Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=[O:49].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C:45]4=[O:49])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Reactant: O=C1CCCN1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nc2cnc3cc(OCCN4CCCC4=O)ccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 19 h
Yield: 65.7 %

Procedure:
A mixture of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (0.500 g, 1.76 mmol), triphenylphosphine (0.462 g, 1.76 mmol), and 1-(2-hydroxyethyl)pyrrolidin-2-one (0.200 mL, 1.77 mmol) in THF (17 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.277 mL) was added dropwise, and the reaction mixture was allowed to warm to ambient temperature and stirred for 19 hours. Solid unreacted 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (0.150 g, 0.42 mmol) was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 98:2 dichloromethane:methanol) to provide 0.456 g of 1-{2-[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}pyrrolidin-2-one an off-white, waxy solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:22]([N:29]1[CH2:35][CH2:21][CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:19]3)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)c1cnc2c(C3CCN(Cc4ccccc4)C3)cccc2c1
Yield: 32.9 %

Procedure:
3-(Phenylsulfonyl)-8-vinylquinoline (210 mg, 0.71 mmol, prepared according to WO2007039219) was reacted with benzyl methoxymethyl trimethylsilylmethyl amine (253 mg, 1.07 mmol) in dichloromethane (2 ml) in the presence of trifluoroacetic acid for 20 minutes. The solution was washed with a saturated aqueous solution of NaHCO3 solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (100% dichloromethane) to give the title compound as a colourless oil (100 mg, 33%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](/[C:16]1[C:25]([CH3:26])=[C:24]([O:27]C(=O)C)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CO.Cl>O>[CH:7](/[C:16]1[CH:25]([CH3:26])[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC/C=C/c1nc2ccccc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCC/C=C/C1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.1 %

Procedure:
30 ml of an aqueous solution of 6.30 g (45.6 mmols) of potassium carbonate was added to a solution of 2.47 g (7.60 mmols) of 2-(trans-1-nonenyl)-3-methyl-4-acetoxyquinoline, 250 ml of methanol and 50 ml of water and stirred at room temperature for 13 hours. This solution was neutralized with 1N hydrochloric acid, after which the solvent was distilled off under reduced pressure, to which 100 ml of chloroform was added, followed by washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=1:2) to obtain 1.66 g (yield 77%) of 2-(trans-1-nonenyl)-3-methyl-4-quinolone.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([CH2:12][CH2:13][CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCCc1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCCCc1ccccc1
Yield: 48 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in solution prepared in (a) was reacted as in Example 12 with 16.4 g (0.118 mole) of 3-phenyl-1-propanol (98%) using 46.4 g (0.459 mole) of triethylamine in 100 ml of additional acetonitrile followed by using the extracting, washing and concentration procedures of Example 12 through the first evaporation. The viscous, oily residue was partitioned between water and ethyl ether (300 ml each). The organic layer was separated and washed with four 200 ml portions of water, the aqueous wash being finally neutral to pH paper. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 19.5 g of a light-yellow, viscous oil which solidified on standing. The solid was recrystallized using ethyl ether and petroleum ether (bp range 30°-60° C.) to give 12.1 g (48%) of title compound as white solid, mp 56.5°-58° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=3[F:28])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH:25][C:40](=[O:41])[CH2:39][C:38]([NH:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])=[O:43])=[CH:23][C:22]=3[F:28])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(CN(C)C)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a solution of the amine 150 (334 mg, 0.85 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid (27) (355 mg, 1.70 mmol), 1-hydroxybenzotriazole (275 mg, 2.04 mmol) in dimethylformamide (8.5 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (391 mg, 2.04 mmol) and the reaction mixture was stirred at room temperature until completion of the reaction. The dimethylformamide was evaporated and the residue was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated to afford title compound 146 as a white solid (180 mg, 36% yield). 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.64 (s, 1H), 8.52-8.50 (m, 1H), 8.08-8.06 (m, 2H), 7.88 (d, J=12.9 Hz, 1H), 7.78 (m, 2H), 7.51-7.38 (m, 4H), 7.07 (s, 2H), 6.92 (m, 1H), 6.65 (m, 1H), 3.86 (s, 3H), 3.65 (s, 2H), 3.48 (s, 2H), 2.18 (s, 6H). MS (m/z): 585.2 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=C1CCC(=O)N1[O:25][C:26](=O)[CH2:27][CH:28]([C:34](=[O:56])[NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:2]([O:9][NH:10][C:26](=[O:25])[CH2:27][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:34]([NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:56])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: CCCCCC(CC(=O)ON1C(=O)CCC1=O)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(CC(=O)NOCc1ccccc1)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C

Procedure:
The coupling of fragment A and B is comprised of the following steps: (a) a solution of 14 in dimethylformide or any suitable solvent is treated with triethylamine followed by a solution of 8 in dimethylformamide or any suitable solvent to yield 3-(1-(2-(S)-benzyloxymethylpyrrolidine-1-carbonyl)-2-(S)-methylpropyl-carbamoyl)-octanoic acid tert-butyl ester 15; (b) treatment of 15 in dichloromethane with trifluoroacetic acid to yield 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl carbamoyl)-octanoic acid 16; (c) treatment of a solution 16 and hydroxysuccinamide 7 with dicyclohexylcarbodiimide or any suitable imide to afford 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methylpropylcarbamoyl)-octanoic acid 2,5-dioxo-pyrrolidin-1-yl ester 17; (d) fragment C is introduced by treatment of a suspension of O-benzylhydroxyamine hydrochloride 18 in dimethylformamide with triethylamine followed by a solution of 17 in dimethylformamide to afford N4-benzyloxy-N 1-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl)-2-pentyl-succinamide 19. (f) hydrogenating 19 with hydrogen gas and palladium hydroxide in activated carbon wherein actinonin 1 is thereby formed (Scheme 4, FIG. 3C).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]1)=[O:12].[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[C:3]([C:11]([N:13]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]2)=[O:12])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(c1cccc([N+](=O)[O-])c1O)N1CC[C@@H](O)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)N2CC[C@@H](O)C2)c1O
Yield: 62.8 %

Procedure:
A solution of 7.83 g (26 mmol, 1 eq) of (2-hydroxy-3-nitrophenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone at 84% in 100 ml of methanol was stirred at hydrogen atmospheric pressure in the presence of 728 mg (10% by weight) of palladium on carbon at 10% for 16 hours. The reaction medium was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/300G, Spot II) eluted with dichloromethane/methanol (96/4). 3.63 g of (3-amino-2-hydroxyphenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone were obtained in the form of a yellow amorphous solid. Yield=63%. SiO2/CH2Cl2 90: MeOH 10, developing with KMnO4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11]C)[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:33])C(=O)C1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:33])=[C:9]([CH3:11])[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cc1c(I)c2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of (S)-tert-butyl 2-((4-chloro-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate (1.0 g, 2.86 mmol, 1.0 eq) in DMF (20 mL), NIS (0.675 g, 3.00 mmol, 1.05 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography to afford (S)-tert-butyl 2-((4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate as white solid (1.0 g, 77% in yield) which was converted to the title compound as described in Example 30 above, LCMS m/z 519.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3C)oc2C)c1)C(=O)O
Yield: 43 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-o-tolyl-oxazole, the title compound was obtained in 43% yield as a pale brown solid. MS: (M+H)+ 419.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Li]CCCC.O1CCCC1.[CH:21]([N:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25](=[O:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)([CH3:23])[CH3:22]>C(OCC)C.C1COCC1.C(OCC)C>[CH:35]1([N:24]([CH:21]([CH3:23])[CH3:22])[C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([CH:30]([OH:31])[C:2]3[CH:7]=[CH:6][C:5]4[O:8][CH2:9][O:10][C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)N(C(=O)c1ccc(C(O)c2ccc3c(c2)OCO3)cc1)C1CCCCC1
Temperature: -20 °C

Procedure:
To a stirred solution of 4-bromo-1,2-(methylenedioxy)benzene (1.00 g, 6.0 mmol) in ethyl ether (30 mL) at 0° under an argon atmosphere is added n-BuLi (3.75 mL of 1.6 M solution in hexane). Tetrahydrofuran (10 mL) is added. The reaction mixture is cooled to -20° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (0.82 g, 3.0 mmol) in THF: ethyl ether (4:3, 35 mL) is added rapidly. The reaction is followed by thin layer chromatography until complete. The reaction is quenched at -15° C. by adding water (50 mL) and 1N HCl(20 mL). The reaction is further diluted with water (300 mL) and extracted three times with EtOAc (50 mL portions). The combined extracts are washed twice with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:25]3[N:24]([CH3:23])[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:27]4[N:26]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (85 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (96 mg).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:25]=1[NH2:26]>>[NH2:26][C:25]1[CH:27]=[CH:28][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:30][C:24]=1[F:23]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(F)c3)c(F)cn2c1=O
Yield: 9.8 %

Procedure:
Ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (149 mg, 0.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (134 mg, 0.58 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (18 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:1][C:2]1[C:3]([F:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred solution of 1-chloro-2-fluoro-benzene (13.0 g, 0.1 mol) in THF (250 mL) at −75° C. was added dropwise 2.5 M BuLi in hexane (40 mL, 0.1 mol) over 45 min. After additional stirring for 30 min at −75° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)-piperidine-1-carboxylate (21.76 g, 0.08 mol) in THF (100 mL) was added dropwise over 30 min. The mixture was allowed to warm from −70° C. to 0° C. The mixture was quenched with satd aq NH4Cl, extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (19.2 g, 70%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1H), 2.06 (m, 1H), 2.87 (m, 1H), 3.15 (m, 1H), 3.25 (m, 1H), 3.9 (m, 1H), 4.2 (m, 1H), 7.18 (m, 1H), 7.60 (m, 2H). MS (E/Z): 342 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].[C:28]1([CH2:34]C=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([CH2:15][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: O=CCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2

Procedure:
(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]acrylic acid methyl ester was synthesized starting from Intermediate 4 (350 mg, 1.13 mmol), according to the procedure described in Example 31, Step A, using phenylacetaldehyde (0.25 ml, 2.3 mmol) and NaBH(OAc)3 (360 mg, 1.69 mmol). The product was obtained as a yellow solid (378 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:34]2=[O:36])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(O)(CCNC(C)(C)c1ccc(Br)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-(4-bromophenyl)propan-2-ylamino)-5-methyl-3-phenylhex-5-en-3-ol (60 mg, 149.3 μmol) in CH2Cl2 (15 mL) was added Et3N (75.5 mg, 746.3 μmol). The mixture was cooled to 0° C. and triphosgene (44.3 mg, 149.3 μmol) was added under nitrogen. The solution was stirred at 0° C. for 1 h. The reaction was quenched with water (15 mL) and extracted with CH2Cl2 (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrate under vacuum. The residue was purified by preparative TLC (petroleum ether: EtOAc =3:1) followed by preparative HPLC to afford 3-(2-(4-bromophenyl)propan-2-yl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one. 1H NMR δ 7.45-7.26 (m, 7H), 6.78-6.73 (d, 2H), 4.81 (s, 1H), 4.59 (s, 1H), 3.33-3.27 (m, 1H), 3.05-2.95 (m, 1H), 2.60-2.44 (m, 3H), 2.28-2.18 (m, 1H), 1.65 (s, 3H), 1.59 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:32]([F:37])([F:36])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH:32]([F:37])[F:36])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(OC(F)F)nccc2c1=O
Yield: 8.5 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (50 mg, 0.123 mmol), sodium chlorodifluoroacetate (19 mg, 0.13 mmol) and potassium carbonate (34 mg, 0.25 mmol) were heated under reflux in acetonitrile (1 mL) for 6 hours. Sodium chlorodifluoroacetate (19 mg, 0.13 mmol) and acetonitrile (1 mL) were further added to the reaction solution and heated under reflux for 18 hours. After restored to room temperature, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain a low-polar compound, 2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-(difluoromethoxy)-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (4.8 mg, 9%), and a high-polar compound, 2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-(difluoromethyl)-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (11.4 mg, 21%) as a pale yellow solid.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH:10]([CH:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:11][C:12]([NH2:14])=[O:13])C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[O:34]=[C:16]1[CH:15]([CH:10]([CH2:11][C:12]([NH2:14])=[O:13])[C:9]([OH:35])=[O:8])[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1
Reactant: NC(=O)CC(C(=O)OCc1ccccc1)C1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)CC(C(=O)O)C1Cc2cn(c3ccccc23)CCCCCCNC1=O

Procedure:
A solution of (3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid benzyl ester (190 mg) in THF/EtOH (5/1, 20 mL) was hydrogenated with 10% Pd/C (170 mg) for 8 hours until TLC indicated that the starting compound was consumed. The solution was filtered through a pad of Celite. The filtrate was evaporated and recrystallized (THF/EtOAc) to give 147 mg of (3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid, melting point: 222°-226° C., MS: 604.2 (M+H)+.