Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=1)=[O:32]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C:34]([CH3:36])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]([CH3:36])[CH3:33])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.069 mmol) in 10 mL of dichloromethane is added 1 mL of acetone and NaB(OAc)3H (30 mg, 0.138 mmol). The resulting mixture is stirred at room temperature for 18 h. Following purification by preparative LCMS gave 7-cyclopentyl-2-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 61%). MS (ESI) m/z 477.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:17][O:16][CH2:15][CH2:14][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1ccc2ccc(C)nc2c1
Temperature: 70 °C
Yield: 56.6 %

Procedure:
A mixture of 2-methylquinolin-7-ol (0.20 g, 1.3 mmol), 1-bromo-2-methoxyethane (0.24 mL, 2.5 mmol) and potassium carbonate (0.52 g, 3.8 mmol) in acetone (5.0 mL, 1.3 mmol) was heated at 70° C. for 12 hours. The cooled reaction mixture was diluted with water (10 mL) extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-50% ethyl acetate/hexanes) to provide title compound (0.16 g, 60%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH2:10][C:9]1([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)COCC(=O)N1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)COCCN1Cc1ccccc1
Temperature: 0 °C

Procedure:
Dissolve methyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate in THF (10 volumes) and cool to 0° C. Add borane dimethylsulfide complex (1.5 eq) and allow to warm to room temperature. Add water (5 volumes) followed by EtOAc (10 volumes). Separate the organic layer, wash with saturated aqueous NaCl, dry over sodium sulfate, filtered, and concentrate to give methyl 4-benzyl-3-methylmorpholine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1>NCCCCO>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:9][CH2:21][CH2:20][CH2:15][CH2:16][OH:22])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Agent: NCCCCO
Product: Cc1cc(F)ccc1N1CCc2c(NCCCCO)nc3c(OC(F)(F)F)cccc3c21
Yield: 133.5 %

Procedure:
1-(2-methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydro-pyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in 4-amino-1-butanol(5 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 16 to obtain 390 mg of desired compound as solid in 74% of yield.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16]([O:19][CH2:20][CH2:21]Cl)[CH2:17][Cl:18]>C(OCCCC)CCC>[Cl:18][CH2:17][CH2:16][O:19][CH2:20][CH2:21][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClCCOCCCl
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: ClCCOCCN(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A mixture of sodium hydride (0.70 g, 0.023 mol, 80% oil dispersion) and diphenylamine (3.4 g, 0.020 mol) in dry dibutylether (30 ml) was heated at reflux temperature for 1 h under an atmosphere of nitrogen. The reaction mixture was cooled to 50° C. and 2,2'-dichlorodiethylether (10 ml) was added and the mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled, filtered and the volatile components were removed in vacuo leaving 4.6 g of crude 2-chloro-1-(2-(diphenylamino)ethoxy)ethane as an oil. This oil was dissolved in dry dibutylether (10 ml) and ethyl (R)-3-piperidinecarboxylate (3.7 g, 0.024 mol) and potassium carbonate (3.3 g, 0.024 mol) were added. The mixture was heated at reflux temperature for 2 h under an atmosphere of nitrogen and then stirred overnight at room temperature. Ethyl acetate (50 ml) was added, the mixture was filtered and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (150 g) using a mixture of n-heptane and THF (4:1) as eluent. This provided 3.8 g (48% calculated from diphenylamine) of the title compound as an oil. TLC: rf=0.22 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: Cl[C:2]1[CH:18]=[N:17][C:5]2[S:6][CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:62]1[CH2:63][CH2:64][N:59]([C:2]2[CH:18]=[N:17][C:5]3[S:6][CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]=3[CH:3]=2)[CH2:60][CH2:61]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCSc2ncc(Cl)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCSc2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure N by using tert-butyl 7-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-1-carboxylate (340 mg, 1.19 mmol), Pd2dba3 (109 mg, 0.119 mmol), XPhos (113 mg, 0.237 mmol), sodium ter-butoxide (228 mg, 2.371 mmol), morpholine (0.13 mL, 1.54 mmol) in toluene (8 mL) at 100° C. for 14 h. Purification by column chromatography (hexanes:EtOAc, 1:0 to 1:1) gave tert-butyl 7-morpholino-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-1-carboxylate. Mass Spectrum (ESI) m/e=338.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[NH2:29][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step (e) using N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)-2-oxoethyl](tert-butoxy)-carboxamide (Step f) (250 mg, 0.50 mmol) and a saturated soln of HCl in EtOAc (10 mL). The title compound (HCl salt) was isolated by filtration as a white solid (195 mg, 83%). MS (ESI, pos. ion) m/z: 473 (M+1). Calc'd for C21H27Cl2N3O3S: 472.43.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:3]=1.[Si]([N:25]=[N+:26]=[N-:27])(C)(C)C>C1(C)C=CC=CC=1>[N:18]1[NH:25][N:26]=[N:27][C:17]=1[C:16]1[CH:19]=[CH:20][C:13]([C:4]2[CH:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(-c2cc(Cl)c3cc(O)ccc3n2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc2nc(-c3ccc(-c4nn[nH]n4)cc3)cc(Cl)c2c1
Yield: 13.4 %

Procedure:
Followed Scheme 4, route A. To a solution of 4-(4-chloro-6-hydroxyquinolin-2-yl)benzonitrile (65 mg, 0.23 mmol) in toluene (2 mL), was added TMSN3 (455 mg, 4.18 mmol) and Bu2SnO (15 mg, 0.069 mmol) at room temperature. The mixture was heated to reflux overnight. The volatiles were removed under reduced pressure. The residue was purified by prep-HPLC to afford Compound 11 (10 mg, 13.5%). 1H NMR (MeOD-d4, 500 MHz): δ 8.34 (d, J=8.5 Hz, 2H), 8.21 (s, 1H), 8.19 (s, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.47 (dd, J=2.5 Hz, J=9.5 Hz, 1H). MS (ESI): m/z 324.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH3:20][C:21]([CH3:26])=[CH:22][C:23](=O)[CH3:24]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]3[N:1]=[C:23]([CH3:24])[CH2:22][C:21]([CH3:26])([CH3:20])[N:6]3[N:5]=2)=[CH:8][CH:9]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CC(=O)C=C(C)C
Product: CC1=Nc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2C(C)(C)C1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and 4-methyl-3-penten-2-one (5 ml) was refluxed for 5 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethyl acetate and hexane to give 6,7-dihydro-2-(4-fluorophenyl)-3-(pyridin-4-yl)-5,7,7-trimethylpyrazolo[1,5-a]pyrimidine (83 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:28]=[CH:27][C:19]2[C:20]([C:23]([O:25]C)=[O:24])=[CH:21][O:22][C:18]=2[CH:17]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:28]=[CH:27][C:19]2[C:20]([C:23]([OH:25])=[O:24])=[CH:21][O:22][C:18]=2[CH:17]=1
Reactant: COC(=O)c1coc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)coc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Methyl 6-(6,7-dimethoxyquinolin-4-yloxy)benzofuran-3-carboxylate (102 mg, 0.269 mmol) was dissolved in dioxane (1.6 mL) and water (0.5 mL), then added 2N aqueous sodium hydroxide (141 □L). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo then diluted with water. The aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified with aqueous 1N hydrochloric acid (282 μL) and the precipitate was collected, washed with water and dried under high vacuum to give 6-(6,7-dimethoxyquinolin-4-yloxy)benzofuran-3-carboxylic acid as a light yellow solid (65 mg). MS (ESI, pos. ion) m/z: 366.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:24]#[N:25])=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.C([O-])=O.[NH4+]>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:24]#[N:25])=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c(C#N)cc3c(N)ncnn23)CC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#N)cc3c(N)ncnn23)CC1
Temperature: 65 °C
Yield: 35.2 %

Procedure:
To a solution of tert-butyl 4-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (160 mg, 0.47 mmol) in MeOH (32 mL) and EtOAc (16 mL), was added Pd(OH)2 (164 mg, 0.118 mmol) followed by ammonium formate (592 mg, 9.40 mmol). The mixture was heated at 65° C. for 1.5 h then cooled to rt. The mixture was filtered through Celite® and the cake was washed with EtOAc (10 mL) and MeOH (10 mL). The filtrate was concentrated to dryness. ISCO® purification (50% EtOAc/Hexane) afforded pure product (56.6 mg, 35%). 1H NMR (400 MHz, DMSO-d6 δ 8.08 (s, 2H), 7.98 (s, 1H), 7.23 (s, 1H), 4.12-4.04 (m, 4H), 3.59-3.50 (m, 1H), 1.98-1.78 (m, 4H), 1.41 (s, 9H); LC-MS m/z[M+H]+ 343.1, RT 3.05 min.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23])=[O:4].[OH-].[Na+].[CH:26]([O:28][CH2:29][CH2:30][O:31][NH2:32])=[CH2:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C>[CH:26]([O:28][CH2:29][CH2:30][O:31][NH:32][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23])=[O:4])=[CH2:27]
Reactant: C=COCCON
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(SC)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(SC)cc1F
Temperature: 65 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of 8-(2-fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (136 mg, 0.41 mmol) in IMS (10 mL) was added a 1.0 M aqueous solution of sodium hydroxide (0.82 mL, 0.82 mmol). The reaction mixture was heated at 65° C. for 1 hour and then cooled to room temperature and concentrated in vacuo. The resultant residue was azeotroped with toluene, and then suspended in THF (10 mL). O-(2-Vinyloxy-ethyl)-hydroxylamine (84 mg, 0.82 mmol), N-N-diisopropylethylamine (0.28 mL, 1.64 mmol), EDCI (157 mg, 0.82 mmol) and HOBt (111 mg, 0.82 mmol) were then added sequentially, before the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in dichloromethane) to afford the title compound as a pale yellow oil (160 mg, 97%). LCMS (method B): RT=2.91 min, [M+H]+=403.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([C:11]2[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[C:22](=[O:24])[CH3:23])=[CH:6][CH:7]=1
Reactant: Fc1cccc2c(NCCc3ccc(Cl)cc3)ccnc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(CCc1ccc(Cl)cc1)c1ccnc2c(F)cccc12

Procedure:
A mixture of 2.0 g of N-[2-(4-chlorophenyl)ethyl]-8-fluoro-4-quinolinamine and 5.0 mL of acetic anhydride was refluxed overnight. The mixture was then cooled, and solvents were removed by reducing pressure. The residue was washed with water and then dried. The resulting oil was passed over a silica gel column with ethyl acetate, and the front running spot was collected, producing 0.8 g of the title product as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[OH-:42].[Na+].[BH4-].[Na+]>C1COCC1.O.C1COCC1.[Hg](OC(C)=O)OC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)([OH:42])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Reactant: [OH-]
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)CCCCC(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
To a solution of 6,6-bis-(4-fluoro-phenyl)-1-[4-(3,4,5,-trimethoxy-benzoyl)-piperazin-1-yl]-hex-5-en-1-one (1.62 g, 2.87 mmol) in dry THF (20 ml) a solution of Hg(OAc)2 (0.9 g, 2.87 mmol) in water:THF (1:1, 6 ml) was added. The mixture was then refluxed overnight. NaOH (3M, 3 ml) was added followed by addition of NaBH4 (54 mg, 1.43 mmol). The mixture was stirred for 4 hrs and separated organic layer was saturated with NaCl
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17](=[O:26])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:13]N(C)C)=[CH:8][CH:7]=1)([OH:3])=[O:2].Cl.[OH-:28].[K+]>>[OH:19][C:18]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=2)=[CH:13][O:28]1
Reactant: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(CCC(=O)O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)CCc1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3.95 g of 2-[4-(2-carboxyethyl)phenyl]-1-dimethylamino-4-phenyl-1-butene-3,4-dione in 100 ml of 2% potassium hydroxide solution was stirred at room temperature for 31/2 hrs. The reaction mixture was poured onto 300 ml of ice-water, acidified with 100 ml of 1 N hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried, filtered, and evaporated. Recrystallization of a sample of the residue from methylene chloride-petroleum ether gave 2-hydroxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone as colorless crystals, m.p. 89°-95° dec., after drying at 50° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10](Cl)[C:11]([CH3:13])=[CH2:12])(=[O:3])[CH3:2].C([N+]([O-:23])(CC)CC)C.O1CCOCC1>[Cu]Cl.O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH:12]=[O:23])(=[O:3])[CH3:2]
Reactant: C=C(C)C(Cl)CCC(C)=CCOC(C)=O
Reactant: CC[N+]([O-])(CC)CC
Agent: Cl[Cu]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCC=C(C)CCC=C(C)C=O
Reaction time: 10 h
Yield: 61.2 %

Procedure:
2.36 g (9.41 mmols) of 6-chloro-3,7-dimethyl-2,7-octadienyl acetate (purity: 92%), 92 mg (0.93 mmols) of copper(I) chloride and 3.65 g (29.6 mmols) of triethylamine N-oxide (purity: 95%) were placed in a flask, to which 5 ml of dioxane was added, followed by agitation of the mixture at 50° C. for 10 hours. 40 ml of water was added to the reaction mixture, after which it was extracted twice each with 70 ml of diethyl ether. The resultant extract was successively washed with each 20 ml of 3% sulfuric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated ammonium chloride aqueous solution, and dried with magnesium sulfate. The solvent was distilled off from the solution and the resultant residue was purified by column chromatography using silica gel [eluent: ethyl acetate/hexane (ratio by volume)=1/9-1/3], thereby obtaining 1.21 g of 8-acetoxy-2,6-dimethyl-2,6-octadienal. Yield: 61%. The results of the instrumental analysis were found to be substantially coincident with those obtained in Example 9(b).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C@H:44]5[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.030 g (0.20 mmole) of trans-4-amino-cyclohexanol hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.2 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.077 g of trans-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-cyclohexyl)-3-methoxy-benzamide (I-69) as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C:19](=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C:19](=[N:2][OH:3])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(=NO)C1
Yield: 68.5 %

Procedure:
1.87 g of hydroxylamine hydrochloride and 3.3 ml of pyridine were added to a solution of 2.0 g of 1-(t-butoxycarbonyl)-3-pyrrolidone in 9 ml of ethanol, and the mixture was refluxed for 2 hours. The solvent was then distilled off from the reaction mixture, saturated aqueous sodium bicarbonate solution was added to the residue, and it was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column, using a 2/1 mixture of benzene and ethyl acetate as eluent, giving 1.482 g of 1-(t-butoxycarbonyl)-3-hydroxyiminopyrrolidine as a mixture of syn- and anti-isomers.