CCN(CC)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCN(CC)Cc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Temperature: 0 °C
Yield: 11 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.400 g, 1.25 mmol) in 4 mL of anhydrous ethanol was prepared and cooled to 0° C. An excess of a commercial solution of sodium methoxide in methanol (0.858 mL, 4.37 M)) was added followed by 3 equivalents of N-amino-2-(diethylamino)acetamide (0.545 g, 3.75 mmol) as a solid. The reaction mixture was heated to reflux temperature in a sealed tube for 2 days. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The residue was purified by preparative HPLC (0.052 g, 11% yield): 1H NMR (CD3OD) δ 8.70 (s, 1H), 8.11–8.02 (m, 3H), 7.67 (d, 1H), 7.29 (td, 2H), 3.8 (s, 1H), 2.68 (q, 4H), 1.15 (t, 3H); ES-MS (m/z) 365 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C@@H:9]([C:21](=[O:33])[NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[N:10](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C@@H:9]([C:21]([NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[O:33])[NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (S)-tert-butyl 7-nitro-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound C of Example 20, 4.45 g, 9.86 mmol) in CH2Cl2 (49 mL) was added TFA (11.4 mL, 148 mmol). The resulting solution was stirred at room temperature for 1 h and then quenched carefully with sat. NaHCO3 until bubbling ceased. The aqueous layer was extracted with CH2Cl2 (3×), and the combined organic extracts were washed with sat. NaHCO3, water and sat. NaCl. The extracts were dried over Na2SO4, filtered and concentrated in vacuo to give 3.38 g of the title compound as a pale yellow solid. 1H NMR (CDCl3, mixture of amide rotamers) δ 8.05 (d, J=6.6 Hz, 1H), 7.97-7.88 (m, 1H), 7.53-7.32 (m, 2H), 7.22-6.94 (m, 4H), 5.25-5.03 (m, 1H), 4.18-3.94 (m, 2H), 3.83-3.65 (m, 1H), 3.35 (dd, J=16.7, 5.1 Hz, 1H), 3.09 (dd, J=17.1, 9.1 Hz, 1H), 2.90-2.70 (m, 2H), 2.18-1.96 (m, 1H), 1.93-1.44 (m, 3H); MS (ESI+) m/z 352.2 (M+H)+.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH2:30][C:31](O)=[O:32].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>CN(C=O)C>[O:23]=[C:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH2:30][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C@@H:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:32]
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: O=C(O)CCN1CCCC1=O
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: CN(C)C=O
Product: O=C1CCCN1CCC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one (0.25 mmol) in dry DMF (3 mL) was added 3-(2-oxopyrrolidin-1-yl)propanoic acid (47 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol). The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with High pH prep-LCMS to provide the title compound (53 mg, 47%) as white powders. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.26-1.51 (m, 6H), 1.55-1.73 (m, 2H), 1.75-2.08 (m, 9H), 2.19-2.37 (m, 5H), 2.56 (t, J=11.91 Hz, 2H), 2.64 (t, J=7.03 Hz, 2H), 2.87-3.14 (m, 5H), 3.43-3.55 (m, 4H), 3.55-3.69 (m, 1H), 3.99 (d, J=13.28 Hz, 1H), 4.54 (d, J=13.28 Hz, 1H). MS (M+1): 446.3