Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([Br:28])[CH:26]=4)[NH:21][C:20]3=[O:29])[CH:16]=2)[CH:11]=[N:10]1>CN(C=O)C>[Br:28][C:25]1[CH:26]=[C:27]2[C@:19]3([CH2:2][C@H:18]3[C:15]3[CH:16]=[C:17]4[C:12]([CH:11]=[N:10][NH:9]4)=[CH:13][CH:14]=3)[C:20](=[O:29])[NH:21][C:22]2=[N:23][CH:24]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncc(Br)cc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of trimethylsulfoxonium iodide (220 mg, 1 mmol) and 60% NaH (120 mg, 3 mmol) in a RBF was added DMF (5 mL). The resulting mixture was stirred for 5 min at rt. A solution of (E & Z)-3-((1H-indazol-6-yl)methylene)-5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (170 mg, 0.5 mmol) in DMF (5 mL) was added. After addition, the resulting mixture was heated at 55° C. (oil temp.) for 2.5 h. Upon cooling to 0° C., it was quenched with ice, sat. NH4Cl, extracted with EtOAc (50 mL×2). Combined extracts were dried (Na2SO4) and concentrated to give light brown liquid. The residue was purified by flash chromatography (eluent: CH2Cl2/MeOH/Et3N 100:5:1 to 100:10:1) to give the title compound as a pale yellow oil which was triturated with CH2Cl2. The resulting precipitates were collected by suction filtration and dried to give the title compound (66 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 11.42 (s, 1H), 8.04 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.51 (s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 2.60 (dd, J=8.0 Hz, J=4.4 Hz, 1H), 2.10 (dd, J=8.8 Hz, J=4.8 Hz, 1H); MS ESI 355.1 [M+H]+, calcd for [C16H11BrN4O+H]+ 355.0.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][C:3]#[N:4])[CH2:27][CH2:28]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: N#CCCl
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 3.22 parts of 2-chloroacetonitrile, 16 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 12.7 parts of sodium carbonate and 225 parts of N,N-dimethylformamide was stirred for 6 hours at room temperature. The reaction mixture was poured onto water. The product was extracted twice with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 16 parts of 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidineacetonitrile as a residue (compound 147).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([O:22][C:23]2[S:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[N:27]=2)[CH:18]=[CH:19][C:20]=1[F:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[F:14][C:15]1[CH:16]=[C:17]([O:22][C:23]2[S:24][C:25]([CH2:29][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[C:26]([CH3:28])[N:27]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: Cc1nc(Oc2ccc(F)c(F)c2)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1nc(Oc2ccc(F)c(F)c2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.054 g, 0.305 mmol) in dichloroethane (2 mL) was added 2-[(3,4-difluorophenyl)oxy]-4-methyl-1,3-thiazole-5-carbaldehyde (0.072 g, 0.282 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.092 g, 0.434 mmol). The mixture was stirred for 5 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a yellow solid (0.077 g, 51%). 1H NMR (400 MHz, DMSO-d6): δ 7.59-7.47 (m, 2H), 7.18 (m, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 4.23 (s, 2H), 2.47 (m, 1H), 2.17 (s, 3H), 1.59 (m, 1H), 1.29 (m, 1H), 1.18 (m, 1H). ES-MS m/z 416.98 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([O:29]C)=[O:28])=[CH:18][C:17]=3[CH:31]=2)=[CH:9][CH:8]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([OH:29])=[O:28])=[CH:18][C:17]=3[CH:31]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
In methanol (20 ml) and THF (20 ml) was dissolved methyl 7-[4-(2- ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.13 g). To the solution was added 1N sodium hydroxide solution (3 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.12 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(I)c2nc1OC
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc2cc(Cl)c(Cl)c(-c3cccnc3)c2nc1OC
Yield: 29.2 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline (Preparation 108, 0.2 g, 0.519 mmol), 3-pyridylboronic acid (Rec. Trav. Chim. Pays-Bas. 84, 439 (1965)) (0.077 g, 0.623 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) and potassium carbonate (0.143 g, 1.038 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was heated under reflux for 16 hours. After being cooled, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 99:1, by volume) to afford the title compound (0.051 g, 29%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
A solution of 2,5-Dibromo-pyridine (22.2 g, 93.7 mmol, 1.0 equiv.) in toluene (1.2 L) was treated with nBuLi (70.25 ml, 112.4 mmol, 1.2 equiv.) dropwise at −78° C. The resulting solution was stirred at −78° C. for about 30 minutes, and DMF (11 ml, 141 mmol, 1.5 equiv.) was added. The reaction solution was warmed up gradually to RT and then stirred overnight. When TLC and MS showed the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was directly purified by column chromatography (SiO2, 10-30% EtOAc/Hexanes gradient elution) to afford 5-Bromo-pyridine-2-carbaldehyde (1038, 5.45 g, 31% yield) as yellowish white solid. For 1038: C6H4BrNO, LCMS (EI) m/e 187 (M++H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:39]O>>[CH3:39][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:3]
Reactant: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 54 %

Procedure:
A mixture of 1-(7-carboxyheptyl)-2,4,5-triphenyl-imidazole (0.5 g), concentrated sulphuric acid (2 ml) and methanol (100 ml) was heated at reflux for 24 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 ml), washed with water (50 ml), saturated NaHCO3 solution (50 ml), water (50 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient gave 1-(7-methoxycarbonylheptyl)-2,4,5-triphenylimidazole (0.28 g, 54%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=3)[NH2:16])=[CH:10][N:4]2[N:3]=1.C(#N)C.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[CH:17]=3)=[CH:10][N:4]2[N:3]=1
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
A 40 mL vial is charged with 5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-aniline (0.85 g, 3.28 mmol), acetonitrile (14 mL) and pyridine (0.450 mL). The mixture is added trimethylacetyl chloride (0.628 mL, 0.0051 mol) and stirred for 20 min at 80° C. The mixture is concentrated, taken up in EtOAc (35 mL) and washed once with HCl (20 mL, 1M) and then NaOH (20 mL, 1M). Organic layer is dried, concentrated and purified on silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (1.05 g, 94% yield). LCMS m/z=343.5 [M+H]+, tR=2.39 min. (compound same as Example 118)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]#[N:29])[N:24]=[CH:23]1>>[C:28]([CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:26]=1)#[N:29]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: N#CCc1c[nH]cn1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(CC#N)c3)cc2c1=O
Yield: 47 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (1H-imidazol-4-yl)-acetonitrile according to the GPB affording 18.5 mg (47%) of a yellow powder. Rt=2.56 min.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([OH:22])[CH2:19][C:20]#C>>[F:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([C:20]#[C:19][CH2:18][OH:22])=[CH:3][C:4]=2[O:16][CH3:17])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(Br)ccc1Oc1cccc(F)n1
Reactant: C#CCCO
Product: COc1cc(C#CCO)ccc1Oc1cccc(F)n1

Procedure:
According to the procedure of example 11 (a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.98 mmol; 300 mg) and 3-butyn-1-ol by propargylic alcohol (2.50 mmol; 150 μL), the title compound was obtained as a yellow solid (71%, 191 mg) after purification on silica gel (cyclohexane/ethyl acetate gradient).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][C:27]([C:29]5[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=5)=[CH:28][N:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.O[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[N:39]1([O:34][C:33](=[O:35])[C:32]2[CH:31]=[CH:30][C:29]([C:27]3[N:26]=[C:24]4[N:23]([CH:28]=3)[N:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([N:12]5[CH2:11][CH2:10][CH:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:14][CH2:13]5)=[CH:20][CH:19]=3)[S:25]4)=[CH:37][CH:36]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: COCCCCCOC1CCN(c2ccc(-c3nn4cc(-c5ccc(C(=O)O)cc5)nc4s3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCCCCOC1CCN(c2ccc(-c3nn4cc(-c5ccc(C(=O)On6nnc7ccccc76)cc5)nc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (1.28 g) and 1-hydroxybenzotriazole (465 mg) in dichloromethane (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (943 mg), and the mixture was stirred overnight at ambient temperature. The reaction mixture was evaporated in vacuo. To the resulting precipitate was added water (50 ml), and the solid was washed with water and IPE (50 ml) and dried under reduced pressure for 3 hours to give 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imdazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid benzotriazol-1-yl ester (1.26 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-])=O.Cl[C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:19]([N:21]([C:30]2[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=2[Cl:41])COCC[Si](C)(C)C)=[O:20])[CH:13]=1>>[Cl:41][C:31]1[C:32]([O:39][CH3:40])=[CH:33][C:34]([O:37][CH3:38])=[C:35]([Cl:36])[C:30]=1[NH:21][C:19](=[O:20])[N:18]([C:14]1[N:15]=[CH:16][N:17]=[C:12]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:34](=[O:37])[CH:33]=[CH2:32])[CH:13]=1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(Cc2ccccn2)c2cc(Cl)ncn2)c1Cl
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2ccccn2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Yield: 13 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2G (Example 123), substituting 2-nitro-phenylamine and 1-(6-chloro-pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-pyridin-2-ylmethyl-3-(2-trimethylsilanyl-ethoxymethyl)-urea (preparation shown below) in step (d) to afford the title compound (35 mg, yield: 13% over five steps). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 9.65 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 7.80 (t, 1H), 7.66 (d, 1H), 7.31-7.25 (m, 3H), 7.17 (t, 1H), 7.09 (t, 1H), 6.91 (s, 1H), 6.45 (dd, 1H), 6.39 (s, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.17 (s, 2H), 3.94 (s, 6H); MS (ESI): 594 [M+H]+.
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[CH:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:26][CH: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])[CH2:16][CH2:15]2)=O)=CC=1)([O-])=O>O1CCCC1.O>[CH:13]([N:14]1[CH2:19][CH2:18][N:17]([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])[CH2:16][CH2:15]1)=[NH:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CC(C(=O)N4CCN(C=NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(C=N)CC4)C3)[C@H](C)[C@H]12
Yield: 25.6 %

Procedure:
98 mg of 4-nitrobenzyl (1R,5S,6S)-2-(2-[4-(N-4-nitrobenzyloxycarbonylformimidoyl)piperazin-1-yl-carbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl-thio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 5 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 250 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 1(b), to give 12 mg of the title compound as a powder.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][C@@H:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:26][C:27]([O:29][CH3:30])=[O:28])[O:12][CH2:11][C@H:10]1[C:45]([OH:47])=[O:46])=O)(C)(C)C>O1CCOCC1>[CH3:30][O:29][C:27]([NH:26][C@H:25]([C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C@@H:13]1[CH2:14][NH:9][C@H:10]([C:45]([OH:47])=[O:46])[CH2:11][O:12]1)=[O:44])[CH:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:28]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)CO1)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](C(=O)O)CO1)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
4M HCl in dioxane was added to a solution of (3S,6R)-4-(tert-butoxycarbonyl)-6-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-3-carboxylic acid in Dioxane at room temperature and the reaction stirred until complete by LC/MS (8 hrs). The solvent was removed in vacuo to afford the title compound, LC/MS.M+1, +ESI=532.3
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20]Br>C(#N)C>[Br:20][C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[NH:11][N:10]=1
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(Br)n[nH]c2c1
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
6-(1H)-indazole carboxylic acid methyl ester (1.5688 g, 8.90 mmol) and cesium carbonate (4.38 g, 13.44 mmol) were dissolved in acetonitrile (89 ml) at 25° C. Bromine (0.554 ml, 10.75 mmol) was added and the reaction mixture was allowed to stir for 20 min. The reaction was stopped, quenched by addition of saturated aqueous sodium hydrogen carbonate (30 mL) and 10% aqueous sodium thiosulfate (30 mL), and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×50 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The title compound (2.241 g, 8.79 mmol, 99% yield) was recovered as a light orange/white solid. LC-MS: [M+1]=255.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:41])[C:13]=2[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:45](O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:45])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:14]([CH3:41])[C:13]=2[CH:42]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Ethyl 3-({[4-({[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}amino)propanoate (0.78 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (3.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (3.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.70 g, 94%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CC(=O)CC>C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2nc(-c3ccc(Cl)cc3)c(CCCOc3ccccc3OC)o2)CC1
Yield: 69.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), ethyl isonipecotate (1.57 g) and 2-butanone (10 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was diluted with ethyl acetate (100 ml), and the organic layer was washed with a 10% aqueous solution of citric acid (50 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give ethyl N-[4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-oxazolyl]isonipecotate as pale yellow prisms (345 mg, 69%).