Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C1(P(O[NH2:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:36][N:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: CC(C)c1n[nH]c(=O)c2ccccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1nn(N)c(=O)c2ccccc12
Reaction time: 0.75 h
Yield: 109.2 %

Procedure:
A mixture of the product of Example 1A (30.0 mg, 0.159 mmol) and KOtBu (1 M in THF, 0.32 mL, 0.32 mmol) in THF (1 mL) was stirred for 45 minutes, and O-(diphenylphosphoryl)hydroxylamine (57.6 mg, 0.247 mmol) [Klotzer, W.; Stadlwieser, J.; Raneburger, J. Organic Syntheses 1986, 64, 96-103] was added and stirred overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to give 35.3 mg of crude product as a tan solid, which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (dd, 1H), 8.09 (d, 1H), 7.92 (ddd, 1H), 7.84 (ddd, 1H), 6.31 (s, 2H), 3.63 (quin, 1H), 1.30 (d, 6H); LC/MS (APCI) M/Z 204.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:20])[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:11][CH:10]=1)[CH3:2].N1C=CC=CC=1.[C:27]1([S:33]Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:1]([N:3]([S:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:4](=[O:20])[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:13][CH:14]=1)[CH3:2]
Reactant: ClSc1ccccc1
Reactant: CCNC(=O)OCCOc1ccc(OC(C)CC)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)Oc1ccc(OCCOC(=O)N(CC)Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate (1.50 g, 5.34 mmol) and pyridine (1 ml, 11.75 mmol) in 20 ml of methylene chloride at RT is added phenylsulfenyl chloride (1.54 g, 10.70 mmol). The reaction mixture is stirred for 2 hours, after which it is poured into ice water and extracted with ether. The combined organic layers are washed with 10% HCl, with water until neutral and with brine and dried. After filtration and removal of the solvent, the product is purified by prep. TLC to give O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethyl-N-phenylsulfenylcarbamate, MS m/e 390 (M+ +H) (compound 23, Table A).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17].[OH-].[Na+]>>[Br:11][C:12]1[S:13][C:14]([CH:8]=[O:9])=[CH:15][C:16]=1[CH3:17]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6250.6 %

Procedure:
Phosphoryl chloride (5.3 ml, 0.57 mmol) was added dropwise to N,N-dimethylformamide (8.8 ml, 0.11 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 2-Bromo-3-methylthiophene (5.00 g, 28.2 mmol) was added dropwise thereto under ice-cooling and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was neutralized with a 2N aqueous sodium hydroxide solution under ice-cooling. The reaction mixture was extracted with diethyl ether and the organic layer was dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give 5-bromo-4-methyl-2-thiophenecarbaldehyde (1.41 g, yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Yield: 49.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH2:30]>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([O:7][CH2:8][CH2:9][CH2:10][C:23]2[CH:24]=[C:19]([CH3:29])[CH:20]=[CH:21][C:22]=2[S:25]([OH:30])(=[O:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Reactant: OCCCOC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)c(CCCOC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Cyclohexyloxy)propan-1-ol (820 mg) synthesized in Reference Example 47 was dissolved in dichloromethane (20 mL), triethylamine (1.1 mL), p-toluenesulfonyl chloride (1.2 g) and 4-dimethylaminopyridine (63 mg) were added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (1.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:32])[C:21]=1[C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[C:23]=1[CH3:31])[C:16](O)=[O:17]>>[CH3:32][C:20]1[CH:19]=[C:15]([CH:14]=[C:13]([CH3:12])[C:21]=1[C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[C:23]=1[CH3:31])[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:17]
Reactant: Cc1cc(C(=O)O)cc(C)c1-c1ccc2c(c1C)OCO2
Reactant: Nc1ccc2cccnc2c1
Product: Cc1cc(C(=O)Nc2ccc3cccnc3c2)cc(C)c1-c1ccc2c(c1C)OCO2

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (17 mg, 0.12 mmol) and 3,5-dimethyl-4-(4-methyl-benzo[1,3]-dioxol-5-yl)-benzoic acid (D62) (41 mg, 0.15 mmol) as a yellow oil. MS(ES): MH+ 411, M-H+ 409.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](=[O:10])[CH3:9].[Cr](Cl)([O-])(=O)=[O:13].[NH+]1C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:13])[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cc1ccccc1C
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1C
Yield: 15.4 %

Procedure:
A mixture of 7 g (47.23 mmol) 1-o-Tolyl-propan-2-one, 30.5 g (0.141 mol) pyridinium chlorochromate and 11.2 g (0.141 mol) pyridine in 200 ml DCM was heated to reflux for 16 h. The mixture was filtered through a pad of silica and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/n-hexane 1:4. The product fractions were evaporated to yield 1.178 g (15%) of the title compound.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.27 g of Z-Thr(tBu)-OH and 1.56 g of H-Pro-NH2 are dissolved in 60 ml of acetonitrile, the solution is cooled to 0°C and 3.11 g of dicyclohexylcarbodiimide are added. After 1 hour at 0°C and 20 hours at room temperature the dicyclohexylurea is filtered off and the filtrate is evaporated and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with dilute citric acid solution, soda solution and water, and is dried with sodium sulphate and evaporated. On thin layer chromatography on silica gel plates the colourless residue shows Rf45 = 0.76; Rf43c = 0.70; Rf52 = 0.62.
Reaction SMILES: C([C:3]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH2:11])[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Cl)[N:13]=2)[N:4]=1)C.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:35](#N)[CH3:36]>>[NH2:11][C:6]1[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[OH:19])[N:13]=2)[N:4]=[CH:3][C:7]=1[C:8]([O:10][CH2:35][CH3:36])=[O:9]
Reactant: OB(O)c1ccccc1O
Reactant: CCc1nn(-c2cccc(Cl)n2)c(N)c1C(=O)O
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1N
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a vial containing the title compound from Example 10 Step A (200 mg, 0.75 mmol) were added 2-hydroxyphenylboronic acid (125 g, 0.90 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (53 mg, 0.075 mmol). Acetonitrile (4 mL) and sodium carbonate (1.9 mL, 1.0 M aqueous, 1.9 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction vial was capped and the reaction mixture was stirred at 85° C. After 18 h, the reaction mixture was allowed to cool to room temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 75% EtOAc in hexanes, then 75 to 100% EtOAc) provided the title compound: LCMS m/z 324.9 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 10.69 (s, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 3.5 Hz, 1H), 7.83 (s, 1H), 7.72-7.68 (m, 2H), 7.39-7.35 (m, 1H), 7.07-7.05 (m, 1H), 7.02-6.99 (m, 1H), 6.63 (br s, 2H), 4.32 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19](C(O)(C)C)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.[Br:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-:32].[K+].[K+]>C(#N)C.ClCCl>[Br:27][CH2:28][CH2:29][O:32][C:19]1[C:18]([CH3:25])=[C:17]2[N:16]([CH:20]=1)[N:15]=[CH:14][N:13]=[C:12]2[O:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH3:26])=[CH:4]2
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(C(C)(C)O)c(C)c34)ccc2[nH]1
Reactant: BrCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCBr)c(C)c34)ccc2[nH]1
Yield: 100.6 %

Procedure:
A mixture of Example 1 (300 mg, 0.96 mmol), 1,2-dibromoethane (1.5 mL, 17.4 mmol), and potassium carbonate (1.0 g, 7.2 mmol) in acetonitrile (10 mL) was heated at 50° C. for 6 h. The mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in dichloromethane to provide the title compound (405 mg, 100%) as a white solid. MS: (M+H)+=419.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC.O>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH2:16][Cl:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: CC(C)(CCl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(CCl)C(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-t-butyl-1-benzoylhydrazine (1 g, 0.005M) in toluene (40 ml) cooled to 5° C. was added 3-chloro-2,2-dimethylpropionylchloride (1.2 g, 0.007M) and 50% aq. sodium hydroxide (0.45 g, 0.0056M) so as to maintain the temperature below 10° C. The mixture was warmed to room temperature and stirred 1 hr. The mixture was diluted with hexane (40 ml) and water (10 ml). The white solid product N'-t-butyl-N-(beta-chloropivaloyl)-N'-benzoylhydrazine was isolated by suction filtration, washed with 50 ml hexane and 50 ml water and dried.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:23]([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: N#Cc1c(-c2cccnc2)[nH]c2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)c(C#N)c2ccc(F)cc21
Reaction time: 1 h

Procedure:
A flask is charged with 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile (Example 140, 50 mg, 0.21 mmol) and DMF (2 mL), and 60% sodium hydride (25 mg, 0.63 mmol) is added. The mixture is stirred at room temperature for 30 min before addition of iodomethane (45 mg, 0.315 mmol). After 1 h, saturated NaHCO3 aqueous solution (3 mL) is added to quench the reaction and the mixture is filtered and purified on Xbridge C18 eluting with a 9:1 to 1:9 water-acetonitrile gradient to give 6-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.77 (s, 3H), 7.19-7.26 (m, 1H), 7.66-7.76 (m, 3H), 8.14-8.19 (m, 1H), 8.80 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 293.1210 [(M+H+CH3CN)+ calcd for C17H14FN4: 293.1203].
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:10]1=[O:29].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].[NH:43]1[CH2:48][CH2:47][CH:46]([C:49]2[C:50](=[O:55])[NH:51][N:52]=[CH:53][CH:54]=2)[CH2:45][CH2:44]1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:26])[F:27])[C:10](=[O:29])[C@H:9]([NH:8][C:31]([N:43]2[CH2:44][CH2:45][CH:46]([C:49]3[C:50](=[O:55])[NH:51][N:52]=[CH:53][CH:54]=3)[CH2:47][CH2:48]2)=[O:32])[CH2:15][CH2:14]1
Reactant: O=c1[nH]nccc1C1CCNCC1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(c2ccn[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Triethylamine (11.5 mg, 0.104 mmol) was added to a solution (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one (32 mg, 0.104 mmol) and p-nitrophenyl chloroformate (20 mg, 0.104 mmol) in tetrahydrofuran (1 mL) at 0° C. After 0.5 h, triethylamine (42 mg, 10.416 mmol) and 4-piperidin-4-ylpyridazin-3(2H)-one (19 mg, 0.104 mmol) were added and the mixture was allowed to warm to ambient temperature. After 1 h, the mixture was quenched with water, extracted with ethyl acetate, and washed with 1 N NaOH solution. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→10% methanol/dichloromethane) gave the title compound (30 mg). MS 528.1999 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.C1(C2[O:23]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12]([CH3:13])=[O:23])[N:9]=[C:8]([NH2:14])[N:7]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Solvent: ClCCl
Product: CS(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 16 h
Yield: 90.2 %

Procedure:
To a stirred suspension of 3.00 g (14.5 mmol) 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-yl-amine in 150 ml dichloromethane was added 7.56 g (29.0 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The resulting crystals were collected by filtration and washed with dichloromethane to afford 2.92 g (90%) 4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 223 (M+, 50), 177 (32), 160 (25), 148 (23), 118 (100), 90 (23), 63 (24).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1.C(OCC)(=O)C>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (3.2 g, 6 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide (1.25 g, 6.1 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, 2% methanol/dichloromethane, 4% methanol/dichloromethane, 6% methanol/dichloromethane, and then dichloromethane/methanol/concentrated ammonia 746/36/4 to give the title compound: Rf =0.32 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]([OH:14])=[O:13].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.Br>C(#N)C>[Br-:10].[C:12]([CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:4]1)([OH:14])=[O:13]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1cccc2ccccc12
Reactant: O=C(O)CBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)Cn1c[n+](Cc2cccc3ccccc23)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-bromoacetic acid (2.15 g, 15.46 mmol) was added to the solution and refluxed for 2.5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[Cl:14][C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:44]=[C:30]4[CH:31]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)[CH2:32][C:33](=C)[CH2:34][CH2:35][N:29]4[N:28]=3)=[CH:22][C:21]=2[O:45][CH3:46])[CH:19]=1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[Cl:14][C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:44]=[C:30]4[CH:31]([C:37]5[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=5)[CH2:32][C:33](=[O:2])[CH2:34][CH2:35][N:29]4[N:28]=3)=[CH:22][C:21]=2[O:45][CH3:46])[CH:19]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of sodium periodate (138 mg, 0.645 mmol) in water (5.0 mL) was added over a 10 min period, via pipet, to a vigorously stirred solution of the N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (100 mg, 0.215 mmol, from example 133) and osmium tetroxide (5.47 mg, 0.022 mmol) in THF (5.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound as the TFA salt (60 mg, 47% yield). LC-MS (M+H)+ 467.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.24 (1 H, br. s.), 8.12 (1 H, d, J=1.5 Hz), 7.33 (1 H, d, J=2.1 Hz), 7.19-7.24 (1 H, m), 7.07-7.18 (5 H, m), 4.71 (1H, dd, J=8.5, 4.0 Hz), 4.54-4.64 (1 H, m), 4.45-4.54 (1 H, m), 3.90 (3 H, s), 3.44 (1 H, dd, J=14.3, 8.5 Hz), 3.16 (1 H, dd, J=14.3, 4.0 Hz), 2.89-3.06 (2 H, m).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([OH:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccnn3-c3ccccn3)CS[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccnn3-c3ccccn3)CS[C@H]12
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirring suspension of (7R)-7[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (100 mg, 0.16 mmol) and anisole (0.6 mL) in dichloromethane (1.2 mL) at 0° C. was added trifluoroacetic acid (1.2 mL). After 30 min at 0° C., the solvent was removed with a rotary evaporator. The residue was dissolved in ethyl acetate, and was extracted with saturated aqueous sodium bicarbonate. The aqueous extracts were washed with ether, and were then acidified to pH 4-5 using aqueous HCl. This was extracted with ethyl acetate, and the organic extracts were washed with water and brine, and were dried (sodium sulfate) and concentrated. The resulting oil was triturated with hexane to afford the title compound (60 mg, 75%) as a pale yellow solid. 1H NMR (acetone-d6) δ3.55 (d, 1, J=18), 3.63 (d, 1, J=16), 3.71 (d, 1, J=16), 3.79 (d, 1, J=18), 5.25 (d, 1, J=4), 5.89 (dd, 1, J=4, 9), 6.44 (d, 1, J=2), 7.2-7.4 (m, 6), 7.78 (d, 1, J=2), 7.92 (d, 1, J=10), 8.02 (dt, 1, J=2, 10), 8.18 (d, 1, J=9), 8.48 (dd, 1, J=2, 8).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.N1CCCCC1.Cl>N1C=CC=CC=1>[C:3]([C:2]1[C:1](=[O:7])[NH:8][C:9]2[C:10]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)([OH:5])=[O:4]
Reactant: Nc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)c1cc2ccccc2[nH]c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
2 Grams of malonic acid was dissolved in 15 ml of pyridine, then 1.2 g of o-aminobenzaldehyde and 2 ml of piperidine were added thereto, and the mixture was stirred at 90° C. for 5 hours. The reaction mixture was poured in an aqueous solution of hydrochloric acid and the crystals precipitated were collected by filtration. Recrystallized from methanol-chloroform to obtain 1.2 g of 3-carboxycarbostyril in the form of colorless needle-like crystals.