Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]#[C:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[N:24][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(O)(=O)C>[Fe].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([C:18]#[C:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[N:24][CH:25]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of tert-butyl [5-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)pyridin-3-yl]carbamate (1.60 g, 3.52 mmol), methanol (37 mL), acetic acid (7.3 mL), water (3.7 mL) and iron (905 mg, 16.2 mmol) was stirred at 60° C. for 3 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate and extracted with ethyl acetate once. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 94%). LCMS calculated for C23H29N4O4(M+H)+: m/z=425.1.
Reaction SMILES: [CH:1]([O:3]C1C=CN=CC=1)=[O:2].[C]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(=O)(O)[O-].[Ni+2].C(=O)(O)[O-].I([O-])(=O)=O.[Mg+2].I([O-])(=O)=O>[N:12]1[CH:17]=[CH:16][C:15]([C:1]([OH:3])=[O:2])=[CH:14][CH:13]=1
Reactant: O=COc1ccncc1
Reactant: C1CCNCC1
Agent: [Ni+2]
Agent: O=C([O-])O
Agent: [C]=O
Product: O=C(O)c1ccncc1
Reaction time: 2 h

Procedure:
A 100-ml. inner capacity stainless steel autoclave of a shaker type is charged with 22.0 grams (0.179 mol) of 4-pyridyl formate. Further piperidine of 1.0 mol as solvent and nickel bicarbonate of 0.045 mol and magnesium iodate of 0.050 mol as catalyst, are added thereto per mol of starting formic acid ester. Carbon monoxide is introduced into the autoclave under pressure. The reaction is conducted for 2.0 hours at 260° C. and 500 kg./cm.2 gauge. After termination of the reaction, the autoclave is cooled and the reaction product is taken away therefrom. The unreacted 4-pyridyl formate is distilled off. Further distillation of the remaining liquor gives pyridine-4-carboxylic acid in a yield of 4.43 grams (0.036 mol) corresponding to a conversion of 20.1% based on the starting formic acid ester.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([F:31])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:29])[F:30])=[C:23]([F:31])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: Fc1cc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)ccc1OC(F)F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)F)c(F)c3)cc2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.4 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3-fluoro-4-difluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-3-fluoro-4-difluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.6 g of the trans isomer (yield 81%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[NH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[N:14]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[C:12]=1[Cl:29]>ClCCl>[NH2:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][F:7])=[CH:19][CH:18]=2)[N:14]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[C:12]=1[Cl:29]
Reactant: COC(=O)c1nc(-c2ccc(CO)cc2)cc(N)c1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(CF)cc2)cc(N)c1Cl
Reaction time: 0.25 h
Yield: 32 %

Procedure:
(Diethylamino)sulfur trifluoride (0.73 mL, 5.5 mmol) was added dropwise to a solution of methyl 4-amino-3-chloro-6-(4-hydroxymethylphenyl)pyridine-2-carboxylate (1.46 g, 5.0 mmol) in dichloromethane (35 mL) at 0° C. The reaction mixture was stirred for 15 minutes and then quenched with ice followed by water. The product was extracted with ethyl acetate and the organic phase was washed with brine and concentrated. The residue was purified by column chromatography (dichloromethane/hexane) giving methyl 4-amino-3-chloro-6-(4-fluoromethylphenyl)pyridine-2-carboxylate (480 mg, 1.6 mmol), mp 95-97° C.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:11]([CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]1)=[C:10]2[C:40]([O:42]C)=[O:41])(=[O:6])=[O:5]>CO.O>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)[C:11]([CH2:27][N:28]1[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:32][CH2:33]1)=[C:10]2[C:40]([OH:42])=[O:41])(=[O:6])=[O:5]
Reactant: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Yield: 93.2 %

Procedure:
Potassium hydroxide (1.42 g, 25.4 mmol) was added to a solution of methyl 6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.0 g, 5.07 mmol) in methanol (60 mL) and water (20 mL), and the resulting mixture was heated to reflux for 5 h. The solvent was removed under reduced pressure, and the residue was adjusted to pH˜5-6 with 2N HCl and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.73 g, 81% yield). MS (m/z) 578.2 (M+H+).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11])[CH2:2][CH3:3].BrBr.[OH2:14]>>[OH:14][C:8]1[C:9](=[O:10])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:11])[NH:6][CH:7]=1
Reactant: O
Reactant: CCCn1c(=O)cc[nH]c1=O
Agent: BrBr
Product: CCCn1c(=O)[nH]cc(O)c1=O
Temperature: 0 °C
Yield: 70 %

Procedure:
To an ice-cooled solution of 3-propylpyrimidine-2,4(1H,3H)-dione (3.00 g) in H2O (100 ml) was added dropwise bromine (1.56 g) until the solution was colored pale yellow. An ice cold saturated NaHCO3 solution was added carefully to the reaction mixture. The alkalized solution was refluxed for 12 hours. After removal of the solvent, the residue was recrystallized from ethanol to give 5-hydroxy-3-propylpyrimidine-2,4(1H,3H)-dione (2.32 g, 70% yield).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].[CH3:35][OH:36]>>[CH3:35][O:36][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cn1
Reactant: CO
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OC

Procedure:
To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br[C:21]1[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.Cl[Pd]Cl>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:21]3[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cccc(B(O)O)c2)cc1
Reactant: COC(=O)c1csc(Br)n1
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(-c2cccc(OCc3ccc(OC)cc3)c2)n1
Temperature: 180 °C

Procedure:
3-(4-methoxybenzyloxy)phenylboronic acid (697 mg, 2.7 mmol, 1.5 eq.), methyl 2-bromothiazole-4-carboxylate (400 mg, 1.8 mmol, 1.0 eq.), dicyclohexyl (2′,6′-dimethoxybiphenyl-2-yl) phosphine (74 mg, 0.18 mmol, 10 mol %) and PdCl2 (20 mg, 0.090 mmol, 5 mol %) were dissolved in toluene (6 mL) and added to a solution of K3PO4 (828 mg, 3.6 mmol, 2.0 eq.) in water (0.6 mL). The reaction mixture was heated 20 min at 180° C. in a microwave reactor, allowed to cool, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude 23 was used in the next step without purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:21])[CH2:19][Cl:20])[C:15](=[O:22])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])O.[Na+].[Cl-].[Ca+2].[Cl-].Cl>CO>[Cl:20][CH2:19][C:18]([NH:17][CH:16]1[C:15](=[O:22])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][CH3:1])[CH2:7][S:8][C@H:9]12)=[O:21]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Ca+2]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 70.7 %

Procedure:
2 g of 3-acetoxymethyl-7-chloroacetamido-3-cephem-4-carboxylic acid and 483 mg of sodium hydrogen carbonate were dissolved in 20 ml of 60% v/v aqueous methanol, and 30 g of anhydrous calcium chloride were added. The mixture was then stirred at 70° C. for 50 minutes, after which it was diluted with 50 ml of ice-water, its pH was adjusted to a value of 1-2 by the addition of hydrochloric acid, and it was extracted three times, each time with 50 ml of ethyl acetate. The ethyl acetate extracts were combined, washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure to give 1.3 g of 7-chloroacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid in an impure state as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.CCN(C(C)C)C(C)C.C(OC(ON1C(=O)CCC1=O)=O)(C)(C)C>>[NH2:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[N:11]1[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To di-tert-butyl {4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}imidodicarbonate (77 mg, 0.13 mmol), 4.0 M HCl in dioxane (1.0 mL, 4.0 mmol) was added. After 1 h, the volatile solvents were removed under reduced pressure then the residue (HCl salt) was dried under high vacuum for 20 min. The residue was dissolved in DCM (0.9 mL) at 0° C. and DIPEA (0.35 mL, 2.0 mmol) and 1-[(tert-butoxycarbonyl)oxy]pyrrolidine-2,5-dione (28.9 mg, 0.134 mmol) were added. The mixture was stirred at room temperature for 90 min., then quenched with aq. NaHCO3 and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic layers were dried, then concentrated under reduced pressure to give a yellow residue. The residue was purified by chromatography on silica using a CombiFlash® apparatus (0 to 25% MeOH in hexanes) to give the sub-title compound as a light yellow powder (36 mg, 72%). LCMS calc. for C18H28N7O2 (M+H)+: m/z=374.2. Found: 374.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>O1CCCC1>[CH3:10][O:9][C:6]1[C@@H:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:20]=2[F:19])[N:8]=[C:3]([O:2][CH3:1])[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=1
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Reactant: Fc1cc(C(F)(F)F)ccc1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](Cc2ccc(C(F)(F)F)cc2F)C(OC)=N[C@H]1C(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 3.32 g (18 mmol) of commercially available (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction to ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes) afforded 5.5 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[C:12](=[O:22])[C:11]([C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])=[C:10]3[OH:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]([F:18])([F:19])[F:20])[N:13]([CH3:21])[C:12](=[O:22])[C:11]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[C:10]3[OH:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(C3=CCCCC3)c(C(F)(F)F)nc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(C3=CCCCC3)c(C(F)(F)F)nc21

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g) by treatment of tert-butyl 2-(6-cyclohexenyl-4-hydroxy-1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 95 (a)) with TFA. MS (ESI, pos. ion) m/z: 426 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 13.02 (s, 1 H), 10.39 (t, J=5.6 Hz, 1 H), 8.35 (s, 1 H), 5.52-5.79 (m, 1 H), 4.15 (d, J=5.6 Hz, 2 H), 3.66 (s, 3 H), 2.04-2.37 (m, 4 H), 1.57-1.89 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]([C@H:49]1[CH2:53][CH2:52][N:51](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:50]1)[C:3]([C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:12]([CH3:35])[C@@H:13]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]3[C:15]=2[C:16]([O:18]CC2C=CC([N+]([O-])=O)=CC=2)=[O:17])[CH2:7][N:6]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:4].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][N:2]([C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)[C:3]([C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:12]([CH3:35])[C@@H:13]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH2:7][NH:6]1)=[O:4]
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)N(C)[C@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)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)N(C)[C@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-{N-methyl-N-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]carbamoyl}-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] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.45 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 700 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 30 mg of the title compound as a powder.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][O:8][C:9](=[O:31])[C@H:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](N)=[C:25]([CH3:30])[CH:24]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].N([O-])=O.[Na+].[I-:36].[K+]>O>[CH3:7][O:8][C:9](=[O:31])[C@H:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([I:36])=[C:25]([CH3:30])[CH:24]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: [I-]
Reactant: COC(=O)[C@H](Cc1ccc(N)c(C)c1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(I)c(C)c1)NC(=O)OCc1ccccc1
Temperature: -1 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A suspension of sulfuric acid (0.3 mL), water (36 mL) and N-(benzyloxycarbonyl)-4-amino-3-methyl-L-phenylalanine methyl ester hydrochloride salt (2.9 mmol, 1.1 g) was heated to obtain a clear solution. Then, it was cooled to −1° C. (ice-bath) and a solution of sodium nitrite (5.8 mmol, 400 mg) in water (8 mL) was added dropwise. The reaction mixture was stirred for 30 min, and a solution of potassium iodide (8.7 mmol, 1.5 g) in water (6 mL) was added to obtain a brown suspension. After stirring for 30 min, the reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Then, the reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated sodium bisulfite solution (100 mL) and brine solution (100 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave a crude product, which was purified by silica gel chromatography using a Biotage (40m) column to afford 0.84 g (64% yield) of N-(benzyloxycarbonyl)-4-iodo-3-methyl-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C19H20INO4 (M+Na) 476.0329, found 476.0336.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:27]=[C:21]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:28].Cl[C:30]1[C:35]([CH:36]=[O:37])=[C:34]([N:38]2[CH2:51][CH2:50][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[C:48]([F:49])=[C:40]3[C:39]2=[O:52])[N:33]=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:49][C:48]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[N:41]2[CH2:50][CH2:51][N:38]([C:34]3[N:33]=[CH:32][CH:31]=[C:30]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:27]=[C:21]6[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][N:20]6[N:19]=5)[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=4)[C:35]=3[CH:36]=[O:37])[C:39](=[O:52])[C:40]=12
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C

Procedure:
A suspension of 135a (385 mg, 1 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (347 mg, 1 mmol), K3PO4 (424 mg, 2 mmol), NaOAc (164 g, 2 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (41 mg, 0.05 mmol) in CH3CN (50 ml) was heated at 100° C. under an N2 balloon for 4 h. Analysis of reaction mixture by LCMS showed completed conversion to the desired product. The reaction mixture was cooled to room temperature and diluted with DCM (50 ml) and water (80 mL). The aqueous layer was separated and extracted with DCM (3×50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The dark residue was purified by silica gel column chromatography eluting with DCM/MeOH (from 80/1 to 30/1) to afford 135b (285 g, 50%) as yellow solid. MS: [M+H]+ 571
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:12][NH:11][C:10]1=[O:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:12][NH:11][C:10]1=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one (10 g, 28.2 mmol) in 40 mL of CH2Cl2 is added TFA (25 mL) at room temp., and the reaction solution is stirred at room temp. for 1 hr, then concd via rotary evaporation (bath temp<20° C.). The residue is diluted with CH2Cl2 (100 mL), and washed with NH4OH (10 mL) and then water (2×20 mL) and dried (Na2SO4). The reaction mixture is adsorbed on silica and chromatographed (5% methanol—CH2Cl2) to give 6.0 g (85.0%) of (3S, 6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3): δ 6.91 (s, 1H), 4.91 (s, 1H), 4.39 (s, 2H), 3.87 (d, J=9.80 Hz, 1H), 3.48 (t, J=6.02 Hz, 1H), 3.43 (dd, J=15.45 Hz and 4.90 Hz, 1H), 2.30 (tt, J=10.92 Hz and 3.39 Hz, 1H), 2.13 (m, 1H), 1.91 (m, 4H), 1.73 (m, 2H), 1.65 (m, 1H), 1.40 (q, J=11.68 Hz, 4H), 1.24 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16])([CH3:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].S(=O)(=O)(O)O>>[CH3:7][C:4]1([CH3:5])[CH2:3][C:2]([CH3:1])([CH3:8])[C:9]2[C:10](=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:16]1
Reactant: Cc1ccc(C(C)(C)CC(C)(C)O)c(O)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc2c(c1)OC(C)(C)CC2(C)C

Procedure:
To 2.16 g (11.7 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl) 5-methyl-phenol (Compound 45) was added under nitrogen 50 ml of 20% aqueous sulfuric acid. The reaction mixture was heated at reflux for 13 h and then cooled. The organic layer was separated and the aqueous layer was extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCO3 solution, water again and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDCl3): & 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s), 2.26 (3H, s), 6.63 (1H, s), 6.72 (1H, d, J~7.9 Hz), 7.15 (1H, d, J~7.9 Hz).