Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([CH3:52])[N:43]2[C:42]1=[O:53]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([CH3:52])[N:43]2[C:42]1=[O:53])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7R,10aS)-7-methyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-o-tolylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (17 mg, 0.031 mmol) and Intermediate 72 (7.5 mg, 0.035 mmol) to give a white solid (18 mg, 69% yield). Anal. Calcd. for C43H54N4O4S m/z 722.7. found: 723.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37-6.88 (m, 14H), 5.28 (d, J=5.2 Hz, 1H), 4.99-4.85 (m, 1H), 4.83-4.70 (m, 1H), 4.66-4.56 (m, 1H), 4.09-3.83 (m, 2H), 3.53 (d, J=14.5 Hz, 1H), 3.31 (dd, J=15.0, 5.0 Hz, 1H), 3.15-2.93 (m, 4H), 2.90-2.64 (m, 4H), 2.63-2.49 (m, 2H), 2.48-2.30 (m, 3H), 2.19 and 2.13 (s, 3H), 2.09-1.43 (m, 11H), 1.32 (d, J=6.9 Hz, 3H), 1.44-1.16 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Solvent: CC(C)O
Product: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
A solution of (7-bromo-3-nitroquinolin-4-yl)-(2-methylpropyl)amine (30.9 g, 105 mmol) in acetonitrile (1.8 L) and isopropanol (200 mL) was added to a Parr vessel. A mixture of 5% platinum on carbon (3.0 g) and acetonitrile:isopropanol (20 mL) was added, and the vessel was purged with nitrogen. The vessel was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for two hours. After one hour, the pressure had decreased to 20 psi (1.4×105 Pa) and was readjusted to 40 psi (2.8×105 Pa). The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine as an oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:30][CH2:29]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl>[C:35]([N:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:29][CH2:30]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1)(=[O:37])[CH3:36]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C(C)=O)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a solution of Compound (6) (8 mg, 0.02 mmol) in DCM (2.0 mL) was added acetic anhydride (0.1 mL) and pyridine (0.1 mL) and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between EtOAc (25 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo (32 mg). The crude material was purified by reverse phase preparative LCMS: Acetonitrile/water (0.1% formic acid) to give Compound (8) (2.14 mg, 20%). ESI-MS m/z calculated for [M+H]+: 544.2. found: 544.1. 1H NMR (400 MHz, CD3CN) δ 7.85 (s, 1H), 7.63-7.54 (m, 4H), 7.40 (s, 1H), 7.05 (br s, 1H), 4.21-4.14 (m, 1H), 3.93 (td, J=8.9, 3.2 Hz, 1H), 3.76-3.67 (m, 3H), 3.49-3.43 (m, 1H), 3.11 (d, J=1.0 Hz, 3H), 2.93 (d, J=4.8 Hz, 3H), 2.77-2.64 (m, 1H), 2.46-2.36 (m, 1H), 1.95-1.81 (m, 2H), 1.73 (d, J=2.4 Hz, 3H), 1.14-1.02 (m, 3H), 0.69-0.58 (m, 1H).
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[Cl:20]C1C=C(C=CC=1)C(Cl)=O>>[Cl:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:4]=1)[C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:9]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Product: O=C1CCCCCN1C(=O)c1cccc(Cl)c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 3-chlorobenzoyl chloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc(F)cc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-fluorobenzyl bromide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH2:22])=[N:19][C:20]=2[NH2:21])=[CH:10][C:11]=1[O:12][CH3:13].C[O:26]C1C=C(C=C(OC)C=1OCCOC)C=O.NC1N=C(N)C=C(O)N=1>>[NH2:22][C:18]1[N:19]=[C:20]([NH2:21])[C:15](=[CH:14][C:9]2[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([O:23][CH3:24])[CH:8]=2)[C:16](=[O:26])[N:17]=1
Reactant: COCCOc1c(OC)cc(C=O)cc1OC
Reactant: COCCOc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Agent: Nc1cc(O)nc(N)n1
Product: COCCOc1c(OC)cc(C=C2C(=O)N=C(N)N=C2N)cc1OC

Procedure:
A process for preparing Tetroxoprim starting from 3,5-dimethoxy-4-methoxyethoxy-benzaldehyde and 2,4-diamino-6-hydroxy-pyrimidine, by successive hydrogenation, halogenation and hydrogenolysis of the 2,4-diamino-6-oxo-5-(3,5-dimethoxy-4-methoxyethoxy-benzylidene)-pyrimidine obtained in the initial reaction.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[CH3:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36].[Cs+].[I-].[Na+].C(#N)C>O>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:37][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: CC(C)(C)C(=O)[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 30 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.40 g, 0.81 mmol), cesium 2,2-dimethyl-propionate (0.38 g, 1.63 mmol), sodium iodide (0.121 g, 0.81 mmol) and acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 30 minutes) to afford the title compound. Isolated yield: 30%. 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.38 (m, 1H), 7.33 (t, 1H), 7.22 (dd, 1H), 6.71-6.65 (m, 1H), 4.77-4.68 (m, 1H), 4.12-3.94 (m, 2H), 3.88-3.74 (m, 2H), 3.36-3.28 (m, 2H), 3.18-3.12 (m, 1H), 3.07-3.03 (m, 2H), 2.37 (d, 3H), 2.15-2.06 (m, 2H), 2.00-1.97 (m, 2H) 1.44 (dd, 3H); 1.08 (d, 9H),
Reaction SMILES: ClCCCl.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:19]([N:26]1[CH2:29][CH:28]([C:30](O)=O)[CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[SH:40]>C(Cl)Cl>[C:22]([O:21][C:19]([N:26]1[CH2:29][CH:28]([C:30]2[S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)[CH2:27]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1ccccc1S
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3s2)C1
Temperature: 80 °C

Procedure:
To 10 mL DCE was added 533 mg (3.7 mmol) phosphorus pentoxide and 1.57 mL (7.36 mmol) bis-trimethylsilyl ether and the mixture was heated at 80° C. for 15 minutes. 0.19 g (0.92 mmol) N-boc-azetidine-3-carboxylic acid and 108 μL (1.01 mmol) 2-aminothiophenol were added and the mixture heated at 85° C. for 20 minutes. After cooling to room temperature the mixture was diluted with 20 mL DCM and washed with 1 M Na2CO3 (2×10 mL). The organic layer was dried with Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 1:1).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.BrC1OC(C(Cl)=O)=CC=1.O.[NH2:24][NH2:25]>O>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:24][NH2:25])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NN
Agent: O=C(Cl)c1ccc(Br)o1
Solvent: O=S(Cl)Cl
Solvent: O
Product: NNC(=O)c1ccc(Br)o1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-furan-2-carboxylic acid (38.2 g, 200 mmol) and thionylchloride (163.1 g, 1.37 mol) was stirred at 70° C. overnight. The mixture of 5-bromo-furan-2-carbonyl chloride was evaporated, solved in tetrahydrofuran (10 ml) and added to a mixture of hydrazine monohydrate (120.1 g, 2.4 mol), followed by stirring for 0.5 hours at <5° C. Water (50 ml) was added followed by filtration. The crystalline product was recrystallized from ethanol (125 ml, 96%). Yield 21.2 g (52%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[N:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13](I)([CH3:15])[CH3:14]>C(#N)C>[CH:13]([N:10]1[N:9]=[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]2=[N:11]1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cccc2[nH]nnc12
Solvent: CC#N
Product: CC(C)n1nc2cccc([N+](=O)[O-])c2n1
Temperature: 50 °C

Procedure:
To a hot, stirred solution (50° C) of 20.0 g. of 4-nitrobenzotriazole in 600 ml. of acetonitrile is added 4.2 g. of sodium hydroxide pels and 20.0 g. of isopropyl iodide. The solution is then heated to reflux for 30 hours, filtered and the solvent removed by evaporation to yield an oil. The oil is extracted with concentrated hydrochloric acid (3 × 200 ml.) to leave behind a solid material. The solid is washed with water and air dried to yield crude 2-isopropyl-4-nitrobenzotriazole. The analytical sample is recrystallized from petroleum ether, m.p. 65°-67° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: OCc1ccco1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To the solution of furan-2-ylmethanol (500 mg, 5.1 mmol) in CH2Cl2 (10 mL) and triethylamine (1.54 g, 15.3 mmol) at 0° C. was added dropwise methanesulfonyl chloride (695 mg, 6.1 mmol). The mixture was stirred at 0° C. for 15 min and was quenched with 10 mL of water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: CN(C)CCN.[CH3:7][O:8][CH2:9][CH2:10][O:11][N:12]1C(=O)C2=CC=CC=C2C1=O.C(O)(=O)C.[C:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:27](=[N:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[CH3:28])[CH:35]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: COCCON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: COCCON=C(C)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
N,N-Dimethylethylenediamine (2.54 mL, 22.0 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (3.32 g, 15.0 mmol) in EtOH (50 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (20 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (3.02 g, 10.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1) afforded N-{4-chloro-2-[1-(2-methoxyethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 185 (3.0 g, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.40, br s, 1H, 7.65, d, J=8.8 Hz, 1H, 7.47, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H, 4.37, m, 2H, 3.71, m, 2H, 3.41, s, 3H, 2.32, s, 3H. HRMS (M+) 374.0308.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:14]([N:16](CC)CC)[CH3:15].C(Cl)(=O)OCC.C(N)C.O1CCCC1>O1CCCC1>[CH2:14]([NH:16][C:11]([C:10]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[S:8][CH:9]=1)=[O:13])[CH3:15]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1csc2c1CCCC2=O
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCNC(=O)c1csc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (the compound of Preparation Example 4) (98 mg) in tetrahydrofuran (2 mL) was added 0.11 mL of triethylamine (0.11 mL) and ethyl chlorocarbonate (58 μL) on an ice bath. After stirring for 30 minutes, a solution (1 mL) of 2M ethylamine-tetrahydrofuran was further added dropwise and the solution was stirred for 20 minutes. After the solution was extracted with water, then was extracted with ethyl acetate, and washed with saturated sodium chloride water. After the organic layer was dried with anhydrous sodium sulfate, the solvent was removed by evaporation and the title compound (100 mg) was obtained as a reddish-brown solid.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.CCOCC.CS(O)(=O)=O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: CS(=O)(=O)O
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 2.4 ml of boron trifluoride ethyl ether, 0.34 ml of methanesulfonic acid and 3.13 ml of trimethyl borate. The mixture was heated at 30° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.49 g. The yield of the desired product was 39%.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:16]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1>C(O)C>[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:16]=1[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Reactant: CC(C)(N)COc1ccc(Cl)nn1
Solvent: CCO
Product: Cc1ccc(Cl)c(OCC(O)CNC(C)(C)COc2ccc(Cl)nn2)c1
Yield: 62.4 %

Procedure:
A solution of 4.6 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine obtained in Example 1 (a) and 5.0 g of 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane in 50 ml of ethanol was refluxed for 4 hours. The solvent was evaporated under reduced pressure a solution of the residue in 100 ml of benzene was extracted with 30 ml of 10% hydrochloric acid. The aqueous layer was made alkaline with 10% sodium hydroxide and extracted with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a column of Florisil (50 g) using chloroform as an eluent. From the eluate was obtained 5.7 g of 1-(2-chloro-5-methylphenoxy)-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino)-2-propanol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:34](O)[CH2:35][OH:36].C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:18][CH2:34][CH2:35][OH:36])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(OCCO)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 300 mg, 0.864 mmol), p-toluenesulfonic acid monohydrate (8.2 mg, 0.043 mmol) and ethylene glycol (1.45 mL) was stirred at rt overnight. The resulting suspension was treated with NaHCO3 (aq) and diluted with water. The precipitate was collected by filtration, washed with water and dried to provide 4-bromo-7-(2-(2-hydroxyethoxy)propan-2-yl)-9H-carbazole-1-carboxamide as a white solid (324 mg, 96%). 1H NMR (400 MHz, methanol-d4) δ 8.65 (1H, d, J=8.58 Hz), 7.77 (1H, d, J=1.10 Hz), 7.75 (1H, d, J=8.14 Hz), 7.44 (1H, dd, J=8.36, 1.54 Hz), 7.40 (1H, d), 3.69 (2H, t, J=5.17 Hz), 3.32-3.34 (2H, m), 1.68 (6H, s). Mass spectrum m/z 413, 415 (M+Na)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:17](=[O:18])[C:16]2[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 5-chloro-2-methoxybenzoyl chloride (2.05 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added dropwise triethylamine (1.7 mL, 12 mmol) and the reaction mixture was allowed to warm to ambient temperature for 12 h. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.8 Hz, 1H), 7.45-7.76 (m, 2H), 12.43 (s, 1H). MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH2:1]([C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCc1ccc[n+]([O-])c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1c([N+](=O)[O-])cc[n+]([O-])c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
While cooling a mixture of 3-ethyl-2-methylpyridine 1-oxide (7.35 g, 53.6 mmol) and sulfuric acid (22.7 g, 231 mmol) in an ice bath, fuming nitric acid (3.64 ml, 87.9 mmol) was added dropwise, which was stirred at 80° C. for 8 hours. The reaction mixture was cooled to room temperature and then poured into ice. The obtained aqueous solution was extracted three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain the title compound (3.37 g, yield: 34.5%) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To DMF (80 mL) solution of the compound obtained in Example 137 (5,7 g) was added potassium carbonate (3.6 g) and iodomethane (1.6 mL) at 0° C., and the mixture was stirred for 17 hours at room temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1), to give the captioned compound (4.8 g, 81%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+].BrBr.O>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11][C:12]#[N:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#CSc1cc(C(=O)O)ccc1N
Temperature: -15 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
4-Aminobenzoic acid (13 g) and ammonium thiocyanate (6.9 g) were suspended in methanol (200 ml) and cooled at −15° C. on an ice bath. A methanol solution (40 ml) containing bromine (4.7 ml) was added slowly dropwise thereto. The mixture was warmed to room temperature and stirred for 2 hours, iced water (500 ml) was added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give 4-amino-3-thiocyanatobenzoic acid (9.4 g, Y.:53%) as white crystals.