Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12][N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:36][CH:37]=1)[CH2:22][C:23]#[CH:24]
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: OC1CCNCC1
Solvent: ClCCl
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCC(O)CC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.230 g, 0.42 mmol) in anhydrous dichloromethane (4 ml) under argon was added a solution of 4-hydroxypiperidine (0.424 g, 4.2 mmol) in anhydrous CH2Cl2 (4 ml). The clear solution was stirred at room temperature for 1.5 hours under argon, then partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate solution (100 ml). The organic layer was washed with 5% aqueous sodium carbonate (100 ml), and dilute brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with ether to give a white precipitate, which was collected by filtration , washed with ether and dried in vacuo over P2O5 (0.206 g, 89%), mp 208-210° C.; 1H-NMR (DMSO-d6) 1.50 (s, 9H, But), 1.33 (m, 2H), 1.65 (m, 2H), 2.17 (m, 2H), 2.72 (m, 2H), and 3.50 (m, 1H), (piperidine ring protons), 3.24 (s, 1H, C≡CH), 3.57, 3.60 (2×s, 5H, N3-Me , 2-CH2), 4.39 (s, 2H, CH2C≡C), 4.55 (d, J=4.1 Hz, 1H, OH), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.9 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.81, 7.87 (2×s, 2H, 5-H, 8-H); MS (ESI, m/z) 551, 553 [(M+H)+, 100%, 37% rcspectively; Cl isotopic pattern].
Reaction SMILES: [C:1](#[N:6])C/C=C/C.[C:7](#[N:12])[CH2:8]/[CH:9]=[CH:10]\[CH3:11].[C:13](#[N:18])CCC=C>>[CH:1]#[N:6].[C:13](#[N:18])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]#[N:12]
Reactant: C/C=C\CC#N
Reactant: C=CCCC#N
Reactant: C/C=C/CC#N
Product: C#N
Product: N#CCCCCC#N

Procedure:
The isomerization of cis-2-pentenenitrile (boiling point 127° C./1013 mbar) gives rise to the target products trans-3-pentenenitrile (boiling point 143° C./1013 mbar) and cis-3-pentenenitrile (boiling point 146° C./1013 mbar), and also small amounts of 4-pentenenitrile (boiling point 146° C./1013 mbar) and trans-2-pentenenitrile (boiling point 144° C./1013 mbar). Trans-3-pentenenitrile, cis-3-pentenenitrile and 4-pentenenitrile can be used, after distillative removal, for the hydrocyanation with hydrogen cyanide to give adiponitrile. cis- and trans-2-pentenenitrile can be recycled into the isomerization stage after distillative removal.
Reaction SMILES: CS[CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:20]=4)[O:16][N:15]=3)=[CH:13][C:7]=2[N:6]=1.[CH:36]1C=C([Cl:42])C=C(C(OO)=O)C=1.[O-:47][S:48](S([O-])=O)=[O:49].[Na+].[Na+].Cl.CCOC(C)=O>ClCCl.CCOC(C)=O>[ClH:42].[CH3:36][S:48]([CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:31])[C:27]([F:28])([F:29])[F:30])=[C:21]([C:32]([F:35])([F:33])[F:34])[CH:20]=4)[O:16][N:15]=3)=[CH:13][C:7]=2[N:6]=1)(=[O:49])=[O:47]
Reactant: O=S([O-])S(=O)[O-]
Reactant: CSCCc1nc2cc(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(-c2nc(-c3ccc4[nH]c(CCS(C)(=O)=O)nc4c3)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[2-(methylthio)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (400 mg) in dichloromethane (8.0 ml) was added mCPBA (534 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a Na2S2O4 aqueous solution, followed by stirring for 1 hour. The reaction solution was extracted three times with EtOAc, and the organic layer was combined, dried over anhydrous MgSO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (chloroform:CH3OH=10:1) to obtain a yellow oily substance. This was dissolved in EtOAc, and a 4M-HCl/EtOAc solution was added thereto, followed by concentration. The residue was washed with IPE to obtain 2-[2-(methylsulfonyl)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride (146 mg) as pale yellow powders.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[CH2:13][CH2:12][CH:11]([CH3:14])[C:10]2=[O:15])=[CH:6][CH:5]=1.[H][H].[CH3:20]N(C)C=O>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[CH2:13][CH2:12][C:11]([CH3:20])([CH3:14])[C:10]2=[O:15])=[CH:16][CH:17]=1
Reactant: CC1CCC(=Cc2ccc(Cl)cc2)C1=O
Reactant: CN(C)C=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 0 °C

Procedure:
2.4 g of sodium hydride (60% oily sodium hydride washed with anhydrous benzene) was added to 100 ml of anhydrous dimethylformamide under nitrogen atmosphere while stirring. 24 g of 2-(4-chlorobenzylidene)-5-methylcylopentanone (prepared in Example 3) was added to the mixture, followed by stirring at room temperature until generation of hydrogen was terminated. After the addition of 15 g of methyl iodide, the mixture was stirred for a further 2 hours at 60° C. The reaction mixture thus obtained was allowed to cool, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure. The residue was solidified with the addition of a small amount of hexane to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CS(C)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 3.7 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.71 g, 3.7 mmol). The product was isolated as a white foam. Yield 1.17 g (69%). mp 140°-145° C. FDMS m/e=455 (M+ of free base). α[D]589 =+4.59 (c=1.00, dimethylsulfoxide).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([N:21](COC)[C:22]3[N:23]=[N:24][CH:25]=[CH:26][CH:27]=3)(=[O:20])=[O:19])=[C:13]([F:31])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C=C(Cl)C=CC=2OC2C(Cl)=CC(S(/N=C3/N(COC)N=CC=C/3)(=O)=O)=C(F)C=2)C=CN=1.FC(F)(F)C(O)=O.CO.Cl.O>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26][CH:27]=3)(=[O:19])=[O:20])=[C:13]([F:31])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COCN(c1cccnn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Agent: COCn1nccc/c1=N\S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Agent: Cl
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cccnn3)cc2Cl)ccn1
Reaction time: 24 h

Procedure:
4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamide and 4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide, (Preparation 875, 93 mg, 0.17 mmol) in trifluoroacetic acid (1 mL, 10 mmol) was stirred for 24 hours. The reaction mixture was concentrated and the residue was taken in methanol (1 mL, 20 mmol) and 2 M of hydrogen chloride in water (1 mL, 2 mmol). After stirring for two days, the reaction mixture was concentrated and the residue liophilized from acetonitrile-water to give 76 mg of product as a hydrochloride salt.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]1[N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: COc1cccc2c1C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1-c1c(ccn1CC(C)O)C2
Reaction time: 0.58 h
Yield: 45.3 %

Procedure:
A solution of 2.04 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). There was obtained 1.1 g (45%) of (RS)-1-(8-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.NC1C=CC=C(C)N=1.NC1C=CC([F:30])=C(C)N=1>>[F:30][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(N)ccc1F
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Agent: Cc1cccc(N)n1
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1F

Procedure:
In a similar procedure, N-(6-methylpyridin-2-yl)-2,2-dimethylpropionamide was prepared from 2-amino-6-methylpyridine. 1H NMR (CDCl3) δ: 8.02-8.04 (1H, d), 7.95 (1H, broad s), 7.54-7.60 (1H, t), 6.86-6.88 (1H, d), 2.44 (3H, s), 1.31 (9H, s). Similarly, N-(5-fluoro-6-methylpyridin-2-yl)-2,2-dimethylpropionamide was prepared from 2-amino-5-fluoro-6-methylpyridine. 1H NMR (CDCl3) δ: 8.02 (1H, dd), 7.95 (1H, broad s), 7.35 (1H, t), 2.44 (3H, d), 1.32 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22](C)[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:25]([O:27][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])=[O:26])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a mixture of p-bromophenacyl bromide (242 mg, 0.87 mmol) in DCM (1.5 mL) and DMA (1.5 mL), under nitrogen, was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.87 mmol) and N,N-diisopropylethylamine (531.8 μL, 3.05 mmol) and the resulting mixture was stirred at 35° C. for 3 h, concentrated under vacuum, dissolved in DCM (30 mL), and washed with water (2×5 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title intermediate.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCOc1ccc(/C=C/C(=O)OC)cc1

Procedure:
Trans methyl 4-hydroxycinnamate (20.0 g, 11.2 mmol), 1-bromohexane (18.5 g, 112 mmol) and potassium carbonate (16.6 g, 120 mmol) were stirred under reflux in butanone. The mixture was allowed to cool after 16 hours, evaporated to dryness and the residue was partitioned between DCM and water. The DCM layer was removed and dried (Na2SO4) and evaporated to leave a yellow solid methyl (E)-3-(4-hexyloxyphenyl)-2-propenoate which was recrystallized from petroleum. Yield=20.0 g, 71%.
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:59])[C@H:12]([CH3:58])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:57])[CH2:22][C@@H:23]([O:55][CH3:56])[C@@H:24]([N:29]([CH3:54])[C:30](=[O:53])[C@H:31]([CH:50]([CH3:52])[CH3:51])[NH:32]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.C(NCC)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:59])[C@H:12]([CH3:58])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:57])[CH2:22][C@@H:23]([O:55][CH3:56])[C@@H:24]([N:29]([CH3:54])[C:30](=[O:53])[C@H:31]([CH:50]([CH3:51])[CH3:52])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Yield: 86.4 %

Procedure:
According to the general procedure A, from #175 (560 mg, 0.690 mmol, 1 eq.) in dichloromethane (9 mL), and N,N-diethylamine (6.0 mL), was synthesized the crude desired compound, which was purified by by silica gel chromatography (Gradient: 0 to 50% methanol in dichloromethane) to afford #176 (351 mg, 87%) as a yellow oil. LC-MS (Protocol Q1): m/z 589.5 [M+H+], retention time=0.72 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:13]([F:15])[F:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[ClH:16].[H][H]>[Pd].CO>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:13]([F:14])[F:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C#N)ccc1C(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(CN)ccc1C(F)F
Yield: 62.7 %

Procedure:
Purge a mixture of methyl 5-cyano-2-(difluoromethyl)benzoate (9.37 g, 44.4 mmol, 1.0 equiv), palladium (10% on carbon, 3.00 g, 2.82 mmol, 0.064 equiv), and MeOH (50 mL) with nitrogen; then add hydrochloric acid (37 wt % aqueous, 8.0 mL, 105.6 mmol, 2.38 equiv); and stir the resulting suspension under 275 kPag of hydrogen at room temperature overnight. Remove the solids by filtration; concentrate the filtrate under reduced pressure; and dry the resulting material in a 40° C. vacuum oven overnight to give the title compound as a light brown solid (7.01 g, 83% yield). ES/MS (m/z) 216 (M+1).
Reaction SMILES: [Mg].Cl[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].BrCCBr.[C:12](Cl)(=O)[CH:13]([CH3:15])[CH3:14].Cl.C[CH2:20][O:21]CC>>[CH3:5][C:4]([CH3:7])([CH2:3][C:20](=[O:21])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:6]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)CCl
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Product: CC(C)CC(=O)CC(C)(C)C

Procedure:
Mix magnesium turnings (45 mg, 1.85 mmol) and 1-chloro-2,2-dimethylpropane (74.6 mg, 0.7 mmol) in anhydrous ether (9 mL). Heat and stir vigorously, then add, by dropwise addition, 1,2-dibromoethane (156 mg, 0.839 mmol) in anhydrous ether (1.5 mL). Reflux for 12 hours, place under an argon atmosphere and cool to 0°-5° C. Add, by dropwise addition, a solution of isobutyryl chloride (0.533 mmol) in anhydrous diethyl ether (1.5 mL). Stir at 0°-5° C. for 1.5 hours, pour into a mixture of ice and concentrated hydrochloric acid (0.15 mL) and separate the organic phase. Wash with ethyl acetate, 5% aqueous sodium carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give 2,2,6-trimethyl-4-heptanone.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH2:8][F:9])(=[O:5])=[O:4].[CH2:12]([O:15][C:16]([N:18]1[C@H:22]([CH2:23][C:24]2[S:28][C:27]3=[CH:29][N:30]=[CH:31][N:26]3[CH:25]=2)[CH2:21][C@H:20]([S:32][C:33]2[C@H:34]([CH3:50])[C@@H:35]3[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:36]3[C:37]=2[C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]>>[F:1][C:2]([F:11])([F:10])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:12]([O:15][C:16]([N:18]1[C@H:22]([CH2:23][C:24]2[S:28][C:27]3=[CH:29][N:30]([CH2:7][CH2:8][F:9])[CH:31]=[N+:26]3[CH:25]=2)[CH2:21][C@H:20]([S:32][C:33]2[C@H:34]([CH3:50])[C@@H:35]3[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:36]3[C:37]=2[C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: O=S(=O)(OCCF)C(F)(F)F
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4cn(CCF)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
2-Fluoroethyl trifluoromethanesulfonate (76.4 mg) is added to 41.1 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 23-a), and the mixture is stirred in an argon atmosphere at room temperature for 2 hr. The solvent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol 1:1) to give 54.1 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-(2-fluoroethyl)imidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a yellow viscous material.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH2:15].C(O)(=O)C>C(O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=Cc1ccncc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
1-Boc-piperazine (4.0 g, 21.5 mmol), 4-vinylpyridine (2.94 g, 27.9 mmol), and acetic acid (1.29 g, 21.5 mmol) were mixed in ethanol and heated to reflux for 48 h. The mixture was cooled to room temperature and concentrated under vacuum to provide 1-Boc-4-[2-(4-pyridinyl)ethyl]-piperazine (2.9 g, 45%) as an off white solid. The product was used without further purification.
Reaction SMILES: [C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])C)[CH:5]([CH3:7])[CH3:6].[C:17](O)(=O)CCC>>[C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH2:10][CH2:12][CH3:17])[CH:5]([CH3:6])[CH3:7]
Reactant: CCCC(=O)O
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Product: CCCC(=O)OC(OOC(=O)SC)C(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) and replacing isobutyric acid with n-butyric acid affords O-(1-butanoyloxyisobutoxy) S-methyl thiocarbonate (14) as an oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.O[N:25]1[C:29]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:18]([NH:25][CH3:29])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
400 mg of 1-benzhydrylazetidin-3-carboxylic acid (synthesized according to the method described in WO2005/49602) was dissolved in 4 ml of dimethylformamide, and 683 mg of triethylamine, 122 mg of methylamine hydrochloride, 304 mg of 1-hydroxybenzotriazole and 431 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.[OH-].[Na+]>>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Yield: 10.6 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (0.31 g, 0.70 mmol) produced in Example A32(iv), 2-chloro-2-oxoethyl acetate (0.55 g, 4.0 mmol), and 8N aqueous sodium hydroxide solution (1 mL), and in the same manner as in Example A30, the title compound (37 mg, 11%) was obtained as a pale-yellow powder.