Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc(B(O)O)ccc1Cl
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(Cl)c(N)c2)c(C)c1
Temperature: 70 °C

Procedure:
(3-amino-4-chlorophenyl)boronic acid (1.0 g, 5.834 mmol), methyl 4-bromo-3-methylbenzoate (1.337 g, 5.834 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (476 mg, 0.583 mmol), aqueous potassium carbonate (11.57 mL, 1M, 11.57 mmol) and acetone (53 mL) were mixed and heated in a 70° C. oil bath for 1.5 hours to complete the coupling. Volatiles were removed from the crude mixture under reduced pressure. The resulting mixture was treated with water followed by ethyl acetate extraction. The combined extracts were dried over Na2SO4, filtrated and concentrated under reduced pressure to afford a dark oil. The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge, 0-40% EtOAc in hexanes) to afford methyl 3′-amino-4′-chloro-2-methylbiphenyl-4-carboxylate. LCMS calc.=275.07; found=276.23 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[CH:10]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:24]=[O:25]>[OH-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:24]=[O:25]
Reactant: COc1cc(-c2c(F)cccc2F)n(C)n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nn(C)c(-c2c(F)cccc2F)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-3-methoxy-1-methyl-1H-pyrazole (0.5 g, 2.2 mmol) (i.e. the product of Step C) in dimethylformamide (5 mL) at 80° C. was added phosphorus oxychloride (0.31 ml, 3.3 mmol). After 2 h the reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with sodium hydroxide (1 N, about 5 mL) and water. The resulting mixture was extracted with diethyl ether (2×) and the combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in dichloromethane as eluant) to provide the title compound (0.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCC1CCc2ccccc2N1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCC2CCc3ccccc3N2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(aminomethyl)-1,2,3,4-tetrahydroquinoline hydrochloride and DBU in DME. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])=[C:22]([CH:25]=1)[C:23]#[N:24].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]([CH2:27][CH2:28][OH:29])[CH2:30][CH2:31][OH:32])#[N:24]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: N#Cc1cc(N)ccc1N(CCO)CCO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N(CCO)CCO)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.5 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g), 5-amino-2-[bis(2-hydroxyethyl)amino]benzonitrile (2.0 g), 1-hydroxybenzotriazole (1.5 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.0 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=100:1) to give an oily substance. Diisopropyl ether was added to the oily substance to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (0.9 g), melting point: 158–159° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CC(O)C>[NH:11]([C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: OCc1ccnc(Cl)c1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1cc(CO)ccn1
Temperature: 100 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
To a stirred suspension of (2-chloro-4-pyridinyl) methanol (0.885 g, 6.16 mmol) in 2-propanol (9 mL) was added hydrazine monohydrate (6.0 mL, 124 mmol). The resulting suspension was allowed to stir for 24 h at 100° C. Solvent was evaporated. The residue was purified by silica gel column chromatography with gradient of MeOH (5-20%) in CH2Cl2 to afford 36 (223 mg, 26%) as a white solid. LRMS: calc 139.1; found 140.2 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1cnccn1
Product: N=C(NCCSCc1cnccn1)N[N+](=O)[O-]

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]pyrazine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrazinylmethylthio)ethyl]guanidine. Similarly by the procedure of Example 2 (iii), there is prepared N-methyl-N'-nitro-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.
Reaction SMILES: C([CH:8]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:9]([O-:11])=[O:10])C1C=CC=CC=1>[Pd].CO>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:12][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COCCOCCNC(Cc1ccccc1)C(=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCCOCCNCC(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
(Fourth Step) Activated carbon (219 mg) supporting 10 wt% palladium was added to a methanol (27 mL) solution of benzyl[2-(2-methoxy-ethoxy)ethylamino]acetate (2.19 g, 8.19 mmol) at room temperature. Hydrogen gas purging was performed, and then, in a hydrogen atmosphere, the mixture was stirred at room temperature for 7 hours. Pd/C were removed by a glass filter in which a celite pad was laid, and the celite layer was washed with methanol. The filtrate was concentrated under reduced pressure to obtain [2-(2-methoxyethoxy)ethylamino]acetic acid (1) (1.38 g, 7.78 mmol) as a yellow oily material, with a yield of 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH2:28][N:29]1[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]1[CH3:35]>O1CCOCC1>[CH3:35][C:30]1[N:29]([CH2:28][CH2:27][NH:26][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:33]([CH3:34])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: Cc1ccc(C)n1CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NCCn2c(C)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
9.1 g (0.05 mol) of 3,4-dimethoxybenzoic acid and 8.2 g (0.05 mol) of carbonyldiimidazole in 50 ml of dioxane are stirred at 60° C. for 15 min. After addition of 6.2 g (0.045 mol) of 1-(2-aminoethyl)2,5-dimethylpyrrole in 20 ml of dioxane to the mixture it is stirred at room temperature for 20 h, concentrated, and aqueous sodium bicarbonate solution is added and the mixture is extracted with methylene chloride. The extract is chromatographed over an alumina column, and the product is crystallized using ethyl acetate/ether/ligroin. Yield: 6.9 g (46% of theory), Melting point: 82°-84° C. Elemental analysis: C17H22N2O3 (302.37) calculated: C 67.5 H 7.3 N 9.3 O 15.9 found: C 67.3 H 7.2 N 8.8 O 16.6
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18](OCC)=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C[O-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:23]=2)[NH:24][C:10]1=[O:11]
Reactant: CCOC(=O)c1cc(F)ccc1N
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
A solution of 2,4-dichlorophenyl isocyanate (18.8 g, 0.10 mol) in acetone (50 ml) is metered at room temperature into a solution of ethyl 5-fluoroanthranilate (18.3 g, 0.10 mol) in acetone (70 ml). After addition is complete the mixture is stirred at 90° C. for 2.5 hours. 1.80 ml of a 30% strength solution of methanolic sodium methoxide (0.010 mol) are metered in and the mixture is stirred under reflux for a further 2 hours. After cooling, the product is filtered off with suction and washed with 3×15 ml of acetone. The acetone-moist precipitate is treated with dilute hydrochloric acid and the residual acetone is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 31.7 g of 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione (yield: 97.5% of theory) of melting point 313° to 314° C. are obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=O>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:11]([CH3:16])([CH3:12])[CH3:9])=[O:18])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=CC1CCN(C(=O)O)CC1
Reactant: CCN1CCNCC1
Product: CCN1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 78 %

Procedure:
In operating analogously to preparation LXXIII, starting with N-ethylpiperazine and the t-butyl ester of 4-formyl-1-piperidinecarboxylic acid, the product sought after is obtained as a colourless oil (yield=78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([C:14]#[N:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:16])[C@H:10]([C:14]#[N:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](C#N)C1
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Temperature: 50 °C

Procedure:
80.2 A suspension of (3S,4S)-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (212 mg) in 10 ml of THF and 2.32 g of Ag2O and 0.62 ml of CH3I was heated in a sealed tube to 50° C. for 16 h. The suspension was filtered and the filtrate chromatographed on silica (heptane/AcOEt, 3:1) to give 161 mg of (3S,4S)-3-cyano-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless oil. MS 171.4 ([M-isobutene+H]+)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[OH-].[Na+].[CH3:19][N:20]([CH3:23])[CH:21]=O>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:19][N:20]([CH3:23])[CH3:21])[CH:14]=[O:16])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethylformamide (81 grams) was added dropwise to phosphorus oxychloride (138 grams) keeping the temperature at 20°-30° C. by external cooling. The mixture was stirred for 15 minutes at room temperature and then 4-chlorophenylacetic acid (50 grams in 30 ml DMF) was added. After heating to 65°-75° C. for 20 hours, the reaction mixture was cooled, poured onto 1 kilogram of ice and made basic to pH12 with 50% sodium hydroxide, and then heated on a steam bath for 1 hour. The precipitate which formed was filtered, washed with water, dried in vacuo, and then recrystallized from ethyl acetate yielding the desired product, m.p. 117°-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2s1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2s1
Yield: 94.7 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-2-carboxylic acid ethyl ester (5.97 g, 15.6 mmol), 1-bromopinacolone (4.20 g, 23.4 mmol), and K2CO3 (6.46 g, 46.8 mmol) in acetone (100 mL) are reacted analogous to Example 1D to provide the title compound (7.10 g, 95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].Cl>CC#N.O1CCOCC1>[Cl:32][C:33]1[C:34]([F:40])=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]4[CH2:18][CH2:17][NH:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 60 °C
Yield: 68.6 %

Procedure:
1-tert-butyl 2-methyl (2S,4R)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (12) (0.45 g, 1.0 mmol) was dissolved in MeCN (11 ml) under nitrogen. 3-Chloro-2-fluoroaniline (153 mg, 1.05 mmol) was then added followed by 4M HCl in dioxane (1.2 ml). The resulting mixture was heated overnight at 60° C. The reaction mixture was cooled to −8° C. and the resulting solids collected by filtration and washed with diethylether. The solids were dissolved in methanol, loaded onto an SCX column and eluted with methanol followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) as a clear gum (316 mg, 69%): 1H NMR Spectrum: (DMSO-d6) δ1.45-1.58 (2H, m), 2.02-2.11 (1H, m), 2.32-2.40 (1H, m), 2.57-2.67 (1H, m), 3.08-3.13 (1H, m), 3.42-3.48 (1H, m), 3.64 (3H, s), 3.95 (3H, s), 4.54-4.64 (1H, m), 7.05-7.10 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.48-7.57 (2H, m), 7.85 (1H, s), 8.38 (1H, s), 9.56 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Yield: 97.6 %

Procedure:
A solution of 4.05 g (17.9 mmol) of 4-azido-1-t-butoxycarbonylpiperidine from Step A in 50 mL of methanol was hydrogenated with 350 mg of 10% Pd/C under a hydrogen balloon for 16 h when the reaction was complete by TLC (10% ethyl acetate/hexanes). The catalyst was filtered off and the volatiles removed in vacuo to give 3.5 g of title compound which was used directly in subsequent reactions.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:16]=1)[C:8](N(OC)C)=[O:9])(=[O:3])[CH3:2].[CH3:23][Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Mg]Br.Cl>C1COCC1.C(OCC)(=O)C.O>[C:8]([C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:16]=[C:15]([S:17]([F:22])([F:18])([F:20])([F:21])[F:19])[CH:14]=1)(=[O:9])[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(NC(C)=O)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Acetylamino-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (1.2 g) was dissolved in absolute THF (30 ml) and stirred at 0° C. with lithium hexamethyldisilazide (721 μl; density: 0.8 g/l; 23% in tert-butyl methyl ether) for 30 min. At 0° C., methylmagnesium bromide (2.87 ml, 3 M in diethyl ether) was then added dropwise while stirring. After stirring at RT for 2.5 h, further methylmagnesium bromide (1 ml, 3 M in diethyl ether) was added and the mixture was stirred again for 2.5 h. For workup, 1 N hydrochloric acid was added dropwise while cooling with ice, followed by water and ethyl acetate. The organic phase was removed and the water phase was extracted twice more with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered and concentrated. The crude product (1.03 g) was combined with a crude product prepared in the same way (75 mg) and purified using silica gel with dichloromethane-methanol as the eluent. 860 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].C[Si]([N:18]=[N+:19]=[N-:20])(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[C:12](=[O:13])[NH:20][N:19]=[N:18]1
Reactant: COc1cc(N=C=O)c(Cl)cc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: COc1cc(-n2nn[nH]c2=O)c(Cl)cc1F
Yield: 76.7 %

Procedure:
In the manner of Example 2, Step E, the reaction of 3.2 g (0.016 mole) of 2-chloro-4-fluoro-5-methoxyphenyl isocyanate with 3.2 g (0.028 mole) of trimethylsilyl azide produced 3.0 g of 1-(2-chloro-4-fluoro-5-methoxyphenyl)-1,4-dihydro-5H-tetrazol-5-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16]C(=O)C)[CH2:13][C@H:12]2[CH2:20][NH:21][S:22](=[O:25])(=[O:24])[NH2:23])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>ClCCl.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([SH:16])[CH2:13][C@H:12]2[CH2:20][NH:21][S:22](=[O:24])(=[O:25])[NH2:23])=[O:10])=[CH:26][CH:27]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(C)=O)C[C@H]2CNS(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)N2C[C@@H](S)C[C@H]2CNS(N)(=O)=O)cc1
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-acetylthio-2-sulfamoylaminomethylpyrrolidine (982 mg: 2.35 mmole) in a mixture of dichloromethane (2 ml) and methanol (10 ml), 1N-sodium hydroxide (2.8 ml) is added under ice cooling. The mixture is stirred for 15 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-mercapto-2-sulfamoylaminomethylpyrrolidine (783 mg). Yield: 89%. NMR δ(CDCl3) ppm: 1.6 to 2.0(m, 2H), 2.4 to 2.7(m, 1H), 3.1 to 3.8(m, 4H), 3.81(s, 3H), 3.9 to 4.2(m, 2H), 4.6 to 5.0(m, 2H), 5.04(s, 2H), 5.97(br s, 1H), 6.89(d, J=8.6 Hz, 2H), 7.30(d, J=8.6 Hz, 2H). IR ν (CHCl3) cm-1 : 3668, 3424, 1683.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15](S(C3C=CC=CC=3)=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:41]([C:44]1[CH:57]=[CH:56][C:47]([CH2:48][O:49][C:50]([NH:52][CH2:53][CH2:54][SH:55])=[O:51])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15]([S:55][CH2:54][CH2:53][NH:52][C:50]([O:49][CH2:48][C:47]3[CH:56]=[CH:57][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)=[O:51])[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12

Procedure:
Following a procedure similar to that described in Example 21(b), but using the S-oxide isomer of lower polarity of the 4-nitrobenzyl (1R,5S,6S)-6-[1-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 2) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O)[CH3:19].CO>[Cl-].[Cl-].[Zn+2].C(N(CC)CC)C>[C:13]([C:9]1[N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][CH2:22][C:21]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:18][CH3:19])[C:3]2=[N:11][C:10]=1[CH3:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Reactant: CCc1cccc(C)c1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C)cn12
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A mixture of 8-amino-3-carboethoxy-2,6-dimethylimidazo[1,2-a]pyridine (1.4 g, 6 mmol), 2-ethyl-6-methylbenzaldehyde (0.9 g, 6.5 mmol), ZnCl2 (1.0 g, 7.4 mmol), NaB(CN)H3 (0.41 g, 6.5 mmol) and MeOH (30 ml) was refluxed for 5 h. More ZnCl2 (0.2 g) and NaB(CN)H3 (0.1 g) were added. The reaction mixture was refluxed for additional 2 h. Triethylamin (2 ml) was added and the mixture was stirred at R.T for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride as eluent. 1.1 g (50%) of the title compound was obtained.