Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][CH:41]([F:43])[F:42])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[C:35]([C:27]1[C:26]([O:39][CH2:40][CH:41]([F:43])[F:42])=[C:25]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:44])=[O:2])[CH:8]=3)[NH:12][CH:11]=2)[CH:30]=[C:29]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH:28]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: COC(=O)C=C(C)c1ccc2c(c1)c(-c1cc(C(C)(C)C)cc(C(C)(C)C)c1OCC(F)F)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=CC(=O)O)c1ccc2[nH]cc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)c2c1

Procedure:
3-{1-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2-difluro-ethoxy)-phenyl]-1H-indol-5-yl}-but-2-enoic acid methyl ester (493 mg, 0.79 mmol) was dissolved in methanol (4 mL)/dioxane (8 mL) and treated with 1N NaOH (5.5 mL) at 60° C. for 4 h. Diluted with 1N HCl (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic portions were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to provide crude material. The material was purified using radial chromatography by elution with hexane/ethyl acetate gradient to provide 158 mg (43%) of a lightyellow solid. Mp. 135-145° C. 1H NMR (250 MHz, CDCl3): δ 8.40 (bs, 1H), 7.92 (s, 1H), 7.47 (m, 3H), 7.39 (m, 2H), 6.26 (d, J=1.1), 5.49 (tt, 1H, J=55.3, J=4.3), 3.69 (td, 2H, J=14.0, J=4.0), 2.68 (d, 3H, J=1.0), 1.50 (s, 9H), 1.37 (s, 9H). MS [EI−] 468 (M−H)+. Analytical (C28H33NO3): Calculated C, 71.62; H, 7.08; N, 2.98. Found: C, 69.95; H, 7.38; N, 2.70.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCC1N
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCCCC1NCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-1,2-cyclohexanediamine (200 mg) and 3-((benzyloxycarbonyl)amino)propionaldehyde (65 mg) in methylene chloride (4 mL), sodium triacetoxyborohydride (133 mg) and acetic acid (18 μL) were added at room temperature, and the mixture was stirred at the same temperature for 5 hours and 30 minutes. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain tert-butyl (2-((3-((benzyloxycarbonyl)amino)propyl)amino)cyclohexyl)carbamate (C39, 137 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N(C(=O)CCCOCCO)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(CCCCOCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 4-(2-hydroxyethoxy)butyramide (2.7 g, 7.5 mmol) in THF (20 mL) was slowly added 1 M lithium aluminum hydride in THF (11.3 mL, 11.3 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and then quenched by slow addition of 15% aqueous sodium hydroxide at 0° C. until no gas formation was observed. After stirring for 10 minutes at room temperature, a solid formed and the reaction mixture was filtered and the precipatate washed with THF three times. The filtrate was then concentrated and the residue was dissolved in dichloromethane and this solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.13 g of the title intermediate (82% yield).
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][CH2:30][NH2:31])[CH2:25][CH2:26][CH3:27].Cl>C(#N)C.C(OCC)(=O)C>[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][CH2:30][NH:31][CH:13]1[CH2:12][C:11](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:14]1=[O:15])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCN)CCCC
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCN1C(=O)CC(NCCN(CCCC)CCCC)C1=O
Reaction time: 6 h

Procedure:
N-nonyl maleimide (0.02 mM) prepared as described in Example 12 above in 2 ml of acetonitrile was treated with one equivalent of triethylamine and one equivalent of N,N-dibutylethylenediamine. The reaction mixture was stirred for six hours and then the acetonitrile was evaporated. The residue obtained was treated with cold aqueous dilute hydrochloric acid solution and ethyl acetate, with stirring for one hour. The ethyl acetate layer was then separated and concentrated to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH:14]=O)[C:4](=[O:16])[CH:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:5]4[C:6]5[C:11](=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=5)[C:2]([Cl:1])=[CH:3][C:4]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(Cl)c2ccc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To 3 mL of a chloroform solution containing 69 mg of (4,7-dichloro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 94 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 24 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 86 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 109 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4,7-dichloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12].Cl.Cl.C[Si](C)(C)CCOC[N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([C:31]3[CH:32]=[N:33][N:34]([C:36]4([CH2:40][C:41]#[N:42])[CH2:39][NH:38][CH2:37]4)[CH:35]=3)[C:25]=2[CH:24]=[CH:23]1>>[C:41]([CH2:40][C:36]1([N:34]2[CH:35]=[C:31]([C:30]3[C:25]4[CH:24]=[CH:23][NH:22][C:26]=4[N:27]=[CH:28][N:29]=3)[CH:32]=[N:33]2)[CH2:39][N:38]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:13][CH2:11][CH3:12])=[O:10])=[N:6][CH:7]=2)[CH2:37]1)#[N:42]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 5-bromopyridine-2-carboxylic acid, ethylamine (2.0 M in tetrahedrofuran solution) and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=428.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxyindole (55 mg, 0.41 mmol) in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, water was added and the precipitate was collected by filtration, washed with water followed by ether, and dried under vacuum over phosphorus pentoxide to give 4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (90 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2cc(Cl)cnc2[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc2cc(Cl)cnc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirred solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.986 g, 4.68 mmol) N,N-dimethylformamide (20 ml) at room temperature under a nitrogen atmosphere was added potassium carbonate (0.647 g, 4.68 mmol). After 30 minutes iodomethane (0.321 ml, 5.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was coated onto hydromatrix and purified by column chromatography (silica gel; heptane/ethyl acetate 4/1) to give methyl 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19]N(C)C)[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.Cl.[C:27]([NH2:30])(=[NH:29])[CH3:28].C[O-].[Na+]>CO.C(Cl)Cl.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:30]=[C:27]([CH3:28])[N:29]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g (2.8 mmole) of 8-chloro-1-(2-chlorophenyl)-4-[(dimethylamino)methylene]-3,4-dihydro-5H-2-benzazepine-5-one-2-oxide, 1.0 g (11 mmole) of acetamidine hydrochloride and 2.0 ml (9.9 mmole) of a 4.46M methanol solution of sodium methoxide in a mixture of 20 ml of methanol and 20 ml of methylene chloride was stirred at room temperature for 2 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Recrystallization of the residue from a mixture of ether and methylene chloride gave a colorless solid, mp 215°-216° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([C:18]#[N:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:7][CH:6]=[C:5]([C:18]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:19]=2)[N:4]=1)#[N:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)nc1C#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1C#N
Yield: 25.4 %

Procedure:
tert-Butyl 3-(2,6-dicyano-3-pyridyl)propanoate (0.31 g, 1.20 mmol) and methyl thiosalicylate (0.40 g, 2.40 mmol) were dissolved in toluene (30 ml), and triethylamine (0.75 ml, 5.41 mmol) was added thereto. The mixture was refluxed for 18 hrs, and the solvent was evaporated. The residue was washed with hexane-ethyl acetate to give the titled compound (0.12 g, 25%) as white amorphous solid.
Reaction SMILES: [CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])C.[Li+].CC1(C)[CH2:15][CH:14]([CH3:16])[O:13]C=N1.[C:18](#[N:21])[CH2:19][CH3:20]>C1COCC1>[NH2:21][C:18]([CH2:19][CH3:20])=[CH:3][C:1]1[O:13][CH:14]([CH3:15])[CH2:16][C:5]([CH3:6])([CH3:7])[N:4]=1
Reactant: CCC#N
Reactant: CC1CC(C)(C)N=CO1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(N)=CC1=NC(C)(C)CC(C)O1
Temperature: 25 °C
Yield: 981.9 %

Procedure:
To a solution of 11.0 mmoles of lithium diisopropylamide (11.1 g diisopropylamine; 50 mL of 2.4 M n-butyl lithium in n-hexane) in 100 mL THF, kept at 78° C. under a nitrogen atmosphere, was added a solution of 5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazine (14.1 g; 0.10 mole) in 100 mL THF. The reaction mixture was then allowed to stir at -78° for 2 additional hours at which time a solution of propionitrile (8.3 g; 0.15 mole) in 50 mL THF was added. The reaction mixture was allowed to warm to room temperature and was quenched with 75 mL saturated NH4Cl solution. A 100 mL portion of ether was added, the organic layer was separated, washed with brine, and dried (K2CO3). After the K2CO3 was removed by filtration, the filtrate was concentrated in vacuo to give 21.2 g of a yellow liquid which was distilled to yield 15.5 g (79% yield) of product as a pale yellow oil, b.p. 140° C. at 4 mm Hg.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:3]1[CH3:18].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C([O-])(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:25]([O:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11])=[C:3]1[CH3:18])(=[O:27])[CH3:26]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1C(C)=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@@H]12

Procedure:
To a freshly prepared solution of 2,2,2-trichloroethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate in methylene chloride, prepared from 100 mg. (0.317 mmole) of the 1-beta-oxide by Examples 11 and 12) was added 24 microl. (0.317 mmole) of pyridine, 29 microl. (0.317 mmole) of acetic anhydride and 4 mg. of 4-dimethylaminopyridine. Infrared spectral analysis indicated clean conversion to the desired acetate. Following water wash and drying, evaporation to dryness gave 2,2,2-trichloroethyl 1-acetoxy-2-methylcarbapen-2-em-3-carboxylate [ir (CH2Cl2) 1780, 1725, 1700 cm-1 ; Rf 0.7-0.75 (4:1 chloroform:ethyl acetate].
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[C@H:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:13][C@@H:12]([SH:27])[CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].F[C:29](F)(F)[C:30]([O-])=[O:31].C(Cl)(=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O.N1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[C@H:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:13][C@@H:12]([S:27][C:30](=[O:31])[CH3:29])[CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2C[C@H](S)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Reactant: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CCCc1cnc(N2C[C@H](SC(C)=O)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of 397 mg (1 mmol) (3R,5S)-1-(5-Propyl-pyrimidin-2-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol (the trifluoro-acetate salt was extracted with aqueous saturated NaHCO3/EtOAc) in 6 ml pyridine were treated at 0° C. with 0.14 ml (2 mmol) acetyl chloride and stirred for 5 h at RT. The reaction was poured on ice water and extracted wit Et2O (3×). The organic phases were washed with aqueous 1 N HCl and 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography on silica gel (CH2Cl2/Et2O 100:0 to 95:5) gave 383 mg (87%) (3R,5S)-Thioacetic acid S-[1-(5-propyl-pyrimidin-2-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-3-yl]ester, MS: 440 (MH+).
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH:30]6[CH2:34][CH2:33][CH2:32][CH2:31]6)[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CCOC(=O)C#CC1CCCC1
Solvent: ClC(Cl)Cl
Product: O=c1cc(C2CCCC2)n2c(n1)O[C@H](COc1ccc(C3C4CCCC3CCC4)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and cyclopentyl-propynoic acid ethyl ester (see Example 102) employing the procedure described in Example 95. [α]D25 −4.80 (c 0.5, CHCl3).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([CH2:28]O)=[CH:23][CH:22]=1>ClCCl>[Cl:3][CH2:28][C:24]1[C:25]([CH3:27])=[N:26][C:21]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[F:10])=[CH:22][CH:23]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
1.67 g (1.017 ml, 14.02 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 2.0 g (70.1 mmol) [6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-yl]-methanol in 115 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:6) gave 1.79 g (83%) of 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[C:24](#N)[CH3:25]>>[CH2:24]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:25]
Reactant: CC#N
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]-piperidine (0.185 g, 0.72 mmol), acetonitrile (10 ml), potassium carbonate (0.2 g, 1.44 mmol) 1-iodoethane (0.06 ml, 0.75 mmol). Yield: 0.15 g (73%). The amine was converted to several different salts and recrystallized from ethanol/diethyl ether. Hydrochloric acid salt m.p. 273-275° C., hydrobromic acid salt m.p. 267-268° C., fumaric acid salt m.p. 204-206° C., oxalic acid salt m.p. 163-165° C., sulfate salt m.p. 263-265° C., maleic acid salt m.p. 112-113° C. MS m/z (relative intensity, 70 eV) 285 (M+, 12), 271 (15), 270 (bp), 147 (7) 133 (8).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([OH:14])=O)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.S(Cl)([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=C(O)C1(c2cccs2)CCOCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(c2cccs2)CCOCC1

Procedure:
4-(2-Thienyl)tetrahydropyran-4-carboxylic acid was reacted with thionyl chloride and a catalytic amount of DMF in methylene chloride under heating to obtain 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride. A THF solution of 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride was added dropwise to a THF solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 4-(2-thienyl)tetrahydropyran-4-carbohydrazide.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>N1C=CC=CC=1>[C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCO
Solvent: c1ccncc1
Product: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
Trityl chloride (18.8 g, 67.4 mmol) was added to an ice cold (0° C.) stirring solution of 14a (9.9 g, 67.4 mmol) in 80 mL of pyridine. The reaction mixture was warmed to room temperature and stirred under argon for 2 days, during which time a white byproduct formed. The solvent was removed under reduced pressure, and the resulting material was redissolved in ice cold THF. The insoluble byproduct was removed by filtration, and the filtrate was dried under reduced pressure to obtain 22.6 g (86%) of an orange oil 15a. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.43 (6H, m, p-Ar), 7.29 (6, m, m-Ar), 7.22 (3H, m, o-Ar), 3.65 (3H, s, CO2CH3), 3.05 (2H, t, 3JH—H=6.6 Hz, HO—CH2), 2.29 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.54-1.71 (4H, m, 2CH2), 1.33-1.45 (m, 2H, CH2). HRMS (EI): m/z calcd 388.2038 (C26H28O3), found 388.2039 [M]+.