Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:12]2=[N:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:22][CH3:23])C1C=CC=CC=1>CO.Cl.[OH-].[OH-].[Pd+2]>[CH2:22]([C:9]1[N:8]=[C:12]2[NH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=1)[CH3:23]
Reactant: CCc1nc2c(C)cc(C(=O)OC)nc2n1Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCc1nc2[nH]c(C(=O)OC)cc(C)c-2n1
Reaction time: 24 h
Yield: 47 %

Procedure:
A mixture of 750 mg of the crude product of Step F in MeOH (30 mL), concentrated aqueous HCl (1 mL), and 100 mg of moist Pearlman's catalyst were shaken under 1 atm. H2 for 24 hours. The reaction was incomplete so 100 mg more of the catalyst was added and the reaction was shaken as described above for an additional 24 hours. Filtration, concentration, and extraction from dilute NH4OH with EtOAc followed by drying (Na2SO4), concentration, and purification (SiO2, 5% MeOH/EtOAc) gave 250 mg of the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:6]=1[CH:7]=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:10]3[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH:9]=3)[CH:7]=[O:8])=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: O=Cc1cc(I)ccc1OCCO
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(2-hydroxyethoxy)-5-iodobenzaldehyde and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 5.53 g (86% of theoretical); C22H16ClNO3 (M=377.820); calc.: molpeak (M+H)+: 378/380 (Cl); found: molpeak (M+H)+: 378/380 (Cl); HPLC-MS: 5.79 minutes (method B).
Reaction SMILES: [S:1]1[C:5]([CH2:6]O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:13][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2ccccc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of commercially available benzo[b]thiophen-2-ylmethanol (123 mg; 0.73 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (242 mg; 0.73 mmol), and with PPh3 (191 mg; 0.73 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)benzo[b]thiophene as a yellow/orange oil which was directly used for the next reaction.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([C@H:25]1[CH2:30][C@H:29]2[C@H:31]3[C@H:40]([CH2:41][CH2:42][C@:27]2([CH3:28])[C@H:26]1[O:44][C:45](=[O:48])[CH2:46]Br)[C@@H:39]1[C:34](=[CH:35][C:36](=[O:43])[CH2:37][CH2:38]1)[CH2:33][CH2:32]3)[CH3:24]>CC(C)=O>[CH2:23]([C@H:25]1[CH2:30][C@H:29]2[C@H:31]3[C@H:40]([CH2:41][CH2:42][C@:27]2([CH3:28])[C@H:26]1[O:44][C:45](=[O:48])[CH2:46][O:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@@H:39]1[C:34](=[CH:35][C:36](=[O:43])[CH2:37][CH2:38]1)[CH2:33][CH2:32]3)[CH3:24]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 63.9 %

Procedure:
To 100 ml of 30% aqueous acetone are added 1.0 g of myristic acid and 0.8 g of potassium carbonate, followed by addition of 1.16 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 5 hours. After cooling, the reaction mixture is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography, elution being carried out with 600 ml of toluene-diisopropyl ether (19:1). The eluate is evaporated under reduced pressure to remove the solvent, giving a light-yellow viscous oil. This product is allowed to stand at room temperature (15°-25° C.) to give 1.0 g of the above-identified compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].Cl>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A 100 ml round-bottomed flash was charged with pyridine (30 ml) and 7.10 g (34.8 mmol) of (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone from Example I, then cooled to 0° C. under an atmosphere of nitrogen. Butanoyl chloride (4.10 g, 38.3 mmol) was added dropwise to the solution via syringe. The reaction mixture was stirred for 30 min at 0° C., warmed to 23° C. over 15 min then poured into 1N aqueous hydrochloric acid (400 ml). The aqueous solution was extracted with EtOAc (2×200 ml). The combined EtOAc extracts were successively washed with 5% aqueous sodium bicarbonate solution (300 ml), saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate (5 g), filtered and concentrated in vacuo to provide 9.8 g of crude product as a solid. Recrystallization from ethyl acetae/hexanes (2:1, 35 ml) yielded 7.61 g (80%) of pure (±)-6-(4'-butanoyloxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless needles, m.p. 112°-113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)(=[O:25])=[O:24])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OC)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
To a mixed solution of ethyl 7-amino-5-methoxy-1H-indole-2-carboxylate (0.40 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.38 g) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85-35:65), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (370 mg, yield 57%) as colorless needle crystals. melting point 158-159° C.
Reaction SMILES: [C-:1]#[N:2].[Li+].[Cl:4][C:5]1[C:6]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([N:15]1[CH2:19][CH2:18][C@@H:17](O)[CH2:16]1)[CH:9]=[CH:8]2.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:4][C:5]1[C:6]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([N:15]1[CH2:19][CH2:18][C@H:17]([C:1]#[N:2])[CH2:16]1)[CH:9]=[CH:8]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](O)C3)ccc12
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#C[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 60 °C

Procedure:
Lithium cyanide (4 mL, 0.5M in DMF) was added to N-[6-chloro-2-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (0.21 g) in N,N′-dimethylformamide. The reaction mixture was heated at 60° C. for 10 hours. A saturated solution of sodium bicarbonate was added and the reaction mixture extracted with ethyl acetate. The combined organics were washed with brine, dried and concentrated. Purification (SiO2, iso-hexane:ethyl acetate 1:1 as eluant) gave the title compound as a solid (0.066 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]3=[O:17])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2cc(N3CCN(C)CC3)ccn2c1=O
Temperature: 70 °C
Yield: 106.8 %

Procedure:
Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (755 mg, 3.0 mmol), the product of Step 3 of Example 58, was suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 6.0 mL (6.0 mmol) of N-methylpiperazine and the reaction mixture was heated at 70° C. for 8 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) was dissolved in 125 mL of methylene chloride and the methylene chloride solution was washed with 125 mL of saturated sodium chloride solution (brine). The aqueous layer was extracted with 125 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 1.01 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][C@H:9]1[NH:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.I[CH3:39].[H-].[Na+].O>C1COCC1>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][O:7][CH2:8][C@H:9]1[N:14]([CH3:39])[C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@@H](c2ccccc2)[C@H]1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-5-oxo-2-phenylpiperizine-1-carboxylate (6.6 g, 12.4 mmol) and iodomethane (1.0 mL, 16.1 mmol) in THF (50 mL) was added NaH (0.55 g, 13.6 mmol) at 0° C. After stirring overnight, the reaction was stopped with water (50 mL). The product was extracted with ether, and purified by washing with 0.5 mol/L KHSO4 solution, saturated NaHCO3 solution and saturated brine in order. The organic layer was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation from the filtrate under reduced pressure to give tert-Butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-methyl-5-oxo-2-phenylpiperizine-1-carboxylate 6.5 g (96%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][C:33](=[O:35])[CH3:34])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.03 g (0.06 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-aminopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine, 0.02 mL (0.12 mmol) of acetic anhydride, 0.025 mL (0.3 mmol) of pyridine and a catalytic amount of DMAP in 0.5 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH2Cl2:methanol, 9:1) to give the title compound. Mass Spectrum (ESI) m/e=538 (M+1 35Cl, 35Cl), 540 (M+1 35Cl, 37Cl), and 542 (M+1 37Cl, 37Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)n[nH]1
Yield: 111.6 %

Procedure:
A suspension of methyl 3-nitro-1H-pyrazole-5-carboxylate (10 g, 58.4 mmol) and 10% Pd on charcoal (1.2 g) in methanol (150 Ml) was stirred under 50 psi pressure of hydrogen gas for 16 h. The reaction mixture was filtered over a bed of Celite and the filtrate was concentrated to give 9.2 g of methyl 3-amino-1H-pyrazole-5-carboxylate which was used as such in the next reaction. MS (ESI) m/z 142.3 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[S:10])[NH2:9])[CH2:4][CH2:3]1.Br[CH2:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])=O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:10][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])[N:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Reactant: CN1CCN(C(N)=S)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3cccc(C(=O)O)c3)cs2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Methyl-piperazine-1-carbothioic acid amide (2.47 mmol) and 3-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=304.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[NH:22][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[N:22]([CH2:13][C:15]([F:18])([F:17])[F:16])[C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@@H]1CCC[C@@H]1O3
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CC(F)(F)F)[C@@H]1CCC[C@@H]1O3
Yield: 161.6 %

Procedure:
Compound 135 was prepared according to General Method 6 (EXAMPLE 3) from (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline (20 mg, 0.057 mmol) and NaBH4 pellets (excess) in 7 mL TFA to afford 20 mg of (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-7-(2,2,2-trifluoroethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline. This material (20 mg, 0.046 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 6 mL of 1:1 acetic acid:concentrated HCl (0.01 M) heated at 90° C. for 4 h to afford 15 mg (83%) of Compound 135, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ12.10 (bs, 1H), 7.15 (s, 1H), 7.10 (d, J=8.8, 1H), 7.01 (d, J=8.8, 1H), 4.14 (m, 1H), 3.94 (m, 2H), 3.72 (ddd, J=10.5, 7.6, 3.4, 1H), 2.18 (m, 2H), 2.01 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: CSc1ccc(O)cc1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1ccc(OCc2cscn2)cc1

Procedure:
A mixture of 4-chloromethyl thiazole hydrochloride (3.0 g, 17.6 mmol), 4-methylsulfanyl-phenol (2.5 g, 1 eq.) and K2CO3 (6.1 g, 2.5 eq.) in acetone (60 mL) was heated to reflux for 48 hours. After cooling, the solid was filtered off. The filtrate was evaporated to dryness in vacuo. The crude product was redissolved in diethyl ether. The solution was washed twice with 2N NaOH solution and then with H2O. After being dried over Na2SO4, removal of the solvent afforded the desired product as an off-white solid.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-aminopyridine (9.41 g, 100 mmol) and triethylamine (16.7 mL, 120 mmol) in CH2Cl2 (300 mL) at 0° C. was added trimethylacetyl chloride (14.8 mL, 120 mmol) dropwise over 15 min. The reaction was warmed to rt and stirred overnight. The mixture was concentrated in vacuo, the residue partitioned between EtOAc and H2O, and the layers separated. The aqueous layer was made basic with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-(pyridin-3-yl)-2,2-dimethylpropanamide as a tan solid. 1H NMR (CDCl3, 300 MHz) δ 8.57 (d, 1H), 8.33 (dd, 1H), 8.17 (ddd, 1H), 7.69 (br s, 1H), 7.27 (dd, 1H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.Br[CH2:9][C:10](=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:1][S:2][CH:3]1[N:6]([CH2:9][C:10](=[O:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:5](=[O:7])[CH2:4]1
Reactant: CSC1CC(=O)N1
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Product: CSC1CC(=O)N1CC(=O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Methylthioazetidin-2-one (470 mg., 4 mmole) and 1-bromo-3-p-nitrophenylpropan-2-one (1.05 g., 4.07 mmole) were converted into the title compound using the process described in Example 1.1. The title compound was obtained as a yellow gum (176 mg., 15% yield). νmax (CHCl3): 1765 (β-lactam C=O), 1735 (ketone C=O), 1605 (aromatic C=C), 1530 and 1355 (aromatic NO2) cm-1. δ(CDCl3): 1.98 (s, 3H, SCH3), 2.98 (dd, J 15, J' 3Hz, 1H, β-lactam CHH), 3.42 (dd, J 15, J' 6Hz, 1H, β-lactam CHH), 3.80 (d, J 18Hz, 1H, NCHH), 3.88 (s, 2H, COCH2Ar), 4.38 (d, J 18Hz, 1H, NCHH), 4.82 (dd, J 6, J' 3Hz, 1H β-lactam CH), 7.43 (d, J 8.5Hz, 2H, Ar-H), 8.22 (d, J 8.5Hz, 2H, Ar-H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.OOS([O-])=O.[K+]>CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>[F:12][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[N:10]([CH3:11])[C:20]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: CNc1cc(C#N)c(F)cc1N
Reactant: O=Cc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(F)c2)nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-2-fluoro-5-methylamino-benzonitrile (0.15 g, 0.00090 mol) and 5-Fluoro-pyridine-3-carbaldehyde (0.11 g, 0.0090 mol) in DMF (5 mL) and H2O (2 mL) was added OXONE® monopersulphate (0.19 g, 0.0012 mol). The reaction mixture was stirred at room temperature for 5 h, and was diluted with 10% K2CO3 solution to PH˜8-10 and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 5-fluoro-2-(5-fluoropyridin-3-yl)-1-methyl-1H-benzimidazole-6-carbonitrile (398) as a brown solid. C14H8F2N4; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.47 (d, 5.4 Hz, 1H), 8.29 (d, J=9.6 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 3.98 (s, 3H); MS (M+1): 271.1. HPLC purity: 99.44%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27](O)=[O:28])=[CH:25][N:26]=3)[CH:23]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:30][C:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([NH:37][S:34]([C:31]4([CH3:30])[CH2:33][CH2:32]4)(=[O:36])=[O:35])=[O:28])=[CH:25][N:26]=3)[CH:23]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=C(O)c1cnc2ccc(N3CCCCC3c3cc(F)cc4c3OCCO4)cn12
Reactant: CC1(S(N)(=O)=O)CC1
Product: CC1(S(=O)(=O)NC(=O)c2cnc3ccc(N4CCCCC4c4cc(F)cc5c4OCCO5)cn23)CC1

Procedure:
The title compound was prepared by the method similar to that of Example 31 employing 6-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int 42) and 1-Methylcyclopropane-1-sulfonamide (int-50) to afford an enantiomeric mixture, which was purified by chiral chromatography employing CHIRALPAK AD-H column with n-HEXANE:ETHANOL, 60:40 Isocratic solution as eluent. MS (ESI): m/z 515.2 (M+H); 1H NMR (600 MHz, DMSO-d6) δ 11.88 (1H, s), 8.74 (1H, s), 8.55 (1H, s), 7.65-7.64 (1H, d, J=10.4 Hz), 7.52-7.50 (1H, d, J=10.4 Hz), 6.51-6.45 (2H, m), 4.45-4.42 (3H, m), 4.30-4.22 (2H, m), 3.64-3.62 (1H, d), 2.79-2.73 (1H, m), 1.90-1.78 (4H, m), 1.57-1.53 (8H, m), 1.23-1.03 (2H, m) ppm.