Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.[N+](C1C=CC=CC=1N=NC1C=C(C(CC)(C)C)C=C(C(CC)(C)C)C=1O)([O-])=O>>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
When using the procedure of Example 1 an equivalent amount of 2-nitro-2'-hydroxy-5'-tert-octylazobenzene is substituted for 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene, the above noted product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:13]C(=O)OC(C)(C)C)[CH2:10][CH2:11][OH:12].FC(F)(F)C(O)=O>ClCCl>[NH2:13][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH2:10][CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CCO)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 85A, 800 mg (2.50 mmol) were dissolved in 20 ml of dichloromethane and admixed at 0° C. with 1.92 ml (25.0 mmol) of trifluoroacetic acid, then stirred at room temperature for 1 hour. The mixture was freed from the solvent and from the trifluoroacetic acid on a rotary evaporator. The crude product was taken up in 20 ml of toluene and again concentrated on a rotary evaporator under reduced pressure. Purification took place by chromatography on silica gel. By elution with ethyl acetate it was possible to separate off apolar impurities. Elution with dichloromethane/methanol/26% strength ammonia solution (10:1:0.1) gave 673 mg (79% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:9])[S:5][C:6]=1[CH:7]=O.Cl.[NH2:11][C:12]([NH2:14])=[NH:13].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:14][C:12]1[N:11]=[CH:7][C:6]2[S:5][C:4](=[O:9])[NH:3][C:2]=2[N:13]=1
Reactant: N=C(N)N
Reactant: O=Cc1sc(=O)[nH]c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=O)[nH]c2n1
Temperature: 110 °C

Procedure:
Compound 85 (1.22 g, 7.47 mmol), guanidine hydrochloride (2.13 g, 22.4 mmol), K2CO3 (1.03 g, 7.47 mmol), and NaHCO3 (1.88 g, 22.3 mmol) was suspended in DMF and heated for two days at 110° C. Upon consumption of the starting material as determined by TLC, the solvent was removed under vacuurn. The solid residue was triturated with water. An analytically pure sample of 86 was obtained by HPLC (ODS-A C18; 3-97% CH3CN/H2O gradient; 1.0 mL/min). Tan solid: HPLC Rt=1.63 min; Rf=0.45 (2% H2O, 8% Methanol, 90% Ethyl acetate); 1H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 6.67 (s, 2H); MS (+)-ES [M+H]+ 169; Elemental analysis for C5H4N4OS.0.1 CH3CN.0.1 H2O: calc'd: C, 35.88; H, 2.61; N, 32.99; S, 18.42. Found: C, 35.96; H, 2.75; N, 32.56; S, 18.42.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cn1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-Methyl-2-[N-(3-cyano-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[C:1]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH:15]([OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccccc1)c1cccc(C(O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
1,3 dibenzoylbenzene 2 (2.00 g, 6.98 mmol) was dissolved in anhydrous ethanol (20 mL) under an inert atmosphere of nitrogen gas. The reaction mixture was cooled to 0° C. followed by the addition of sodium borohydride (0.090 g, 2.094 mmol). The reaction mixture was stirred for 4 h and quenched the addition of a small amount of water. The reaction mixture was concentrated under reduced pressure and the products were extracted from water with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 30:70) afforded 3-benzoyl benzhydrol 5 (0.601 g, 2.084 mmol) in a 30% yield.
Reaction SMILES: [C:1]([CH:5]1[C:9](O)=[CH:8][O:7][C:6]1=[O:11])([CH3:4])([CH3:3])[CH3:2].O.[NH2:13][NH2:14]>CCO>[C:1]([C:5]1[C:6](=[O:11])[N:13]=[N:14][C:9]=1[CH2:8][OH:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)C1C(=O)OC=C1O
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1=C(CO)N=NC1=O
Yield: 101.9 %

Procedure:
3-tert-Butyl-4-hydroxy-2-furanone (6.6 g, 42 mmol) was dissolved in EtOH (75 mL) with hydrazine hydrate (6.6 mL, 0.21 mol) and was heated at reflux for 16h. The solvent was evaporated and the residue azeotroped with xylene ( 3×50 mL) to afford the title compound (7.2 g, 100%) as a colourless solid. mp 169-172° C. 1H NMR (360 MHz, d6-DMSO) δ1.26 (9H, s), 4.41 (2H, d, J=5.2 Hz), 4.97-5.01 (1H, m), 9.30 (1H, br s), 11.05 (1H, br s). MS (ES+) 171 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH3:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>N1C=CC=CC=1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([NH:1][C:15](=[O:18])[CH2:16][CH3:17])[O:3][N:4]=[C:5]2[N:6]([CH3:14])[C:7]1=[O:13]
Reactant: CCC(=O)Cl
Reactant: Cn1c(=O)c2c(N)onc2n(C)c1=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1onc2c1c(=O)n(C)c(=O)n2C
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
0.588 g of 3-amino-5,7-dimethyl-isoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was dissolved in 15 ml of pyridine under heating. Then, 1.5 g of propionyl chloride was added to the solution, and the mixture was stirred at 80° C. for 4 hours. The solvent was removed from the reaction solution under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The chloroform layer was taken and dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on a column of silica gel, and the column was eluted with chloroform:acetone:formic acid (20:1:0.1). The intended compound was recovered from the resultant eluate and recrystallized from isopropyl ether-acetone to give 0.345 g of colorless prisms, melting point: 150°-152° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([N:28]3[CH2:31][C:30]([OH:33])([CH3:32])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)=[CH:4][C:3]=1[F:34].[CH3:35]B1OB(C)OB(C)O1>>[F:34][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([N:28]3[CH2:31][C:30]([OH:33])([CH3:32])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)[CH:6]=[N:7][C:2]=1[CH3:35]
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cnc(Cl)c(F)c2)C1
Reactant: CB1OB(C)OB(C)O1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C)(O)C2)cc1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 52 using 6′-chloro-5′-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 134) and trimethyl-boroxine. HPLC (Condition 4) tR=5.26 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=477.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 3H) 2.42-2.55 (m, 3H) 3.50-3.65 (m, 4H) 5.46 (d, J=0.78 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.74 (d, J=10.56 Hz, 1H) 7.83 (d, J=8.60 Hz, 2H) 7.97-8.05 (m, 1H) 8.37 (s, 1H) 8.71-8.78 (m, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[BH4-].[Na+]>CO>[OH:17][CH:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(=O)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-{4′-[3-Methyl-4-(2-oxo-4-phenyl-butyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.015 g, 0.03 mmol) in MeOH was treated with sodium borohydride (0.001 g, 0.03 mmol) and stirred at room temperature for 5 minutes. Aqueous workup provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Agent: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: O=c1ccc2c(-c3ccccc3Cl)cc(O)cc2n1-c1c(Cl)cccc1Cl

Procedure:
5-(2-Chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxy-2(1H)-quinolinone was prepared from 5-(2chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 8) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 416.05 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.49-7.56 (m, 3H); 7.31-7.41 (m, 5H); 6.63 (d, J=2.0 Hz, 1H); 6.46 (d, J=9.5 Hz, 1H); 5.97 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Yield: 61.8 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (8.9 g, 39.6 mmol) (as prepared in example 1) was reacted with 14.6 mL (118.8 mmol) of trimethylacetylchloride in dichloromethane (35 mL) and pyridine (9.6 mL) as described in example 2 to yield 7.94 g of the desired compound in 1:1 ratio.
Reaction SMILES: [F:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]([Br:8])=[CH:6][C:5]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2N)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(4-fluoro5-bromo-2-nitrophenyl)amino]-piperidinecarboxylate (D43) (0.91 g, 2.2 mmole) was suspended in ethanol (25 ml) and Raney nickel (50% aqueous suspension, 100 mg) was added at room temperature; the mixture was heated to 45° C. and hydrazine monohydrate (3.0 ml) was added over 10 min. After 1 hr more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated to yield the title compound as an orange brown gum, 0.83 g, 98%. LC/MS—96% m/e 388/390 (M+H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[C:12]1[C:7](=[C:8]([Cl:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+].[Br:27]Br>ClCCl>[Br:27][C:14]1[C:15](=[O:18])[CH2:16][CH2:17][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=1[C:12]1[C:7](=[C:8]([Cl:21])[C:9]([O:19][CH3:20])=[CH:10][CH:11]=1)[CH2:6]2
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)c(Cl)c1C2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (555 mg, 1.82 mmol) in anhydrous dichloromethane (18.2 mL) was treated with sodium bicarbonate (765 mg, 9.1 mmol) and bromine (0.093 mL, 1.82 mmol). The mixture was stirred at room temperature for 30 minutes and then diluted with CH2Cl2 (50 mL) and washed with water (50 mL). The organic phase was dried over MgSO4, filtered through a pad of silica gel (10 mL) with a 10 mL CH2Cl2 rinse, and the solvent evaporated under vacuum. The residue (0.55 g) was lyophilized from benzene to afford 4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.S(O)(O)(=O)=O.[CH3:44][N:45]1[C:49]([NH2:50])=[C:48]([NH2:51])[CH:47]=[N:46]1>O1CCCC1.O.C(Cl)(Cl)Cl>[NH2:50][C:49]1[N:45]([CH3:44])[N:46]=[CH:47][C:48]=1[NH:51][C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15]
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N

Procedure:
To a solution of (2S)-2-[(benzyloxycarbonyl)amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid (22.0 g) and triethylamine (6.7 g) in tetrahydrofuran (240 ml) was added methyl chloroformate (6.2 g) followed by stirring under ice-cooling for 30 minutes. To the reaction mixture was added a solution of 1-methyl-1H-pyrazole-4,5-diamine sulfate (12.6 g) and triethylamine (13.4 g) in water (50 ml) at the same temperature. The mixture was stirred at the room temperature for 1 hour. To the reaction mixture was added chloroform (240 ml), and the layers were separated. The organic layer was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:10]([CH2:9][CH:8]([C:3]1([CH2:2][NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)[N:12]1[CH:16]=[C:15]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:14]=[N:13]1)#[N:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C1(CN)CCCC1
Solvent: ClCCl
Product: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C1(CNC(=O)c2ccccc2)CCCC1
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a solution of 3-[1-(aminomethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 μL, 0.060 mol) in DCM (1.0 mL), was added TEA (17 μL, 0.12 mmol). After 15 minutes, the solvent was removed in vacuo and the mixture was purified via preparative-HPLC/MS (C18 eluting first with a gradient of H2O and ACN containing 0.1% TFA, followed by chromatographic purification, eluting with a gradient of H2O and ACN containing 0.15% NH4OH) to afford the product (7 mg, 27%).
Reaction SMILES: Cl[C:2]1[N:7]([CH:8]([CH3:10])[CH3:9])[S:6](=[O:12])(=[O:11])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.C(N(CC)CC)C.[CH2:22]([OH:24])[CH3:23]>>[CH:8]([N:7]1[S:6](=[O:12])(=[O:11])[N:5]=[C:4]([O:13][CH3:14])[N:3]=[C:2]1[O:24][CH2:22][CH3:23])([CH3:10])[CH3:9]
Reactant: CCO
Reactant: COC1=NS(=O)(=O)N(C(C)C)C(Cl)=N1
Solvent: CCN(CC)CC
Product: CCOC1=NC(OC)=NS(=O)(=O)N1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28.7 parts by weight of 5-chloro-6-isopropyl-3- methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide were added, a little at a time, in the course of 10 minutes, to a stirred mixture of 12.2 parts of triethylamine and 90 parts of absolute ethanol at 20°-25° C. After 3 hours' stirring at 25° C., the reaction mixture was evaporated down under reduced pressure, the residue was taken up in methylene chloride and the solution was washed with 10% strength sodium carbonate solution. After drying over magnesium sulfate, chromatography over alumina and evaporating down under reduced presure, 24 parts of 6-isopropyl-33-methoxy-5-ethoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 81°-85° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[N:15][CH:16]=2)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].[N:24]([O-])=[O:25].[Na+]>>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:24]=[O:25])=[CH:16][N:15]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(NCCc2ccc(C)nc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(N(CCc2ccc(C)nc2)N=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a three-necked bottle, 5-(2-p-methylphenylaminoethyl)-2-methylpyridine 4.5 g and 2N HCl 200 ml was added, heated to 30° C. and stirred to complete dissolution, then cooled with ice-water bath to 0-5° C., added dropwise with NaNO2 aqueous solution (13.8 g of NaNO2 dissolved in 50 ml of water). After dropwise addition, the temperature was elevated and the reaction was performed at room temperature for 1 h. To the reaction liquor, saturated NaHCO3 solution was slowly added dropwise until no gas generated. A great quantity of solid appeared, stirred for 1 h, suction filtrated, washed with water to obtain light yellow solid powder, dried and weighed to obtain 2-methyl-5-(N-nitroso-2-p-methylphenylaminoethyl)pyridine 4.3 g. Yield was about 85%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([OH:7])=O.[NH2:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]([OH:33])=[O:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([NH:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]([OH:33])=[O:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1cccc(O)c1

Procedure:
2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.33 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b), and 6(b) to give powder of 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.447 g.).
Reaction SMILES: C([N:5]([C:13]1[C:17]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[CH:16][NH:15][C:14]=1[C:24]([O:26]C)=O)[C:6]([NH:8]C(OC)=O)=[NH:7])(OC)=O.C[O-].[Na+]>CO>[NH2:7][C:6]1[NH:8][C:24](=[O:26])[C:14]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:13]=2[N:5]=1
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1c(Cc2ccsc2)c[nH]c1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(Cc3ccsc3)c[nH]c2c(=O)[nH]1
Yield: 85 %

Procedure:
Methyl 3-(N,N′-bis-carbomethoxyguanidinyl)-4-(3-thienylmethyl)-1H-pyrrole-2-carboxylate, obtained from Example 23 (3.94 g, 0.01 mol), sodium methoxide (1.62 g, 0.03 mol) and methanol (100 mL) were stirred together and boiled under reflux for six hours. The solvent was evaporated in vacuo and the residue was treated with water (200 mL) containing acetic acid (10 mL). The solid was collected by filtration and crystallized from ethanol to give 2.1 g (85%) of 2-amino-7-(3-thienylmethyl)-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidine as pale-yellow needles, mp 222-224° C. with gas evolution, followed by resolidification and remelting at 268-270° C. (lit.1 271-272° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7](=[O:21])[C:8]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:9]=3[NH:10][C:11](=[O:15])[C:12]=2[O:13]C)=[CH:2]1>Cl.C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:8]2[C:7](=[O:21])[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[C:12]([OH:13])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: COc1c(-c2ccsc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccsc2)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
A solution of 4-(3-thienyl)-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.74 g) in 2.4N HCl/THF (1:1, 600 mL) was allowed to stir at room temperature for 48 hours. The reaction mixture was partitioned between ether and water. The organic portion was dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized twice from ethyl acetate/hexanes (2:1) to afford the title compound (0.173 g); mp 248° C. (dec.); NMR: 11.75 (bs, 1), 10.45 (bs, 1), 7.80 (d, 1, J=8.6), 7.64 (m, 1), 7.48 (m, 2), 7.33 (dd, 1, J=8.6, 2.0), 7.15 (dd, 1, J=5.0, 1.2). Analysis for C14H8O3NSCl: Calculated: C, 55.00; H, 2.64; N, 4.58; Found C, 54.77; H, 2.81; N, 4.56
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][N:30]3[CH2:31][CH2:32][C@H:28]([F:27])[CH2:29]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CC[C@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and (S)-3-fluoropyrrolidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=0.984 min, m/z=517; 1H NMR (CDCl3) 1.43 (d, 3H), 1.84-2.09 (m, 4H), 2.11-2.29 (m, 5H), 2.61 (m, 1H), 2.71-2.87 (m, 3H), 4.96 (s, 1H), 5.13 (s, 1H), 5.53 (m, 1H), 6.71 (d, 2H), 6.98 (t, 2H), 7.18 (m, 3H), 7.20 (m, 1H).