Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C1COCC1.C(O)C>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:12][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:5]=1
Reactant: CC(C)N
Reactant: BrCc1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)NCc1ccncc1
Reaction time: 24 h

Procedure:
4-Bromomethylpyridine (1 g) was suspended in THF:ethanol (5:1) and cooled to 0–5° C. Isopropylamine (1.01 ml) was added and the resultant mixture allowed to reach room temperature. After 24 h, the mixture was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with DCM:methanol 1:1, 3:7, 1:4 and methanol) to give an impure sample of the title compound. Further purification using SPE (silica, eluting with DCM, ethyl acetate, acetonitrile, methanol) gave the title compound (0.25 g) as a white solid.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:12]([O:16][C:17](=[O:22])[CH2:18][C:19]([CH3:21])=O)[CH:13]([CH3:15])[CH3:14].[CH3:23][O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28]>C(O)C>[CH2:12]([O:16][C:17]([C:18]1[CH:10]([C:9]2[C:4]3[C:5](=[N:1][O:2][N:3]=3)[CH:6]=[CH:7][CH:8]=2)[C:26]([C:25]([O:24][CH3:23])=[O:30])=[C:27]([CH3:28])[NH:29][C:19]=1[CH3:21])=[O:22])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCC(C)C
Reactant: O=Cc1cccc2nonc12
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1c1cccc2nonc12

Procedure:
3 g of 2,1,3-benzoxadiazole-4-aldehyde, 3.2 g of acetoacetic acid isobutyl ester, 2.3 g β-aminocrotonic acid methyl ester and 10 ml of ethanol are stirred under reflux for 3 hours. The mixture is subsequently evaporated and the residue is chromatographed on silica gel with chloroform/acetic acid ethyl ester (8:1) to yield the title compound. The product is recrystallised from diisopropyl ether and methylcyclohexane, m.p. 148°-158°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](CN)=[CH:4][N:3]=1.C([N:12](CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc(Cl)nc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)nc1)c1ccccc1
Reaction time: 8 h
Yield: 105.7 %

Procedure:
14.25 g (0.1 mol) of 2-chloro-5-aminomethylpyridine and 11.1 g (0.11 mol) of triethylamine are dissolved in 150 ml of methylene chloride. 14.8 g (0.105 mol) of benzoyl chloride are then added dropwise at about 20° C. and the reaction mixture is subsequently stirred overnight at room temperature. It is washed three times with water and the organic phase is dried and concentrated. 24.6 g (99.8% of theory) of 2-chloro-5-benzoylaminopyridine are obtained as white crystals of melting point 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]O)[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.S(Cl)(Cl)=O.[Cl-].[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][NH:37][CH:34]5[CH2:36][CH2:35]5)[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: NC1CC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CNC4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 282) (196 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with cyclopropylamine in DMF according to the general procedure of example 288. Obtained as a light brown (96 mg, 45%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([C:27](=[O:28])[N:26]([CH3:38])[CH3:25])=[CH:37][CH:36]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:12])[F:13]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: CN(C)C(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1C(=O)c1ccc(C(=O)N(C)C)cc1
Yield: 17.8 %

Procedure:
To a stirred solution of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (400 mg, 1.57 mmol) and triethylamine (0.4 ml, 2.84 mmol) in EtOAc (25 ml) was added a solution of 4-dimethylcarbamoylbenzoyl chloride (350 mg, 1.66 mmol) in EtOAc (25 ml). The resultant mixture was stirred at ambient temperature for 24 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with EtOAc as eluent to give the title compound as a solid (120 mg, 0.28 mmol). NMR: 1.1-1.13 (m, 6H), 1.6 (s, 3H), 2.9 (s, 3H), 3.1 (s, 3H), 3.25 (m, 1H), 3.4 (m, 1H), 4.25 (s, 2H), 4.65 (s, 1H), 4.9 (s, 1H), 5.2 (s, 1H), 7.3-7.4 (dd, 4H); m/z 428.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)([CH2:17][CH2:18][CH:19]=[CH2:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C(OCC)C>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[O:29]1)([CH2:17][CH2:18][CH:19]=[CH2:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
While under an atmosphere of argon, a solution of tert-butyl 2-(tert-butoxycarbonylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate (1.35 g, 2.89 mmol) in freshly distilled (THF 5 mL) was cooled to 0° C. and treated with sodium bis(trimethylsilyl)amide (6 mL, 1.0 M in THF) under argon. After stirring for 10 min, iodomethane (2.04 g, 14.4 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 8 CV) gave tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (1.27 g, 91%). Rf 0.35 (20% ethyl acetate in heptane). ESI MS found for C26H48BNO6 m/z [482.3 (M+1)].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH3:7][C@@H:8]1[O:15][C:13](=[O:14])[C@H:12]([CH3:16])[O:11][C:9]1=[O:10]>>[C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH3:7][C@H:8]1[O:15][C:13](=[O:14])[C@@H:12]([CH3:16])[O:11][C:9]1=[O:10]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Reactant: CC(O)C(=O)O
Product: C[C@H](O)C(=O)O
Product: C[C@H]1OC(=O)[C@@H](C)OC1=O

Procedure:
The PLA resin can be formed by polymerizing lactide. Lactide is a dimeric form of lactic acid, in which two lactic acid molecules are condensed to form a cyclic diester. Like lactic acid, lactide exists in a variety of enantiomeric forms, i.e., “L-lactide”, which is formed from two L-lactic acid molecules, “D-lactide”, which is formed from two D-lactic acid molecules, and “meso-lactide”, which is formed from one L-lactic acid molecule and one D-lactic acid molecule. In addition, 50/50 mixtures of L-lactide and D-lactide that have a melting temperature of about 126° C. are often referred to as “D,L-lactide”. Any of these forms of lactide, or mixtures thereof, can be polymerized to form a PLA resin for use in this invention. The L/D ratio in the PLA resin is controlled through the ratio of these enantiomeric forms of lactide that are used in the polymerization. In an especially preferred process, mixtures of L-lactide and meso-lactide are polymerized to form a polymer having a controlled level of D-lactic acid enantiomeric units. Suitable processes for polymerizing lactide to form PLA having controlled L/D ratios are described, for example, in U.S. Pat. Nos. 5,142,023 and 5,247,059, both incorporated herein by reference.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5](=[O:34])[C@:4]([CH2:1][CH:2]=[O:37])([CH3:35])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CN2CCOCC2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of 42 mg (0.08 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one (Example 121, Step N) in THF (6 mL) and water (2 mL) added a catalytic amount of osmium tetroxide. After 3 min, 87 mg (0.41 mmol) of sodium periodate was added. The resulting white slurry was stirred at room temperature for 4.25 h, and then filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, and then was diluted with a mixture of water and saturated aqueous sodium chloride and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 75% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA provided the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]([C:7]1[N:11]=[CH:10][N:9]([CH2:12]Cl)[N:8]=1)([CH3:6])[CH2:4][CH3:5].[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:2][C:3]([C:7]1[N:11]=[CH:10][N:9]([CH2:12][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[N:8]=1)([CH3:6])[CH2:4][CH3:5]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CCC(C)(C)c1ncn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 23.1 %

Procedure:
0.98 g of 3-(1,1-dimethylpropyl)-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.11 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.29 g of {[3-(1,1-dimethylpropyl)-1H-1,2,4-triazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (30), hereinafter) shown by below formula.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: SCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl mercaptan.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:24]([O-])=O.Cl.C(O)(C)C.[H][H]>CO.[Pd]>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[O:8][C:7]3[C:2]([NH2:1])=[C:3]([NH2:24])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(N)c3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(N)c(N)c3O2)cc1

Procedure:
Toluene-4-sulfonic acid (2R)-8-amino-7-nitro-2,3-dihydro-benzo(1,4)-dioxin-2-ylmethyl ester (4.1 g, 11 mmole) was dissolved in 200 mL of methanol to which 0.50 g of 10% palladium on carbon had been added. 4 N isopropanol HCl (10 mL) was then added and the mixture treated with 60 psi of hydrogen on a Parr apparatus overnight. The mixture was filtered through celite and concentrated in vacuum to give 4.6 g of the (R)-enantiomer of the title compound as a pink solid (m.p. 178–180° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[C:13]2[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]1=2)#[CH:10].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:25][N:22]1[CH2:23][CH2:24][C:12]2[N:11]([C:9]#[C:10][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]=2[CH2:21]1
Reactant: Cc1ccc(Br)nc1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)nc1

Procedure:
A mixture of 2-bromo-5-methyl-pyridine (250 mg, 1.45 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (391 mg, 1.74 mmol), TBAF.3H2O (1.374 g, 4.36 mmol) and dichloro bistriphenylphosphine palladium(II) (51 mg, 0.072 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×100 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (neutral alumina, eluent-0.5% MeOH in DCM) to yield 2,8-dimethyl-5-(5-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 8.41 (s, 1H), 7.5 (m, 2H), 7.4 (d, 1H), 7.18 (s, 1H), 7.08 (d, 1H), 3.6 (s, 2H), 3.0 (t, 2H), 2.83 (t, 2H), 2.58 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [B:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([OH:3])[OH:2].C(=O)(O)[O-].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:13][C:12]([CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([B:1]([OH:3])[OH:2])=[CH:16][CH:15]=1)=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CCCOc1ccc(B(O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 30.8 %

Procedure:
A solution of 1A (200 mg, 0.89 mmol), potassium bicarbonate (313 mg, 3.1 mmol), and benzyl bromide (0.163 mL, 1.4 mmol) in DMF (2 mL) was heated at 60° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and hydrochloric acid (1 N). The aqueous layer was extracted with EtOAc (2×) and then the combined organics were washed with water (3×) and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (30 to 100% EtOAc in hexane) to afford 1B (86 mg, 28%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 2.08 (m, 2H), 2.56 (t, J=7.0 Hz, 2H), 4.00 (m, 2H), 5.12 (s, 2H), 6.84 (2×d, 2H), 7.32 (m, 5H), 7.7-7.5 (2×d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=1[CH2:20][NH2:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:21][CH2:20][C:19]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=2[O:17][CH3:16])=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: COc1ccc(OC)c(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1nc(C(=O)NCc2cc(OC)ccc2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (0.1 mmol) in DMF (0.1 mL) was added 2,5-dimethoxybenzylamine (0.2 mmol), Et3N (0.2 mmol), and TBTU (0.1 mmol) sequentially. The reaction mixture was stirred at ambient temperature for 16 hours and water was added. The precipitates were collected and purified by column chromatography to provide the titled compound. 1H NMR (400 MHZ, DMSO-d6) δ 8.81 (t, J=6.4 Hz, 1H), 7.31 (broad s, 2H), 7.07 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.79 (dd, J=2.8, 8.8 Hz, 1H), 6.72 (d, J=3.2 Hz, 1H), 4.49 (q, J=7.2 Hz, 2H), 4.42 (d, J=6.4 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 3H), and 1.33 (t, J=7.2, 3H). MS (m/e) positive mode: 357 (M+H)+, 379 (M+Na)+; negative mode: 355 (M−H)−.
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.FC(F)(F)C(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
Solvent: O=S1(=O)CCCC1
Solvent: O=C(O)C(F)(F)F
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, 1.96 g of ferric chloride, 0.40 ml of trifluoroacetic acid and 1.95 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 0.70 g. The yield of the desired product was 55%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:5]([NH:6][CH3:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.C1CCCCC=1.C(=O)([O-])[O-].[Na+].[Na+].[N:28]([C:31]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=1[CH3:39])=[C:29]=[S:30]>C(O)C.[Pd]>[NH2:10][C:8]1[C:5]([NH:6][CH3:7])=[C:4]([NH:13][C:29]([NH:28][C:31]2[C:32]([CH3:39])=[CH:33][C:34]([CH3:38])=[CH:35][C:36]=2[CH3:37])=[S:30])[CH:3]=[C:2]([F:1])[CH:9]=1
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Reactant: CNc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CNc1c(N)cc(F)cc1NC(=S)Nc1c(C)cc(C)cc1C
Yield: 32.4 %

Procedure:
In 75 mL of ethanol was mixed 1.30 g (6.04 mmol) of 4-fluoro-N-methyl-2,6-dinitroaniline, 3.7 mL (36 mmol) of cyclohexene and 5.1 g (2.4 mmol, 40 mol %) of 10% palladium on carbon (50% water, Degussa type). The mixture was refluxed for 2.5 h and filtered into a flask containing 0.77 g (7.3 mmol) of sodium carbonate and 1.07 g (6.04 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The resulting slurry was refluxed for 4 h, concentrated and slurried in dichloromethane. The slurry was filtered, concentrated and purified by flash chromatography eluting with a 70% hexanes/ethyl acetate mixture to give 0.65 g (32%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:17]2[CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24]#[N:25])[CH:10]=2.[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.CN(C=O)C>ClCCl>[C:24]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:17]1[CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:13][C:12]2=1)#[N:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccccc2N)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 53.1 %

Procedure:
Suspend N-[9-(2-amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 109) (116 mg, 0.3 mmol) in anhydrous dichloromethane (3 mL) under nitrogen. Add methanesulfonyl chloride (0.028 mL, 0.36 mmol) and pyridine (0.032 mL, 0.39 mmol), followed by anhydrous DMF (2 mL) to effect solution. Stir 5.5 h at room temperature. Add additional methanesulfonyl chloride (0.010 mL, 0.13 mmol) and pyridine (0.010 mL, 0.12 mmol) and stir 18 h at room temperature. Dilute with dichloromethane and wash with 1N hydrochloric acid. Backwash the aqueous portion with dichloromethane. Combine the organic portions and wash with brine, dry (MgSO4), filter, and concentrate in vacuo to provide 74 mg of a yellow oil. Absorb the oil on silica with THF and a small amount of methanol and purify by flash chromatography. Elute with a step gradient of 10% ethyl acetate/dichloromethane, 25% ethyl acetate/dichloromethane, and 50% ethyl acetate/dichloromethane to obtain 19 mg (14%) of a light yellow solid. MS (ES): m/z 465 (M+1), 463 (M−1); 1H NMR(DMSO-d6): δ 9.43 (s, 1H), 8.02 (s, 1H), 7.88 (d, 1H, J=7.5 Hz), 7.43-7.36 (m, 3H), 7.31 (dt, 1H, J=7.6, 1.0 Hz), 7.12 (dt, 1H, J=7.5, 0.9 Hz), 6.21 (d, 1H, J=7.5 Hz), 5.54 (s, 2H), 4.06 (m, 1H), 3.12 (s, 3H), 3.04 (dd, 1H, J=15.4, 5.3 Hz), 2.70 (m, 2H), 2.59 (dd, 1H, J=15.4, 8.4 Hz), 2.41 (m, 1H), 1.97 (m, 1H), 1.85 (m, 1H), 1.02 (m, 6H).