Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][C:33](Cl)=[O:34])(=[O:30])[CH3:29]>>[C:28]([O:31][CH2:32][C:33](=[O:34])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: CC(=O)OCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (20 mg, 150 μmol). Yield 16 mg (70%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([NH:40][C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:44][C:45]([F:50])([CH3:49])[C:46](O)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:44][C:45]([C:49]1[N:32]([CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[C:31]2[CH:30]=[CH:29][C:28]([NH:40][C:41](=[O:43])[CH3:42])=[CH:27][C:26]=2[N:25]=1)([F:50])[CH3:46]
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
HATU (1.58 g, 4.17 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (1.00 g, 3.79 mmol) were added to a solution of 2,2-difluoropropanoic acid (0.43 g, 3.98 mmol) and DIPEA (0.80 mL, 4.55 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred overnight and the solvent was concentrated. The intermediate was heated to 80° C. for 3 h in glacial AcOH (100 mL), and the solvent was concentrated. The crude product was recovered in DCM (300 mL), washed with saturated NaHCO3 solution (3×100 mL), brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was purified by normal-phase MPLC using MeOH 5% and Acetone 10% in DCM to provide the title compound as a white solid. Yield: 1.07 g (83%); MS (ESI) (M+H)+=338.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH:13]=[CH2:14])=[C:4]([NH2:24])[N:3]=1.CN1CCOCC1.COC1N=C(OC)N=C(Cl)N=1.Cl.[CH3:44][O:45][C:46](=[O:55])[C@H:47]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[NH2:48]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:48][C@H:47]([C:46]([O:45][CH3:44])=[O:55])[CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])=[O:20])=[CH:22][CH:23]=2)[CH:13]=[CH2:14])=[C:4]([NH2:24])[N:3]=1
Reactant: C=CC(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CC(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution containing 950 mg eq) of 4-[6-(2,6-diamino-4-hydroxypyrimidin-5-yl)hex-1-en-3-yl]benzoic acid as prepared in step F, 351 mg (1.2 eq) Of N-methylmorpholine, and 10.0 ml of anhydrous dimethylformamide, was vigorously stirred at ambient temperature for 5 minutes. To this solution was added 556 mg (1.1 eq) of 2,4-dimethoxy-6-chloro-1,3,5-triazine and this mixture was then stirred at room temperature for 40 minutes. Following additipn to the solution of 351 mg (1.3 eq) of N-methylmorpholine, and 795 mg (1.3 eq) of dry dimethyl-L-glutamate hydrochloride, the mixture was continuously stirred overnight at room temperature and the solvent then removed under reduced pressure. The product was dissolved in chloroform, and extracted with saturated aqueous sodium bicarbonate to remove unreacted acid, triazine and triazinone. The organic extract was dried over magnesium sulfate, filtered and evaporated to dryness to yield the product which was further purified by flash chromatography eluting with 1:10 methanol:chloroform. M.S. m/z=485.2269 (M+, calc. for C24H31N5O6 : 485.2274). 1H-N.M.R. (CDCl3, 300 MHz): 1.03-1.35 (m, 2H, CH2 --CH2CH2); 1.62 (m, 2H, CH2 --CH--CH=); 2.15 (t, 2H, CH2 -pyr, J=7.5 Hz); 2.0-2.5 (m, 4H, 2×CH2(glu) ; 3.18 (m, 1H, CH--C=); 3.56 (s, 3H, CH3O); 3.66 (s, 3H, CH3O); 4.70 (m, 1H, CHglu); 4.8-5.0 (m, 2Holef.,); 4.89 (s (broad), 2H, NH2); 5.6-5.9 (m, 3H, NH2 +CH=CH2); 7.08 (d, 2Harom., J=8 Hz); 7.50 (m, 1H, NHglu); 7.63 (d, 2Harom., J=8 Hz); 11.25 (s (broad), 1H, NHpyr).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=O)[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:12][O:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]2=[N:3][C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: COC(=O)CCCCC(=O)Nc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Product: COC(=O)CCCCc1nc2ccc(C)nc2n1-c1ccccc1
Yield: 37.7 %

Procedure:
Method B applied to 2-chloro-6-methyl-3-nitropyridine (86 mg, 0.5 mmol) and 5-phenylcarbamoyl-pentanoic acid methyl ester (141 mg, 0.6 mmol) afforded the title compound as viscous oil (61 mg, 38%). 1H NMR (DMSO) δ 1.52-1.73 (m, 4H), 2.22 (t, J=6.8Hz, 2H), 2.48 (s, 3H), 2.75 (t, J=6.8Hz, 2H), 3.53 (s, 3H), 7.13 (d, J=8.0 Hz), 7.47-7.63 (m, 5H), 7.93 (d, J=8.0Hz).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.Cl.[NH:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:11].[CH3:18]OC(N(C)C)OC>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:10]1[C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[C:2]=2[CH:18]=[N:11]1)[CH3:17]
Reactant: CCOC(=O)CNN
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2=O
Temperature: 190 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of cyclohexane-1,3-dione (50.7 g, 452 mmol) in N,N-dimethylformamide (700 mL) was added ethyl hydrazinoacetate hydrochloride (70 g, 452 mmol). The reaction mixture was stirred for 5 minutes before addition of dimethoxymethyl-dimethyl-amine (53.9 g, 452 mmol). The reaction mixture was divided into 50 vials, which were heated in a microwave at 190° C. for 2 minutes. After cooling to room temperature, the combined reaction mixture was concentrated in vacuo to remove most of the N,N-dimethylformamide. Water (200 mL) was added, and the resulting dark brown mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined, washed with brine (600 mL), dried over sodium sulfate and concentrated in vacuo to afford a brown oil, which was placed in a fridge overnight. The resulting yellow precipitate was filtered and washed with petroleum ether to give (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (79 g, 79%) as yellow crystals. 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (s, 1 H), 4.89 (s, 2 H), 4.26 (m, 2 H), 2.80 (t, J=6.4 Hz, 2 H), 2.51 (t, J=6.4 Hz, 2 H), 2.20 (t, J=6.4 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H). MS calcd. for C11H14N2O3 222, obsd. (ESI+) (M+H)+ 223.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(-c2ccccc2)cc1
Yield: 73.5 %

Procedure:
Example 32 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 4-isocyanato-1,1′-biphenyl (0.0266 g) to give the title compound (0.0314 g). LC-MS (System A): Rt 2.65 mins, Mass Spectrum m/z 470 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)[CH:13]=[C:12]([C:25]([O:27]C)=[O:26])[CH:11]=1)#[N:2].[OH-].[Li+].Cl>O1CCCC1>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]2)[CH:13]=[C:12]([C:25]([OH:27])=[O:26])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(OCC2COC(C)(C)O2)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(OCC3COC(C)(C)O3)cc(C(=O)O)c2)c(C#N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2′-cyano-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4′-methylbiphenyl-3-carboxylate (72 mg, 0.19 mmol) in tetrahydrofuran (3 mL) was added 2.5 M of aq. lithium hydroxide solution (1 mL, 2.5 mmol). The reaction mixture was stirred at 60° C. overnight. The aqueous solution was acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The combined organic layers were concentrated in vacuo to get the title compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:32][CH2:33][C:34]([OH:36])=[O:35]>C[O-].[Na+].CO>[C:30]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([CH3:27])[S:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:7])[N:9]=1)#[N:31]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(C)sc4c3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccc(Oc3ccc4c(C#N)nc(C(=O)NCC(=O)O)c(O)c4c3)cc2s1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-(2-methyl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (113 mg, 0.26 mmol) and glycine (390 mg, 5.20 mmol) in 0.5 M sodium methoxide/methanol (9.9 mL) was refluxed for forty-five hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (35 mL) and extracted with methyl tert-butyl ether (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (7.4 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (92 mg): MS: (+) m/z 434.93 (M+1), (−) m/z 432.87 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:31][C:32](=O)[CH2:33][C:34](=[O:46])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[CH:45]=[CH:44][N:43]=[N:42]2)[CH:36]=1)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:32](=[O:31])[CH2:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]3[CH:45]=[CH:44][N:43]=[N:42]3)[CH:36]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (150 mg, 0.57 mmol) according to the general procedure M. Obtained as a light yellow solid (110 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH:16]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CO)cc1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-(benzyloxy)-4-methylphenyl)methanol (entire amount) in DMSO (15 mL) was added 2-iodoxybenzoic acid (3.20 g), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate (250 mL) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.50 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: Cc1ccccc1C=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1C
Yield: 67 %

Procedure:
Upon boiling a solution of 6.0 g 2-methylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 158°C (ethanol) is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[N:7]=1)=[CH2:5])C.[Br:14]N1C(=O)CCC1=O>C1COCC1.O>[Br:14][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[N:7]=1)=[O:5]
Reactant: C=C(OCC)c1ccc(F)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)CBr)ccc1F
Reaction time: 0.17 h

Procedure:
A solution of 2-(1-ethoxy-ethenyl)-5-fluoro-6-methyl-pyridine obtained from Step A (15.3 g) in THF (200 mL) and water (8 mL) was treated with N-bromosuccinimide (12.02 g) at room temperature. After stirring for 10 min, the reaction was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluted with a gradient of ethyl acetate in hexanes) to give 2-bromoacetyl-5-fluoro-6-methyl-pyridine, together with an unidentified impurity. This product was used in the next step. 1H NMR (500 MHz, CDCl3): δ 7.98 (dd, 1H), 7.44 (t, 1H), 4.83 (s, 2H), 2.57 (d, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([O:25][CH2:26][C@@H:27]([C:35]([O:37]CC1C=CC=CC=1)=[O:36])[NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:24])[C@@H:13]([CH3:22])[O:14]CC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:11][C@H:12]([C:23]([O:25][CH2:26][C@@H:27]([C:35]([OH:37])=[O:36])[NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:24])[C@@H:13]([CH3:22])[OH:14]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H](N)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Yield: 93.9 %

Procedure:
Benzyl O-(N-benzyloxycarbonyl-O-benzyl-L-threonyl)-N-(trifluoroacetyl)-L-serinate (500 mg) was dissolved in acetic acid (10 ml) and the solution was hydrogenated over 10% palladium on activated carbon at 40 psi (500 mg) under 3 atomospheric pressure of hydrogen at room temperature for 1 hour. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in a small amount of methanol and the solution was diluted with diethyl ether to give a white precipitate. The precipitate was crystallized from aqueous methanol to give 230 mg of pure O-(L-threonyl)-N-(trifluoroacetyl)-L-serine as a white powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:21]([CH:18]2[CH2:20][CH2:19]2)=[O:22])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2cnc3ccccc3n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL) was cooled to 0° C. and cyclopropanecarbonyl chloride (0.91 mL, 0.01 mol) was added dropwise over 10 min. The reaction mixture was stirred overnight at room temperature, diluted with water (50 mL) and stirred for 30 min. The resulting solid was filtered, dried, and recrystallized from toluene to afford N-[3-(quinoxalin-2-yl)phenyl]cyclopropanecarboxamide (2.0 g, 69% yield). LCMS calculated for C18H15N3O (M+H): 290.34. found 290. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.45 (1H, br. s), 9.48 (1H, s), 8.52 (1H, s), 8.20-8.05 (2H, m), 8.05-7.80 (4H, m), 7.50 (1H, m), 1.90-1.75 (1H, m), 1.40-1.32 (4H, m).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:45]([CH3:47])[CH3:46])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH:45]([CH3:47])[CH3:46])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 32.3 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (220) (80.0 mg, crude) was synthesized as a colorless liquid from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (219) (300.0 mg, 0.459 mmol) following the procedure described 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (207).
Reaction SMILES: ClCCl.Cl([O-])(=O)(=O)=O.[CH2:9]([C:11]1(CCC#N)[C:20]2[C:19]3[NH:21][C:22]4[C:27]([C:18]=3[CH2:17][CH2:16][N+:15]=2[CH2:14][CH2:13][CH2:12]1)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:10].[OH-].[Na+]>O>[CH2:9]([C:11]1([CH:13]([CH3:12])[C:14]#[N:15])[C:20]2[N:15]([CH2:16][CH2:17][C:18]3[C:19]=2[N:21]=[C:22]2[C:27]=3[CH:26]=[CH:25][CH:24]=[CH:23]2)[CH2:14][CH2:13][CH2:12]1)[CH3:10]
Reactant: CCC1(CCC#N)CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC1(C(C)C#N)CCCN2CCC3=c4ccccc4=NC3=C21

Procedure:
40 ml. of dichloromethane are added to a suspension of 1.00 g. of 1-ethyl-1-(2-cyanoethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3 -a)quinolizinium perchlorate in 100 ml. of distilled water, and the pH of the mixture is adjusted to 10 to 11 with 40% sodium hydroxide solution. During this operation the mixture is cooled with water and stirred in argon atmosphere. After some minutes of stirring the separated red organic phase is removed, and the aqueous phase is extracted with 20 ml. of dichloromethane. The organic solutions are combined, dried over magnesium sulfate, and the solvent is evaporated in vacuo. The obtained 0.75 g. of red, oily residue is triturated with 1 ml. of methanol, and the resulting orange-red crystals are filtered off. 0.72 g. of (1-ethyl-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinolizin-1-yl)-propionitrile are obtained; m.p.: 122-123° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CS(C)=O>[O:31]1[CH2:30][CH:29]1[CH2:27][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[C:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1
Reactant: ClCC1CO1
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 54 %

Procedure:
To a solution of 50% aqueous DMSO (280 ml), containing sodium hydroxide (5.60 g, 140 mmol) was added 7-hydroxy 2,3,-diphenylchromone (44.01 g, 140 mmol) and the resultant mixture was stirred until most of the solid went into the solution. Epichlorohydrin was then introduced into the suspension. The solution was stirred at room temperature (RT) for 2.5 days and solid formed during the reaction was collected from time to time (about twice a day). The white solid (total=47.58 g) was recrystallized from isopropyl alcohol several times to afford 28.15 g of relatively pure white prisms, m.p. 143°-145°; yield 54%. The mother liquor was concentrated to produce more crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27](O)[C:26]3[C:21](=[CH:22][C:23]([CH3:30])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].[CH2:38]([O:45][C:46](=[O:49])CBr)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[C:28]([O:33][CH3:32])=[C:27]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[C:26]3[C:21](=[CH:22][C:23]([CH3:30])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc3cc(C)ccc3c(C(=O)OCc3ccccc3)c2OC)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4.5 g 4-{2-[(4-Hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 30 ml of DMF, 3.7 g of cesium carbonate and 2.6 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was purified by re-crystallising from ethyl acetate/heptane. Yield: 5 g.