Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH3:6][N:7]1[C:15]2[C:10](=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>[Pd].CO>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:7]2[CH3:6]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(N)cccc2n1C
Yield: 99.6 %

Procedure:
In a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol was dissolved 1.37 g (5.52 mmol) of ethyl 1-methyl-4-nitro-2-indolecarboxylate. Thereafter 0.30 g of 10% palladium/carbon was added to the solution and catalytic hydrogenation was then conducted at ambient temperature under normal pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.2 g (>99%) of ethyl 4-amino-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([Cl:36])(C)(C)C>C(OCC)(=O)C>[ClH:36].[CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(Cc2ccccc2)CCC(c2[nH]c3ccccc3c2CCCC(=O)O)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
4-(2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)butanoic acid (260 mg, 0.6 mmol) was dissolved in ethyl acetate (50 ml). Me3SiCl (153 μl, 1.2 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 171 (197 mg, m.p. 90-93° C., 70%) was obtained as a white solid (purity <95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Reactant: CC(N)C(C)(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(Nc1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 120 °C

Procedure:
To a solution of 2-(2-chloro-phenyl)-1-[7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone, 31, (0.036 g, 0.080 mmol) in N-methylpyrrolidinone (2 mL) is added diisopropylethylamine (0.071 mL, 0.410 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.035 g, 0.240 mmol). The mixture is heated to 120° C. for 4 hours. The reaction crude product is then purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.54 (s, 1H), 7.42-7.38 (m, 1H), 7.32-7.10 (m, 7H), 4.36 (s, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 467.0 (100, M++H).
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=O)[CH2:4]2)[O:2]1.NCCN.[N+:30]([CH3:33])([O-:32])=[O:31]>>[CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[CH:33][N+:30]([O-:32])=[O:31])[CH2:4]2)[O:2]1
Reactant: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CCC(=O)[C@@]4(C)CC[C@@]12O)OCCO3
Reactant: C[N+](=O)[O-]
Solvent: NCCN
Product: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CCC(=C[N+](=O)[O-])[C@@]4(C)CC[C@@]12O)OCCO3
Temperature: 25 °C

Procedure:
To a solution of 3,3-ethylenedioxy-9α-hydroxyandrost-5-en-17-one (3.46 g) in nitromethane (75 ml) under a nitrogen atmosphere 1,2-diaminoethane (0.1 ml) was added at reflux temperature. After 24 hours of refluxing the reaction was almost complete as measured by TLC. After cooling to room temperature the reaction mixture was concentrated under reduced pressure to give a solid, which was purified by column chromatography (silica gel; methylene chloride/diethyl ether 1/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:36]=[CH:35][CH:34]=[CH:33][C:21]=1[C:22]([NH:24][NH:25]C(OC(C)(C)C)=O)=[O:23]>Cl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:36]=[CH:35][CH:34]=[CH:33][C:21]=1[C:22]([NH:24][NH2:25])=[O:23]
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NNC(=O)OC(C)(C)C)nc2ccc(F)cn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NN)nc2ccc(F)cn12
Yield: 78 %

Procedure:
2.3 167 mg (0.341 mmol) of tert-butyl N′-{2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoyl}hydrazinecarboxylate are stirred for 1 hour in 5 ml of 4 N HCl/dioxane. The reaction mixture is evaporated to dryness and lyophilised, giving 114 mg (78%) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzohydrazide as hydrochloride; MS-FAB (M+H+)=390.8; Rf (HPLC, polar method): 1.00 min. This is employed in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[N:11]=[C:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:9]=1[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].Cl[CH:33]([CH3:37])[C:34]([NH2:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:36][C:34](=[O:35])[CH:33]([CH3:37])[O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:9]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(Cl)C(N)=O
Reactant: CC(C)Cc1nc2ccc(O)cc2c(-c2ccccc2F)c1CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cc1nc2ccc(OC(C)C(N)=O)cc2c(-c2ccccc2F)c1CNC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl [4-(2-fluorophenyl)-6-hydroxy-2-isobutylquinolin-3-yl]methylcarbamate (0.20 g, 0.47 mmol) and 2-chloropropionamide (0.076 g, 0.71 mmol) in N,N-dimethylformamide (20 ml) was added potassium carbonate (0.098 g, 0.71 mmol), and the mixture was stirred at 75° C. for 24 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and 0.1N hydrochloric acid (150 ml). The aqueous layer was separated and extracted with ethyl acetate (100 ml). The organic layer and the extract were combined and the mixture was washed with saturated brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography and crystallized from diisopropyl ether-ethyl acetate to give tert-butyl [6-(2-amino-1-methyl-2-oxoethoxy)-4-(2-fluorophenyl)-2-isobutylquinolin-3-yl]methylcarbamate (0.15 g, yield 65%) as pale-yellow crystals.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(O[C:7]([C:9](=[C:14]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12])=O)C.[BH4-].[Na+].[OH-].[K+].Cl>C(O)C.O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:14](=[C:9]2[CH2:7][O:13][C:11](=[O:12])[CH2:10]2)[C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(CC(=O)O)=C(c1ccc(F)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(=C2COC(=O)C2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
13.6 g of powdered anhydrous calcium chloride are added to a solution of 3-ethoxycarbonyl-4-(4-fluorophenyl)-4-(4-methanesulfonylphenyl)-3-butenoic acid, prepared in Example 43, in 500 ml of ethanol. The mixture is stirred at room temperature and a solution of 7.5 g of sodium borohydride in a mixture composed of 1.5 g of potassium hydroxide, 10 ml of water and 10 ml of ethanol is added dropwise while cooling with an ice bath. After 4 hours at room temperature, the reaction medium is cooled to 0° C. and 6N hydrochloric acid solution is added dropwise. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate and evaporated under vacuum and the residue is crystallized from isopropyl ether. The crystals obtained are recrystallized from methanol to give 5 g of 4-[1-(4-fluorophenyl)-1-(4-methanesulfonylphenyl)methylidene]dihydrofuran-2-one in the form of a mixture (50/50) of the two isomers, (E) and (Z), which are crystals melting at 160°-164° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1[NH2:4].[H-].[Na+].[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-])=O>CN(C=O)C>[NH2:12][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:4])=[O:18]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-dichloro-aniline (322 mg, 2.0 mmol) in DMF was treated with 95% NaH (53 mg, 2.1 mmol) at 0° C., and then 2-nitro-benzoyl chloride was added (390 mg, 2.1 mmol). After stirring for 2 h at rt, the mixture was concentrated and co-evaporated with water, diluted with CH2Cl2, washed with aq. NaHCO3, dried and concentrated. The crude residue was dissolved in EtOH, and subjected to hydrogenation at 1 atm overnight, filtered through Celite and concentrated to give the crude product 2-amino-benzamide.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=[C:13]2[F:16])=[CH:4][CH:3]=1.[F:26][C:27]1[C:32]([F:33])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:16][C:13]1[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=1)=[CH:4][CH:3]=[C:2]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:32]([F:33])[C:27]=1[F:26])[CH:15]=2
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(Br)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(-c3ccc(OCCCCCCCC)c(F)c3F)ccc12

Procedure:
From 7-bromo-9-fluoro-2-octyloxyphenanthrene by reaction with 2,3-difluoro4-octyloxyphenylboronic acid, sodium carbonate and tetrakis(triphenylphosphine)-palladium (0) in toluene/ethanol/H2O.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.C(Br)(Br)(Br)[Br:14]>>[Br:14][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc([N+](=O)[O-])ccc1CO
Product: Cc1cc([N+](=O)[O-])ccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.55 g (27.2 mmol) (2-methyl-4-nitro-phenyl)-methanol 10.8 g (40.8 mmol) triphenylphosphine and 13.7 g (40.8 mmol) carbon tetrabromide is added at 0° C. The reaction mixture is stirred at room temperature for 1 h. After that the reaction mixture is filtered and the filtrate is concentrated in vacue. The residue is purified by chromatography (silicagel, 100% hexane=>100% EtOAc) to afford the title compound as an oil.
Reaction SMILES: [BH4-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][C:13](O)=[O:14])=[CH:11][C:6]=2[CH:5]=[CH:4]1.Cl.COCCOC.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O.CC(C)=O.COCCOC>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][OH:14])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: O=C(O)Cc1ccc2sccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(C)=O
Solvent: O
Product: OCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To 5 mL of 1,2-dimethoxyethane was suspended 2.95 g of sodium borohydride, to which were dropwise added 1,2-dimethoxyethane (25 mL) solution of 10 g of (1-benzothiophen-5-yl)acetic acid, and 11 mL of 6.9 mol/L hydrochloride/1,2-dimethoxyethane solution, which was then stirred at room temperature for 1 hour. To this reaction mixture was dropwise added 5 mL of acetone, which was then stirred for 30 minutes. Thereto were added 20 mL of water, 30 mL of toluene and 2 mL of 2 mol/L hydrochloric acid. Next, after the pH was adjusted to 9.5 with 20 mL of 2 mol/L sodium hydroxide aqueous solution, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. Thereto were added cyclohexane and toluene. The precipitate was collected by filtration to provide 7.84 g of 2-(1-benzothiophen-5-yl)ethanol as white solid form.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](OC(C)(C)C)=[O:8])=[C:2]1[NH:14][C:15]([O:17]C(C)(C)C)=O.C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[NH:6]1[C:7](=[O:8])[C:15](=[O:17])[NH:14][C:2]2[S:1][CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)Nc1ccsc1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2ccsc2[nH]c1=O
Yield: 78.1 %

Procedure:
A mixture of di-t-butyl thiophene-2,3-dicarbamate (1.53 g, 4.87 mmol), diethyl oxalate (15 ml) and acetic acid (15 ml) was refluxed for 48 hours. The precipitate was filtered off, washed with water and dried to yield 0.64 g (78%) of the title compound. M.p. >340° C. 1H-NMR (DMSO-d6, δ): 6.74 (d, 1H), 7.13 (d, 1H), 12.28 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=[O:23])[N:5]2[CH:6]([C:11]([O:13][CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])[CH:7]([CH3:10])[C:8](=[O:9])[C@H:4]12.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[OH:9][CH:8]1[C@@H:4]2[C:3]([O:2][CH3:1])([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22](=[O:23])[N:5]2[CH:6]([C:11]([O:13][CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])=[O:12])[CH:7]1[CH3:10]
Reactant: COC1(NC(=O)COc2ccccc2)C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(=O)[C@@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: COC1(NC(=O)COc2ccccc2)C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(O)[C@@H]21
Yield: 12 %

Procedure:
Pivaloyloxymethyl 6-methoxy-2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapenam-3-carboxylate (79 mg., 0.17 mmole) in 10 ml. of methylene chloride was reduced at -78° C. with tetrabutylammonium borohydride (11 mg., 0.04 mmole), the reaction monitored, and crude product isolated according to Example 3. Chromatography on silica gel (3:1 methylene chloride:ethyl acetate as eluant), monitored by ir, gave pivaloyloxymethyl 1-hydroxy-6-methoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [9.8 mg., 12%; Rf 0.3 (4:1 chloroform:ethyl acetate); ir (CH2Cl2) 1770, 1750, 1670 cm-1 ].
Reaction SMILES: CO.CN(C)C=O.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])([O-])=O>Cl.O.[Fe]>[NH2:8][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1ccccc1Sc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Sc1ccccc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a mixture of 40 ml of concentrated hydrochloric acid, 60 ml of methanol and 40 ml of N,N-dimethylformamide was suspended 2-(2-nitrophenylthio)benzonitrile followed by addition of 8.64 g of powdered iron en bloc, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was then diluted with water and the precipitate was extracted with ether. This extract was washed with aqueous sodium hydrogen carbonate solution and water in that order and dried over magnesium sulfate. The solvent was then distilled off and the residue was subjected to column chromatography (Wakogel C200) using ethyl acetate-n-hexane (1:4) as the eluent. The crystals obtained were recrystallized from ethyl acetate-n-hexane to give 4.8 g of the title compound as white crystals, m.p. 86°-89° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CS(C)=O>O>[C:5]([C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: C1CNCCN1
Reactant: N#Cc1cccc(F)c1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCNCC2)c1
Temperature: 100 °C
Yield: 143.1 %

Procedure:
A mixture of 3-fluorobenzonitrile (3.0 g, 25 mmol), piperazine (11.8 g, 137 mmol) and dimethylsulphoxide (20 ml) is heated at 100° C. for 48 hours under an atmosphere of nitrogen. The reaction mixture is then cooled, poured into water (200 ml) and the resultant precipitate collected. This solid is chromatographed on silica gel (dichloromethane) to give the title compound as a white solid (6.7 g). 1H NMR (DMSO, 500 MHz) δ7.15-7.40 (m, 4H), 3.28 (m, 3H), 3.12 (m, 1H), 2.80 (m, 1H), 2.59 (m, 3H).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:26]=[CH:25][C:19]([C:20](OCC)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=C(NC1CCN(c2ccc(CO)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4-(4-benzamidopiperidin-1-yl)benzoate (4.2 g, 11.9 mmol) in THF (400 mL) was cooled to 0° C. under nitrogen and treated with DIBAL-H (1.0 M in THF, 47 mL, 47 mmol). The mixture was warmed to room temperature and stirred for 1 hour. Then, the reaction mixture was quenched with Rochelle's salt (10% aqueous), concentrated to remove the THF, brine (300 mL) was added, and the organic phase was extracted with CH2Cl2 (3×200 mL), dried over anhydrous MgSO4, filtered, and concentrated, to afford N-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)benzamide as a yellow solid that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Br:10]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(F)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (19.3 mL, 171 mmol) in CH2Cl2 (100 mL) was added iron (3.15 g, 56 mmol). To this stirred suspension was added a solution of bromine (11 mL, 214 mmol) in CH2Cl2 (25 mL) drop wise over 30 min. The resulting mixture was stirred at rt overnight. The reaction mixture was slowly poured into saturated aqueous Na2S2O3 (200 mL), and the resulting mixture was stirred at rt for 30 min. This was extracted with CH2Cl2 (3×80 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1,5-dibromo-2,4-difluorobenzene (40 g, 86% yield) as a brown oil. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.79 (t, J=7.0 Hz, 1H), 7.00 (t, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:24]([C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)[N:25]=1)=[O:15]
Reactant: COC(=O)C(=O)C=Cc1ccccc1Cl
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
4-(2-Chloro-phenyl)-2-oxo-3-butenoic acid methyl ester (4.9 g, 21.9 mmol) prepared in Step 2 and 4-bromophenylhydrazine hydrochloride (5.0 g, 22.4 mmol) was added to acetic acid (50.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting yellow liquid residue was crystallized from diethyl ether to give 5.3 g of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:23][C:21]1[N:22]=[C:18]([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:24])[CH2:13][CH:14]=2)[S:19][CH:20]=1
Reactant: Cc1csc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)n1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1csc(C2=CCN(CCCC(=O)c3ccc(F)cc3)CC2)n1
Reaction time: 3 h

Procedure:
A 1.4 g. portion of 3,6-dihydro-α-(p-fluorophenyl)- 4-(4-methyl-2-thiazolyl)-1(2H)-pyridinebutanol, prepared as described in Example 12, in 30 ml. of acetic acid is stirred at room temperature. A 24 ml. portion of chromic acid in acetic acid is added dropwise. The mixture is stirred for 3 hours and then allowed to stand overnight. The mixture is poured onto ice water and neutralized with sodium carbonate. The mixture is extracted 3 times with ether. The extracts are dried over magnesium sulfate, filtered and evaporated, giving an oil which solidifies. This solid is recrystallized twice from aqueous methanol yielding a tan solid, m.p. 81°-82° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:26])=O>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][Cl:26])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CO
Reactant: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
{4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methanol (0.20 g, 0.604 mmol) was added to neat thionyl chloride (1 ml) over a period of 5 minutes. The resulting solution was stirred for 30 minutes, concentrated to dryness and the residue was subjected to an azeotropic distillation with toluene (2×10 ml). The resulting solid was triturated with acetonitrile (5 ml) filtered and dried to a constant weight in a vacuum oven at 40° C. to give the hydrochloride salt of N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.21 g, 100%) as a white solid; Mass Spectrum: (M+H)+ 352.