Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=N)OCC)[CH:19]=1.C([O-])(=O)C.[Na+]>C(O)C>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(c1ccc(N)c(N)c1)n1ccnc1
Reactant: CCOC(=N)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccc2[nH]c(-c3cccnc3)nc2c1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 5.05 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-1,2-benzenediamine, 6.45 parts of ethyl 3-pyridinecarboximidate dihydrochloride, 4.27 parts of sodium acetate and 80 parts of absolute ethanol was stirred first for 16 hours at room temperature and for 1 hour at reflux. The reaction mixture was evaporated. There were added successively 50 parts of water and ammonium hydroxide. The product was filtered off, washed with water and 2-propanol and crystallized from ethanol. The product was filtered off and dried, yielding 5.1 parts (70%) of 5-[1-(1H-imidazol-1-yl)ethyl]-2-(3-pyridinyl)-1H-benzimidazole; mp. 253.7° C. (compound 189).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@]2(C(=O)Nc3cc(Cl)ccc32)N1CC1CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)CCC(=O)N2CC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac) (2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step H) (114 mg, 0.274 mmol) in DMF (2 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (10.98 mg, 0.274 mmol) followed by (2-(chloromethoxy)ethyl)trimethylsilane (48.4 μL, 0.274 mmol). The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred at room temperature for 24 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with 1M LiCl, sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[CH:4][CH:3]=1.[C:15](OC)(=[O:17])[CH3:16]>>[C:15]([O:14][CH2:13][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:17])[CH3:16]
Reactant: OCC(CO)CCc1ccc(Br)cc1
Reactant: COC(C)=O
Product: CC(=O)OC[C@@H](CO)CCc1ccc(Br)cc1

Procedure:
To a solution of 4.6 g of 4-(4-bromophenyl)-2-(hydroxymethyl)butanol in 300 ml of methyl acetate was added 33.1 g of the above PPL preparation. The mixture was stirred while the progress of the reaction was monitored by HPLC method A. When the consumption of diol was complete, the mixture was immediately filtered and the filtrate was concentrated to an oil under vacuum. The oil was purified by flash chromatography on 200 g of silica with 3:1 ethyl acetate:hexane to obtain 4.82 g of the desired product as an oil. The 1-naphthyl carbamate derivative of a small portion of the product was prepared and analyzed by HPLC method B to determine that the product was 99% R and 1% S; the R isomer eluted at 9.4 minutes, and the S isomer at 12.6 minutes.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CCCCCC.[CH3:19][C:20](=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:20]([CH3:21])([CH3:19])[CH2:1][C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)=[CH:23]1
Reactant: CC(C)=C1C=Cc2ccccc21
Reactant: Cc1csc(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1csc(CC(C)(C)C2=CCc3ccccc32)n1
Temperature: -78 °C
Reaction time: 14 h

Procedure:
A solution of 2,4-dimethyl-1,3-thiazole (3.2 g, 28.1 mmol) in 20 ml of tetrahydrofuran was cooled to −78° C. and 15% n-butyl-lithium in hexane (17.5 ml, 28 mmol) was added during 15 min with stirring. The resulting yellow suspension was stirred for 20 min and then a solution of 1-(1-methylethylidene)-1H-indene (4.6 g, 29 mmol) in 5 ml of tetrahydrofuran added with vigorous stirring while the temperature was maintained at −78° C. The reaction mixture was allowed to reach room temperature and for 14 h. The resulting mixture was hydrolyzed with a saturated ammonium chloride solution.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].CC1C=CC(S(O[CH2:41][C@H:42]2[CH2:47][O:46][CH2:45][CH2:44][O:43]2)(=O)=O)=CC=1>CN(C)C=O>[O:43]1[CH2:44][CH2:45][O:46][CH2:47][C@@H:42]1[CH2:41][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1N(C[C@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93.1 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.30 g, 1.07 mmol) and cesium carbonate (0.56 g, 1.71 mmol) in N,N-dimethylformamide (7 mL) was stirred at ambient temperature under nitrogen for 40 min. To this mixture was added potassium iodide (0.05 g, 0.28 mmol) and (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (0.38 g, 1.40 mmol). The reaction was warmed to 60° C. and stirred for 2 h. The solvent was removed under reduced pressure, and the residue was suspended in ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure and the product was purified by flash column chromatography with dichloromethane/t-butyl methyl ether (19:1) to afford 1′-[(2S)-1,4-dioxan-2-ylmethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.38 g, 93%) as a colorless solid: mp 147-149° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.34-7.28 (m, 1H), 7.17 (d, J=7.2 Hz, 1H), 7.09-7.02 (m, 2H), 6.51 (s, 1H), 6.16, 6.12 (s, 1H), 5.89-5.86 (m, 2H), 4.81, 4.80 (2ABq, 2H), 3.99-3.55 (m, 8H), 3.46-3.38 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.9, 156.0, 155.9, 149.01, 148.98, 142.7, 142.6, 142.5, 142.4, 132.3, 132.2, 129.02, 128.97, 123.94, 123.87, 123.6, 119.7, 119.5, 109.6, 109.4, 103.14, 103.07, 101.64, 101.62, 93.74, 93.72, 80.5, 80.4, 73.3, 73.2, 69.4, 69.2, 66.8, 66.7, 66.53, 66.49, 58.3, 58.2, 41.9, 41.7; MS (ES+) m/z 381.9 (M+1).
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]1[CH2:16][CH2:15][CH2:14][S:13]1.[CH3:17][N:18]=[C:19]=[S:20].C>CCCCCC.C(O)CC.C(OC(C)C)(C)C.C(OCC)(=O)C.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:17][NH:18][C:19]([C:12]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][N:6]=2)[CH2:16][CH2:15][CH2:14][S:13]1)=[S:20]
Reactant: CN=C=S
Reactant: c1cnc(C2CCCS2)cn1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CNC(=S)C1(c2cnccn2)CCCS1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
A mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 70 cc) is added dropwise and in the course of 15 minutes to a 1.6 M solution of n-butyllithium in hexane (119 cc), kept under a nitrogen atmosphere and at a temperature of about -60° C. A solution of 2-pyrazinyltetrahydrothiophen (19.5 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 70 cc) is then added in the course of 15 minutes. After stirring for 15 minutes, a solution of methyl isothiocyanate (12.7 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 30 cc) is added in the course of 15 minutes. The reaction mixture is subsequently stirred for 45 minutes at -65° C. and then for 1 hour whilst allowing the temperature to rise gradually to about 20° C. It is then run into a mixture of ethyl acetate (300 cc) and distilled water (500 cc). After decantation, the aqueous solution is extracted twice with ethyl acetate (400 cc in total). The organic extracts are combined, washed three times with distilled water (1500 cc in total), dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 70° C. The product obtained (33.3 g) is chromatographed on neutral silica gel (330 g) contained in a column of diameter 4.2 cm. Elution is carried out successively with a cyclohexane/ethyl acetate mixture (90/10 by volume; 4000 cc) and then with a cyclohexane/ethyl acetate mixture (80/20 by volume; 7000 cc), 500 cc fractions being collected. Fractions 13 to 22 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The product obtained (11 g) is dissolved in a boiling mixture of propanol and diisopropyl ether (75/25 by volume; 48 cc); decolourising charcoal (0.2 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 18 hours at 5° C. The resulting crystals are filtered off, washed with a propanol/diisopropyl ether mixture (75/25 by volume; 10 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. N-Methyl-2-pyrazinyltetrahydrothiophen-2-carbothioamide (4.9 g), melting at 127° C., is thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(NCCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CCNC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of N-(3-nitrophenethyl)-2,2,2-trifluoroacetamide (9.05 g, 34.5 mmol) in MeOH (125 ml) at RT was added 10% Pd/C (50% H2O wet) (3.67 g, 1.73 mmol). The resulting suspension was placed under H2 (3 atm) at RT overnight. The reaction was filtered through Celite® and the cake rinsed with MeOH. The filtrate was concentrated to provide N-(3-aminophenethyl)-2,2,2-trifluoroacetamide as an oil (7.83 g, 98% yield). 1H NMR (300 MHz, CDCl3): δ 7.16-7.12 (m, 1H), 6.62-6.58 (m, 2H), 6.54-6.53 (m, 1H), 6.34 (brs, 1H), 3.61 (q, J=6.40 Hz, 2H), 2.80 (t, J=6.40 Hz, 2H), 2.68 (brs, 2H); MS (ESI) m/z: 233.3 (M+H+).
Reaction SMILES: Cl[CH:2]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[O:6][C:7]=1[CH2:8][O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:19]1([CH:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:3]2[CH:4]=[C:5]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:6][C:7]=2[CH2:8][O:9][CH3:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1oc(-c2ccc(OC)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-(methoxymethyl)furan-2-yl}-2-methoxypyridine (0.4 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.4 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 70% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.45 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (91 mg, 14%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.[H-].C([Al+]C(C)C)(C)C.CO.O>C(Cl)Cl>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([OH:14])[CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: OCCC(O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 5.0 g of ethyl-4-chlorobenzoylacetate in 100 ml of methylene chloride cooled to -30° C., 77.3 ml of diisopropylaluminium hydride (1.0 mol/l toluene solution) was added, and the resulting mixture was stirred for 30 minutes and then brought back to room temperature over 3 hours, and 4.14 g of methanol and 24.3 g of water were added carefully, and the mixture was stirred for another 1.5 hours. The precipitate was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate=1/1), to obtain 2.45 g of the title compound as a pale yellow oily substance.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:34]([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:35]1
Reactant: OCC1CCNC1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCC(CO)C2)c(C(=O)O)c1
Yield: 25 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and rac-pyrrolidin-3-yl-methanol and obtained in 25% yield. MS (m/e): 313.0 MH−(100%).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([NH:31][CH2:32][C:33]4[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)=[N:29][CH:30]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:19]1([C:18]2[C:13]3[C:12]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH:31][CH2:32][C:33]5[CH:34]=[N:35][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:37][CH:38]=5)=[N:29][CH:30]=4)=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3ccc(C(F)(F)F)nc3)nc2)c2c(C3CCCC3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncnc(C5CCCC5)c34)cn2)cn1
Reaction time: 3 h
Yield: 26 %

Procedure:
To [5-(7-benzenesulfonyl-4-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (53, 0.010 g, 0.017 mmol) in 0.597 mL of tetrahydrofuran under nitrogen, tetra-n-butylammonium fluoride (0.0557 mL, 1.00 M in tetrahydrofuran, 0.0557 mmol) was added. The reaction was stirred for 3 hours, then quenched with water. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% methanol in dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (P-0104, 0.002 g). MS (ESI) [M+H+]+=453.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.BrC1C=CC([Cl:25])=C(Cl)C=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[CH:2][C:7]=1[Cl:25]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Product: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 42.4 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-1,2-dichlorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 19 (230 mg, yield 42.4%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].CI.[CH3:18]N1C2C=C(C(OC)=O)C=CC=2N=C1>C1COCC1>[CH3:18][N:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: COC(=O)c1ccc2ncn(C)c2c1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)ncn2C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of methyl 1H-benzo[d]imidazole-6-carboxylate (9.5 g, 53.9 mmol) in THF (100 mL) had NaH (2.59 g, 64.7 mmol) added at 0° C. After stirring for 30 min, CH3I (13.23 g, 93.2 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was then quenched by addition of water and extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a mixture of two isomeric products methyl 1-methyl-1H-benzo[d]imidazole-6-carboxylate and methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate (8.0 g, Yield 78%). LCMS (m/z): 191.06 (M+1). This crude mixture was used directly in the next step.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34]4)=[CH:28][CH:27]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1COCC1.ClCCl>[CH2:38]([N:35]1[CH2:36][CH2:37][CH:33]([O:32][C:29]2[CH:30]=[CH:31][C:26]([CH2:24][C:16]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[S:19][C:15]=3[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:10][CH:11]=3)=[CH:27][CH:28]=2)[CH2:34]1)[CH3:39]
Reactant: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OCCN5CCCC5)cc4)sc4ccccc34)cc2)C1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCN1CCC(Oc2ccc(Cc3c(-c4ccc(OCCN5CCCC5)cc4)sc4ccccc34)cc2)C1
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
The ketone of Example 170 (112 mg, 0.20 mmol) in THF (3 mL) was treated with lithium aluminum hydride (25 mg) at 0° C. for 1 h, then quenched with water (1 mL) and sodium hydroxide (5.0M, 1 mL). Stirring continued for 20 min. The reaction mixture was diluted with brine (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white foam-like material. This material was dissolved in dichloromethane (5 mL), treated with triethylsilane (0.25 mL) and trifluroacetic acid (0.20 mL) at 0° C. for 1 h, and then concentrated under reduced pressure. The residue was extracted with dichloromethane (50 mL×3) which was washed with saturated aqueous sodium bicarbonate (50 mL). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product as a colorless oil (87 mg, 78%).
Reaction SMILES: C(O)C=C.CC(C)([O-])C.[K+].[C:11]([S:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][CH:17]=1)(=O)[CH3:12].C([O:31][CH:32]1[NH:35]C(=O)C1)(=O)C>O1CCCC1>[CH2:23]([O:22][C:20]([C:19]1[CH:26]=[CH:27][C:16]([CH2:15][S:14][CH:11]2[NH:35][C:32](=[O:31])[CH2:12]2)=[CH:17][CH:18]=1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Reactant: CC(=O)OC1CC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc(CSC2CC(=O)N2)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
Allyl alcohol (27 ml) in dry tetrahydrofuran (50 ml) was added dropwise to a solution of potassium tert-butoxide (4.93 g, 0.044 moles) in dry tetrahydrofuran (100 ml). After stirring for 5 minutes a solution of allyl 4-(acetylthiomethyl)benzoate (10.1 g, 0.04 moles) in dry tetrahydrofuran (100 ml) was added dropwise. After stirring for 15 minutes a solution of 4-acetoxyazetidin-2-one (5.16 g, 0.04 moles) was added dropwise. The mixture was stirred for 1 hour and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous was extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated. Flash chromatography (silica gel, ethyl acetate-petrol) gave 4-(4-Allyloxycarbonylbenzylthio)azetidin-2-one as an oil (9.1 g, 82% yield. 1H NMR δ (CDCl3) 2.84 (1H, dd, H3a), 4.31 (1H, dd, H3b), 3.88 (2H, s, S--CH2), 4.68 (1H, dd, H4), 4.78 (2H, m, CH2O), 5.35 (2H, m, CH2CH--), 6.05 (1H, m, CHCH2), 6.07 (1H, br. singlet, N--H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc([N+](=O)[O-])cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, yellow solid (79 mg, 89%), MS (ISP) m/z=356.5 [(M+H)+], mp 313.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
Following the general method as outlined in Intermediate 223, starting from tert-butyl{2-[(4-aminophenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 222) and benzoyl chloride, the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.