Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:13])([CH3:12])[CH2:4][NH:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].C(OCC)(OCC)(OCC)C.[C:25]1(C)[C:26](S(O)(=O)=O)=[CH:27]C=[CH:29][CH:30]=1>>[CH3:10][C:7]1([CH3:11])[CH2:6][N:5]2[C:29]([CH2:30][CH2:25][CH2:26][CH3:27])([O:1][CH2:2][C:3]([CH3:13])([CH3:12])[CH2:4]2)[O:9][CH2:8]1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CC(C)(CO)CNCC(C)(C)CO
Agent: CCOC(C)(OCC)OCC
Product: CCCCC12OCC(C)(C)CN1CC(C)(C)CO2
Temperature: 25 °C

Procedure:
3-(3-Hydroxy-2,2-dimethyl-propylamino)-2,2-dimethyl-propan-1-ol (128.0 g, 0.68 mol), triethyl orthoacetate (162.0 g, 1.00 mol) and toluene sulfonic acid (2.0 g) were charged into a oven dried round bottom flask equipped with a stirring bar, distillation head and under nitrogen. The resulting solution was heated until the theoretical amount of methanol was collected. The reaction was cooled to room temperature and triethylamine added to neutralize the acid. Fractional vacuum distillations (twice) afforded the product as a water clear liquid, boiling point 101-103° C. at 0.44 torr. Yield: 156 g (90.5%).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Br:14][C:15]1[N:20]=[C:19]([C:21](O)([CH3:23])[CH3:22])[CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][CH2:18][CH2:19][CH:21]([CH3:23])[CH3:22].[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([F:11])([CH3:23])[CH3:22])[N:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(O)c1cccc(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)c1cccc(Br)n1
Product: CCCC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Add (bis(2-methoxyethyl)amino)sulfur trifluoride (2.05; mL, 11.11; mmol) dropwise to a cooled solution of 2-(6-bromo-pyridin-2-yl)-propan-2-ol (2; g, 9.26 mmol) in dichloromethane (46.3; mL) at −78° C. Upon addition, warm to room temperature and stir overnight. Add a saturated aqueous solution of sodium bicarbonate and stir until gas evolution stops. Filter through a 50; mL hydrophobic IST Phase Separator Frit®, concentrate and purify by silica gel chromatography, gradient eluting from 3:97; to 5:95; and then to 10:90; using dichloromethane:iso-hexane to give the title compound as a colorless liquid (5.13; g, 71%). 1H NMR (CDCl3) δ 1.66; (s, 3H), 1.73; (s, 3H), 7.37; (dd, 2H), 7.53; (m, 2H). 19F NMR (CDCl3) δ-143.37; (s, 1F).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:3]1.FC(F)(F)C(O)=O>ClCCl>[C:19]1([C:4]2[NH:3][C:2](=[O:1])[C:6]3([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)[N:5]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccccc1)NC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)=NC12CCNCC2

Procedure:
To a solution of tert-butyl 4-oxo-2-phenyl-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (45 mg, 0.137 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). After 2 h the reaction was concentrated to give the title compound. MS: m/z=230.1 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.ClC1C=CC(NN=C2CCCC(=O)C2)=CC=1>O.FC(F)(F)C(O)=O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Agent: O=C1CCCC(=NNc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
A suspension of p-chlorophenylhydrazine hydrochloride (8.06 g, 45 mmol) in water is added over a 10 min. period to a solution of 1,3-cyclohexanedione (5.05 g, 45 mmol) in water, stirred for 16 h and filtered. The filtercake is washed with water and air-dried. The thus-obtained cyclohexane-1,3-dione mono-(4-chlorophenyl)-hydrazone (45 mmol th.) is dissolved in trifluoroacetic acid (TFA) (30 mL), heated at 80° C. for 16 h, cooled to room temperature, poured into ice-water and filtered. The filtercake is air-dried and recrystallized from ethanol/water to afford the title product as a tan solid, 4.2 g (42% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: CC1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9](CCOC3C=CC=CC=3)C2=O)[S:4][C:3]=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.Cl.CC1SC=C(CN)N=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:10][C:11]4[N:7]=[C:5]([CH3:6])[S:4][CH:3]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(CN)cs1
Agent: Cl
Product: Cc1nc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)cs1
Yield: 71 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (2-methylthiazol-4-yl)methanamine dihydrochloride, the title compound was obtained as a colorless solid in 71% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 3H), 6.28 (t, J=5.2 Hz, 1H), 6.10 (s, 1H), 4.63 (d, J=5.2 Hz, 2H), 4.43 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2 H), 2.71 (s, 3H), 2.49 (s, 3H); MS (ES+) m/z 445.2 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:17]2=[O:41])=[CH:11][CH:10]=1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:21]=[C:19]1[NH:18][C:17](=[O:41])[CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:42])=[O:5])=[CH:10][CH:11]=2)[S:20]1
Reactant: CC(C)(C)OC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
To a solution of 4-(2,4-dioxo-3-tritylthiazolidin-5-ylmethyl)phenoxyacetic acid t-butyl ester (6.2 g) in toluene (25 ml) was added p-toluenesulfonic acid mono-hydrate (204 mg) and the mixture was heated under reflux for 3 hours. At elevated temperature ethyl acetate (10 ml) was added and the mixture was stirred at 25° C. for 1.5 hours. The precipitated crystals were filtered to give the desired compound (2.5 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[CH:18]=[C:17]([Cl:19])[N:16]=[CH:15]1)[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[Cl:19][C:17]1[N:16]=[CH:15][N:14]([C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])[CH:18]=1
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C=CCOc1cc(N)ccc1-n1cnc(Cl)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Iron powder-325 mesh (737 mg, 12.5 mmol) was added to a round bottom flask charged with a mixture of 1-(2-(allyloxy)-4-nitrophenyl)-4-chloro-1H-imidazole (500 mg, 1.8 mmol), absolute methanol (10 mL), and ammonium chloride (768 mg, 14 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 30 min. The reaction mixture was filtered, and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-(4-chloro-1H-imidazol-1-yl)-3-allyloxyaniline (380 mg, 83% yield). LC-MS (M+H)+250.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.48 (d, J=1.22 Hz, 1H), 6.97-7.02 (m, 2H), 6.26-6.32 (m, 2H), 5.87-5.98 (m, 1H), 5.20-5.34 (m, 2H), 4.48 (d, J=5.19 Hz, 2H), 3.86 (br s, 2H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([Cl:50])=[C:29]([C:46]([CH3:49])=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[Cl:50][C:28]1[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[N:36]=2)=[C:46]([CH3:49])[CH:47]=[CH:48][C:27]=1[NH:26][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 49.5 %

Procedure:
Using 3 -(1 cyano-1 -methylethyl) benzoic acid (95 mg, 0.50 mmol), oxalyl chloride (55 μL, 0.63 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 51%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:37][NH2:38]>C(Cl)Cl>[OH:37][NH:38][C:14](=[O:15])[CH2:13][CH:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(SC(CC(=O)NO)Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (6.02 mmol) of 3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutanoic acid in 50 mL of CH2Cl2 at 25° C. under argon is added 0.2 mL of DMF followed by 6.02 mL (12.03 mmol, 2 eq) of 2 M solution of oxalyl chloride in CH2Cl2. After stirring at 25° C. for 3 hours, the mixture is cooled to 0° C. and 3.7 mL (30.08 mmol, 5 eq) of O-trimethylsilylhydroxylamine is added. This mixture is then stirred at 25° C. for 18 hours. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The product is purificatied by flash silica gel chromatography to afford N-hydroxy-3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutyramide as a yellow crystalline solid. (1.7 g, 81%): 1H-NMR (300 MHz, DMSO-d6) δ (TMS) 2.2(m, 2H), 2.81 (m, 2H), 3.6(m, 1H), 3.75(s, 6H), 6.89-7 (m, 3H), 7.17-7.35(m, 5H), 8.85(s, 1H), 10.5(s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: CSc1nccc(I)n1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(C(=O)Cc2ccc(F)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
20 g (79 mmoles) of 4-iodo-2-methylthiopyrimidine in 165 mL of tetrahydrofuran under argon is cooled to −70° C. 45.5 mL of isopropylmagnesium chloride (2M in THF) is then slowly added to the reaction mixture, keeping the temperature at −70° C. After 30 min., a solution of 4-fluorophenyl acetyl chloride (13.7 g, 79 mmoles) in 65 mL tetrahydrofuran is added dropwise to the reaction mixture which is further stirred at −78° C. for 1 hour and allowed to reach 0° C. After 30 min. at 0° C., the reaction is poured into ice-water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the oily purified by chromatography on silica gel (ethyl acetate/hexane 4/1) affording 9.5 g of 2-(4-Fluoro-phenyl)-1-(2-methylthio-pyrimidin-4-yl)-ethanone as yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([SH:13])[N:3]=1.[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([S:13][C:4]1[N:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Oc1nc(S)nn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1nc(SCc2ccccc2)nn1-c1ccccc1
Reaction time: 24 h

Procedure:
The product of stage (b) (20 g), ethanol (300 ml) and sodium hydroxide (5 g) were stirred together for 10 minutes. Benzyl chloride (12.3 ml) was added, and the mixture was heated under reflux with stirring for 24 hours. The solvent was removed in vacuo, and the residue was treated with water. The pH was adjusted to 1.0 with concentrated hydrochloric acid, and the solid was filtered, washed with water and recrystallises from ethanol to give 21.75 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][N:8]2[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CC1(c2ccccn2)CNc2cc(Br)ccc21
Product: CC(=O)N1CC(C)(c2ccccn2)c2ccc(Br)cc21

Procedure:
Following similar methods to those described in Preparation 335 using 6-bromo-3-methyl-3-pyridin-2-yl-2,3-dihydro-1H-indole (1.2 g, 4.1 mmol), acetyl chloride (360 μL, 5 mmol) and TEA (721 μL, 5 mmol) gave the title compound as a pale yellow oil. MS: [M+H]+=331.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:17])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][C:27]([CH3:34])([CH2:31][CH2:32][CH3:33])[C:28](Cl)=[O:29].[CH3:35][C:36]([CH3:43])([CH2:40][CH2:41][CH3:42])[C:37](O)=[O:38]>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([N:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:28](=[O:29])[C:27]([CH3:34])([CH3:26])[CH2:31][CH2:32][CH3:33])=[C:20]([O:25][C:37](=[O:38])[C:36]([CH3:43])([CH3:35])[CH2:40][CH2:41][CH3:42])[CH:19]=1)=[O:17])[CH3:14])(=[O:3])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC(C)(C)C(=O)O
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: CN(CC(=O)c1ccc(O)c(O)c1)Cc1ccccc1
Agent: CS(=O)(=O)O
Product: CCCC(C)(C)C(=O)Oc1ccc(C(=O)CN(C)C(=O)c2ccccc2)cc1OC(=O)C(C)(C)CCC

Procedure:
Using a procedure similar to that described above in Example 3A, 3,4-dihydroxyphenyl N-benzyl-N-methylaminomethyl ketone methanesulfonate is reacted with two mole equivalents of 2,2-dimethylpentanoyl chloride in 2,2-dimethylpentanoic acid to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl N-benzoyl-N-methylaminomethyl ketone methanesulfonate as a white crystalline solid. This salt is debenzylated by catalytic hydrogenation in the presence of palladium-on-charcoal hydrogenation catalyst, in the same manner as the debenzylation procedure described above in Example 124, to yield 3,4-bis(2,2-dimethylpentanoyloxy)-phenyl methylaminomethyl ketone methanesulfonate as a white crystalline solid. This salt is catalytically hydrogenated in anhydrous ethyl alcohol in the presence of 10 percent palladium-on-charcoal hydrogenation catalyst until one mole equivalent of hydrogen is absorbed. There is thus obtained 3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(methylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[N:3]=1.[CH3:10][Si:11]([CH2:14][N:15]=[N+:16]=[N-:17])([CH3:13])[CH3:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:17]=[N:16][N:15]([CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:9]=2)[N:3]=1
Reactant: C#Cc1cccc(Br)n1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-ethynylpyridine (Example 465, Step 1) (350 mg, 1.92 mmol) and trimethylsilylmethyl azide (323 mg, 2.50 mmol) were combined in t-BuOH (4.0 mL) and water (3.0 mL). CuSO4.5H2O (24 mg, 0.096 mmol) in water (0.50 mL) was added, followed by sodium ascorbate (76 mg, 0.39 mmol) in water (0.50 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a yellow residue that was purified by flash chromatography (0-50% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]2[CH2:16][S:17][C@@H:18]3[CH:38]([NH:39][C:40](=[O:47])[CH2:41][C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)[C:37](=[O:48])[N:19]3[C:20]=2[C:21]([O:23]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:22])=[O:10])C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:38]([NH:39][C:40](=[O:47])[CH2:41][C:42]3[S:43][CH:44]=[CH:45][CH:46]=3)[C:37](=[O:48])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])([OH:10])=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=NOCC(=O)OC(c3ccccc3)c3ccccc3)CS[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 81.9 %

Procedure:
To a solution of diphenylmethyl 3-(diphenylmethoxycarbonylmethoxyiminomethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylate (187 mg) in methylene chloride (4 ml) are added anisole (0.8 ml) at 0° C., and trifluoroacetic acid (0.8 ml) under argon atmosphere, and the mixture is stirred for 10 minutes at room temperature. After evaporation of the methylene chloride and trifluoroacetic acid, the mixture is treated with ether to give 3-(carboxymethoxyiminomethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (86 mg). m.p. 158°-163° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([O:7]C)=[O:6].[OH-].[K+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)OC)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 3,5-dichloro-4-dodecyloxybenzoate, (˜0.78 mol, as above) was dissolved in methanol (1000 mL) and THF (500 mL). 85%-Potassium hydroxide (100 g, 1.52 mol) was dissolved in water (200 mL) and added to the solution. The starting material oiled out, but on gentle heating dissolution was achieved. After stirring at room temperature for 15 minutes the solution was poured into ice cold 2N-HCl with good stirring whereupon the product precipitated out. The white solid was filter off, washed well with water, and air-dried to remove as much of the water as possible. The solid was then suspended in acetonitrile (˜1000 mL) and stirred mechanically for about 1 hr. The solid was then filtered off washed with acetonitrile and air-dried. Yield, 290.6 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Br:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc(Br)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(Br)c4)c(C(=O)O)s3)c2cc1OC
Yield: 8.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-bromophenylboronic acid (30 mg, 0.15 mmol) gave 4-(3-Bromo-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (4.0 mg, 9%) as a white solid. MS 460 m/z (M+1).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][N:8](CC2C=CC=CC=2)[C@@H:7]([CH3:17])[CH2:6]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][C@@H:5]1[CH2:9][NH:8][C@@H:7]([CH3:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1CN[C@@H](C)C1
Yield: 94.1 %

Procedure:
A 2.93 g (12.61 mmol) sample of (2S,4S)-4-acetylamino-2-methyl-1-N-benzylpyrrolidine, from Example 1, step g above, was dissolved in 50 mL of methanol, 0.60 g of 10% Pd/C was added and the mixture shaken under 4 atm of hydrogen at room temperature for 13 hours. The mixture was concentrated, the catalyst was removed by filtration, and the solvent removed to afford 1.688 g (94.1% yield) of the title compound as a white solid. MS M/Z: 143 (M+H). NMR (CDCl3) δ: 1.16 (d, 3H, J=6 Hz), 1.63 (m, 1H), 1.79 (m, 1H), 1.95 (s, 3H), 2.65 (m, 1H), 3.28 (m, 1H), 3.41 (m, 1H), 4.40 (m, 1H), 5.81 (br, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[CH2:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:12]1[O:14][CH2:13]1.O>CCCCCC.O1CCCC1>[CH2:16]([O:15][CH2:11][CH:12]([OH:14])[CH:13]=[CH2:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [Li]CCCC
Reactant: c1ccc(COCC2CO2)cc1
Agent: C[S+](C)C
Agent: [I-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.64 M solution of n-butyllithium in hexane (35.7 mL) was added to a solution of trimethylsulfonium iodide (19.9 g) in tetrahydrofuran (300 mL) at −25° C. The mixture was stirred at the same temperature for 30 minutes. Benzyl glycidyl ether (5.00 mL) was added to the reaction solution at the same temperature, and then the mixture was warmed to room temperature over two hours and 50 minutes. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (6.98 g).