Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][N:7]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CCC4(CC3)OCCO4)cnc2N)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (6.1 g, 15.83 mmol) was dissolved in MeOH (150 mL) and EtOAc (80 mL) the reaction mixture was flushed with N2 for 15 min, Then Pd—C (DEGASSA) (6 g, 5.64 mmol) was added, the reaction mixture was then charged with hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered through Celite, which was washed with EtOAc and methanol. The filtrate was concentrated to yield the crude product, which was used in the next step reaction without purification. LCMS (m/z): 388.0 (MH+), 0.79 min.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([F:19])=[C:12](CN(OC)C)[N:13]=1)=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[NH2:8][C:9]1[S:10][C:11]([F:19])=[CH:12][N:13]=1
Reactant: CON(C)Cc1nc(NC(=O)OC(C)(C)C)sc1F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(F)s1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-4-(N-methoxy-N-methyl-aminomethyl)-5-fluorothiazole (3.6 g, 12.4 mmol) in 1,4-dioxane (60 mL) was saturated with dry HCl gas and held overnight. The mixture was evaporated to dryness to leave the 2-amino-5-fluorothiazole dihydrochloride salt (3.3 g, 100% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)O)[CH3:2].[I-].[Na+].Cl[Si](Cl)(C)C>C(#N)C>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nn2c1C(O)c1ccc(O)cc1
Agent: C[Si](C)(Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
To a stirred suspension of 2.607 g (8.8 mmol) of the product of Step D and 5.257 g (35.1 mmol) of sodium iodide in 12 mL of acetonitrile was added 2.13 mL (17.5 mmol) of dichlorodimethylsilane via syringe under a nitrogen atmosphere. The reaction mixture which immediately darkened was stirred for 20 min at room temperature, then partitioned between EtOAc and brine. The organic layer was washed with aqueous sodium bicarbonate, 10% aqueous sodium thiosulfate, then dried (MgSO4), filtered and evaporated. The residue was crystallized from EtOAc-hexane to afford 2.214 g (90%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[I-].CC[O-].[Na+].[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[NH:20][C:19](=O)[CH2:18][C:17]2=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[N:20]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCBr
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Product: CCCN1CCCN(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting propyl bromide or iodide in the presence of sodium ethylate, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-propyl 8-chloro 1,2,4,5-tetrahydro 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = C3H7, R4 = C6H5) melting at 192°-194° C. upon recrystallisation in ethanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)[N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35]([Cl:38])(=[O:37])[CH3:36].Cl.CCO>C(Cl)Cl>[ClH:38].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([O:24][C:35](=[O:37])[CH3:36])[CH2:20]3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2nc(-c3cccc(CN4CCC(O)C4)c3)n[nH]2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc(-c3cccc(CN4CCC(OC(C)=O)C4)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of (RS)-1-{3-[5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-pyrrolidin-3-ol hydrochloride (1:1) (mixture of tautomers) (50 mg, 0.13 mmol) in CH2Cl2 (5 ml) was treated with triethylamine (26 mg, 0.26 mmol 2 eq.) and stirred for 30 min. at r.t. Acetyl chloride (11 mg, 0.13 mmol, 1 eq.) was added and stirring was continued for 1.5 hrs. After removal of the solvent the residue was chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4. The resulting product was dissolved in ethanol at r.t. and an excess 1.45 N HCl/EtOH solution (0.1 ml, 0.14 mmol) was added. After 30 min. stirring the solvent was evaporated and the residue dried under high vacuum at 40° C. overnight affording the title compound (53 mg, 0.12 mmol, 96% yield) as a colorless solid. MS: m/e=393.2 (M+H+)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:23]3[CH2:24][CH2:25][CH:20]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:21][CH2:22]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Clc1ccc(-c2ccncc2)nn1
Product: c1cc(-c2ccc(N3CCC(N4CCCCC4)CC3)nn2)ccn1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-pyridin-4-yl-pyridazine and 4-piperidinopiperidine. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (dd, 2H), 8.04 (m, 3H), 7.40 (d, 1H), 4.53 (d, 2H), 2.95 (t, 2H), 2.56 (m, 1H), 2.45 (m, 4H), 1.82 (d, 2H), 1.48 (m, 6H) 1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]C1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Yield: 383.4 %

Procedure:
To a suspension of 2-chloro-3-nitrobenzoic acid (100 g, 495 mmol) in MeOH (600 mL) was added TsOH (20 g, 10%). Then the mixture was heated at reflux overnight. The solvent was removed. The residue was diluted with EtOAc (1 L). Then the pH was adjusted to around 9 by progressively adding saturated NaHCO3. The organic layer was separated. The aqueous layer was extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (96 g, 90.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (dd, J=1.8 Hz, 7.9 Hz, 1H), 7.81 (dd, J=1.5 Hz, 7.7 Hz, 1H), 7.45 (dd, J=7.7 Hz, 7.9 Hz, 1H), 3.94 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[K+].C([Li])(C)(C)C.[B:18](OCCCC)([O:24]CCCC)[O:19]CCCC.Cl>C1COCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([B:18]([OH:24])[OH:19])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
A solution of 6-Bromo-1H-indole (1.5 g, 7.65 mmol) in THF (10 mL) was added dropwise to a suspension of potassium hydride (0.31 g, 7.65 mmol) in THF at 0° C. After fifteen minutes at 0° C., the solution was cooled to −78° C. and a t-butyl lithium solution (1.7 M in pentane, 9.0 mL, 15.3 mmol) was added dropwise via syringe while maintaining a temperature below −55° C. After 15 minutes, the solution was cooled to −78° C. and treated with a tributyl borate (4.14 mL, 15.3 mmol). The solution was stirred at −78° C. for 2 hours and then allowed to warm to −10° C. The solution was the added 75 mL of 1 M HCl, warmed to room temperature and separated. The aqueous phase was extracted with diethyl ether (3×75 mL) and the combined organics were extracted with 1 M NaOH (4×40 mL). The aqueous layers were combined, adjusted to pH ˜2 with 6 M HCl and extracted with diethyl ether (4×50 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using 3.5-5% methanol/dichloromethane to give 838 mg (68% yield) of the desired product. MS (ESI(+)) m/e 161 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A solution of tert-butyl{1-[2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 2, 150 mg, 0.37 mmol) in dioxane (4 mL) was treated at room temperature under vigorous stirring with a solution of HCl in dioxane (4M, 2 mL). After 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was extracted three times with dichloromethane (3×50 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 113 mg (100% yield) of the crude product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[NH:5][CH3:6].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>C(Cl)(Cl)Cl>[Cl:21][CH2:22][C:23]([N:5]([CH3:6])[C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CNc1cc([N+](=O)[O-])ccc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])cc1N(C)C(=O)CCl
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
2-Methoxy-N-methyl-5-nitroaniline (D85) (0.68 g, 3.7 mmole) and triethylamine (0.68 ml, 4.9 mmole) were stirred in chloroform (10 ml) as chloroacetyl chloride (0.39 ml, 4.9 mmole) was added. The solution was stirred for 30 min, acidified with 2M HCl, and separated. The organic portion was dried (Na2SO4) and evaporated in vacuo to give the crude title compound as a black solid (1.01 g, quantitative).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CN(C)C=O.[N+:12]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][O:19][C:20]2=[O:25])([O-:14])=[O:13].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)(=O)C>[CH3:1][C:24]1[C:15]([N+:12]([O-:14])=[O:13])=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:25])[O:19][CH:18]=[CH:17]2
Reactant: CC(C)(C)[O-]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Alternatively, to a solution of potassium tert-butoxide (8.72 g, 0.0777 mol) in N,N-dimethylformamide (250 mL, 3.2 mol) was added a mixture of acetic acid, chloro-, 1,1-dimethylethyl ester (4.335 g, 0.02878 mol) and 5-nitro-1H-isochromen-1-one (5.0 g, 0.026 mol) in N,N-dimethylformamide (50 mL, 0.6 mol) at −20° C. After 1 h, the reaction was poured onto hydrochloric acid (16 mL) and water (35 mL). The aqueous solution was extracted with dichloromethane, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was treated with trifluoroacetic acid (35 mL, 0.45 mol ) for 0.5 h and was removed under reduced pressure. The residue was stirred with potassium carbonate (6.98 g, 0.0505 mol) in N,N-dimethylformamide (200 mL, 2 mol) at 50° C. for 1 h. The reaction was cooled and added with 1 N hydrochloric acid (262 mL), extracted with dichloromethane (80 mL×3), washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the mixture was purified by flash chromatography to afford the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:25]([CH:30]2[CH2:33][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:31]2)[O:24][N:23]=1)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11].C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:28][CH2:29]2)=[C:25]([CH:30]2[CH2:31][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:33]2)[O:24][N:23]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11]
Reactant: Cc1ccc(Cl)c(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(NC(=O)CC(CC(=O)O)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
tert-Butyl 4-(2-Chloro-5-methylphenylcarbamoyl)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]butanoate (1.09 g) and toluene (3.2 mL) were mixed. To the mixture was added trifluoroacetic acid (3.2 mL) at ice temperature and the mixture was stirred at RT for 30 min. After water (5 mL) was poured into the reaction mixture dropwise at ice temperature, aqueous 4 N sodium hydroxide was added to the mixture dropwise and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/5→1/3→1/2→2/1→methanol/chloroform=1/8) to give the title compound (905 mg). The title compound was analyzed using a chiral column. The retention time of the title compound was 6.6 min., and the optical purity thereof was 94.8% ee.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:28]=[C:29]([CH3:30])[C:22]=12.ClCCl>BrC1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[N:27]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[N:28]=[C:29]([CH3:30])[C:22]=23)=[C:14]([F:19])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: CC(=O)N(Cc1ccccc1)c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(Cc5ccccc5)C(C)=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Yield: 74.4 %

Procedure:
To a stirred solution of N-benzyl-N-(3-fluoro-4-hydroxyphenyl)acetamide (34 mg, 0.13 mmol) and 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (29 mg, 0.1 mmol) (prepared in Example 43, step E) in 400 μL bromobenzene in a capped reaction vial was added DMAP (25 mg, 0.20 mmol). The solution was heated to 150° C. overnight. The reaction was cooled to ambient temperature and loaded onto a Biotage 12S column with dichloromethane and eluted with ethyl acetate to provide the desired product as a tan solid (38 mg, 74% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.O=C1NC2C=C(C(O)=O)C=CC=2SC1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].Cl>C1COCC1.O>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C1CSc2ccc(C(=O)O)cc2N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
6-Hydroxymethyl-4H-benzo[1,4]thiazin-3-one. To a 0° C. suspension of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (400 mg, 2 mmol) in THF (19 mL) was added Et3N (0.32 mL, 2 mmol) and the resulting solution was treated with iso-butylchloroformate (0.3 mL, 2 mmol). The resulting suspension was stirred at 0° C. for 2 h, filtered and the solid was washed with THF. The filtrate was cooled to 0° C., treated with NaBH4 (150 mg, 4.3 mmol) and slowly treated with H2O (10 mL). The resulting suspension was warmed to RT and stirred for 18 h. The suspension was neutralized using 1 N HCl and diluted with H2O (100 mL). The organic layer was extracted with EtOAc (3×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The resulting residue was purified on SiO2 (0-10% CH3OH/CH2Cl2) to provide 330 mg (89%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H9NO2S, 195.04; m/z found, 196.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.26 (d, J=7.9, 1H), 7.01-6.98 (m, 2H), 4.55 (s, 2H), 3.40 (s, 2H).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7](=O)[CH2:8]2)[CH2:3][CH2:2]1.Cl.[Br:12][C:13]1[CH:14]=[C:15]([NH:19]N)[CH:16]=[CH:17][CH:18]=1.C(O)C>Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:16]([C:6]3[CH2:5][N:4]4[CH:9]([CH2:1][CH2:2][CH2:3]4)[CH2:8][C:7]=3[NH:19]2)=[CH:17][CH:18]=1
Reactant: O=C1CCN2CCCC2C1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: Brc1ccc2c3c([nH]c2c1)CC1CCCN1C3
Yield: 26.6 %

Procedure:
Hexahydroindolizin-7(1H)-one (4.58 g, 32.9 mmol) and 3-bromophenylhydrazine hydrochloride (8.08 g, 36.2 mmol) were combined in concentrated hydrochloric acid (40 ml) and ethanol (15 ml) and heated at 105° C. for 48 h. Upon cooling, the solid was filtered off and partitioned between methylene chloride and 6 N NaOH solution. The organic layer was removed and concentrated to provide 8-bromo-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (2.55 g, 26%). The original filtrate was concentrated and partitioned between methylene chloride and 6 N NaOH solution. The organic layer was removed and concentrated, and the residue was purified by column chromatography (eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride) to provide the title compound (1.31 g, 14%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.44-7.43 (d, J=1.7 Hz, 1H), 7.31-7.29 (d, J=8.4 Hz, 1H), 7.06-7.03 (dd, J=Hz, 1H), 3.79-3.76 (m, 1H), 3.22-3.17 (m, 1H), 2.91-2.85 (m, 2H), 2.79-2.74 (m, 1H), 2.64-2.59 (m, 2H), 2.38-2.31 (m, 1H), 1.81-1.70 (m, 2H), 1.68-1.66 (m, 1H); ESI MS m/z 292 [M+H]+.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@@H:22]3[CH2:26][C@H:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:15][CH2:14]2)=[O:11])=CC=1)([O-])=O.O1CCCC1.Cl>O>[C:10]([CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:15][CH2:14]1)([OH:11])=[O:9]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(CC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(CC(=O)O)CC4)C3)[C@H](C)[C@H]12
Yield: 64.8 %

Procedure:
A solution of 0.5 g of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-homopiperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 15 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 0.26 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 90 minutes in the presence of 0.5 g of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The washed aqueous solution was then concentrated by evaporation under reduced pressure, and the concentrate was purified by reverse phase column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B), using 1% v/v aqueous methanol as the eluent. Those fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and lyophilized, to give 170 mg of the title compound as a powder.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][CH2:11][CH2:12][CH2:13][OH:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:10][CH2:11][CH2:12][CH:13]([Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[OH:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)C(O)CCBr
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diisopropylethylamine (25.488 g, 34.35 mL, 0.197 mol) was added dropwise to the solution of 3-bromopropanol (25 g, 0.18 mol), t-butyldimethylsilyl chloride (29.81 g, 0.197 mol), and DMAP (0.880 g, 7.2 mmol) in methylene chloride (250 mL) placed in a dry 500 mL three-necked, round-bottomed flask kept at ice bath and equipped with a Teflon-coated magnetic stirring bar, a 50 mL pressure-equalizing dropping funnel, a stopper, and a reflux condenser connected to an argon flow line. The reaction mixture was stirred at room temperature for 24 hours, washed successively with water (2×150 mL), dilute ammonium chloride solution (1×100 mL), and brine (2×150 mL). The organic solution was dried (sodium sulfate), the solvent was removed in vacuo, and the residual oil was distilled: bp 62°-64° C. (2 mm Hg); ; 1H-NMR (CDCl3, 200 MHz) δ3.71 (t, J=6.1 Hz, 2H), 3.46 (t, J= 7.0, 2H), 2.00 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H); CIMS m/e 253.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]3[S:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4]1>>[S:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]3[S:20][C:19]([CH2:21][OH:22])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4]1
Reactant: O=Cc1ccc(/C=C/c2cccc(-c3ccsc3)c2)s1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc(/C=C/c2cccc(-c3ccsc3)c2)s1

Procedure:
Using sodium borohydride, the resulting aldehyde compound is reduced in a customary manner to give the captioned alcohol compound.