Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[NH2:50][CH:51]([CH:60]([OH:63])[CH2:61][F:62])[CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]>C1COCC1>[C:1]([NH:11][C@H:12]([C:16]([NH:50][CH:51]([CH:60]([OH:63])[CH2:61][F:62])[CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
To a solution of Cbz-Valine (396 mg, 1.58 mmol) in THF (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (300 mg, 1.57 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (240 mg, 1.57 mmol) and dimethylaminopyridine (DMAP) 129 mg 1.06 mmol). The resulting mixture was stirred for 5 min, then was added a solution of t-butyl 3-amino-5-fluoro-4-hydroxy-pentanoate (215 mg, 1.04 mmol) in THF (10 mL) and it was stirred at rt for 18 h. The mixture was filtered and the THF solution was evaporated, and the residue was purified by chromatography over silica gel (hexane-EtOAc, 3:2) to give 290 mg (68%) of the titled compound as a white solid. 1HNMR (CDCl3), 0.905 (d, 3H, J=7), 0.965 (d, 3H, J=7), 1.428 (s, 9H), 2.07-2.16 (m, 1H), 2.50-2.57 (m, 1H), 2.64-2.70 (m, 1H), 3.52 (bs, 1H, OH), 3.92-3.96 (m, 2H), 4.20-4.27 (m, 1H), 4.40 (bs, 1H), 4.49 (bs, 1H), 5.10 (s, 2H), 5.31-5.4 (m, 1H, NH), 6.86-6.93 (m, 1H, NH), 7.350(s, 5H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([CH2:30][O:31]C)[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1.B(Br)(Br)Br>C(Cl)Cl.C(OCC)C>[F:34][C:2]([F:1])([F:33])[CH:3]([CH2:30][OH:31])[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16][N:17]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:9][CH:10]=1
Reactant: COCC(Oc1ccc(NC(=O)C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Nc3ccc(OC(CO)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (rac)-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-(2,2,2-trifluoro-1-methoxymethyl-ethoxy)-phenyl]-amide (240 mg), product of example 54) in methylene chloride was treated at RT and under an argon atmosphere with BBr3 (0.5 molar in methylene chloride, 2 ml) and stirred 2 h at RT. The reaction mixture was then taken up in diethyl ether, washed with aqueous 1N HCl, the layers were separated, the organic layer dried over sodium sulfate and evaporated off to give the desired (rac)-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-(2,2,2-trifluoro-1-hydroxymethyl-ethoxy)-phenyl]-amide crystalline light red solid. MS (ESI): 487.3 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([C:15]([CH3:17])=[O:16])C(OCC)=O)[CH3:8].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])=[C:22]([F:32])[CH:21]=1>CC(C)=O>[CH2:7]([CH2:9][C:15](=[O:16])[CH2:17][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])=[C:22]([F:32])[CH:21]=1)[CH3:8]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(=O)CCc1ccc(C(C)C(=O)O)c(F)c1
Yield: 59.9 %

Procedure:
To a suspension of anhydrous potassium carbonate (0.86 g, 6.2 mmol) in acetone (40 mL), ethyl 2-ethylacetoacetate (0.56 mL, 3.45 mmol) was added under stirring. After stirring for 15 minutes at room temperature, compound (20) (0.95 g, 3.45 mmol) was added, and the reaction mixture was refluxed for 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was treated with dichloromethane (50 mL). The organic layer was washed with a sodium bicarbonate solution and saline, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (7:2) solution followed by conventional decarboxylation and hydrolysis to give 0.55 g (45%) of compound (23) of interest as clear colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]4[CH2:20][CH2:19][CH2:18][C:17](=O)[C:16]=4[CH:15]=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:23].[C:24]([NH2:28])(=[O:27])[CH2:25][CH3:26].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>FC(F)(F)C1C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]4[CH2:20][CH2:19][CH:18]=[C:17]([NH:28][C:24](=[O:27])[CH2:25][CH3:26])[C:16]=4[CH:15]=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:23]
Reactant: CCC(N)=O
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4=O)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: FC(F)(F)c1ccccc1
Product: CCC(=O)NC1=CCCc2c1cncc2-c1ccc2c(c1)CCC(=O)N2C
Temperature: 102 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a stirred suspension of 1-methyl-6-(8-oxo-5,6,7,8-tetrahydro-isoquinolin-4-yl)-3,4-dihydro-1H-quinolin-2-one) (919 mg, 3 mmol, example 70) and propionic acid amide (658 mg, 9 mmol) in trifluorotoluene (30 mL) was added trifluoromethane sulfonic acid (585 mg, 3.9 mmol) and the reaction was stirred at 102° C. After 4 h, a solution of trifluoromethane sulfonic acid (158 mg, 1.05 mmol) in trifluorotoluene (5 mL) was added and the reaction mixture stirred for further 8 h. After this time, propionic acid amide (219 mg, 3 mmol) and a solution of trifluoromethane sulfonic acid (158 mg, 1.05 mmol) in trifluorotoluene (5 mL) were added and the stirring continued at 102° C. over night. The reaction mixture was allowed to cool down to room temperature and aq. NaOH 2 M (30 mL) was added. The resulting mixture was extracted with dichloromethane (3×) and the organic phases washed with aq. sat. NaCl solution (2×). The combined organic phases were dried over Na2SO4, filtered and evaporated. Crystallization of the crude product (dichloromethane/ethyl acetate/heptane) afforded the title compound (915 mg, 84% yield) as off-white crystals. MS: 362.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8](C=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C=O.[ClH:18].[C:19](O)(=O)[CH3:20]>>[Cl:18][CH2:1][C:2]1[C:3]2[C:8]([C:19]([CH3:20])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cc1c2ccccc2cc2ccccc12
Reactant: Cl
Reactant: CC(=O)O
Agent: C=O
Product: Cc1c2ccccc2c(CCl)c2ccccc12

Procedure:
9-methyl anthracene was reacted with formalin and HCl in glacial acetic acid to produce the starting material 9-(chloromethyl)-10-methylanthracene (0.44 gms). The 9-(chloromethyl-10-methyl anthracene (0.44 gms.) was dissolved in 10 mls of dioxane with heating to 70° C. Stannous chloride dihydrate (0.412 gms) was added and the mixture was reacted with stirring at 70° C. for 40 minutes under nitrogen gas. The reaction was then cooled and the solution quenched with methanol. The solution was filtered to remove the methyl lepidopterene. This solid was then redissolved in methylene chloride and filtered to remove any insoluble material. The methylene chloride solution of the lepidopterene was quenched with methanol to precipitate the lepidopterene and filtered to remove the material. 0.2 grams of a colorless, crystalline solid were obtained. (See also H.-D. Becker, J.Org.Chem., 44, 1337(1979)
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:28][CH:29]1[CH2:31][CH2:30]1>CCO.CCO.CCO.CCO.[Ti]>[Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 8 h

Procedure:
A mixture of 10 g (24 mmol) of tert.butyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 31 g (430 mmol) of hydroxymethyl-cyclopropane and 1.80 g (8 mmol) of tetraethyl orthotitanate is stirred at 125° overnight, the solution obtained is evaporated to dryness, the residue is taken up in chloroform and stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution. The resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate and hexane there is obtained cyclopropylmethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 135°-136°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[N:10]3[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=[C:9]3[C:6]2=[N:7][CH:8]=1)[CH3:2].Cl.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C(N(CC)CC)C.Cl>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[NH:10][C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[C:5]([CH:4]=1)[C:11]([N:23]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH3:22])=[O:12])[CH3:2]
Reactant: CCc1cnc2c(c1)C(=O)N1C(=O)C(C)(C(C)C)N=C21
Reactant: CNCCCC(=O)O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)N(C)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 7-ethyl-2-isopropyl-2-methyl-5H-imidazo[1′,2′:1,2]pyrrolo[3,4-b]pyridine-3(2H),5-dione (5.47 g, 20.19 mmol) in anhydrous N,N-dimethylformamide is treated successively with 4-(methylamino)butyric acid hydrochloride (3.29 g, 21.2 mmol) and triethylamine (4.29 g, 42.39 mmol). The resulting mixture is stirred at room temperature under nitrogen for 2.5 hours. After this period, the reaction mixture is diluted with water, acidified with concentrated hydrochloric acid and extracted with ether. The organic extract is dried over magnesium sulfate, vacuum filtered through diatomaceous earth and concentrated in vacuo to give the title product as a white solid, mp 42-49° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[N:27]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[O:15][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[N:27]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(F)n2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 3.67 mmol) in DMF (18 mL) was added NaH (60% in mineral oil, 367 mg, 9.17 mmol) and the mixture was stirred at room temperature for 10 minutes. 2,6-Difluoropyridine (1.00 mL, 11.0 mmol) was added and the mixture was heated at 70° C. overnight. Work-up and purification gave 4-[(4-bromo-phenyl)-(6-fluoro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (1.60 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.O.C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1N1CCc2ccccc21
Temperature: 180 °C
Yield: 85.7 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (30 mg 76 μmol) and indoline (0.10 ml, 790 μmol) were mixed in xylene (mixture of isomers, 0.75 ml) and heated in a microwave oven at 180° C. for 20 min. When cool again, water (0.75 ml) and acetic acid (0.75 ml) were added to the mixture, causing separation of two phases. The aqueous phase was separated and subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The yellow oily residue was dissolved in EtOAc (20 ml). This solution was washed with 1% aqueous NaHCO3 (20 ml) and brine (10 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (31 mg, 85%) as a pale yellow powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.NC1C=CC=CC=1>CN(C=O)C>[C:1]([NH:4][CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:7]([NH:40][C:38]1[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(C(=O)O)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
3-(Acetylamino)-2-[4-(tert-butoxycarbonyl)phenyl]propanoic acid (222 mg, 0.72 mmol), EDCI (207 mg, 1.08 mmol), and HOBT (127 mg, 0.94 mmol) were dissolved in DMF (7 mL) and stirred for 5 minutes before adding aniline (99 μL, 1.08 mmol). After stirring at room temperature for 18 h, the solution was concentrated. The resulting residue was taken up in EtOAc, washed (water, sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica (0-4% MeOH/DCM) afforded tert-butyl 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoate as an off-white solid. 1H NMR (DMSO-d6) δ10.18 (s, 1H), 8.08 (t, J=5.9 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.56 (d, J=7.6 Hz, 2H), 7.46 (d, j=8.2 Hz, 2H), 7.25 (t, J=7.9 Hz, 2H), 7.00 (t, J=7.5 Hz, 1H), 4.03 (dd, J=8.2, 6.3 Hz, 1H), 3.51 (ddd, J=13.2, 8.4, 5.0 Hz, 1H), 3.42 (dt, J=12.9, 6.5 Hz, 1H), 1.74 (s, 3H), 1.50 (s, 9H). MS (ESI) calcd [M+H]+ 383.2, found 383.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl.CN(C1C=CN=CC=1)C>[C:21](=[O:22])([O:23][CH3:24])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[Cl:12]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of 4-tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) in dichloromethane (200 mL) was added Et3N (50.5 g, 0.50 mol), DMAP (1 g) and methyl chloroformate (35.4 g, 0.38 mol) at 0° C. The reaction was allowed to warm to room temperature and stirred for additional 30 min. The reaction mixture was washed with H2O and the organic layer was dried over Na2SO4 and concentrated to give 4-tert-butyl-2-chlorophenyl methyl carbonate (56.6 g, 92%), which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:22]I.O>CS(C)=O>[CH3:22][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: CI
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C(=O)c1nc2ccccc2n1C)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.0 g) prepared in Example 5 was suspended in dry DMSO (20 ml), sodium hydride (0.16 g) was added in an argon atmosphere and stirred at room temperature for 1 hr. Methyl iodide (0.62 g) was added and stirred at room temperature for 2 hrs. The mixture was poured into water and extracted with chloroform. The chloroform layer was dried over anhydrous Na2SO4, and the solvent was distilled off to obtain the residue. Purification of the residue by column chromatography on silica gel gave the title compound (0.99 g).
Reaction SMILES: O.[NH:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][CH:16]3[CH:11]([CH2:12][CH:13]([C:19]([OH:21])=[O:20])[NH:14][CH2:15]3)[CH2:10]2)=[N:5][N:4]=[N:3]1.Cl>C(O)CCCCCCCCC>[CH2:6]([O:20][C:19]([CH:13]1[CH2:12][CH:11]2[CH:16]([CH2:17][CH2:18][CH:9]([CH2:8][CH2:7][C:6]3[NH:2][N:3]=[N:4][N:5]=3)[CH2:10]2)[CH2:15][NH:14]1)=[O:21])[CH2:7][CH2:8][CH2:9][CH2:18][CH2:17][CH2:16][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1
Agent: Cl
Solvent: CCCCCCCCCCO
Solvent: O
Product: CCCCCCCCCCOC(=O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1

Procedure:
A solution of 2.5 g (8.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid monohydrate in 50 ml decyl alcohol saturated with hydrogen chloride (g) is heated at 120° C. overnight. The mixture is concentrated in vacuo and the residue purified by SPE (Oasis HLB) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].NC1C=C2C(=CC=1)C(=O)OC2.[I:38]C1C=C(C(C)(C)CC(=O)C(O)=O)C=CC=1>>[I:38][C:20]1[CH:19]=[C:18]([C:16]([CH3:24])([CH3:17])[CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]2[CH:2]=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:6](=[O:7])[O:5][CH2:4]3)=[O:26])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(CC(=O)C(=O)O)c1cccc(I)c1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: Nc1ccc2c(c1)COC2=O
Product: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1)COC2=O)c1cccc(I)c1

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(3-iodophenyl)-4-methyl-2-oxo-valeric acid, melting point 160-161° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.[CH:19]1([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH:32][C:33]1[C:40]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=1[C:45]([CH3:48])([CH3:47])[CH3:46].C(O)(C)C>CO>[OH:32][C:33]1[C:40]([C:41]([CH3:43])([CH3:42])[CH3:44])=[CH:39][C:36]([CH:37]=[N:1][C@@H:2]2[C:17](=[O:18])[N:4]3[C:5]([C:14]([O-:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]23)=[CH:35][C:34]=1[C:45]([CH3:48])([CH3:47])[CH3:46].[CH:26]1([NH2+:25][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CC(C)O
Solvent: CO
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 29.2g of 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid in 600 ml of methanol was added 18.1g of dicyclohexylamine and stirred at room temperature for 1 hour. To a semitransparent solution thus obtained was added 24.0g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde and stirred at room temperature for 2 hours and stirring was continued after adding 50g of molecular sieve 3A for further 5 hours. After filtration of the reaction mixture, the filtrate was condensed under reduced pressure to give a crystalline product which after an addition of isopropanol was collected by filtration. To a solution of 13.4g of dicyclohexylammonium 7β-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-acetoxymethyl-3-cephem-4-carboxylate thus obtained in 200 ml of methanol was added dropwise 4.74g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 40 ml of methanol at -15° C, and after completion of the addition the stirring was continued for another 10 minutes at the same temperature and then 1g of 2,6-di-tert.-butyl-p-cresol was added to the reaction mixture. After stirring for another 10 minutes at 0° C, 5.60 ml of triethylamine was added to the solution, which was then condensed to about 50 ml under reduced pressure, diluted with 300 to 400 ml of chloroform and washed three times with the same volume of water. On drying over anhydrous magnesium sulfate the solvent was removed under reduced pressure, the residue extracted with ether, the extract was condensed and added with n-hexane to give a precipitate, which was collected by filtration affording 13.03g of the desired product as a yellow powder. Crystallization of this powder from n-hexane-chloroform yielded a pure sample melting at 139°-141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Yield: 88.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XLVI) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2Cl2 (927 mg, 5 mmol %) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give 5-nitro-3,3′-bipyridin-4-amine (XLVII) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 400 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).