Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[O:22][CH2:21][CH2:20][N:19]([C:23](=[O:47])[NH:24][C@H:25]([C@H:33]([OH:46])[CH2:34][N:35](C)[C:36](OCC[Si](C)(C)C)=O)[CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[N+](CC)(CC)(CC)CC.[F-]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[O:22][CH2:21][CH2:20][N:19]([C:23](=[O:47])[NH:24][C@H:25]([C@H:33]([OH:46])[CH2:34][NH:35][CH3:36])[CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CN(C(=O)N[C@@H](CC2CCOCC2)[C@H](O)CN(C)C(=O)OCC[Si](C)(C)C)CCO1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CNC[C@@H](O)[C@H](CC1CCOCC1)NC(=O)N1CCO[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A 10 mL flask was charged with methyl 2-((S)-(3-chlorophenyl)((R)-4-((2S,3R)-3-hydroxy-4-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(tetrahydro-2H-pyran-4-yl)butan-2-ylcarbamoyl)morpholin-2-yl)methoxy)ethylcarbamate (30 mg, 0.043 mmol) dissolved in MeCN (4 mL) and Et4NF (14 mg, 0.094 mmol) was added. The mixture was stirred for 0.5 h under reflux. After stirring, it was monitored by HPLC until the reaction ended. The solution was concentrated in vacuo and purified by HPLC to give the target compound (2.97 mg, 12%). 1H NMR (MeOD) 1.27-1.30 (m, 2H), 1.32-1.40 (m, 2H), 1.51-1.62 (m, 2H), 1.65-1.80 (m, 2H), 2.70 (s, 3H), 1.75-1.90 (m, 2H), 1.90-3.10 (m, 4H), 3.65 (s, 3H), 3.80-3.95 (m, 5H), 4.05-4.20 (m, 1H), 4.30 (m, 1H), 7.25-7.40 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:15]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]4[N:22]=[CH:23][CH:24]=[CH:25][N:26]=4)[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1cccc(Oc2ncccn2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ncccn2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(2-pyrimidinyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(2-pyrimidinyloxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale yellow crystalline solid of melting point 220-221° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[N:10]=[CH:11][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([OH:41])=O)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:53][CH2:52][C@@H:51]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:45]([O:44][C:42]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:9]1[C:14]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:28])[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[N:13][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([N:49]2[CH2:53][CH2:52][C@@H:51]([NH:54][C:55]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:61])[CH2:50]2)=[O:41])=[CH:11][N:10]=1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4CC4C(=O)O)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4CC4C(=O)N4CC[C@@H](NC(=O)OC(C)(C)C)C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylic acid (100 mg, 0.15 mmol) and tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (31 mg, 0.17 mmol) in DMF (0.6 mL) at room temperature was added HATU (57 mg, 0.15 mmol) followed by the addition of DIEA (48 mg, 65 μL, 0.37 mmol) and reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1M HCl solution, and then with brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to obtain tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-[(3R)-3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]cyclopropyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate, which was dissolved in of 50% TFA-DCM (1 mL) mixture and stirred for 25 minutes at room temperature. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DMSO (1 mL), filtered and purified using reverse phase HPLC (10 to 99% MeOH in H2O with HCl modifier) to obtain [2-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropyl]-[(3R)-3-aminopyrrolidin-1-yl]methanone.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([Br:16])[CH:13]=[CH:14][CH:15]=1.[CH:17](=[O:19])[CH3:18]>C1COCC1>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=1[CH:17]([OH:19])[CH3:18]
Reactant: CC=O
Reactant: Clc1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (6 mL, 12 mmol) in THF (10 mL) was added 3-chlorobromobenzene (1.91 g, 9.98 mmol) in THF (5 mL) at −78° C. under nitrogen, the resulting mixture was stirred at −78° C. for 1 h, then a solution of acetaldehyde (0.66 g, 15 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.64 (d, J=6.8 Hz, 3H), 2.98 (d, J=10.4 Hz, 1H, —OH), 5.58 (m, 1H), 7.04 (t, J=8.1 Hz, 1H), 7.31 (dd, J=8.1, 1.2 Hz, 1H), 7.49 (dd, J=8.1, 1.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[H-].[Na+].Cl[NH2:15].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)C.O>[CH2:1]([O:4][C:5]([C:7]1[N:8]([NH2:15])[CH:9]=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc[nH]1
Reactant: NCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(=O)c1cccn1N
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid allyl ester (Example 1a, 0.75 g, 4.96 mmol) in N,N-dimethylformamide (20 mL) at 25° C. was added sodium hydride (0.316 g, 7.29 mmol) and stirred for 1 h. A solution of monochloroamine (36 mL, 7.19 mmol) in diethyl ether (0.2 M) was added and stirred for 1 h and then treated with saturated aqueous sodium bicarbonate solution (50 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (0.90 g) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 4.75 (2H, m), 5.28 (1H, dd, J1=10.0 Hz, J2=1.2 Hz), 5.40 (1H, dd, J1=17.2 Hz, J2=1.6 Hz), 6.03-5.90 (2H, m), 6.87 (1H, dd, J1=4.0 Hz, J2=1.6 Hz), 6.97 (1H, t, J=2.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[C:10]([CH3:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:14][CH:15]=2)[C:10]([CH3:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccc(C#CCCCO)cc12
Product: Cc1cn(C(=O)OC(C)(C)C)c2ccc(C#CCCCOS(C)(=O)=O)cc12

Procedure:
In analogy to example 5.4, 5-(5-Hydroxy-pent-1-ynyl)-3-methyl-indole-1-carboxylic acid tert-butyl ester and methanesulfonyl chloride were converted to yield 5-(5-Methanesulfonyloxy-pent-1-ynyl)-3-methyl-indole-1-carboxylic acid tert-butyl ester as yellow viscous oil, MS: 392 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:16][OH:17])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:16]=[O:17])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1CO
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccc(Br)cc2)oc1C=O
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A solution of [2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-methanol (17.9 g, 60.4 mmol) in CH2Cl2 (450 mL) is treated at ambient temperature with acetic acid 1,1-diacetoxy-3-oxo-1□5-ioda-2-oxa-indan-1-yl ester (39 g, 92 mmol, Dess Martin reagent). The suspension is stirred 1 h and is partitioned between 10% aqueous Na2S2O3 solution (250 mL) and CH2Cl2 (150 mL). The organic layer is washed with saturated NaHCO3 (2×250 mL), and the combined aqueous layers are back-extracted with Et2O (300 mL). The combined organic layers are dried (Na2SO4) and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (6:1) to give an offwhite solid (14.4 g, 81%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:25][CH3:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-n-propylbenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23](=O)[C:24]#[CH:25])[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1.Cl.[OH:30][C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[NH:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:34]=[C:32]([C:31]([OH:30])([CH3:36])[CH3:35])[N:33]=3)[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)cs1
Temperature: 75 °C
Yield: 11.5 %

Procedure:
To a solution of 5-chloro-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(2-methyl-thiazol-4-ylmethoxy)-3H-pyrimidin-4-one from Step C (87 mg, 0.21 mmol) in acetonitrile (2 mL) was added 2-hydroxy-2-methylpropionamidine HCl (44 mg, 0.32 mmol) and potassium carbonate (87 mg, 0.63 mmol) and the slurry was heated at 75° C. for two hours and at ambient temperature for eighteen hours. The reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (12 mg, 11% yield). MS (M+H): 499; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.77 (s, 3H), 5.59-5.68 (m, 2H), 7.26 (s, 1H), 7.55-7.59 (m, 2H), 7.93 (s, 1H), 8.14 (d, J=8.60, 1H), 8.78 (d, J=5.08, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1C#N
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
Trifluoroacetic acid (0.856 mL) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D19) (105 mg) in dichloromethane (1.5 mL) at RT. The resulting solution was stirred for 1.5 hours. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[6-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E7) (69 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.65 (2H, t), 2.97 (2H, t), 4.98 (1H, m), 7.36 (1H, d), 7.56 (1H, d), 7.72 (2H, t), 8.12 (1H, s), 8.42 (1H, dd), 8.51 (1H, d), 11.22 (1H, s), 12.12 (1H, br s). MS (ES): C23H20N4O4 requires 416. found 416.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C:9]([CH3:10])([C:11]([O:13][CH3:19])=[O:12])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCC#N)C(C)(C)C(=O)O
Reactant: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N(CCC#N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
62 g (0.23 mol) of N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalanine were dissolved in 350 ml of DMF and 50 g of KHCO3 were added. Few minutes after, 30 ml of methyl iodide (MeI) were dropped and the mixture was stirred at room temperature for 6 hours. Then a further 15 ml of MeI were added. The mixture was left at room temperature overnight. After dilution with 1.5 l of water, the solution was extracted with ethyl acetate (3 times). The organic phases were washed with a small amount of water, dried over sodium sulfate, evaporated and dried at the mechanical pump. 60.5 g (97%) of methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate were thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6](/[CH:7]=[N:8]/[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][C:18]3[C:9](=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[N:8]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(/N=C/c2ccc(OC)cc2)c1
Reactant: O=CCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(-c3ccccc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
A mixture of (E)-methyl 3-(4-methoxybenzylideneamino)benzoate (1.1 g, 4.08 mmol, 1.00 equiv), 2-phenylacetaldehyde (480 mg, 4.00 mmol, 1.00 equiv), hydrochloric acid in tetrahydrofuran (0.5 mL, 10M) and DMSO (2 mL) was placed in a 10-mL sealed tube and stirred overnight at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum and purified via Flash-Prep-HPLC (H2O/CH3CN=10% increasing to H2O/CH3CN=60% within 5 min; Detector, UV 254 nm) affording 70 mg (5%) of methyl 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([NH:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:19][N:18]=[C:17]([N:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH3:29])[N:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].CCN(CC)CC.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([NH:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:19][N:18]=[C:17]([N:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH3:29])[N:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:46]([N:45]([CH3:49])[CH3:44])=[O:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(O)cc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(OC(=O)N(C)C)cc1

Procedure:
A solution of (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-hydroxyphenyl)propanoic acid ethyl ester (1.0 eq), DMAP (1.0 eq), Et3N (1.2 eq) and dimethylcarbamyl chloride (1.2 eq) in CH2Cl2 was stirred at 22° C. for 8 hr. The mixture was diluted with EtOAc, and the resulting solution was washed successively with water, 0.5 M citric acid, sat. NaHCO3 and sat. NaCl. The CH2Cl2/EtOAc extracts were treated with MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 6:4 hexanes/EtOAc to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[C:31]([O:43]CC2C=CC=CC=2)[CH:30]=1)[C:12]([O:14][C@H:15]([CH3:27])[C@H:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])[CH3:17])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.[Pd]>[OH:43][C:31]1[CH:30]=[C:29]([CH2:28][C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[C:12]([O:14][C@H:15]([CH3:27])[C@H:16]([O:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH3:17])=[O:13])[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
200 mg of 10% Pd—C pre-mixed with 10 mL of methanol was added to a solution of (1R,2R)-1-methyl-2-phenylcarbonyloxypropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.6 g, 3.9 mmol) in 40 mL of tetrahydrofuran under a nitrogen atmosphere. The resulting mixture was stirred under hydrogen at room temperature for 2 hrs. After filtration and washing with methanol, the filtrate was concentrated and chromatography (silica gel, 30% ethyl acetate in hexane) of the residue afforded 1.8 g (95%) of (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate. MS (ESI) m/z 474.31 (M+H)+ and 472.18 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:34])[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23](C(=O)C(F)(F)F)[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:34])[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.21 mmol) 4-benzyloxy-1-{2-oxo-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (example 22.1) in 5.0 mL MeOH is added 0.41 mL (0.41 mmol) aqueous 1 M sodium hydroxide solution. The reaction mixture is stirred 2 h at RT. The solvent is evaporated, the residue is dissolved in DMF and purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[CH:12])=NC=1.CCCCCCC.C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: C#CCCCc1ncc(Cl)cn1
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCCC
Product: Clc1cnc2c(c1)CCC2

Procedure:
A solution of 5-chloro-2-(pent-4-ynyl)pyrimidine (H. C. van der Plas, Tetrahedron 1989, 45, 5151-5162) (4.95 g (27.4 mmol) in nitrobenzene (50 ml) was heated to 210° C. for 1.5 hours under a continuous stream of nitrogen. The reaction was followed by TLC (silica gel, heptane: ethyl acetate=2:1; UV detection 254 nm). After completion, the reaction mixture was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The 3-chloro-6,7-dihydro-5H-[1]pyrindine was obtained as a light brown solid (3.21 g, 76%); (calculated) C8H8ClN [153.61]; (found) [M+H]+=154.
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C(OCC)(=O)C>[Fe].O>[CH:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(SC2CCCCC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(SC2CCCCC2)nc1

Procedure:
2-Cyclohexylthio-5-nitropyridine (13.4 grams) was added to a suspension of 50 grams of ammonium chloride and 20 grams of powdered iron in a mixture of 220 ml. of ethyl acetate and 30 ml. of water. The reaction mixture was refluxed for 6 hours. TLC indicated some starting material remained. Additional powdered iron (10 grams) was added and the reaction mixture refluxed for another 2 hours. TLC indicated no starting material remaining. The reaction mixture was filtered, taken up in chloroform, washed with water, dried, and evaporated. The main product residue was crystallized from ethyl acetate-hexanes, 8.4 grams of tan crystals; a second crop was crystalled from chloroform-hexanes with charcoal, 0.8 gram. The second crop was analyzed as follows: