Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23].C(N(CC)CC)C.Cl>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[CH:6]([C@@H:7]1[CH2:11][C@H:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:23])=[O:5]
Reactant: COc1ccc(CS[C@H]2C[C@@H](CO)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CS[C@H]2C[C@@H](C=O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
In methylene chloride (24 ml), oxalyl chloride (0.40 ml) was dissolved. To the resulting solution, a solution of dimethyl sulfoxide (0.44 ml) in methylene chloride (1.6 ml) was added at -78° C., followed by stirring for 10 minutes. To the resulting solution, a solution of (2S,4S)-2-hydroxymethyl-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1 g) in methylene chloride (8 ml) was added dropwise at the same temperature, followed by stirring at -78° C. for 15 minutes and -50 to -60° C. for one hour. To the reaction mixture, triethylamine (2.4 ml) was added, followed by stirring at -14 to -15° C. for 20 minutes. To the reaction mixture, 1N hydrochloric acid was added to make the resulting solution acidic, followed by extraction with methylene chloride. The methylene chloride layer was washed with water and saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby (2S,4S)-2-formyl-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([OH:17])[CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+:19]>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([OH:17])[CH2:10][CH2:11][C:12]([O-:14])=[O:13].[Na+:19]
Reactant: CCOC(=O)CCC(O)c1cccc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C(O)CCC(=O)[O-])c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl (RS)-4-(2,3-dimethylphenyl)-4-hydroxybutanoate (3.66 g) in ethanol (100 mL) is treated with 1 N sodium hydroxide solution (15.5 mL). The reaction mixture is stirred at room temperature for 18 hours, evaporated and the residue azeotroped with toluene to give sodium (RS)-4-(2,3-dimethylphenyl)-4-hydroxy-butanoate (3.2 g) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1.Cl.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:24][C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: ClCc1cccnc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3cccnc3)C2=O)cc1

Procedure:
The title compound 28k was prepared from compound 2 (75 mg, 0.30 mmol), 3-picolyl chloride.HCl (54 mg, 0.33 mmol), sodium iodide (45 mg, 0.30 mmol) and potassium carbonate (124 mg, 0.90 mmol) in a manner similar to that described for 28d in 93.1% (95 mg) yield as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]([CH:23]=2)=[N:20][O:21][N:22]=3)=[CH:11][CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:22]1[O:21][N:20]=[C:19]2[CH:23]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([NH:7][CH3:6])=[CH:14][CH:13]=3)[CH:16]=[CH:17][C:18]=12
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nonc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2ccc3nonc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
510 mg (1.57 eq.) (4-benzo[1,2,5]oxadiazol-5-yl-phenyl)-methyl-carbamic acid tert-butyl ester are dissolved in 10 mL dichloromethane, treated with 0.126 mL (1.05 eq.) trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture is evaporated and the residue column chromatographed (hexane, hexane/ethyl acetate 4:1 then 3:1) to yield the desired product as an orange solid. MS(ES+): 226 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([O:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(CO)CCC(=O)CC2)cc1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C2(COC(C)=O)CCC(=O)CC2)cc1OC
Reaction time: 20 h
Yield: 57 %

Procedure:
The 4-hydroxymethyl-4-(3,4-dimethoxyphenyl)cyclohexanone is dissolved in 20 ml. of pyridine and 10 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water and brine, and evaporated to dryness to give 6.43 g. (57% yield) of 4-acetoxymethyl-4-(3,4-dimethoxyphenyl)cyclohexanone, as an amorphous gum.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:11][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:23][CH2:22]1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(Cc2cc3ccccc3n2C)CC1

Procedure:
1-Methyl-1H-indole-2-carbaldehyde and 1-(2-methoxyphenyl)piperazine were processed as described in Example 7 to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 3.0 (m, 2H), 3.45 (m, 2H), 3.74 (m, 4H), 3.86 (s, 3H), 3.88 (s, 2H), 4.70 (s, 3H), 6.83 (s, 1H), 6.90–7.14 (m, 5H), 7.28 (m, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz). MS (DCI/NH3) m/z 336.1 (M+H)+. Anal. Calcd for C21H25N3O: C, 75.19; H, 7.51; N, 12.53. Found: C, 74.45; H, 7.43; N, 12.37.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccncc4)nc23)CC1
Yield: 56 %

Procedure:
Beginning with 0.065 gm (0.282 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.106 gm (0.593 mMol) 4-pyridinecarbonyl chloride hydrochloride, 0.053 gm (56%) of the title compound was recovered as an amorphous solid by the procedure described in Example 16.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:37]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH2:38]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][CH2:37][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCS(C)(=O)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added methyl vinyl sulfone (38 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 522.1 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].CN1C=CN=C1.[N+:17]([CH:20]=[C:21]1[NH:26][CH2:25][CH2:24][CH2:23][S:22]1)([O-:19])=[O:18]>O1CCCC1>[N+:17]([C:20](=[C:21]1[NH:26][CH2:25][CH2:24][CH2:23][S:22]1)[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])([O-:19])=[O:18]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)C(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution 17.2 g of phenyl chloroformate in 25 ml of tetrahydrofuran was added dropwise to a solution of 9.09 g of 1-methylimidazole in 75 ml of tetrahydrofuran, the temperature of the reaction mixture being kept below 10° by means of an ice bath. Thirty minutes after the addition was completed, a solution of 16.0 g of (B) in 150 ml of tetrahydrofuran was added rapidly dropwise. The stirred mixture then was allowed to warm to room temperature and stirred for two days. The mixture was extracted with methylene chloride, the extracts washed with water, dried (MgSO4) and the solvent stripped off to give an oil. The oil was triturated first with a mixture of methanol and water, then with a cold mixture of methanol and ether to give as residue an orange-yellow solid, which on recrystallization from ethanol gave (66), as a pale yellow solid, m.p.: 95°-6°.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15]([OH:18])[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]2[CH2:14][C@@H:15]([O:18][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:16][CH2:17][C@@H:11]2[CH2:10][N:9]1[C:19](=[O:20])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccccc3)CN2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (3R,7S,9aR)-(3-benzyl-7-hydroxy-octahydropyrido[1,2-a]pyrazin-2-yl)-(3,5-bis(trifluoromethyl)phenyl)-methanone (3.3 g, prepared analogous to example 3 steps 1–8) in dichloromethane (100 mL) was added diisopropylethylamine (2.4 mL) and methanesulfonyl chloride (0.8 mL), at 5° C. The resulting mixture was stirred at room temperature for 15 min. and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 95:5) to afford methanesulfonic acid (3R,7S,9aR)-3-benzyl-2-(3,5-bis(trifluoromethyl)benzoyl)-octahydropyrido[1,2-a]pyrazin-7-yl ester (3.8 g). Rf 0.67 (CH2Cl2/MeOH 95:5) (intermediate 18).
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:35])[CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: CC(C)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(Cc1c[nH]cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To a stirred suspension of 4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (80 mg) at r.t. in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture (suspension) was heated to reflux (turning to a clear light yellow solution when reaching 90° C.) and stirred for 2 hours and 30 minutes, then cooled to r.t. and concentrated to leave a light brown sticky solid. This was taken up in H2O and basified to pH>12 by the addition of 4 N NaOH. The product was extracted with CH2Cl2/MeOH 9:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 85:15) to give 4-(3-methyl-2-phenyl-butyl)-1H-imidazole (8 mg) as colorless gum. MS (ISP): 215.4 ([M+H]+)
Reaction SMILES: O=[C:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O.CN(C)C=O>[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:2]2[CH2:11][CH:10]3[N:5]([CH2:6][CH2:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=43)[CH2:4][CH2:3]2)=[CH:22][CH:21]=1)(=[O:18])[CH3:16]
Reactant: O=C1CCN2CCc3ccccc3C2C1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC2CCN3CCc4ccccc4C3C2)cc1
Reaction time: 1 h
Yield: 14.9 %

Procedure:
A mixture of 1,3,4,6,7,11b-hexahydro-2-oxo-2H-benzo[a]quinolizine (8 g, 0.04 mole; prepared as described by Beke et al), 4-aminoacetanilide (6 g, 0.04 mole), a catalytic amount of p-toluenesulfonic acid (TsOH), 150 ml of toluene and 25 ml of dimethylformamide (DMF) was refluxed for 18 hours with the water produced being collected in a Dean-Stark trap. The solvent was removed in vacuo and the concentrate dissolved in 150 ml of methanol and cooled in an ice bath whereupon 8 g of NaBH4 was added in portions. At this point the mixture was stirred in the cold for 1 hour and at about 18° C. overnight. The solvent was removed in vacuo, the concentrate crystallized from acetone and petroleum ether and recrystallized from benzene and petroleum ether to yield 2 g of the desired product, m.p. 210°-3°.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].C(O[CH:14]=[CH:15][C:16]#[N:17])C.N(C1C=NC=CC=1)N>>[NH2:17][C:16]1[CH:15]=[CH:14][N:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[N:4]=1
Reactant: CCOC=CC#N
Reactant: NNc1cccnc1
Agent: Cl
Product: Nc1ccn(-c2cccnc2)n1

Procedure:
In a typical reaction, 3-hydrazinopyridine.dihydrochloride and an anhydrous alcohol are introduced into a reaction vessel and the alkoxide base is gradually added. The mixture is stirred and the 3-ethoxyacrylonitrile is added. The mixture is stirred at about 80° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:25])([O:23][CH3:24])[CH3:22])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:65][CH2:66]I)(=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61].Cl>O.CN(C)C=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:22])([O:23][CH3:24])[CH3:25])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([O:13][CH2:66][O:65][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])=[O:12])=[N+:2]=[N-:3]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A suspension of 739 mg of the syn isomer of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid, 76 g of potassium carbonate and 3 ml of dimethylformamide was stirred for 10 minutes at 20° C. and after cooling the mixture to 0° to 5° C., the suspension of Step A was slowly added thereto. The mixture was stirred at 0° to 5° C. for 30 minutes and then at 20° C. for one hour and a mixture of 40 ml of water and 1.5 ml of N hydrochloric acid was added thereto. The mixture was vacuum filtered and the recovered product was washed with water and dried to obtain 850 mg of the syn isomer of pivaloyloxymethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: COC1C=CC(C=O)=CC=1[N+]([O-])=O.C(NC(C1CCNCC1)=O)(C)(C)C.[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([N+:49]([O-])=O)[CH:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([NH2:49])[CH:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: COc1ccc(C=O)cc1[N+](=O)[O-]
Product: COc1ccc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc1N

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 4-methoxy-3-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(4-methoxy-3-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.60 min; [M+H]+=350.22 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.47 min; [M+H]+=320.26.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:20]=[O:21])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 9A) in THF (300 ml) was cooled to −78° C. At this temperature, 63.1 ml (107 mmol) of tert-butyllithium solution (1.7 M in n-pentane) were slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=3[C:24]([O:26]C)=O)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=4[C:24]=3[OH:26])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccc(Cl)cc3n2)c(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)c(O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a being cooled suspension of 7-chloro-2-[2,4-bis-(methoxycarbonyl)phenoxymethyl]quinoline (0.3 g) in N,N-dimethylformamide (6 ml), sodium hydride ((60% in mineral oil) 31 mg). After being stirred at same temperature for 30 minutes and successively at ambient temperature for 3 hours, the resulting mixture was poured into a mixture of ethyl acetate and buffer (pH 4.1). The appeared precipitates were collected by filtration and washed with n-hexane to give 7-chloro-2-(5-methoxycarbonyl-3-hydroxybenzofuran-2-yl)quinoline (0.15
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[C:16]([Br:34])=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2-c2ccccc2)c1OC(C)=O

Procedure:
Prepared in analogy to a bromination procedure in that of Example 103(a) from 4-Acetoxy-7-cyano-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 428 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].CCN(C(C)C)C(C)C>CCO>[OH:13][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:29]1[CH2:30][CH2:31][C:24]2([C:23](=[O:32])[N:22]([C:17]3[CH2:18][O:19][C:20](=[O:21])[C:16]=3[CH3:15])[CH2:26][CH2:25]2)[CH2:27][CH2:28]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A)(200 mg, 1.05 mmol) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (300 mg, 1.05 mmol) in 10 mL of EtOH was added DIPEA (271 mg, 2.10 mmol). The resulting mixture was stirred at 80° C. overnight, and then cooled to room temperature; the solvent was removed under vacuum. The residue was purified by flash chromatography (ethyl acetate: MeOH=20:1) to afford title compound. MS-ESI (m/z): 441 (M+1)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2:15][C:16]1C=CC=C[CH:17]=1.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:17]=[CH:16][NH:15]1
Reactant: Nc1ccccc1
Reactant: Oc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C1=Cc2ccccc2ON1
Yield: 78.8 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, aniline and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1.2:2.5. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, water, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 78.8%.