Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C@H:8]([C:18](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:19])[C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[OH:33]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C@H:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][CH3:11])[C:18]([OH:19])=[O:33])=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: CC[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: -10 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of [(1S,2S)-1-((S)-2-oxo-4-phenyl-oxazolidine-3-carbonyl)-2-phenyl-butyl]-carbamic acid tert-butyl ester (4.38 g, 10 mmol) in a mixture of tetrahydrofuran and water (3:1, 60 mL) at −10° C. was added sequentially a solution of hydrogen peroxide in water (11 mL, 100 mmol, 30%) and an aqueous solution (15 mL) of lithium hydroxide monohydrate (1.23 g, 30 mmol). The reaction mixture was stirred at −10° C. and the progress of the reaction was monitored by thin layer chromatography. After 3 hours, TLC analysis indicated almost complete consumption of starting material. Saturated aqueous sodium sulfite solution (100 mL) was added. The mixture was concentrated to half of its original volume under reduced pressure to remove tetrahydrofuran and then extracted with dichloromethane (2×100 mL). The aqueous layer was separated, acidified to pH=2-3 with aqueous citric acid solution and extracted with ethyl acetate (2×300 mL). The organic layers were separated, combined and dried over sodium sulfate, concentrated under reduced pressure and dried in vacuo to give (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-pentanoic acid as a white foam (1.7 g, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O

Procedure:
With the exception that N-t-butoxycarbonyl-cis-4-(t-butyldimethylsilyl)oxy-L-prolinol, instead of N-t-butoxycarbonyl-L-prolinol, was used, the same procedure as in Preparation Example 1-1 was repeated to afford the title compound. 3.8 g (52%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.C(Cl)Cl>C(O)C.[Pd]>[CH3:1][CH:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C1OC(=O)C=C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1OC(=O)C=C1c1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
A solution of 5-methylene-4-phenyl-2(5H)furanone (2.63 mmol) in ethanol (50 mL) containing Pd—C (25 mgs; 5%) was hydrogenated under an atmosphere of hydrogen at room temperature for 24 hr. The catalyst was filtered off using a pad of Celite and the solvent evaporated in vacuo, leaving a colourless semi-solid, which upon flash chromatography using (EtOAc, CH2Cl2; 1:5) as the eluent gave 5-methyl-4-phenyl-2(5H)furanone 27 as a semi-solid in 90% yield. 1H NMR: δ(CDCl3) 3.33 (d, J 4 Hz, 3H, C5-Me), 5.56 (q, J 4 Hz, 1H, C5-H), 6.26 (s, 1H, C3-H) and 7.47 (s, 5H, Ar H's). 13C NMR: 19.71, 65.85, 66.39, 113.67, 127.11, 129.14, 129.87, 131.20 168.79, 172.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]#[C:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(C#CCN2CCCCC2)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCCN2CCCCC2)ccc1N
Reaction time: 8 h
Yield: 59.4 %

Procedure:
1-{3-[3-(methyloxy)-4-nitrophenyl]-2-propyn-1-yl}piperidine (0.29 g, 1.06 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.284 g, 0.07 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.156 g, 0.63 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 6.56-6.64 (m, 3H), 3.83 (s, 3H), 3.40-3.75 (m, 2H), 2.50 (dt, J=19.14, 7.55 Hz, 4H), 2.37-2.45 (m, 2H), 1.86 (dt, J=15.29, 7.74 Hz, 1H), 1.63-1.70 (m, 2H), 1.59 (ddd, J=14.97, 7.55, 1.10 Hz, 2H), 1.45 (s, 1H), 0.92 (td, J=7.33, 1.10 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:4][C:5]([S:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[C:6]([N:8]([CH2:14][CH3:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:7]=1.[C:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:14]([N:8]([C:6]1[CH:7]=[C:2]([N:43]2[CH2:44][CH2:45][N:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:41][CH2:42]2)[C:3]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:4][C:5]=1[S:16]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)(=[O:18])=[O:17])[CH2:9][CH2:10][N:11]([CH3:12])[CH3:13])[CH3:15]
Reactant: CCN(CCN(C)C)c1cc(Cl)c(S(=O)(=O)N2CCCCC2)cc1S(=O)(=O)N1CCCCC1
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCN(CCN(C)C)c1cc(N2CCN(c3ccccc3)CC2)c(S(=O)(=O)N2CCCCC2)cc1S(=O)(=O)N1CCCCC1
Temperature: 90 °C
Reaction time: 9 h

Procedure:
2.63 g (5.1 mmol) of N-[5-chloro-2,4-bis-(piperidine-1-sulfonyl)-phenyl]-N-ethyl-N′,N′-dimethylethane-1,2-diamine, prepared as described below, are dissolved in 12 ml of 4-phenylpiperazine, and the reaction mixture is stirred at 90° C. for 9 hours. Workup entails extraction with ethyl acetate/water, drying of the combined organic phases over sodium sulfate, and removing the extractant under reduced pressure in a rotary evaporator. This is followed by purification by chromatography on silica gel (40-63μ, Merck Darmstadt; mobile phase=dichloromethane/methanol=20/1).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[CH:35][C:36]=1[Cl:37]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH2:39][CH2:38][C:33]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:31]([Cl:30])[CH:32]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2ccc(Cl)c(Cl)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(3,4-Dichloro-phenyl)-ethylamine. MS (ESI): 503.1 (MH+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=3)[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][CH2:55][CH3:56])=[CH:52][CH:53]=3)[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 1f (84.1 g, 102.1 mmol) in tetrahydrofuran (400 mL) was added tetrabutylammonium fluoride (53.4 g, 204.2 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours and quenched with 100 mL of saturated aqueous sodium bicarbonate. The resulting mixture was washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 1g as yellow oil (56.3 g, 77.8%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.34 (m, 13H), 7.25 (m, 3H), 7.04 (m, 2H), 6.99 (m, 2H), 6.77 (m, 2H), 4.90 (m, 3H), 4.69 (d, 1H), 4.49 (d, 1H), 4.16 (t, 1H), 4.10 (d, 1H), 4.00 (m, 2H), 3.98 (m, 2H), 3.81 (m, 1H), 3.70 (m, 1H), 3.68 (m, 1H), 3.66 (m, 1H), 3.29 (d, 1H), 3.06 (s, 3H), 1.75 (bs, 1H), 1.38 (t, 3H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:19]#[N:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].CO[Na].CO>>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:7])[N:9]=1)#[N:20]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccccc2c1O
Reactant: NCC(=O)O
Agent: CO[Na]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccccc12
Reaction time: 48 h
Yield: 80.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (89 mg, 0.33 mmol), glycine (375 mg, 5 mmol), and a 0.5 N solution of MeONa in MeOH (8 mL, 4 mmol) was refluxed with stirring for 48 h before it was concentrated in vacuo. The residue was dissolved in water (20 mL). The solution was washed with diethyl ether before its pH was adjusted to 2 to 3 by addition of aqueous 6 N HCl. The resulting suspension was extracted with ethyl acetate (1×30 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish solid (72 mg); MS-(−)-ion: M−1=270.2.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[C:8]2[C:9]([CH3:15])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[CH2:6][CH:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:4]1.[Br:22]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:22][C:11]1[CH:10]=[C:9]([CH3:15])[C:8]2[CH:3]([CH2:2][Br:1])[O:4][CH:5]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:6][C:7]=2[C:12]=1[O:13][CH3:14]
Reactant: BrBr
Reactant: COc1ccc(C)c2c1CC(C1CCCCC1)OC2CBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(Br)cc(C)c2c1CC(C1CCCCC1)OC2CBr
Yield: 55 %

Procedure:
A solution of 2.04 g (5.8 mmol) of 1-bromomethyl-3-cyclohexyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benxopyran (the product of Step 2 of Example 33) in 20 mL of dry methylene chloride was cooled to 0° C. and treated with 0.38 mL (7.4 mmol) of bromine. The resultant solution was stirred for 25 minutes at 0° C. and then poured into 30 mL of a saturated aqueous solution of sodium bisulfite. The cloudy mixture was extracted with 200 mL of diethyl ether and the organic extract was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from hexane/ether to afford 1.36 g (55% yield) of the title compound.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].C1C2C(=CC=CC=2)C=CC=1N[C:17](=[O:24])[C@H:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH2:19]>CS(C)=O>[NH2:19][C@H:18]([C:17]([OH:24])=[O:2])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccc2ccccc2c1
Reactant: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 72 h

Procedure:
Assay mixtures were prepared containing 0.613 μg LAPM, 10 μg/mL bovine serum albumin (BSA). 0.1M phosphate buffer, pH 7.2, in a total volume of 2.7 mL. Measured amounts of compounds 5 to be tested for inhibitory activity were added in additional 0.1M phosphate buffer to a total volume of 3 mL. After 72 hours at 0°-5°, 1 mL of the enzyme/inhibitor mixture was treated with 4 μL of 0.2M (L)-leucine-β-napthylamide in dimethylsulfoxide, and the rate of increase of fluorescence at 410 nm, while exciting at 310 nm. was measured. Control experiments were performed identically, except no inhibitor was present. The concentration of the selected compound 5 observed to decrease reaction rates by one-half was used to determine the value of IC50 for each compound. This was accomplished by subtracting one-half the concentration of enzyme present in the sample mixtures (1.6×10-9M) from the inhibitor concentration observed to decrease reaction rates by one-half. The results of these experiments are set forth in Table 2, above.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][C:10]([C:13]2[C:14]([Cl:40])=[C:15]3[C:21]([C:22]4[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=4[O:30][CH3:31])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N)CN>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:12]=[CH:11][C:10]([C:13]2[C:14]([Cl:40])=[C:15]3[C:21]([C:22]4[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=4[O:30][CH3:31])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: COc1cc(F)c(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc(N)c(C(=O)N(C)C)c3)c(Cl)c12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COc1cc(F)c(F)cc1-c1c[nH]c2ncc(-c3cnc(N)c(C(=O)N(C)C)c3)c(Cl)c12
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
2-Amino-5-[4-chloro-3-(4,5-difluoro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide (76 mg, 0.136 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 23° C. for 45 minutes. The solution was concentrated under vacuum and taken up in methanol (10 mL). Ethylenediamine (100 μL, 5.39 mmol) was added, and the mixture was stirred at 35° C. for 20 minutes. Methanol was removed under vacuum. The crude was taken up in methanol (0.5 mL) and water (1 mL) was added. The resulting precipitate was collect by filtration to afford 2-Amino-5-[4-chloro-3-(4,5-difluoro-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide (49.6 mg, 0.108 mmol, 80% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.18 (s, 1H), 8.05 (d, 1H), 7.56 (s, 1H), 7.47 (d, 1H), 7.35 (m, 1H), 7.15 (m, 1H), 6.15 (s, 2H), 6.68 (s, 2H), 2.95 (s, 6H); MS [MH+] m/z: 458.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]([CH3:32])=[CH2:31])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:28]#[C:29][C:30]([CH3:32])=[CH2:31])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: C=C(C)C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 80.1 %

Procedure:
1.86 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.8 g of 1-tributylstannyl-3-methyl-but-3-en-1-ine and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 6 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is filtered under hot conditions and concentrated, and the residue is stirred with hexane. After filtration with suction and drying, 1.43 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate are obtained (80% of theory).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][C:9]=1[O:18][CH3:19].[C:20]([CH2:22][C:23]([N-:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:34])[CH:28]=1)=[O:24])#[N:21]>C(O)C>[OH:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[OH:33])[CH2:26][NH:25][C:23](/[C:22](=[CH:14]/[CH:13]=[CH:12]/[C:11]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([O:18][CH3:19])[CH:10]=1)/[C:20]#[N:21])=[O:24]
Reactant: COc1cc(C=CC=O)ccc1O
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccc(O)c(O)c2)ccc1O

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 4-hydroxy-3-methoxycinnamaldehyde (35 mg, 0.2 mmol) and N-(cyanoacetyl)3,4-dihydroxybenzylamide (40 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (53 mg, 72%). The product gave the following analytical data:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:14][C:12]=2[CH:13]=1.O1CCCC1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH2:21][OH:22])[CH:24]=[CH:25][CH:26]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)O)c3)ccc2o1
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(CO)c3)ccc2o1
Temperature: 60 °C
Yield: 13 %

Procedure:
The product from Example 144 (167 mg, 0.48 mmol) was dissolved into 1 M BH3 in tetrahydrofuran (2 mL, 2 mmol), stirred at room temperature overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc. The organic phase was separated and washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and chromatographed through a short column of silica with a gradient of 0 to 5% MeOH/CH2Cl2, and through a second short column of silica with a gradient of 0 to 5% MeCN/CH2Cl2, collecting and concentrating the material with a mass ion corresponding to a borane complex. This residue was dissolved in methanol (1.5 mL), treated with 0.1 M aqueous hydrochloric acid (0.3 mL), heated at 60° C. for three hours, treated with more 0.1 M aqueous hydrochloric acid (0.1 mL), heated at 60° C. for one hour, concentrated, and chromatographed through a short column of silica with a gradient of 2 to 10% 2 M NH3 in MeOH/CH2Cl2 to provide the title compound as a white powder (13% yield). MS (ESI APCI) m/z 336 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.18 (s, 3H), 1.38-1.53 (m, 1H), 1.73-1.87 (m, 2H), 1.94-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.41-2.60 (m, 2H), 2.94-3.14 (m, 2H), 3.19-3.34 (m, 2H), 4.68 (s, 2H), 6.60 (s, 1H), 7.28-7.34 (m, 1H), 7.40 (dd, 1H), 7.46-7.49 (m, 2H), 7.52 (ddd, 1H), 7.62 (s, 1H), 7.73 (dd, 1H).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C([O:12][C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:24][N:23]([C:25]3[C:26]([F:33])=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=3)[CH2:22]2)=[CH:15][CH:14]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.ClCCl>[F:33][C:26]1[C:27]([CH2:31][OH:32])=[CH:28][CH:29]=[CH:30][C:25]=1[N:23]1[CH2:22][CH:21]([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13](=[O:12])[N:18]([CH3:1])[CH:17]=2)[CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)Oc1ccc(OCC2CN(c3cccc(CO)c3F)C2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(OCC2CN(c3cccc(CO)c3F)C2)ccc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (0.5 ml) was added to a mixture of [3-(3-{[(6-tert-butoxypyridin-3-yl)oxy]methyl}azetidin-1-yl)-2-fluorophenyl]methanol (146 mg) and dichloromethane (1 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (CHCl3/methanol). The purified product thus obtained was mixed with DMF (2 ml), and potassium carbonate (100 mg) and methyl iodide (68 mg) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added to the residue. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/methanol) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}methoxy)-1-methylpyridin-2(1H)-one (82 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[C:12](=[O:29])[NH:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CN(C)C=O.O>[C:38]([O:37][C:35]([C:34]1[CH:33]=[C:32]([CH:44]=[CH:43][CH:42]=1)[CH2:31][N:11]1[C:12](=[O:29])[C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:15][CH2:14]2)[N:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:10]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2C1CCCCC1
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Sodium hydride (0.0699 g, 2.91 mol) was added portionwise at 0° C. to benzyl 1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.03 g, 2.77 mmol) in N,N-dimethylformamide (5 mL) and stirred at 0° C. for 10 minutes. tert-Butyl 3-(bromomethyl)benzoate (0.75 g, 2.77 mmol) was added dropwise at 0° C., the mixture allowed to warm to room temperature, and stirred overnight. The reaction was diluted with water and extracted with ethyl acetate. The extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as an oil (1.37 g, 88%); 1H NMR (DMSO-d6); δ0.97 (m, 1H); 1.20 (m, 4H); 1.53 (s, 9H); 1.53-1.69 (m, 9H); 2.60 (m, 1H); 3.59 (m, 2H); 3.73 (m, 2H); 4.47 (s, 2H); 5.09 (s, 2H); 7.30-7.39 (m, 5H); 7.45-7.50 (m, 2H); 7.73 (m, 1H); 7.81 (m, 1H); MS for C33H43N3O5 m/z 562 (M+H)+.