Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[O:24]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]3[C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:4][CH:3]=2)=[CH:25]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(-c3ccoc3)cc2)c1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (0.08 g, 0.2 mmol) in DME (2.5 mL)was added furan-3-boronic acid (0.027 g, 0.24 mmol), bis(triphenylphosphine)palladium(II)chloride (0.016 g, 0.02 mmol) and saturated NaHCO3 solution (0.8 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 4 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by thin-layer chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from CH2Cl2-hexane to give the title compound (0.01 g, 13.3% yield).
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C@H:34]([NH:36]C(=O)OC(C)(C)C)[CH3:35])=[CH:30][CH:29]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[NH2:36][C@@H:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][C:6]2([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)=[CH:33][CH:32]=1)[CH3:35]
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc([C@@H](C)NC(=O)OC(C)(C)C)cc4)(C4CCCC4)OC3=O)nc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc([C@@H](C)N)cc4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a stirred solution of tert-butyl (1R)-1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)phenyl]ethylcarbamate (0.58 g, 0.98 mmol, example A(91)) in dioxane (2 mL) under argon was added 4 N HCl in dioxane (2 mL). The resulting solution was stirred at 25° C. for 30 minutes. The solvents were completely evaporated and the resultant white solid was recrystalized from ethyl acetate to give the product (0.40 g, 80%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 1.56-1.77 (m, 11H), 2.14-2.18 (m, 2H), 2.57-2.86 (m, 10H), 3.77-3.94 (m, 2H), 4.40-4.43 (m, 1H), 6.6 (brs, 2H), 7.21 (s, 1H), 7.38 (d, J=7.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 8.56 (s, 1H), 11.2 (s, 1H). Anal. Calcd. For C28H35N5O3. 1.0HCl. 1.0H2O: C, 63.74; H, 7.26; N, 13.27. Found: C, 63.60; H, 7.48; N, 13.20. ESIMS (MH+): 527.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:15][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH2:8]
Reactant: C[C@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C[C@H](N)C(=O)O)C(=O)O
Reaction time: 48 h

Procedure:
The Boc-protected diacid, (2S, 4R)-N-t-butoxycarbonyl- 4-methyl glutamic acid, was subjected to a mixture of trifluoroacetic acid:methylene chloride (40:60, 100 mL) for 3 hr at room temperature. The volatiles were removed in vacuo and the residue was azeotroped with toluene (50 mL). Water (150 mL) was added and the aqueous phase extracted with a 5% solution of trioctylamine in chloroform (3 x 200 mL). The combined organic phases were washed with water (50 mL) and the combined aqueous phases evaporated by being placed on a lyophilizer for 48 hr to give the product (4.6 g, 66% in two steps) as a white foam which was recrystallized in acetone and water. mp=169°-170° C., 1H NMR (200 MHz, D2O): δ 3.80 (dd, J=7.3, 7.3 Hz, 1H), 2.55 (m, 1H), 2.15 (ddd, J=14.7, 8.7, 6.6 Hz, 1H), 1.75 (ddd, J=14.6, 7.4, 5.4 Hz, 1H), 1.05 (d, J=7.0 Hz, 3H). Anal. Calculated for C6H11NO4 : C, 44.71; H, 6.88; N, 8.69. Found: C, 44.59; H, 6.85; N, 8.61.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C@H:13]3[O:20][C:21]2[CH:26]=[CH:25][C:24]([C@H:27]3[CH2:29][C@@H:28]3[C:30]([OH:32])=[O:31])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O-:36].[Na+]>CO>[C:18]([C:17]1[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([O:36][CH3:35])=[CH:3][CH:4]=2)=[C:10]2[C:14](=[CH:15][CH:16]=1)[C@H:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]3[CH2:29][C@@H:28]3[C:30]([OH:32])=[O:31])=[CH:25][CH:26]=1)[CH2:12][CH2:11]2)#[N:19]
Reactant: N#Cc1ccc2c(c1Cc1ccc(Cl)nc1)CC[C@H]2Oc1ccc([C@H]2C[C@@H]2C(=O)O)cc1
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2c(C#N)ccc3c2CC[C@H]3Oc2ccc([C@H]3C[C@@H]3C(=O)O)cc2)cn1
Temperature: 90 °C
Reaction time: 24 h
Yield: 13.4 %

Procedure:
(1S,2S)-2-{4-[(R)-4-(6-Chloro-pyridin-3-ylmethyl)-5-cyano-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid (Example 40, 100 mg, 0.22 mmol) is suspended in methanol (10 mL) and sodium hydride (60% in mineral oil, 27 mg, 0.67 mmol) is added. After 6 hours at 90° C. sodium methoxide (130 mg, 2.25 mmol) is added and the mixture stirred for 24 hours at 90° C. The solvent is removed under vacuum and the residue is purified by flash chromatography (0-10% MeOH in CH2Cl2) to give the title compound (Yield: 13 mg). LC (METHOD 3): tR=4.04 min; Mass spectrum (ES+): m/z=441 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3]([C@H:5]1[C@@H:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][NH:2][C:3]([C@H:5]1[C@@H:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirred solution of 74 mg of tert-butyl cis-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1-carboxylate in 4 mL of dichloromethane was slowly added 2 mL of trifluoroacetic acid. The solution was stirred at room temperature for 3 hr. After removal of the volatile material in vacuo cis-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxamide was obtained in quantitative yield. MS: 457.0 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 86 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3-fluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The orange residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 112 mg (86%) of a yellow solid. MS (EI) 428.2 (M)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([CH3:30])=[CH2:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2([CH3:30])[CH2:29][O:9]2)=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)COc1ccc(OCc2ccccc2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(COc2ccc(OCc3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.4 %

Procedure:
3-Chloroperbenzoic acid (1.43 g of 50%, 4.14 mmol) was added to an ice-cooled mixture of 94 (500 mg, 1.97 mmol) and powdered Na2HPO4 (974 mg, 6.86 mmol) in CH2Cl2 (20 mL), and the resulting mixture was stirred at room temperature for 3.5 h. Cold aqueous Na2SO3 (50 mL of 10%) was added, and the mixture was extracted with CH2Cl2 (3×50 mL). The extracts were sequentially washed with cold aqueous Na2SO3 (50 mL of 10%), aqueous NaHCO3 (50 mL) and brine (50 mL). The combined extracts were then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 25% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 25-33% CH2Cl2/petroleum ether gave 2-{[4-(benzyloxy)phenoxy]methyl}-2-methyloxirane (95) (460 mg, 87%) as a white solid: mp (CH2Cl2/pentane) 105-107° C.; 1H NMR (CDCl3) δ 7.44-7.28 (m, 5H), 6.90 (dt, J=9.3, 2.9 Hz, 2H), 6.85 (dt, J=9.3, 2.9 Hz, 2H), 5.01 (s, 2H), 3.97 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.5 Hz, 1H), 2.85 (d, J=4.8 Hz, 1H), 2.71 (d, J=4.8 Hz, 1H), 1.47 (s, 3H). Anal. (C17H18O3) C, H, N.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[C:5]#[N:6].O.[NH2:16]N>C(O)C>[CH3:13][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[N:6][NH:2][C:3]=2[NH2:16])[CH:12]=[CH:11][N:10]=1
Reactant: NN
Reactant: Cc1cc(C(C#N)=CN(C)C)ccn1
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cn[nH]c2N)ccn1
Yield: 35.8 %

Procedure:
To stirred solution of 3-dimethylamino-2-(2-methyl-pyridin-4-yl)-acrylonitrile (1.8 g, 9.61 mmol) in ethanol (18 ml) was added at room temperature hydrazine monohydrate (1.03 ml, 21.1 mmol), the reaction mixture was heated under reflux conditions for 16 h and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH4OH 80:10:1) and crystallization from diethyl ether yielded 4-(2-methyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.6 g, 36%) as an orange solid. MS (ISP) 175.1 [(M+H)+]; mp 230° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:20]=1[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([C:27]([C:24]2[CH:23]=[C:22]([CH2:21][C:20]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:19]=3[F:18])[O:26][N:25]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
The mixture of 5-chloro-3-(piperidin-4-yl)-1H-indole hydrochloride (0.070 g; 0.258 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.062 g; 0.258 mmol), HATU (N,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.098 g: 0.258 mmol) and N,N-diisopropylethylamine (0.113 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.0428 g (36%) of (4-(5-chloro-1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[N:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[N:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ncnc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M55) (0.78 g, 1.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (370 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([OH:26])=[O:16]
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Reactant: COC(=O)c1ccccc1CBr
Product: O=C(O)c1ccccc1COc1ccc(-c2ccccc2)cc1Cl

Procedure:
2-(3-Chloro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 2-chloro-4-phenylphenol (available from TCI America, Portland, Oreg.) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 45 mg. Mass spectrum (ES) MH+=339.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([N+:24]([O-:26])=[O:25])=[CH:8][C:9]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)=[O:4]>CC(C)=O>[CH2:7]([NH:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([N+:24]([O-:26])=[O:25])=[CH:8][C:9]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH:11]=1)=[O:4])[CH2:6][CH2:11][CH3:10]
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CN)c([N+](=O)[O-])cc1Oc1ccccc1
Solvent: CC(C)=O
Product: CCCCNCC(=O)Nc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
Following the same procedure as that of Example 23 except for the use of N-(5-aminoacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide obtained by the procedure of Example 22 andacetonitrile in place of N-[5-(n-butylaminoacetylamino)-4-nitro-2-phenoxyphenyl]methanesulfonamide and acetone as a reaction solvent used in Example 23, N-(5-aminoacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide hydrochloride was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH:32](=O)[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31])[CH3:33]
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Reaction time: 1 h

Procedure:
cis-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.177 mmol) was suspended in 1,2-dichloroethane (6 mL). A solution of acetaldehyde (12 mg, 0.266 mmol) in 1,2-dichloroethane (0.300 mL) and acetic acid (42 mg, 0.708 mmol) was added and the mixture was stirred for 1 hour. Sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. After 16 hours, more sodium triacetoxyborohydride (37 mg, 0.175 mmol) was added and the reaction continued for another 3 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL) then washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (80 mg) was collected as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:69][C:65]2[CH:66]=[CH:67][CH:68]=[C:63]([C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[C:35]([C:39]5[N:43]=[CH:42][N:41]([C:44]([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)([C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=6)[N:40]=5)[CH:34]=4)[N:30]([CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][O:24]4)[N:31]=3)[CH:64]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-fluorophenyl)acetic acid (0.102 g, 0.66 mmol) in 3.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.140 g, 0.726 mmol). The solution was stirred a t room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.330 mmol), dissolved in 2 mL of dichloromethane was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. (Yield not calculated) ES-MS (m/z) 739 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=O.CC([O-])=O.[K+].[NH2:21]O.Cl.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]#[N:21]
Reactant: COCCOc1ccc(C=O)cc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1ccc(C#N)cc1OC
Temperature: 130 °C
Yield: 91.3 %

Procedure:
To a solution of 3-methoxy-4-(2-methoxyethoxy)benzaldehyde (10 g) in AcOH (80 mL) was added KOAc (9.5 g) and NH2OH.HCl (6.7 g). The resulting mixture was heated at 130° C. for 18 h under N2 atmospheres. After reaction finished, the mixture was poured into water (400 mL). The solid was collected, washed with water (100 mL) and air-dried to give 3-methoxy-4-(2-methoxyethoxy)benzonitrile (9 g) as a light yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 7.26 (dd, J=8.4, 1.6, 1H), 7.08 (d, J=1.6, 1H), 6.93 (d, J=8.4, 1H), 4.23-4.20 (m, 2H), 3.88 (s, 3H), 3.82-3.80 (m, 2H), 3.45 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][C:10]([OH:12])=O)=[O:8].[NH2:13][CH:14]1[C:33](=[O:34])[N:16]2[C:17]([C:30]([OH:32])=[O:31])=[C:18]([C:21]([S:23][C:24]3[N:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:22])[CH2:19][S:20][C@H:15]12>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][C:10]([NH:13][CH:14]1[C:33](=[O:34])[N:16]2[C:17]([C:30]([OH:32])=[O:31])=[C:18]([C:21]([S:23][C:24]3[N:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:22])[CH2:19][S:20][C@H:15]12)=[O:12])=[O:8]
Reactant: O=C(O)CS(=O)c1ccccn1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12
Product: O=C(CS(=O)c1ccccn1)NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12

Procedure:
370 mg. of 2-pyridylsulfinylacetic acid and 7-amino-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 341 mg. of 7-(2-pyridylsulfinylacetamido)-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:33](Cl)=[O:34].Cl>O.CC(C)=O>[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:33]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:34]
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccc(CCN)cc1
Reactant: O=C(Cl)N1Cc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reaction time: 2 h

Procedure:
3 g of N-(4-[2-amino-ethyl]-benzenesulfonyl)-N'-butyl-urea (melting point 210°-212° C., prepared by saponification of N-(4-[2-acetylamino-ethyl]-benzenesulfonyl)-N'-butyl-urea with sodium hydroxide solution) are dissolved with 0.4 g of sodium hydroxide in 50 ml of water and 50 ml of acetone and, while stirring, a solution of 2 g of 1-oxo-isoindoline-2-carboxylic acid chloride (melting point 119°-121° C., prepared from 1-oxo-isoindoline sodium and phosgene) in about 50 ml of acetone is added. The temperature of the mixture increases slightly. Stirring is continued for 2 hours at room temperature, whereupon the residue is acidified with dilute hydrochloric acid. The precipitate is reprecipitated from dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl-urea melts at 188°-190° C.