Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[NH:7][CH2:8][CH3:9].[CH3:16][CH:17]([CH2:21][S:22][CH3:23])[C:18](O)=[O:19].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClC(Cl)C>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N:7]([CH2:8][CH3:9])[C:18](=[O:19])[CH:17]([CH3:16])[CH2:21][S:22][CH3:23]
Reactant: CCNc1sc(-c2cccnc2)nc1Cl
Reactant: CSCC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethylamine (800 mg, 3.33 mmol) in dichloroethane (30 mL) was added 2-methyl-3-methylsulfanyl-propionic acid (prepared according to literature reference J. Org. Chem. 1996, 51, 1026-1029) (894 mg, 6.66 mmol) and N,N-dimethylaminopyridine (814 mg, 6.66 mmol) followed by triethylamine (0.2 mL, 1.44 mmol). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 9.99 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (715 mg, 60%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH2:40])=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH:40][C:2]3[N:21]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: FC(F)COc1ccccc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5ccccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-Difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.371 g, 1.20 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.471 g, 1.80 mmol) in a manner analogous to Example 311a and 311b to give product (0.388 g, 60%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.75 (d, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.42 (m, 3H), 7.26 (m, 1H), 7.15 (m, 1H), 7.05 (m, 2H), 6.22 (br m, 1H), 4.39 (m, 2H), 3.45 (m, 4H), 2.76 (m, 4H), 1.41 (s, 9H). MS=536 (MH)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:22][CH2:23][CH2:24]Cl)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:13]([O:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:22][CH2:23][CH2:24][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)([CH3:14])([CH3:15])[CH3:16]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Temperature: 25 °C
Yield: 36 %

Procedure:
4-phenyl piperidin (0.21 g, 1.2 mmol), compound 19 (0.3 g, 0.86 mmol), KI (0.43 g, 2.59 mmol) and K2CO3 (0.59 g, 4.3 mmol) were added to 50 mL CH3CN, and the solution was refluxed under argon atmosphere for 12 h. After cooling to room temperature, the inorganic salts were filtered, and the filtrate was evaporated to dryness. The residue was redissolved in CH2Cl2 and chromatographed on a silica gel TLC plate that was developed with the following eluents: 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as yellow oil (36% yield). 1H NMR (CDCl3) δ 8.492 (dd, 1H, Ar), 7.619 (ddd, 1H, Ar), 7.571 (t, 2H, Ar), 7.272 (t, 2H, Ar), 7.203 (d, 2H, Ar), 7.167 (t, 1H, Ar), 7.107 (m, 2H, Ar), 7.024 (t, 2H, Ar), 3.770 (s, 2H, —CH2—), 3.695, (s, 2H, —CH2—), 3.003 (d, 2H, —CH2—), 2.524 (t, 2H, —CH2—), 2.459 (m, 1H, —CH—), 2.367 (t, 2H, —CH2—), 2.01 (ddd, 2H, —CH2—), 1.783 (m, 6H), 1.359 (s, 9H, —C(CH3)3). Mass Spec.=472.34 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[CH3:33][NH:34][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(F)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(F)c3)c2O1

Procedure:
The title compound was prepared (0.026 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.055 g, 0.18 mmol) and methylamine (0.12 g, 3.9 mmol). mp 238-240° C.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl>CO.[Fe]>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1cc(F)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 5.55 g (31.876 mmole) of 4,5-difluoro-2-nitroaniline in 50 mL of MeOH, were added 100 mL of 2N HCl and 8.90 g (159.380 mmole) of iron powder. The reaction mixture was stirred at room temperature for 2 hr and then filtered. The filtrate was neutralized with conc. NH4OH to ~pH 8. The resulting suspension was filtered again and the filter cake was washed thoroughly with MeOH. The filtrate and washings were combined, concentrated to ~100 mL, and extracted with CHCl3 (100 mL×3). The CHCl3 solution was washed with a sat. NaCl solution (100 mL×2), dried (Na2SO4), and evaporated. The residue was coevaporated with CHCl3 to give 3.515 g (77%) of 10. This material was used in the next reaction without further purification. A brown crystalline sample of 10 was obtained by recrystallization from CCl4. 1H NMR (DMSO-d6): d 6.44 (t, 2, 3-H and 6-H, JF-H =10.5 H), 4.59 (br. s, 4, 2×NH2).
Reaction SMILES: Cl.C([NH:4][C@H:5]([C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:6][C:7](=[O:9])[OH:8])=O.[CH3:24]O>>[CH3:24][O:8][C:7](=[O:9])[CH2:6][CH:5]1[C:10](=[O:11])[NH:12][CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21](=[O:23])[NH:4]1
Reactant: CO
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution containing 11.6 g of hydrogen chloride dissolved in 400 ml of methanol was fed 61.6 g of N-formyl-α-L-aspartyl-L-phenylalanine and the resulting mixture was reacted at 40°-45° C. for 6 hours. Then, the resulting solution was distilled under reduced pressure to remove methanol. The residue was dissolved in 100 ml of dioxane and 200 ml of water. A 20% aqueous sodium carbonate solution was added dropwise to the resulting solution so as to adjust its pH at 7.8 and thereafter further reaction was conducted at 40°-45° C. for 20 hours. Then, the reaction mixture was cooled to room temperature and the crystal thereby deposited was filtered, washed with dioxane and then with water, and dried to obtain 40.6 g of 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: FC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(F)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a solution of the product of Step 1 (252 mg, 1.18 mmol) in isopropyl alcohol (5 ml) was added 2,6-lutidine (197 mg, 214 uL, 1.84 mmol) and potassium iodide (few mg). The resulting suspension was warmed to 80° C. Solid 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (221 mg, 0.591 mmol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80° C. The mixture was concentrated and the resulting residue purified by silica gel chromatography (methylene chloride to methylene/methanol 95:5 gradient) to afford the title compound (160 mg, 54%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1.C(O)(=O)C>[Pd].C(O)C>[CH3:18][C:17]1[NH:20][C:12]2[CH:11]=[C:10]([C:9](=[O:23])[NH:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:15]=[CH:14][C:13]=2[N:16]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2[nH]1
Temperature: 80 °C
Reaction time: 7 h
Yield: 67.3 %

Procedure:
5% palladium/carbon (0.10 g) is added to a mixture of preliminarily purified N-(pyridylmethyl)-4-acetylamino-3-nitrobenzamide (1.00 g), acetic acid (8 ml), and ethanol (12 ml), and then solution is stirred for seven hours at 80° C. under a nitrogen environment. The solids are separated through filtration and the filtrate is then concentrated. Ethyl acetate is added to the residue and crystals are formed. The crystals are separated through filtration, then dried and thus, 2-methyl-5-[(2-pyridylmethyl) carbamoyl]benzimidazole (0.57 g) is obtained. 1H-NMR (CDCl3, δ): 2.52 (3H, s), 4.59 (2H, d, J=5.9 Hz), 7.26 (1H, dd, J=7.1 and 5.1 Hz), 7.33 (1H, d, J=7.8 Hz), 7.50 (1H, d, J=8.4 Hz), 7.72-7.78 (2H, m), 8.08(1H, s), 8.51 (1H, d, J=4.8 Hz), 9.04 (1H, t, J=5.8 Hz), 12.44 (1H, s).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:29])=[CH:23][CH:22]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: S=C(Nc1ccc(Cl)cc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with 4-chlorophenyl isothiocyanate in the manner described in Example 10 to obtain the title compound as the hydrochloride.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21]([NH2:23])[CH3:22]>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:23][CH2:21][CH3:22])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 130 °C
Yield: 55.3 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), ethylamine hydrochloride (0.056 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.099 g, 55%). 1H NMR (500 MHz, CDCl3): δ 7.51-7.46 (m, 2H), 7.43-7.38 (m, 3H), 5.21-5.12 (m, 1H), 2.89-2.80 (m, 2H), 1.72 (s, 9H), 1.01 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.9, 135.2, 131.7, 129.7, 128.7, 125.4, 107.1, 61.7, 39.3, 27.8, 15.0; Mass Spectrum: M−H+ 309.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]=[CH:18][CH:19](O)[CH:20]=[CH2:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:18]([CH:19]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:5]1[S:6][C:2]([I:1])=[CH:3][CH:4]=1)[CH:20]=[CH2:21])=[CH2:17]
Reactant: O=C(O)CCCCCOCc1ccc(I)s1
Reactant: C=CC(O)C=C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C=C)OC(=O)CCCCCOCc1ccc(I)s1
Reaction time: 12 h
Yield: 78.3 %

Procedure:
A mixture of 6-[5-iodo-(2-thienyl)]methoxyhexanoic acid (13.20 g, 37.3 mmol), 1,4-pentadien-3-ol (3.13 g, 37.3 mmol), dicyclohexylcarbodiimide (7.70 g, 37.3 mmol) and 4-dimethylaminopyridine (0.1 g) in DCM (250 mL) is stirred for 12 h under nitrogen. The solid is removed by filtration and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with petroleum ether/diethyl ether (90:10), to give the product as a brown oil (12.27 g, 77%) NMR showed the expected signals.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][CH:8]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(C2CC2)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
2-(4-Cyclopropylphenyl)acetic acid (2.82 g, 16.003 mmol) was combined with (R)-4-benzyloxazolidin-2-one (3.4030 g, 19.204 mmol) in toluene (14 mL) The suspension was treated with triethylamine (6.6917 mL, 48.010 mmol) and then heated to 80° C. The solution was treated dropwise with a solution of pivaloyl chloride (1.9893 mL, 16.003 mmol) in toluene (3.5 mL). The reaction was heated overnight at 80° C. The reaction was cooled and washed with 2N HCl and then separated. The aqueous layer was washed with toluene, and the combined organics were then washed with 2N HCl, water, saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product was subjected to chromatography on SiO2 eluting with 9:1 hexanes/ethyl acetate to yield (R)-4-benzyl-3-(2-(4-cyclopropylphenyl)acetyl)oxazolidin-2-one (3.43 g, 64%). 1H NMR (CDCl3, 400 MHz) □ 7.33-7.20 (m, 5H), 7.16-7.11 (m, 2H), 7.05 (d, J=8.2, 2H), 4.70-4.63 (m, 1H), 4.32-4.14 (m, 4H), 3.26 (dd, J1=3.2, J2=13.3, 1H), 2.75 (dd, J1=9.5, J2=13.3, 1H), 1.93-1.85 (m, 1H), 0.98-0.92 (m, 2H), 0.72-0.66 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]([C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)=[O:11])=[CH:13]1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)ccn1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)ccn1

Procedure:
Compound 4ee was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 53 mg (0.20 mmol) of 3-(2-methyl-pyridine-4-carbonyl)-1H-quinolin-4-one 3h, 3 mL of anhydrous dimethylformamide, and 49 mg (0.26 mmol) of 2-fluorobenzylbromide. The crude product 4ee was purified by flash chromatography to yield 21 mg of a colorless solid 4ee: LC-MSD, m/z for C23H17FN2O2, [M+H]+=373.5, [M+2H]+=374.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.296 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.60 (s, 3H), 5.43 (s, 2H), 7.02-7.20 (m, 3H), 7.32-7.40 (m, 2H), 7.40-7.47 (m, 3H), 7.64 (t, 1H), 8.44 (m, 2H), 8.60 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][O:20][CH3:21]>CC(C)=O>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(O)cccc2o1
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cccc2oc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-hydroxy-2-methylbenzofuran (7.1 g, 0.048 M), anhydrous powdered potassium carbonate (19.87 g) and acetone (82 ml), was added dropwise bromomethoxymethane (11.99 g, 7.88 ml, 0.0959 M) with ice cooling. After the addition was complete the reaction mixture was stirred at room temperature overnight, filtered and evaporated. The residual oil was distilled to give 4-methoxymethoxy-2-methylbenzofuran, b.p. 94°-97° C./0.8 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([F:21])=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([F:21])=[CH:14][C:15]([NH:18][C:19]([NH:24][CH2:23][CH2:22][NH2:25])=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(N=C=S)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Reactant: NCCN
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate (0.42 g) in methylene chloride (50 mL) is added dropwise over 15 minutes to 1,2-ethylenediamine (0.45 mL) in solution in methylene chloride (100 mL). The mixture is stirred for 10 minutes at room temperature, then rotary evaporated. The residue is triturated for 30 minutes with ether (100 mL). The resulting white suspension is filtered and the solid is dried in vacuo overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]4[C:35]5[CH:36]=[CH:37][CH:38]=[N:39][C:34]=5[CH2:33][O:32][C:31]5[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: O=C1CN([C@@H]2CCNC2)Cc2ccc(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CC[C@@H](N3CC(=O)Nc4cc(Cl)ccc4C3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of (R)-8-chloro-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.198 g, 0.58 mmol) in acetonitrile/water (8:2) (5.8 mL) was added K2CO3 (0.655 g, 4.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.183 g, 0.48 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.077 g, 28%). 1H-NMR (CDCl3): δ1.55 (s, 6H), 1.74 (septet, 1H), 2.01 (sextet, 1H), 2.32-2.60 (m, 6H), 2.76 (t, 1H), 3.26 (pentet, 1H), 3.43 (d, 1H), 3.46 (s, 2H), 3.74 (s, 2H), 5.27 (bs, 2H), 6.12 (t, 1H), 6.78 (d, 1H), 6.96 (s, 1H), 7.06 (dd, 1H), 7.13 (d, 1H), 7.19-7.27 (m, 2H), 7.44 (d, 1H), 7.55 (dd, 1H), 8.47 (dd, 1H), 8.49 (s, 1H). ESI-MS m/z: 559 (M+1), retention time 1.24.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>C1(C)C=CC=CC=1>[CH3:11][O:12][CH:13]([O:16][CH3:17])[C:14](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[NH2:15]
Reactant: COC(CN)OC
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: COC(OC)C(N)=Cc1cccc(Cl)c1Cl

Procedure:
A mixture of 65.7 g. (0.375 mole) of 2,3-dichlorobenzaldehyde and 39.4 g. (0.375 mole) of 2,2-dimethoxyethylamine was refluxed azeotropically in 150 cc. of toluene. When all the water was removed (1-2 hours), the solution was concentrated and distilled to give 2,2-dimethoxy-N-(2,3-dichlorobenzylidene)ethylamine, b.p. 140° C. (0.7 mm.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:12]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[S:6][CH:7]=1
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2scc(CBr)c2c1
Yield: 51.8 %

Procedure:
5-Fluoro-3-methyl-benzo[b]thiophene (1.7 g, 10.24 mmol) was reacted with N-bromo succinimide (2 g, 1126 mmol) and benzoyl peroxide (2 mg) in CCl4 (15 mL). The resulting reaction mass was refluxed using photoelectric radiation. The reaction was monitored by TLC (100% hexane). The reaction mass was quenched with water and separated the CCl4 layer. The aqueous layer was extracted with chloroform and the organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (100% hexane) afforded 1.3 g of the product (52% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>>[Br:10][C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: C1CSCCN1
Reactant: COc1cc(Br)cc(Br)c1
Product: COc1cc(Br)cc(N2CCSCC2)c1

Procedure:
This material was prepared starting from 1,3-dibromo-5-methoxy-benzene following general procedures described in these Examples, but using thiomorpholine instead of pyrrolidine.