Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[CH2:11][N:10](C)[CH2:9]2)=[CH:4][CH:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:19]=[N:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1Cc2cc(-c3ccc(C(F)(F)F)nn3)ccc2C(c2ccc(Cl)cc2)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3c2ccc(Cl)cc2)nn1
Yield: 33.2 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (69 mg, 0.17 mmol) in 1,2-dichloroethane (5 mL) at 0° C. was added proton sponge (37 mg, 0.17 mmol) and 1-chloroethyl chloroformate (56 μL, 0.51 mmol) dropwise. The resultant mixture was stirred at 0° C. for one hour and then heated at reflux for 1.5 hours. After concentrating the mixture in vacuo, the crude intermediate was taken up in methanol (5.0 mL) and heated at reflux for 1 hour. After concentrating in vacuo, the crude product obtained was purified by preparative thin layer chromatography using 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide as eluent to give 4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (22 mg, 33%) as a light yellow oil: [α]23D +7.5° (c 0.08, methanol). To a solution of the newly obtained tetrahydroisoquinoline (20 mg, 0.051 mmol) in acetonitrile (1 mL) was added L-tartaric acid (8 mg, 0.051 mmol) followed by slow addition of water (4 mL). The resultant solution was lyophilized for two days to give the correspondent L-tartrate salt (>99% AUC HPLC) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 8.39 (d, J=9.0 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 8.03 (dd, J=8.0, 2.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 1H), 4.65-4.53 (m, 3H), 4.42 (s, 2H), 3.80-3.76 (m, 1H), 3.47-3.43 (m, 1H); ESI MS m/z 390 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH2:16]([O:23][C:24](=[O:34])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)(Cl)Cl.CO>[CH2:16]([O:23][C:24](=[O:34])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][NH:33][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CN(C)c1nc(NC[C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (1.50 g, 7.22 mmol) and trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl ester hydrochloride (2.59 g, 8.67 mmol) in 2-propanol (15 mL) was stirred at reflux for 8 days and dissolved in CHCl3 and MeOH. The mixture was poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (H-silica gel, 33% EtOAc in hexane) to give trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (1.20 g, 38%) as a pale yellow solid.
Reaction SMILES: CC1CCCN(C)C1(C)C.C([Li])CCC.[Al](Cl)(CC)CC.[C:22]([Si:26]([CH3:45])([CH3:44])[O:27][C@@H:28]1[CH2:34][C@@H:33]([O:35][Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[CH2:32][C@H:31]2[C@:29]1([CH3:43])[O:30]2)([CH3:25])([CH3:24])[CH3:23]>C1C=CC=CC=1>[Si:26]([O:27][C@@H:28]1[CH2:34][C@@H:33]([O:35][Si:36]([CH2:37][CH3:38])([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:32][C@H:31]([OH:30])[C:29]1=[CH2:43])([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:44])[CH3:45]
Reactant: CC[Si](CC)(CC)O[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CC1CCCN(C)C1(C)C
Agent: CC[Al](Cl)CC
Agent: [Li]CCCC
Solvent: c1ccccc1
Product: C=C1[C@@H](O)C[C@H](O[Si](CC)(CC)CC)C[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 96.2 %

Procedure:
Tetramethylpiperidine (9.66 g, 67.7 mmol) was dissolved in 76 mL of benzene and cooled below 0° C. n-Butyllithium (2.5 M in hexane, 27.5 mL, 68.8 mmol) was added to the benzene solution below 2.5° C. The resulting solution was stirred below 0° C. Et2AlCl (1.8 M in toluene, 39 mL, 70.2 mmol) was added to the reaction below 3° C. followed by a rinse of 5.0 mL of benzene. The resulting solution was stirred at below 0° C. for 30 minutes. The compound of Example 16E (6.36 g, 17.1 mmol) dissolved in 25 mL of benzene was added to the reaction solution at below 1° C. over 10 minutes. 5.0 mL of Benzene was used as a rinse. The reaction was stirred at below 0° C. for 2.7 hours. The reaction mixture was quenched into 441 g of 17.2 wt % NH4Cl solution (cooled to below 5° C.). 104 g of 10 wt % HCl solution was slowly added to the mixture, and pH was adjusted to 2.0. The layers were separated and the aqueous layer was extracted four times with 100 mL of ethyl acetate. The combined organic layers were washed three times with 100 mL of water, then 100 mL of 7.8 wt % NaHCO3, and 100 mL of brine, and then dried over MgSO4. Filtration and concentration in vacuo yielded the title compound (6.13 g, 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:2]=1>[O-2].[Mn+4].[O-2].C(#N)C>[NH2:12][C:9]1[CH:10]=[CH:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: NC1=NN(c2cccnc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: Nc1ccn(-c2cccnc2)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
To a 3-neck, round bottomed flask (100 mL) was charged 1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (1.00 g, 6.17 mmol) and acetonitrile (20 mL). Manganese(IV) oxide (2.68 g, 30.8 mmol) was added, causing an exotherm from 20° C. to 25° C. The reaction was stirred at 60° C. for 18 hours, after which it was filtered through a Celite® pad and the pad was rinsed with acetonitrile (20 mL). Water (20 mL) was added to the combined filtrates and the resulting mixture was concentrated to 10 mL. Water (20 mL) was added and the resulting mixture was again concentrated to 10 mL. The resulting suspension was stirred at 20° C. for 18 hours and filtered. The filter cake was rinsed with water (2×5 mL) and dried to afford the title compound as a brown solid (0.68 g, 69%): mp 169-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.07-8.82 (m, 1H), 8.33 (dd, J=4.6, 1.5 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 8.00 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.42 (ddd, J=8.5, 4.6, 0.8 Hz, 1H), 5.80 (d, J=2.6 Hz, 1H), 5.21 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 157.67, 144.68, 138.00, 136.22, 128.30, 123.95, 123.17, 97.08; ESIMS m/z 161 ([M+H]+).
Reaction SMILES: COC1[O:8][C:7](=[O:9])[CH2:6][CH:5]([CH3:10])O1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([NH:18][CH:5]([CH3:10])[CH2:6][C:7]([OH:8])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1OC(=O)CC(C)O1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CC(CC(=O)O)NCc1ccccc1

Procedure:
The product of Example 2, 2-methoxy-6-methyl-1,3-dioxan-4-one, was reacted with benzylamine in dichloromethane at room temperature for 24 hours. This afforded optically active 3-(N-benzylamino) butyric acid.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17]
Reactant: O=C1CSC(=S)N1
Reactant: N#Cc1cc(C=O)cc(O)c1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#Cc1cc(C=C2SC(=S)NC2=O)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 0.61 g of rhodanine, 0.72 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.35 g, mp>350° C.
Reaction SMILES: [CH2:1]([C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[N:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](O)(=[O:22])[CH2:20][CH3:21]>C(OC(=O)CC)(=O)CC.[Zn]>[C:2]1([CH2:1][CH:8]([NH:9][C:19](=[O:22])[CH2:20][CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cc1ccccc1)c1ccccn1
Reactant: CCC(=O)O
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)NC(Cc1ccccc1)c1ccccn1
Reaction time: 1 h

Procedure:
To a solution of 42.4 g (0.2 mol) of benzyl-2-pyridylketoxime (E. Niemers and R. Hiltmann, Synth. 1976, 593), 2 g of sodium hydroxide and 0.2 g of mercuric chloride in 300 ml of propionic acid and 100 ml of propionic acid anhydride, were added 52.4 g (0.8 mol) of zinc powder with stirring in portions of 0.5 g in the course of one hour. The solution became warm and turned purple. Stirring was continued at 80° C. until the purple colour turned to yellow (ca. 3 hours). The reaction mixture was cooled and filtered. The residue was thoroughly washed with water and then with chloroform and the chloroform solution obtained was successively washed with water, aqueous sodium bicarbonate and again with water. The solvent was distilled off and the residue was sublimed. The oily product was crystallised from a mixture of ethanol and petroleum ether (boiling range 60°-80° C.). N-[2-phenyl-1-(2-pyridyl)ethyl]propionamide was obtained as a white solid, melting point 91°-93° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C@@H:6]12[C:15](=[O:16])[O:14][C:12](=[O:13])[C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>C.[Cl-].[Cl-]>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:15]([OH:14])=[O:16])=[O:13])[CH3:2]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: CCNCC
Agent: C
Agent: [Cl-]
Product: CCN(CC)C(=O)C1CCCCC1C(=O)O
Reaction time: 2 h

Procedure:
Model compound synthesis and hydrolytic kinetics measurement (Scheme 4—FIG. 4): Briefly, N,N-diethylamine (415 μL, 4 mmol) and 1,2-cis-cyclohexanedicarboxylic anhydride (617 mg, 4 mmol) were dissolved in 10 mL dichloride methane. The reaction was kept at room temperature for 2 h with stirring. The solvent was then removed by rotary evaporation to obtain the raw product. The raw product was purified by recrystallizing from benzene to get 2-[(diethylamino)carbonyl]cyclohexanecarboxylic acid. 1H NMR (400 MHz, CDCl3): δ (ppm): 3.60-3.22 (m), 2.77 (m), 2.51-2.45 (m), 1.87-1.66 (m), 1.58-1.46 (m), 1.49-1.39 (m), 1.28 (q), 1.17 (t). Similarly, 2-[(isopropylamino)carbonyl]cyclohexanecarboxylic acid was synthesized. 1H NMR (400 MHz, CDCl3): δ (ppm): 3.83 (q), 2.73 (q), 2.64 (q), 1.87 (m), 1.79 (m), 1.64 (m), 1.45 (m), 1.33 (m), 1.01 (d).
Reaction SMILES: I[C:2]1[C:3]([NH2:22])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:34]=[CH:35][CH:36]=2)O1>>[NH2:22][C:3]1[C:2]([C:35]2[CH:34]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:32]=[CH:31][CH:36]=2)=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1nccc(Oc2ccc(Oc3ccccc3)cc2)c1I
Reactant: CCC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCC(=O)Nc1cccc(-c2c(Oc3ccc(Oc4ccccc4)cc3)ccnc2N)c1
Yield: 49 %

Procedure:
N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 3-iodo-4-(4-phenoxyphenoxy)pyridin-2-amine and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide using Method C (49% yield). HPLC: 98%, RT=4.186 min. MS: m/z=426 [M+H]+, RT=4.18 min. 1H-NMR (DMSO-d6) δ 10.01 (s, 1H), 7.94 (d, 1H), 7.73 (s, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.39 (t, 2H), 7.24 (s, 2H), 7.16-7.01 (m, 8H), 6.35 (d, 1H), 2.32 (q, 2H), 1.07 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CCO>[CH3:14][N:15]([CH:17]=[C:9]1[CH2:8][CH2:7][C:5]2[N:6]=[C:2]([N:1]=[CH:14][N:15]([CH3:17])[CH3:16])[S:3][C:4]=2[C:10]1=[O:11])[CH3:16]
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: CN(C)C=Nc1nc2c(s1)C(=O)C(=CN(C)C)CC2
Temperature: 150 °C
Yield: 58.7 %

Procedure:
A mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (0.5 g, 3 mmol) and N,N-dimethylformamide dimethyl acetal (1.96 mL, 1.76 g, 14.8 mmol) in EtOH (2 mL) was heated under microwave irradiation (300 W, 150° C.) for 30 min. The mixture was concentrated under vacuum before purification by flash column chromatography (50% EtOAc:hexane) to afford the title product as a tan solid (0.49 g, 59%): mp 185-186° C. Anal. RP-HPLC: tR 9.3 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.23 (s, 1H, CH), 7.44 (s, 1H, CH), 3.13 (s, 3H, CH3), 3.11 (s, 3H, CH3), 3.08 (s, 6H, N(CH3)2), 3.00 (t, 2H, J 6.6, CH2), 2.83 (t, 2H, J 6.6, CH2). MS (ESI+): m/z 279.15 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:39]=[CH:40][CH:41]=2)[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19](=[CH:25][NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:29][CH:28]=4)[C:20](=[O:24])[NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1.[CH2:43]1[CH2:47]N([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:44]1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CON>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:39]=[CH:40][CH:41]=2)[C:13]([C:15]2[CH:23]=[C:22]3[C:18](/[C:19](=[CH:25]/[NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH:43]([CH3:47])[CH3:44])=[O:37])=[CH:29][CH:28]=4)/[C:20](=[O:24])[NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCCC(=O)O)cc3)c2)n(C)n1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)/C4=C\Nc3ccc(CCCC(=O)OC(C)C)cc3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a dry 50 mL round bottomed flask, 4-{4-[(6-{3-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-benzoyl}-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-butyric acid (as prepared in Example 324, 50 mg, 0.088 mmol) was dissolved into DMF (1 mL), under Ar(g). PyBOP (60 mg, 0.115 mmol) was then added followed by triethyl amine (0.04 mL, 0.266 mmol) and O-methylhydroxylamine hydrochloride (22 mg, 0.264 mmol). The mixture was stirred at room temperature for 2 h after which the reaction mixture was partitioned between EtOAc (˜10 mL) and brine (10 mL). The organic layer was extracted with brine (3×˜10 mL). The organic layers were combined and then concentrated in vacuo. The crude mixture was then chromatographed over silica (EtOAc/MeOH gradiant was used starting from 1% MeOH up to 5% MeOH). The title compound was isolated in pure form as a yellow solid (27.8 mg, 0.046 mmol, 53%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1C[O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl.CN(C=O)C>[C:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:39])[CH3:37]
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.020 g, 0.041 mmol) was dissolved in dry DCM (2 mL), dry THF (1 mL) and dry DMF (1 mL) then triethylamine (0.012 mL, 0.083 mmol) followed by acetic anhydride (0.008 mL, 0.083 mmol) were added. The reaction was then stirred at room temperature for 5 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (13) (0.019 g, 87% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.61 (s, 1H), 7.63-7.56 (m, 2H), 7.44 (s, 1H), 7.26-7.13 (m, 4H), 6.98-6.90 (m, 3H), 3.61-3.54 (m, 4H), 3.50 (s, 2H), 3.13-2.95 (m, 8H), 2.04 (s, 3H). LCMS Method C: rt 5.62 min; m/z 527.2 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]12([CH3:18])[C:15]([CH3:17])([CH3:16])[CH:12]([CH2:13][CH2:14]1)[CH2:11][C:9]2=[O:10].[CH:19](=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>C1COCC1.CCCCCC>[OH:21][CH:19]([CH:11]1[CH:12]2[C:15]([CH3:17])([CH3:16])[C:8]([CH3:18])([CH2:14][CH2:13]2)[C:9]1=[O:10])[CH3:20]
Reactant: CC=O
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)C1C(=O)C2(C)CCC1C2(C)C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
2.50 ml of 2.5 M n-butylithium hexane solution was added dropwise a tetrahydrofuran solution comprising 4 ml THF and 1.00 ml diisopropylamine at -78° C. and the mixture was stirred for 15 minutes. Then, a THF solution comprising 4 ml THF and 0.91 g camphor was added dropwise to the above solution at -78° C., then the solution was further admixed with 0.27 g of acetaldehyde and stirred for 15 minutes. This reaction solution was admixed with 50 ml of a saturated sodium hydrogen carbonate aqueous solution and restored to room temperature. The reaction product was extracted with diethylether. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then the solvent was removed under a vacuum. The residue was purified by means of silica gel column chromatography (eluent: hexane/ethylacetate=8/2) and 0.94 g of 3-(1-hydroxyethyl)-camphor was obtained (yield: 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1SC.CCN(CC)CC>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]3[N:29]([CH3:28])[CH2:33][CH2:32][N:31]=3)=[CH:8][CH:7]=2)=[O:10])=[O:27])=[N:21][CH:22]=1
Reactant: CSC1=NCCN1C
Reactant: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1CCN=C1NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (74 mg, 0.195 mmol), 1-methyl-2-methylthio-2-imidazoline (25 mg, 0.195 mmol), NEt3 (2 mL) and pyridine (5 mL) was stirred at 80° C. overnight, concentrated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-{[(1-methyl(2-imidazolin-2-yl))amino]methyl}phenyl)carboxamide (52 mg, 65%). MS found for C24H23ClN6O2 (M+H)+: 463.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1nc(Cl)c2ncsc2n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (300 mg, 1.45 mmol) and 3-(trifluoromethyl)benzenamine (304.8 mg, 1.89 mmol) in 10 mL of DMSO was added DIEA (282 mg, 2.18 mmol) in one portion at room temperature. Then the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 40 mL of water, and the solid obtained was filtered, rinsed with water, and dried. The desired product 5-chloro-N-(3-(trifluoromethyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine was obtained (356 mg, 74%) as a yellow solid. LC-MS: 331.0 [M+H]+, tR=1.70 min.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6](=O)[CH2:7][CH3:8].CN[CH:12]1[CH2:17][C:16](C)(C)[NH:15][C:14]([CH3:21])(C)[CH2:13]1>>[CH2:5]([C:13]1[CH:12]=[CH:17][C:16]([NH2:15])=[CH:21][CH:14]=1)[C:6]1[CH:12]=[CH:13][C:14]([NH2:15])=[CH:8][CH:7]=1
Reactant: CCC(C)=O
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
3.58 g (0.03 mol) chloroform; 14.42 g (0.20 mol) 2-butanone; and, 4.0 g (0.1 mol) 4-methylamino-2,2,6,6-tetramethylpiperidine are reacted in a manner analogous to that described in Example 1 hereinabove and the product worked up and recovered. The structure of the compound obtained is represented as follows: ##STR5## wherein n is in the range from 2 to about 5.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[CH:32]=[CH:33][C:34](O)=[O:35]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][CH:39]=[C:29]([O:28][CH3:27])[CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1cccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 50 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3-methoxycinnamic acid under the conditions described in example 86 to yield 50% of the desired product.
Reaction SMILES: [SH:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH2:12]C(C)C)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.C(OC(=O)CNC(=O)[C@H](C)N)C.Cl.C(OC(=O)CNC(=O)[C@H](CC(C)C)N)C>>[SH:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:12])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Agent: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: CCOC(=O)CNC(=O)[C@H](C)N
Agent: Cl
Product: CCOC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NS

Procedure:
This mercaptopeptidyl ester was prepared substantially similarly as HS-Leu-Leu-Gly-OC2H5, above, except that an equivalent amount of L-alanylglycine ethyl ester hydrochloride was used in the coupling reaction instead of L-leucylglycine ethyl ester hydrochloride.