Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12]Cl)=[O:11].[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)=[O:11]
Reactant: O=C1CCNCC1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCC(=O)CC1

Procedure:
The crude [(2,6-dimethylphenyl)aminocarbonylmethyl]chloride, prepared in Preparation B (50 g., 0.25 moles) and 4-piperidone (86 g, 1 mole) are dissolved in 500 ml of ethanol. The mixture is refluxed for two hours, and then cooled and evaporated. The product is recovered by adding aqueous ammonia to the residue, and extracting with methylene chloride. Three portions of methylene chloride are used, which are collected, washed with water, and evaporated to a semi-solid. Upon addition of diethylether, the product crystallizes and is filtered. The resulting crude mixture is boiled with ether and then evaporated to a residue and triturated with hexane to yield pure material, 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]-4-piperidone. This material is of sufficient purity for use in Reaction Sequences 2 to 5.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:33]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:13]([C:15]2[S:16][CH:17]=[C:18]([Cl:20])[CH:19]=2)[N:14]=1)=[O:8].C(Cl)(Cl)Cl.[NH:39]1[CH2:49][CH2:48][CH:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:41][CH2:40]1>C1COCC1>[CH2:46]([O:45][C:43]([CH:42]1[CH2:48][CH2:49][N:39]([C:3]2[C:2]([Cl:1])=[CH:33][C:6]([C:7](=[O:8])[NH:9][C:10]3[S:11][C:12]([N:21]4[CH2:26][CH2:25][N:24]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:22]4)=[C:13]([C:15]4[S:16][CH:17]=[C:18]([Cl:20])[CH:19]=4)[N:14]=3)=[CH:5][N:4]=2)[CH2:40][CH2:41]1)=[O:44])[CH3:47]
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(N4CCN(C5CCCCC5)CC4)s3)cc2Cl)CC1
Reaction time: 5 h

Procedure:
To a solution of 750 mg of the compound of Example 5 in 10 ml of THF, 2.1 ml of ethyl isonipecotate was added at room temperature, the temperature was elevated to 50° C., and the mixture was stirred for 5 hours. To the reaction solution, chloroform was added, and the organic layer was washed with saturated aqueous NaHCO3 and brine and dried over sodium sulfate. After the evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-MeOH=200:1˜100:1) to obtain 881 mg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1>C(O)(=O)C>[C:22]([C:21]1[CH:25]=[C:17]([N:16]2[C:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:1][C:10]3[CH2:14][CH2:13][CH2:12][C:11]2=3)[CH:18]=[CH:19][C:20]=1[OH:26])([OH:24])=[O:23]
Reactant: O=C(CC1CCCC1=O)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCC3)ccc1O

Procedure:
A mixture of 20.5 g. (0.1 mole) of 2-phenacylcyclopentanone, 15.3 g. (0.1 mole) of 5-aminosalicylic acid, and 60 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The filter cake was washed with water, dried and recrystallized from acetic acid to provide 9.5 g. (30%) of crystals, m.p. 198°-199°.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:21]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[F:56])=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=3)[C:34]([OH:36])=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:47]=1>O1CCOCC1>[Cl:19][C:20]1[C:21]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[F:56])=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:47]=1
Reactant: COc1ccc(-c2cc3nc(Oc4ccc(C)c(C(=O)O)c4)n(COCC[Si](C)(C)C)c3cc2Cl)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3nc(Oc4ccc(C)c(C(=O)O)c4)[nH]c3cc2Cl)c(F)c1
Temperature: 80 °C

Procedure:
TBAF (1M in THF) (0.5 mL) was added to a solution of 5-[(6-chloro-5-(2-fluoro-4-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoic acid in dioxane (3 mL). The reaction was heated at 80° C. for 16 h. Volatiles were removed and the residue acidified with 2N aqueous HCl and extracted with EtOAc. The organic phase was washed with water and concentrated. Purification by reverse phase HPLC eluting with 15-90% MeCN:water afforded the title compound as a white solid. LC-MS: calculated for C27H36ClFN2O4 426.08, observed m/e 427.00 (M+H)+ (Rt 1.90 min). 1 H NMR (500 MHz, CD3OD): δ 7.87 (s, 1H) 7.48 (s, 1H) 7.42 (m, 2H) 7.28 (s, 1H) 7.20 (m, 1 H) 6.80 (dd, 1H) 6.75 (dd, 1H) 3.84 (s, 3H) 2.61 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([C:25]#[N:26])=[N:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:25]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[N:9]=[CH:10][CH:11]=[CH:16][N:8]=3)[CH:12]=2)[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:27])[N:9]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2cc(OCc3ccccc3)ccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1nc(C#N)c2cc(OCc3ncccn3)ccc21
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of (5-benzyloxy-3-cyano-indazol-1-yl)-acetic acid tert-butyl ester (4 g, 11.01 mmol) in THF (400 mL) was added Pd/Al2O3 (5%) (4.10 g, 38.5 mmol). The reaction mixture was stirred at 40° C. for 16 h under H2 atmosphere (4 bars). The reaction mixture was filtered through a pad of Celite, which was then washed with CH2Cl2. The combined organics were concentrated under vacuum to give the title compound as a yellow solid. MS (LC/MS): 296.0 [M+Na]+; tR (conditions e): 4.46 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
6.30 g (0.019 mol) of ethyl 4-[4-(4-cyanophenylazo)phenoxy]-butyrate was dissolved in a mixture of 150 mL of dimethylformamide and 40 mL of water in a 500 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 3.8 g (0.095 mol) of NaOH was added through the condenser. Stirring and heating were continued for 1 h after which the reaction mixture was left for cooling to room temperature. The reaction mixture was then poured onto 200 of ice and acidified with 8N HCl until pH 2. The precipitated crude product was recovered by filtration. The precipitate was washed with 100 mL of hot ethanol and left overnight. After filtration and vacuum drying at 50° C. for 22 h. 5.49 g (yield 93%) of 4-[4-(4-cyanophenylazo)phenoxy]-butanoic acid was obtained
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=O)[CH:13]([CH3:15])[CH3:14])=[C:7](C)[CH:6]=1)[CH2:2][CH2:3][CH3:4].B>O1CCCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC(=O)C(C)C)c(C)c1
Agent: B
Solvent: C1CCOC1
Product: CCCCc1ccc(NCC(C)C)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Isobutyric anhydride (2.034 mL, 12.25 mmol) was added dropwise to a stirred solution of 4-butyl-2-methylaniline (2 g, 12.25 mmol) and triethylamine (3.41 mL, 24.50 mmol) in dichloromethane (DCM) (20 mL) under nitrogen. The solution was stirred for 20 hours and then treated with 2M HCl (75 mL) and stirred for 5 minutes. The reaction mixture was extracted with DCM and the combined organic layers were dried over magnesium sulfate. The magnesium sulfate was filtered and the DCM phase concentrated in vacuo to gave N-(4-butyl-2-methylphenyl)-2-methylpropanamide (2.402 g, 10.29 mmol, 84% yield). A stirred solution of N-(4-butyl-2-methylphenyl)-2-methylpropanamide (2.402 g, 10.29 mmol) in tetrahydrofuran (30 mL) under nitrogen was treated dropwise with 1M borane in tetrahydrofuran (BH3 in THF, 30.9 mL, 30.9 mmol; obtainable from, for example, Aldrich). The solution was heated at 60° C. for 2 hours before being quenched with 2M HCl (18 mL) and stirred for a further 15 minutes. It was then basified with aqueous Na2CO3 and extracted with DCM (2×150 mL). The combined organic phases were then dried over magnesium sulfate and concentrated in vacuo. The sample was loaded in dichloromethane and purified on Biotage Flashmaster II on silica (Si) 100 g using a 0-100% dichloromethane-cyclohexane over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give 1.66 g of the title compound as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:25][C:26](=[O:35])[CH:27](Br)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:24]>CN(C)C=O>[CH2:23]([O:25][C:26](=[O:35])[CH:27]([N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:24]
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CCOC(=O)C(Br)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Temperature: 100 °C
Reaction time: 22 h
Yield: 58 %

Procedure:
To the solution of 1.0 g (4.4 mmol) 2-(4-chlorophenyl)benzimidazole (commercially available) in 10 mL N,N-dimethylformamide, 4.6 g (14.0 mmol) cesium carbonate and 3.3 g (13.1 mmol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added and the brown suspension was stirred for 22 h at 100° C. After cooling to room temperature the reaction was poured on water and extracted three times with ethyl acetate. The organic phases were washed with water and brine, dried over magnesium sulfate and filtered. To the filtrate silica gel was added and the solvent evaporated. The adsorbed crude product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate 100:0 to 50:50) to give the desired compound as a colorless solid (58%). MS (Turbo Spray): m/z=397.2 [M+H].
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>CO>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([CH3:16])=[CH:13][C:12]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CO
Product: COC(=O)C=C(C)Nc1ccc(NC(C)=O)cc1
Temperature: 5 °C
Yield: 46.8 %

Procedure:
A suspension of 4-aminoacetanilide (2) (253 g, 1.68 mol) and methyl acetoacetate (215 g, 1.85 mol) in MeOH (0.75 L) was heated to reflux. The resulting solution was held at reflux for 16 h and then cooled to 5° C. The resulting off-white precipitate was filtered and washed with MTBE (3×200 mL) to give butenoate 3 (195 g, 47% yield). The mother liquor was concentrated in vacuo and filtered to give a second crop of 3 as pale pink solids (141 g, 34% yield, 81% overall yield). 1H NMR (DMSO) δ 10.22 (s, 1 H), 9.97 (s, 1 H), 7.57 (d, 2 H), 7.11 (d, 2 H), 4.65 (s, 1 H), 3.56 (s, 3 H), 2.04 (s, 3 H), 1.94 (s, 3 H); 13C NMR (DMSO) δ 169.64, 168.07, 159.33, 136.48, 133.55, 124.52, 119.44, 84.47, 49.77, 23.81, 19.68.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=1[N+:16]([O-])=O)C>C(O)(=O)C.O.[Fe]>[O:3]=[C:4]1[NH:16][C:8]2[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:11][C:7]=2[NH:6][CH2:5]1
Reactant: CCOC(=O)CNc1sc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2c(s1)NCC(=O)N2
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A mixture of methyl 5-(2-ethoxy-2-oxoethylamino)-4-nitrothiophene-2-carboxylate 19 (7.02 g, 24.35 mmol) and iron powder (4.08 g, 73.1 mmol) in acetic acid (100 mL) and water (15 mL) was stirred at 70° C. for 2 h. Quenched with ice/water and the resulting precipitate was collected by filtration to give crude methyl 2-oxo-1,2,3,4-tetrahydrothieno[3,2-b]pyrazine-6-carboxylate 20 (4.74 g, 92%). NMR (400 MHz, DMSO-d6) 3.69 (s, 3H), 3.87 (s, 2H), 7.06 (s, 1H), 7.21 (br s, 1H), 10.28 (br s, 1H). (m/z)=213 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:29])[CH2:26][O:25][C:24](=O)[N:23]2C)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C(O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]([NH:23][CH3:24])([CH3:29])[CH2:26][OH:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)OC[C@@]1(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CN[C@@](C)(CO)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 120 °C
Yield: 9.5 %

Procedure:
A mixture of (R)-4-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-3,4-dimethyl-oxazolidin-2-one (80 mg, 0.2 mmol) in 4.2 M of LiOH aqueous (1.5 mL, 6 mmol) and ethanol (1.5 mL) was heated at 120° C. for 5 hrs. The solvent was concentrated and the residue was washed with water to give white precipitate. The crude was purified with silica gel column eluted with 2 M NH3 in MeOH and DCM from 0 to 8% to give 7 mg of product, 10%. ESI-MS (M−30)+: 339.30, room temperature 1.57 min. 1H NMR (400 MHz, CDCl3) δ: 7.76˜7.70 (m, 3H), 7.51 (d, 1H), 7.17-7.12 (m, 2H), 4.27 (m, 1H), 3.88 (d, 1H), 3.71 (d, 1H), 2.32-2.23 (m, 5H), 1.89 (d, 2H), 1.62 (s, 3H), 1.44 (m, 2H), 1.25˜1.05 (m, 3H), 0.90 (s, 9H)
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl-].[Na+].C([O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=O)C=C>O>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[C:17]2[C:16]=1[CH2:14][CH2:13][C:12]2=[O:11]
Reactant: C=CC(=O)Oc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2c(Br)ccc(O)c21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a mixture of aluminum trichloride (120 g) and sodium chloride (40 g) heated to 100° C. was added 4-bromophenyl acrylate (10.5 g, 50.7 mmol), and the mixture was stirred for 15 min. Then, the mixture was heated to 140° C., and the mixture was stirred for 45 min. The mixture was poured into ice-cooled water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) and recrystallized (ethyl acetate/hexane) to give the title compound (3.82 g, yield 36%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1>Cl>[ClH:9].[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNc1ccccc1
Agent: Cl
Product: CN(c1ccccc1)c1ncccc1[N+](=O)[O-]
Yield: 66.5 %

Procedure:
To 59 g (0.55 mole) of N-methylaniline, stirred and heated at 115°-120° C. under nitrogen atmosphere was added 79 g (0.50 mole) of 2-chloro-3-nitropyridine in four portions at 15 minute intervals. The melt was maintained at 120°-125° C. for 1 hour and then poured into 700 ml of dilute aqueous hydrochloric acid. The precipitate was collected by filtration and dried. The solid was dried and recrystallized as the hydrochloride salt from ethyl acetate-ethereal hydrogen chloride to give 88.3 g (66%) yellow solid. A portion was recrystallized from ethyl acetate-ethyl alcohol to give yellow solid, m.p. 181°-182° C. after undergoing phase changes from 165°-170° C. and at 179° C.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[NH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>C(Cl)Cl>[OH:17][CH:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]2=[O:8])[CH2:12][CH2:13]1
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NC1CCC(O)CC1
Solvent: ClCCl
Product: CC1=C(C)C(=O)N(C2CCC(O)CC2)C1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
126 g (1 mol) of dimethylmaleic anhydride and 115 g (1 mol) of 4-aminocyclohexanol are warmed, in an oil bath whilst stirring, to 120° to 125° C (internal temperature) for 30 minutes. After cooling to 20° C, the reaction product is dissolved in 500 ml of methylene chloride and extracted once with 100 ml of 1 N NaOH, whilst cooling with ice. The reaction product is then washed twice with water and dried over sodium sulphate. The solvent is evaporated and the residue is recrystallised from a 1:1 mixture by volume of ethyl acetate and petroleum ether. 155 g (70% of theory) of N-(4-hydroxycyclohexyl)-dimethylmaleimide are obtained; melting point 109° to 111° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:28][C:29](O)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:28][C:29]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCCCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCCCC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Triethylamine 0.24 ml was added in a methylene chloride 10 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo (3.2.1]octane hydrochloride 0.28 g, and stirred at 0° C. for 30 min. Cyclooctyl acetic acid 0.25 g and WSC 0.40 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 21 hours. The reaction mixture was washed wits saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-cyclooctylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THP 15 ml solution of lithium aluminum hydride 0.12 g and refluxed for 1 hour. The reaction mixture was cooled, then added water and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: acetone=10:1) to obtain the product. Yield: 0.26 g (Yield 61%)
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH:27]([NH:29][CH2:30][CH2:31][S:32][C:33]1[N:34]=[CH:35][N:36]2[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][C:37]=12)=[O:28]>>[CH:27]([NH:29][CH2:30][CH2:31][S:32][C:33]1[N:34]=[CH:35][N:36]2[CH:40]=[C:39]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[S:38][C:37]=12)=[O:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNC=O)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCNC=O)c4s3)[C@H](C)[C@H]12
Yield: 48.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 1.06 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.665 g of 7-(2-formylaminoethyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 818 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(2-formylaminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24].CN1CCOCC1.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>ClCCl>[C:34](=[O:35])([O:24][C:23](=[O:25])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39]
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)OC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.30 g, 0.88 mmol) in dichloromethane (12.5 mL) was added N-methylmorpholine (0.09 g, 0.88 mmol) and iso-butyl chloroformate (0.12 g, 0.88 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 3 h. This mixture was used as a mixed anhydride for the next step amide formation.
Reaction SMILES: [CH2:1]([O:7][C:8]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:7][C:8](=[O:9])[NH:10][C@H:11]1[C:12](=[O:14])[O:17][C@H:15]1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of employing (2R,3S)-2-(hexoxycarbonylamino)-3-hydroxy-butanoic acid (0.27 g, 1.10 mmol) in dry CH2Cl2 (27 mL), Et3N (0.46 mL, 3.31 mmol) and subsequently TBTU (0.42 g, 1.32 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.18 g, 73%), as white solid. [α]25D −25.1 (c 0.1, CHCl3). MS (ESI) m/z: 230 [M−H]+; (ESI) m/z: 228 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (t, J=6.9 Hz, 3H), 1.38-1.21 (m, 6H), 1.34 (d, J=6.4 Hz, 3H), 1.62-1.50 (m, 2H), 4.07-3.93 (m, 2H), 4.84 (dq, J=6.1, 6.4 Hz, 1H), 5.40 (dd, J=6.1, 9.3 Hz, 1H), 8.19 (d, J=9.3 Hz, 1H).