Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][O:22]C1CCCCO1>>[CH2:1]([C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:20][CH2:21][OH:22])[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(Cc2ccccc2)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Product: CC1(Cc2ccccc2)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-benzyl-3-methylindol-2(3H)-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O)[CH2:23][CH2:24][CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1/[CH:29]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: CCCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)cccc1OC
Yield: 42 %

Procedure:
The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-butoxy-3-methoxybenzaldehyde (400 mg, 1.922 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to afford 271 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=6.3 Hz, 3H), 1.42-1.48 (m, 4H), 3.77 (s, 3H), 3.79-3.85 (m, 2H), 6.91-7.01 (m, 4H), 7.52 (d, J=4.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 501.18 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19].Cl>C(OCC)C>[CH:1]1([CH2:7][NH:8][C:18](=[O:19])[CH2:17][Cl:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: NCC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCl)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.66 Grams of cyclohexylmethylamine is dissolved in 200 ml of diethyl ether. Thereto is added 5.06 g of triethylamine. To the resulting mixture is dropwise added, with ice cooling, a solution of 5.65 g of chloroacetyl chloride dissolved in 150 ml of diethyl ether. The mixture is stirred for 1 hour at room temperature and then acidified with 5% hydrochloric acid. The mixture is extracted with diethyl ether. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation and the residue is recrystallized from n-hexane to obtain 6.7 g of N-cyclohexylmethyl-N-(α-chloroacetyl)amine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[OH:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cc2ccccc2o1
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a stirred solution of benzofuran 2-carboxylic acid (2.50 g) in tetrahydrofuran (50 ml) at 0° C. under nitrogen was added a solution of lithium aluminium hydride (1.0M; 7.7 ml) in tetrahydrofuran. Stirring was continued for 2 h, allowing the temperature to rise to RT. The mixture was diluted with diethyl ether (50 ml) and quenched with water (30 ml). The aqueous layer was separated and extracted with diethyl ether (2×25 ml). The combined extracts were washed with water (30 ml), sodium hydroxide solution (1M; 30 ml), water (30 ml), brine (30 ml) and dried (MgSO4). Filtration and evaporation of solvent under reduced pressure yielded the title compound (1.11 g, 49%) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:25](O)=[O:26])=[O:22])[NH:18][C:15]2=[CH:16][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C@H:24]([NH:23][C:21]([C:19]2[NH:18][C:15]3=[CH:16][N:17]=[C:12]([Cl:11])[CH:13]=[C:14]3[CH:20]=2)=[O:22])[C:25](=[O:26])[N:6]2[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]2)=[CH:34][CH:33]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(C(F)(F)F)CC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-trifluoromethyl piperidine (17 mg, 0.11 mmol) was added a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (400 μL) followed by a solution of HATU (50 mg, 0.13 mmol) in DMF (400 μL) and finally a solution of DIPEA (23 μL, 0.13 mmol) in DMF (200 μL). The resulting mixture was stirred at rt for 96 h then solvent was removed in vacuo. The crude material was purified by crystallisation from THF/petroleum ether to give the title compound as a yellow powder. (ES+)=497.23 [M+H]+; RT=3.50 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(OCC)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-aminoindan (100 g), acetic anhydride (84 g), pyridine (65 g) and ethyl acetate (500 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether (800 ml). The solid was filtered off, washed with diethyl ether (500 ml) and with hexane (500 ml) and dried. There was thus obtained 5-acetamidoindan (104.5 g), m.p. 107° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH3:21])=[CH:16][CH:15]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(F)cc1
Product: Cc1nc(N(C)c2ccc(F)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol) and (4-fluoro-phenyl)-methyl-amine (125 mg, 2.52 mmol) by a procedure similar to Example 28 (46.8%). 1H NMR (CDCl3): 7.76 (dd, J=0.9 Hz, J=8.3 Hz, 1H), 7.58-7.52 (m,1H), 7.16-7.00 (m, 6H), 3.60 (s, 3H), 2.73 (s, 3H),
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[N:19][C:14]2=[N:13][C:12]=1[C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23].Cl[C:35](OC(Cl)(Cl)Cl)=[O:36]>O1CCOCC1>[Cl:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=1[NH:10][C:11]1[N:15]2[CH:16]=[CH:17][CH:18]=[N:19][C:14]2=[N:13][C:12]=1[C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:21]=1[C:22]1[O:23][C:35](=[O:36])[NH:25][N:24]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NN)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(-c2n[nH]c(=O)o2)c1

Procedure:
115 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzohydrazide hydrochloride and 26 μl of trichloromethyl chloroformate (diphosgene) are heated under reflux for 2 hours in 5 ml of dioxane. The reaction mixture is evaporated, and water and DCM are added. The aqueous phase is rendered neutral, extracted a number of times with DCM, and the combined organic phases are dried and evaporated. Purification by column chromatography (ethyl acetate/methanol) and washing of the resultant solid by stirring with heptane gives 35 mg (33%) of “A6”; MS-FAB (M+H+)=499.4; Rf (polar method): 1.61 min.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:13]>CN(C)C=O>[CH3:13][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Pyrrolo[2,3-b]pyridine (2.00 g, 16.93 mmol) is dissolved in dimethylformamide (15.0 ml) under an argon atmosphere. Sodium hydride (60% in oil) (0.96 g, 40.0 mmol, 1.5 equiv.) is added at 0° C. over a period of 30 minutes. After 30 minutes' stirring at 0° C., iodomethane (1.49 ml, 24.02 mmol, 1.5 equiv.) is added dropwise. After returning to room temperature, the reaction mixture is stirred for 1 hour. The dimethylformamide is evaporated off under reduced pressure, and the product is taken up in water and extracted with dichloromethane. Purification on a silica column (petroleum ether/ethyl acetate 7/3) allows isolation of the title compound in the form of an oil in a yield of 99%. ##STR31##
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[C-:38]#[N:39].[K+].O>CN(C)C=O>[OH:19][C:5]1[CH:4]=[C:3]([CH2:2][C:38]#[N:39])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=1
Reactant: Oc1ccc(-c2nc3cc(O)cc(CBr)c3o2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 7-(bromomethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (122 mg, 0.40 mmol) in N,N-dimethylformamide (1.5 mL) was added 18-crown-6-ether (202 mg, 0.80 mmol) and potassium cyanide (131 mg, 2 mmol). The reaction mixture was allowed to stir for 2 h and then poured into water and extracted with EtOAc. The organic extracts were washed with brine and dried over MgSO4. Evaporation and flash chromatography (50%-60% EtOAc/petroleum ether) gave (80 mg, 75% yield) of the product as a gray solid, m.p. 170-180° C.; MS m/e 265 (M−H)+. Analysis for C15H10N2O3×1.5H2O
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of isatoic anhydride (20 g, 122 mmol) in dimethylformamide (DMF) was added to a suspension of NaH (60% in mineral oil, 5.39 g, 135 mmol) in DMF and stirred at room temperature for 1 h. Then, 4-fluorobenzyl bromide (16.8 mL, 135 mmol) was added and the mixture stirred at room temperature for 4 h. The solution was poured into water and the solids formed were filtered, washed several times by water and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 30 g (90%) of white solids. M.P. 167° C. 1H NMR (DMSO-d6): δ 5.27 (s, 2H), 7.17 (t, J=8.8 Hz, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.47 (m, 2H), 7.74 (t, J=7.0 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H). Anal. (C15H10FNO3) C, H, N.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[CH:12]=[N:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2]1.CC(C)([O-])C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1>O1CCCC1.O>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:13][CH:12]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=2)[C:11]2[CH:27]=[CH:28][CH:29]=[CH:30][C:10]=2[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(CC(N=C(c2ccccc2)c2ccccc2)c2ccccc2-c2noc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to -65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1 M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystalised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=2)[C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 84 (179 mg, 0.438 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was recrystallized (EtOAc:hexanes) to afford 120 mg (78%) of 85 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (br s, 6H), 2.13 (m, 4H), 6.45 (d, J=16.0 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 6.76 (dd, J=12.3 Hz, 1.7 Hz, 1H), 6.85 (t, J=8.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H) 9.76 (s, 1H), 12.31 (br s, 1H). LRMS (ESI): m/z 353 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][N:3]=1.[CH3:11][CH:12]1[CH2:24][C:16]2[N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[S:19][C:15]=2[C:14](=[O:25])[CH2:13]1>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([CH:13]2[CH:12]([CH3:11])[CH2:24][C:16]3[N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[S:19][C:15]=3[C:14]2=[O:25])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Reactant: O=C(Cl)c1ccc(F)nc1
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C(=O)c1ccc(F)nc1)C(C)C2

Procedure:
A-16 is prepared via general procedure A1 starting from 2-fluoropyridine-5-carbonyl chloride (4.27 g, 26.8 mmol) and N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06) (5.00 g, 22.3 mmol). Yield: 6.20 g. HPLC-MS: tR=0.93 min, (M+H)+=348.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]([F:34])([F:33])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH:29]([F:34])[F:33])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OC(F)F)cc21
Yield: 32.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), sodium chlorodifluoroacetate (253 mg), K2CO3 (172 mg), DMF (3 mL), and water (0.60 mL) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-40% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (110 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])O.[Na+:38].O.[H][H]>C1COCC1.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)[CH3:2].[Na+:38]
Reactant: [H][H]
Reactant: CCOc1ccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 3 h
Yield: 42 %

Procedure:
4-Nitrobenzyl (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.39 g) prepared in accordance to the method described in Tetrahedron Letters, 34, 3211-3214 (1993)] was dissolved in THF (28 mL), and thereto were added under ice cooling sodium hydrogencarbonate in ion-exchange water (28 mL), and 10% palladium-carbon [50% water] (0.14 g). Then the atmosphere was changed with a hydrogen gas, and the mixture was stirred at the same temperature for 3 hours. After filtration of the insoluble materials with Celite, to the filtrate was added chloroform (80 mL). The organic layer was separated, and extracted with ion-exchange water (20 mL). The organic solvent in the aqueous solution separated and extracted was removed over one hour period in vacuo, purified with C18 reverse column chromatography (Wakosil C18 reverse column, mobile phase; ion-exchange water/THF) and lyophilized to give sodium (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.44 g, yield 42%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16]2([CH3:17])[O:21][CH2:20][CH2:19][O:18]2)[CH:3]=1
Reactant: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2cc(CCC3(C)OCCO3)cc(F)c2c1
Temperature: 25 °C
Yield: 53 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)butan-2-one (4.2 g), ethane-1,2-diol (30 ml) and toluene-4-sulphonic acid (0.2 g) were heated under reflux in benzene for 18 hours with continuous removal of water by means of a Dean-Stark trap. The solution was then cooled to room temperature and sodium hydrogen carbonate solution was added. The aqueous layer was washed with ether. The combined organic layers were washed with water and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave a crude product which was dissolved in 60-80 petroleum ether. The precipitated impurities were removed by filtration and the solvent was removed under reduced pressure to give a yellow oil which was triturated with cold 40-60 petroleum ether to give the title compound as pale yellow crystals (2.6 g., 53%; m.p. 51°-53°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11].O.[OH-].[Li+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)CCc1ccc2c(c1)CCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CC(=O)N2CCCc3cc(CCC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 20 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
A solution of ethyl 3-(1-{[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-1,2,3,4-tetrahydroquinolin-6-yl)-propanoate (0.24 g, Reference Example 1) in anhydrous ethanol (4 ml), at 20° C., was treated dropwise with a solution of lithium hydroxide monohydrate (33 mg) in distilled water (1 ml). After stirring for 3 hours at 20° C. the reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. The residue was treated with distilled water (35 ml) and the resulting solution was washed twice with diethyl ether (20 ml), then acidified to pH 3 by addition of hydrochloric acid (0.8 ml, 1N) and then extracted twice with ethyl acetate (25 ml). The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulfate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (191 mg) was subjected to chromatography on silica gel plates (4 plates, 20×20 cm, thickness=0.5 mm), eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound (148 mg) as a white foamy solid. 1H NMR (300 MHz, (CD3)2SO): δ 1.81 (m, 2H); 2.27 (s, 3H); from 2.45-2.70 (m, 4H), 2.82 (t, J=7.5 Hz, 2H); 3.72 (t, J=6.5 Hz, 2H); 3.82 (s, 2H); 3.87 (s, 3H); 6.60-7.50 (m, 8H); 7.82 (d, J=8 Hz, 1H); 8.05 (d, J=8 Hz, 1H); 8.50 (s, 1H); 8.60 (s, 1H). MS (Electron Impact recorded on a Finnigan SSQ 7000 spectrometer at 70 eV) 501 (M+).