Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.Cl[C:24]1[C:29]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][CH:27]=[CH:26][N:25]=1>CC(N(C)C)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:24]4[C:29]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[N:28][CH:27]=[CH:26][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Clc1nccnc1C1CCOCC1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4C4CCOCC4)C3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of cesium carbonate (0.82 g, 2.52 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.18 gg, 0.63 mmol), and 2-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (0.13 g, 0.63 mmol) in DMA (1 mL) was heated to 80° C. for 20 h, then cooled to RT. The resulting suspension was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole as a white solid. [M+1] 370. IC50 (uM) 1.157.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=2)=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(OCCCc3cccc(Br)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(/C=C/c1ccc(OCCCc2cccc(Br)c2)c(C(F)(F)F)c1)(CO)CO
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 197-1 (290 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (200 mg) as a white powder.
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][C@@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[CH:18][N:13]3[C:12]=2[CH3:19])[N:7]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:6]1)(=O)C.C1(OP(O[C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])(OC2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:23]([O:22][C:20]([N:7]1[C@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[CH:18][N:13]3[C:12]=2[CH3:19])[CH2:9][C@H:5]([S:4][C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])[CH2:6]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1sc2cncn2c1C
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3sc4cncn4c3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 40 %

Procedure:
The procedure of Example 23-a) is repeated to prepare 362.4 mg of a mercaptan compound as a yellow oil from 474.5 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonyl-5-(3-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine described in Synthesis Example 10. Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(3-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (255.4 mg) is prepared as a colorless amorphous material from this mercaptan compound and 544.2 mg of allyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: CO[C:3]1O[C:5](OC)=[CH:6][CH:7]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:29]([F:32])([F:31])[F:30])=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19]2.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:23][N:21]1[C:22]2[C:18](=[C:17]([C:29]([F:32])([F:30])[F:31])[CH:16]=[CH:15][C:14]=2[O:13][CH2:12][CH2:11][N:10]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH:19]=[C:20]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COc1ccc(OC)o1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCN)c2n1C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCn3cccc3)c2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
After 1.28 g (9.69 mmol) of 2,5-dimethoxyfuran was added to a solution of 2.91 g (8.81 mmol) of ethyl 7-(2-aminoethoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate in 30 ml of acetic acid, the mixture was stirred at 50° C. for 4 hours and at 70° C. for further an hour. Toluene was added to the reaction mixture followed by concentration under reduced pressure. Ice water was poured onto the resulting residue. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1.96 g of ethyl 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylate.
Reaction SMILES: [C:1]1([N:7]2[C:11](=O)[CH2:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11](=[S:29])[CH2:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=NN(c3ccccc3)C(=S)C2)cc1
Yield: 147.7 %

Procedure:
A mixture of 5.6 g (20 mmol) of 1-phenyl-3-(4-methylphenyl)-4, 5-dihydropyrazol-5-one, 6.1 g (15 mmol) of Lawesson's reagent and 50 ml of toluene was heated under reflux for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1 (v/v)) and recrystallized from diethyl ether-n-hexane to give quantitatively 5.9 g of the object compound as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH:20]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]#[N:23])[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH:20]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]#[N:23])[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CC(=Cc1cc2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O)c1cccnc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: N#CC(=Cc1cc2cccnc2n(-c2cccc(N)c2)c1=O)c1cccnc1
Temperature: 50 °C
Yield: 43.3 %

Procedure:
0.5 g of 3-[1,2-dihydro-1-(3-nitrophenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile, prepared in Example 111, is suspended in 15 ml of methanol and 10 ml of water, in the presence of 0.5 g of iron powder. The suspension is heated to about 50° C. and 0.5 ml of concentrated hydrochloric acid is added dropwise. The reaction mixture is refluxed for 45 minutes and then cooled to room temperature. The residual iron is removed and the filtrate is diluted with water, treated with 0.5 g of potassium carbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried and concentrated to give 0.2 g of 3-[1-(3-aminophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile in the form of a bright yellow solid melting at 280° C., after purification on a silica column (eluent: dichloromethane/methanol 98.5/1.5). Yield 40%.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)([OH:3])=[O:2].[C:19](Cl)(=O)[C:20](Cl)=O.C(O)C>C1C=CC=CC=1>[CH2:19]([O:2][C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)=[O:3])[CH3:20]
Reactant: CCc1cc(C(=O)O)c2ccc(C(C)C)ccc1-2
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(CC)c2ccc(C(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above-mentioned azulene carboxylic acid (3) (4.84 g, 0.002 mole) is suspended in benzene (100 ml), and oxalyl chloride (2.8 g, 0.02 mole) is added dropwise thereto under cooling with ice. The mixture is stirred for 3 hours at room temperature and cooled with ice again. Ethyl alcohol (100 ml) is added dropwise thereto and stirred for 2 hours at room temperature. The mixture is poured into ice-water (300 ml) and extracted with benzene (100 ml). The benzene layer is separated, and then washed with water. The benzene solution is concentrated under reduced pressure, and n-hexane is added thereto to obtain the ethyl ester derivative (2) at a yield of 4.5 g, 83.3%, having a melting point of 48° to 49° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]CC)=O)=[CH:6][CH:5]=1.[H][H].Cl>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Temperature: 50 °C
Yield: 80.7 %

Procedure:
To a slurry of sodium hydride (9.17 grams, 0.23 mole) in 50 milliliters of toluene was added dropwise, a solution of ethyl 4-bromophenylacetate (50 grams, 0.21 mole) in toluene (50 milliliters) at 30-32° C. After addition was completed, the reaction mixture was slowly warmed to 50° C. where the reaction began to rapidly exotherm with evolution of hydrogen gas. The reaction mixture was further heated to 78° C. for 2 hours, cooled to room temperature and then HCl (45 grams) in water (22.5 grams) was slowly added dropwise to neutralize the solution. The layers were separated and the aqueous phase was extracted with diethylether. The combined organic extracts were dried and the solvent was removed to leave a yellow oil. This oil was refluxed for 24 hours in a mixture of glacial acid (60 milliliters) and concentrated HCl (30 milliliters). After cooling, the layers were separated, and the organic layer solidified to provide a yellow solid. This crude product was recrystallized from n-heptane to give a pure product as a white solid (31.2 grams, 82% isolated yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([NH:26][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:22]2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.78 g) and (3R)-1-(4-chlorobenzyl)-3-pyrrolidinamine (2.65 g) in DMF (25 mL) was added K2CO3 (5.79 g). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.58 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 109.3 %

Procedure:
To a solution of [2-(4-amino-phenyl)-ethyl]-carbamicacid tert-butyl ester (10.75 g, 45.49 mmol) in pyridine (125 ml) at 0° C. 4-isopropyl-benzenesulfonyl chloride (10.45 g, 47.76 mmol) was added. The mixture was stirred at 0° C. for 1 h and 16 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a brown oil (20.82 g, 50%).
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)=[O:36]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 3 (40 mg), 2-methoxy-4-nitro-benzoic acid (47 mg), triethylamine (0.07 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg) in dry tetrahydrofuran (3 ml) was stirred at 20° C. for 18 h under a nitrogen atmosphere. The mixture was then partitioned between potassium carbonate solution and dichloromethane. The organic phase was passed through a hydrophobic frit and evaporated. The residue was purified on a silica gel SPE cartridge. Elution with dichloromethane, then with dichloromethane:ethanol:0.880 ammonia; 400 then 200:8:1 gave an oil which was triturated with diethyl ether giving the title compound as a colourless solid (51 mg).
Reaction SMILES: CO[C:3]1[C:4]([CH2:14][C:15]#[N:16])=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BrH:17].[C:18]([OH:21])(=O)C>>[BrH:17].[CH3:18][O:21][C:7]1[C:8]([O:9][CH3:10])=[CH:3][C:4]2[CH2:14][C:15]([NH2:16])=[N:13][C:12]([Br:17])=[CH:11][C:5]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CC#N)c(CC#N)c1OC
Agent: Br
Product: COc1cc2c(cc1OC)CC(N)=NC(Br)=C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Here, 3,4-dimethoxy-o-phenylene-diacetonitrile (3.7 g, 0.017 mol) is suspended in glacial acetic acid (10 ml) and mixed with 30% hydrobromic acid (12 ml) in glacial acetic acid at 20° C. The mixture is stirred for 3 hours at ambient temperature, the precipitate is suction filtered, washed with glacial acetic acid and then with acetone/ether and dried.
Reaction SMILES: C(OC(C[N:12]1[C:16](=[O:17])[C@@H:15]2[C@H:13]1[CH2:14]2)=O)C1C=CC=CC=1.[C:18](=[O:21])(O)[O-:19].[Na+:22]>O1CCCC1.[Pd]>[C@@H:13]12[CH2:14][C@@H:15]1[C:16](=[O:17])[N:12]2[C:18]([O-:19])=[O:21].[Na+:22]
Reactant: O=C(CN1C(=O)[C@H]2C[C@H]21)OCc1ccccc1
Reactant: O=C([O-])O
Agent: [Pd]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])N1C(=O)[C@H]2C[C@H]21
Reaction time: 1 h

Procedure:
A mixture of (1R,4S)-2-benzyloxycarbonylmethyl-2-azabicyclo[2,1,0]pentan-3-one (21 mg, 0.091 mmol), 10% Pd/C (10 mg) and sodium bicarbonate (7.6 mg, 0.91 mmol) in tetrahydrofuran (3 ml) water (1 ml) was hydrogenated at 40 psi on the Parr shaker for 1 hr. The mixture was then filtered and the solid residue was washed with deionized water. The combined filtrate and washings were extracted twice with ether (10 ml) and the aqueous phase was concentrated in high vacuum to a volume of 3.5 ml. This solution was applied to a 1/2" disc (total product content on disc 400 μg) which was incubated on a Staph. aureus MB 108 plate at 37° C. for 60 hrs. This results in a 50 mm zone of inhibition.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Yield: 89.1 %

Procedure:
The title compound (260 mg, 89.1%) was prepared from the compound from step 1 (300 mg, 0.82 mmol) and 4N HCl in dioxane by the procedure described in step 1 of Example 4: MS (ESI) m/z 269 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 3.22 (br, 8H), 5.04 (s, 2H). 6.94 (br, 4H), 7.30-7.43 (m, 5H), 9.00 (br, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[C:9]2[O:13][CH:12]=[CH:11][C:10]=12)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[OH:2][CH2:3][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c2occc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CO)c2ccoc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 7-methanesulfonylamino-benzofuran-4-carboxylic acid methyl ester (6.42 g, 23.8 mmole) in anhydrous tetrahydrofuran (155 mL) was added a solution of diisobutylaluminum hydride (1.5M solution in toluene, 80 mL, 120 mmole) slowly at 0° C. under nitrogen. The ice bath was removed and the reaction mixture was stirred at room temperature for three hours. Methanol (30 mL) was added slowly at 0° C. The reaction mixture was partitioned between ethyl acetate and 0.5 N hydrochloric acid. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 50 to 80% ethyl acetate in hexane to give N-(4-Hydroxymethyl-benzofuran-7-yl)-methanesulfonamide as a solid (5.64 g, 98%). 1H NMR (DMSO-d6) δ: 3.07 (s, 3H), 4.73 (d, 2H, J=5.70 Hz), 5.30 (t, 1H J=5.7 Hz), 7.10 (d, 1H, J=2.2 Hz), 7.21 (s, 2H), 8.05 (d, 1H, J=2.2 Hz), 9.78 (s, 1H). M−H 240.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:18]([CH3:21])[C:19]#[N:20]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([C:5]([O:10][CH:18]([C:19]#[N:20])[CH3:21])=[CH:4][CH:3]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C#N)Oc1ccc(Cl)cc1C=O

Procedure:
A mixture of 5-chlorosalicylaldehyde (78 g., 0.5 mole), finely powdered anhydrous potassium carbonate (103.5 g., 0.75 mole) and acetone (500 ml.) is stirred under reflux and 2-chloropropionitrile (33.6 g., 0.375 mole) is added over a period of about 5 minutes. The mixture is heated under reflux for 1.5 hours and then treated with potassium carbonate (34.5 g., 0.25 mole) followed by more 2-chloropropionitrile (11.2 g., 0.125 mole). Heating and stirring are continued for 31/2 hours, after which the reaction mixture is filtered and the filter-cake washed with acetone. Evaporation of the combined filtrate gives 3-chloro-6-(1-cyanoethoxy)-benzaldehyde which is recrystallized from aqueous methanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)(C)(C)C.[S:19]1[CH:23]=[C:22]([C:24](O)=O)[N:21]=[CH:20]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[S:19]1[CH:23]=[C:22]([C:24]2[NH:15][C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=3[N:14]=2)[N:21]=[CH:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cscn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (4-Amino-3-nitro-phenyl)-carbamic acid tert-butyl ester (1-3, 0.409 g, 1.832 mmol), thiazole 4-carboxylic acid (0.226 g, 1.832 mmol) and diisopropylethylamine (0.81 mL, 4.03 mmol) in N,N-dimethylformamide (10 mL) was reacted at the ambient temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 1.05 g, 2.02 mmmol). After 3 h stirring at the same temperature, the reaction mixture was concentrated under the reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and aqueous 0.5N-NaOH solution (70 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The resulting crude product was triturated with ethyl acetate (5 mL), collected by filtration, and dried under the reduced pressure. The mixture of the intermediate products (1-4a and 1-4b) was dissolved in aqueous 20%(v/v)-acetic acid (50 mL) and heated at reflux for 2 h. The reaction mixture was cooled to the ambient temperature and concentrated in vacuo. The resulting crude thick oil was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (70 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude product was triturated with ethyl acetate (15 mL) and hexanes (2 mL). The resulting solid, 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5), was collected by filtration and dried under the reduced pressure; 1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.27 (s, 1H), 8.24 (s, 1H), 7.27 (bs, 1H), 6.66 (s, 1H), 6.54 (d, 1H, J=7.5 Hz), 4.96 (bs, 2H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(N(CC)CC)C.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([C:34]([CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:35])[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(Cl)Cc1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)Cc1ccco1)CC3
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 1.5 g, (-)-1-(morphinan-3-yl)ethanone, 1.7 g of triethylamine and 15 ml of methylene chloride at ice-bath temperature was added a solution of 1.3 g of 2-furyl acetyl chloride in 10 ml of methylene chloride over a period of 1 hour. After the mixture had been refluxed for 4 hours, it was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml ether and the ether solution was washed with 1 N hydrochloric acid (2×15 ml) then with water and dried over magnesium sulfate. Removal of the solvent gave 1.9 g (90%) of crude (-)-3-acetyl-N-[(2-furylmethyl)carbonyl]morphinan. For analysis, a sample of this compound was distilled, bp 235°-245° (0.05 mm), [α]25D-160.43° (c 0.94, MeOH).