Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([N+:29]([O-])=O)[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[C:24]([NH2:26])[CH:23]=[C:22]([NH2:29])[CH:21]=3)[CH2:18][CH2:19]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(N)cc(N)c2)CC1
Reaction time: 4 h
Yield: 45 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl]-4-(3,5-dinitrophenyl)piperazine was dissolved in ethanol (30 ml) and thereto 10% palladium/carbon (10 mg) was added. The resulting mixture was hydrogenated for 4 hours, and then filtered to remove the 10% palladium/carbon. The filtrate was concentrated and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](OC)=[O:7])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2
Reactant: COC(=O)c1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1csc2ccccc12
Yield: 105.4 %

Procedure:
An ether solution (50 ml) of methyl benzo[b]thiophene-3-carboxylate (15 g) was added dropwise to a suspension of lithium aluminium hydride (3.5 g) in ether (100 ml) followed by reflux for 2 h. Usual work-up gave benzo[b]thiophen-3-yl methanol (13.5 g) as an oil. The oil was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of NaH (5 g of an 80% paraffinsuspension) in tetrahydrofuran (100 ml) followed by reflux for 1 h. Ethyl bromoacetate (35 g) in tetrahydrofuran (50 ml) was added at 60° C. followed by reflux for 1 h. Additional ethyl bromoacetate (20 g) was added followed by reflux for 7 h. The reaction was quenched with water and the volatiles removed in vacuo. The remaining oil was applied to a silica gel column (eluent:ethyl acetate/heptane 2:8) giving ethyl benzo[b]thiophen-3-ylmethyloxyacetate (5 g) as an oil. Reduction with lithium aluminium hydride as described above yielded 3.8 g of 2-(benzo[b]thiophen-3-ylmethyloxy)ethanol as an oil. The title compound 35a was obtained by the method described in EXAMPLE 2 using spiro[isobenzofuran-1(3H),4'-piperidine] and crystallized as the fumarate salt from an acetone/ethanol mixture by addition of fumaric acid. Yield: 0.55 g, mp: 149°-50° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](N)[CH:9]=1)[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cccc(S(C)(=O)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 735 (476.0 mg, 1.16 mmol) in pyridine (3.0 mL) was added methanesulfonyl chloride (135 μL, 1.75 mmol), and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and 1N HCl. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated to provide 550 mg of 744. ##STR123##
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:21][CH2:20]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.1 %

Procedure:
To a solution of {4-[1-(2-chloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (10 mg, 0.021 mmol) in THF (2.0 mL) was added a solution of lithium hydroxide monohydrate (10.2 mg, 0.426 mmol) in water (0.5 mL) at room temperature. The resulting solution was stirred for 15 hours at room temperature under nitrogen atmosphere. The solvent was removed and the aqueous layer was neutralized with 1.0N HCl. The resulting white solids were collected by filtration, washed with water and hexanes, and dried in the air to give {4-[1-(2-chloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (4.5 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 7.9 (dd, J=8.91, 6.65 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=8.03 Hz, 2H), 7.25-7.42 (m, 3H), 7.09-7.23 (m, 1H), 4.27 (d, J=10.79 Hz, 2H), 3.79 (br. s, 4H), 2.43 (s, 4H), 1.65 (d, J=12.05 Hz, 3H), 1.23 (s, 2H). MS cald. for C25H25ClFN2O3 [(M+H)+] 455, obsd. 455.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:10][O:14][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cl)cc(C)[n+]1[O-]
Product: CC(=O)OCc1cc(Cl)cc(C)n1
Reaction time: 8 h

Procedure:
4.0 g (25.4 mmol) of 4-chloro-2,6-dimethylpyridine-1-oxide was dissolved in 12 ml of acetic anhydride. The resultant solution was gradually heated to raise the temperature to the reflux temperature, and the solution was then stirred overnight at the same temperature. The reacted solution was then condensed under reduced pressure to obtain a crude product of acetic 4-chloro-6-methyl-2-pyridinylmethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[OH-]>OP(O)(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(CCc2ccccc2)CCN(Cc2ccccc2)C1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Yield: 32.4 %

Procedure:
4-(2-Phenylethyl)pyridine (8.5 g, 46 mmol) and benzyl chloride (11.64 g, 92 mmol) were refluxed in acetone for 48 h. The precipitated 1-benzyl-4-(2-phenylethyl)pyridinium chloride was filtered, washed with acetone and dried in vacuo at 50° C. to obtain 9.35 g (65%) off the white solid. 1-Benzyl-4-(2-phenylethyl)pyridinium chloride (9.0 g, 29.0 mmol) was suspended in MeOH (100 mL) and cooled to 0° C. in an ice bath. NaBH4 (4.73 g, 207.2 mmol) was added portionwise with vigorous stirring over 40 min. After cooling and stirring for an additional 1 h, the reaction mixture was concentrated under reduced pressure and partitioned between H2O (50 mL) and CH2Cl2 (50 mL). The layers were separated, and the aqueous phase was re-extracted with CH2Cl2 (50 mL). The combined CH2Cl2 extracts were dried over Na2SO4, and concentrated under reduced pressure to provide 7.1 g (91%) of 1-benzyl-4-(2-phenylethyl)-1,2,3,6-tetrahydropyridine as a pale yellow oil. 1H NMR ((CDCl3) δ2.14 (br s, 2, N--CH2 --C H2 --CH =), 2.27 (t, 2, J=8 Hz, N--C H2 --CH2 --), 2.57 (t,2, J=6 Hz, Ph--C H2 --CH2 --), 2.73 (m, 2, Ph--CH2 --C H2 --), 2.97 (br s, 2, N--C H2--CH=), 3.59 (s, 2, Ph-CH2 --N), 5.41 (m, 1, CH=C--), 7.14-7.38 (m, 10, phenyl). 1-Benzyl-4-(2-phenylethyl)-1,2,3,6-tetrahydropyridine (7.1 g, 25.6 mmol) was refluxed in 85% H3PO4 (50 mL) for 80 h. The reaction mixture was basified with 6N NH4OH and extracted with ether (2×100 mL). The ethereal extracts were dried over MgSO4 and concentrated under reduced pressure to a residue. The crude product was purified by radial flow chromatography on silica (hexane,9:acetone,1) to yield 2.3 g (32%) of 1'-benzyl-2,3-dihydrospiro[indene-1,4'-piperidine] as a straw colored liquid. 1H NMR (CDCl3) δ1.53 (br d, 2, piperidyl β-Heq.), 1.96 (dt, 2, piperidyl β-Hax),2.02 (t, 2, Ph--CH2 --C H2 --, J=6 Hz, ), 2.20 (dt, 2, piperidyl α-Hax), 2.90 (m, 4, Ph-C H2 --CH2 -- & piperidyl α-Heq), 3.59 (s, 2, benzyl), 7.14-7.40 (m, 9, phenyl).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[N:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:36])=[CH:6][CH:5]=1.[OH-].[Li+]>O1CCOCC1>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[N:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)=[C:13]([CH3:36])[CH:14]=2)=[C:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[N:22]1
Reactant: COC(=O)c1ccc(C#Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C#Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
To an ambient temperature solution of 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenylethynyl}-benzoic acid methyl ester (32 mg, 0.0599 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (90 μL, 0.180 mmol, 2.0N in water). The reaction mixture is stirred at room temperature overnight. The reaction is concentrated and the residue is partitioned between Et2O and water. The aqueous layer pH is adjusted to approximately 4 and the aqueous layer is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (32 mg, quant). LC-ES/MS m/e 520.2 (M+1), HPLC purity: 100%.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:26][CH:25]=1>>[NH2:16][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=3)=[CH:36][CH:37]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2cc(Cl)nc(N)n2)cc1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Product: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccc(O)cc2)n1

Procedure:
This material was prepared by a method analogous to that described for Example 1, starting from the product from 4-(2-amino-6-chloropyrimidin-4-yl)phenyl tert-butyl carbonate and Intermediate 2R. 1H NMR (DMSO-d6) δ 9.79 (s, 1H), 9.25 (s, 1H), 8.22 (d, 1H), 7.86 (m, 2H), 7.74 (m, 2H), 7.09 (m, 2H), 6.95 (m, 2H), 6.80 (m, 2H), 6.39 (s, 1H), 6.23 (s, 2H); MS ES 406 (M+H)+, calcd 406, RT=2.74 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@H](O)C1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
(3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (2.50 g), triphenylphosphine (5.74 g), and benzoic acid (2.55 g) were dissolved in tetrahydrofuran (60 mL). While this solution was cooled on a sodium chloride/ice bath, azodicarboxylic acid diethyl ester (40% toluene solution, 9.53 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C. or below and then for additional 2 hours at room temperature and was subsequently concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=2:1). The eluted pale brown tar-like material was dissolved in ethanol (60 mL). To this solution, potassium carbonate (4.07 g) dissolved in water (30 mL) was added and the mixture was heat-refluxed for 3 hours while being stirred. Subsequently, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (200 mL). The dichloromethane solution was washed with a saturated aqueous solution of sodium chloride (2×50 mL), was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate: methanol=10:1) to give 2.04 g of (3R,4S)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol as a milky white syrup-like product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[NH4+:14]>C(O)C>[NH2:14][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:6]=1
Reactant: [NH4+]
Reactant: CCCCc1cc(Cl)nnc1Cl
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(N)nnc1Cl
Yield: 36 %

Procedure:
A mixture of 3,6-dichloro-4-n-butylpyridazine (7.1 g, 34 mmol), ethanol (70 ml) and 25% aqueous ammonium hydroxide (70 ml) was heated to 135 deg in a sealed pressure resistant reaction vessel (Parr: achieving a pressure of 90 psi) for 24 hours. After this time the mixture was cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 ml) and water (250 ml) and the aqueous layer re-extracted with dichloromethane (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as a mixture of isomers. Purification by flash chromotography (10-100% ethyl acetate/hexane) gave 3-amino-5-n-butyl-6-chloropyridazine as a white solid (2.3 g, 36%). 1H-NMR (CDCl3) 6.55 (1H, s, 4-H), 4.98 (2H, bs, NH2), 2.57 (2H, t, Bu), 1.58 (2H, m, Bu), 1.37 (2H, m, Bu), 0.91 (3H, t, Bu)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([CH3:32])([CH3:31])[C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:21][C:22]=2[I:23])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>CN(C)C=O.O1CCCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:31])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:21][C:22]=2[I:23])[CH3:35])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=1
Reactant: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCN(c2cc(I)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution of 3.09 g (5.15 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-isobutyramide in 30 ml N,N-dimethylformamide were added at 0° C. 6.8 ml (6.2 mmol) of a 0.91 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring at 0° C. for 40 min 0.352 ml (5.66 mmol) iodomethane were added. The mixture was stirred for 2 days in a closed flask. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give 980 mg (31%) of the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[S:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[N:42]=[CH:41]1>>[CH3:35][C:28]1([CH3:36])[C@H:27]([C:7]2[N:6]([CH2:5][C:4]3[CH:3]=[CH:2][CH:39]=[C:38]([C:43]4[N:42]=[CH:41][S:40][CH:44]=4)[CH:37]=3)[C:10]3[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:14][C:9]=3[N:8]=2)[C@@H:29]1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3cscn3)c2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and thiazole-4-boronic acid pinacol ester in Step A. MS (ESI): mass calcd. for C33H28N4O3S, 560.19; m/z found, 561.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.89-8.87 (m, 1H), 8.23 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.87-7.83 (m, 2H), 7.81-7.78 (m, 1H), 7.77-7.73 (m, 1H), 7.70 (d, J=8.5, 1H), 7.59-7.55 (m, 1H), 7.54-7.52 (m, 1H), 7.43-7.39 (m, 1H), 7.34-7.31 (m, 2H), 7.15-7.11 (m, 1H), 6.99-6.96 (m, 1H), 5.51-5.38 (m, 4H), 2.29 (d, J=8.2, 1H), 2.16 (d, J=8.2, 1H), 1.18 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9]OC(=O)CCC(O)=O)[CH2:7][S:8][C@H:3]12.[SH:23][C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:1][CH:2]1[C:21](=[O:22])[N:4]2[C:5]([C:18]([OH:20])=[O:19])=[C:6]([CH2:9][S:23][C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cn1nnnc1S
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)CCC(=O)O)CS[C@H]12
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A 4.0 ml portion of acetonitrile was added to 0.826 g of 7-amino-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid and 0.32 g of 5-mercapto-1-methyl-1H-tetrazole, and 3.71 g of DCPA was added through a dropping funnel to the mixture under cooling at -5° to 0° C., followed by rinsing the funnel with 0.5 ml of acetonitrile. The mixture was stirred at the same temperature and turned into a solution. Then, the reaction solution was stirred for 45 minutes at 14° to 15° C. to allow the reaction to proceed. The reaction solution was cooled with ice, and poured into ice-water, which was placed in a refrigerator overnight and adjusted to pH 4.0 with 25% aqueous ammonia. The precipitated powder was recovered by filtration, washed with water and acetone successively, and dried, thereby affording 0.722 g (88.0% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR values of the product were in accordance with those of the authentic sample.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].C(O)=O>>[OH:21][C:20]1[N:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:24][N:23]=2)[N:18]=[CH:17][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][C:12]=1[CH3:31]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methylpiperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (22 mg, 0.055 mmol, 43.8%) as a white solid. MS: 403 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 2.43 (s, 3H) 3.28-3.70 (m, 8H) 7.62 (d, J=8.1 Hz, 1H) 7.68 (s, 1H) 7.90 (d, J=8.1 Hz, 1H) 8.02 (dd, J=8.6, 2.3 Hz, 1H) 8.08 (s, 1H) 8.43 (d, J=8.6 Hz, 1H) 8.52 (d, J=2.0 Hz, 1H) 12.74 (br. s., 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35](NC[C@@H](NS(C4C=CC=CC=4)(=O)=O)C(O)=O)=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35]([NH:3][C@H:4]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH2:5][C:6]([OH:8])=[O:7])=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C(CN1CCc2ccc(N3CCNCC3)cc2C1=O)NC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Agent: Cl
Product: O=C(O)C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)c1cccnc1

Procedure:
Following the procedure described for 1-7, but substituting 2(R)-(phenylsulfonylamino)-β-alanine for ethyl 3-amino-3(S)-(3-pyridyl)propionate dihydrochloride, the title compound was prepared. 1H NMR (CD3OD): δ 1.50 (9H, s), 3.00 (2H, m), 3.18 (2H, m), 3.3-3.7 (10H, m), 4.09 (1H, dd), 4.23 (2H, m), 7.2 (2H, m), 7.5-7.6 (4H, m), 7.85 (2H, m), 8.22 (1H, m). ##STR43## N-{[7-(Piperazin-1-yl)-3,4-dihydro-1(1H) -isoquinolinone-2-yl]acetyl}-2(R)-(phenylsulfonylamino)-β-alanine (1-22)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:39])[CH2:11][O:12][C:13]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:39])[CH2:11][O:12][C:13]1[CH:37]=[C:36]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CNC(=O)OC(C)(C)C)COc1cc(F)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: C1CCNC1
Product: CC(CNC(=O)OC(C)(C)C)COc1cc(N2CCCC2)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 80 °C
Yield: 83 %

Procedure:
Using methods substantially equivalent to those described in example 4-F, except that the reaction was heated to 80° C., 2-[2-(3-tert-butoxycarbonylamino-2-methyl-propoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (427 mg, 0.70 mmol, 83%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2-methyl-propoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:30][N:29]=[CH:28][C:27]=1[C:31](Cl)=[O:32]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:27]5[CH:28]=[N:29][O:30][C:26]=5[CH3:25])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cnoc1C
Yield: 80.5 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (162 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and 5-methylisoxazole-4-carbonyl chloride (146 mg, 1.0 mmol), and in the same manner as in Example 162, the title compound (174 mg, yield 80%) was obtained.