Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.[F:21][C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>C1COCC1>[F:21][C:22]1[C:23]([CH:24]([OH:25])[CH2:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:26][CH:27]=[CH:28][N:29]=1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Reactant: O=Cc1cccnc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1CC(O)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
A solution of tert-butyl (3-methylpyridin-4-yl)carbamate (1.00 g, 4.80 mmol, Intermediate D-2) in THF (50 mL) was cooled to −78° C. under an atmosphere of nitrogen. A solution of n-butyllithium (4.80 mL, 2.5 M in hexane, 12.0 mmol) was added slowly maintaining the internal temperature below −65° C. After the addition, the mixture was warmed to 0° C. for 20 minutes (orange suspension turned homogeneous). The solution was then cooled to −78° C. and 2-fluoronicotinaldehyde (0.901 g, 7.20 mol, Intermediate D-1) in THF (5 mL) was added dropwise. After 10 minutes, the dark red/brown mixture was allowed to slowly warm to 0° C. After 30 minutes, the reaction was quenched with NH4Cl/water. The mixture was further diluted with NaHCO3/water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with 75% ethyl acetate/hexane. Pure fractions were combined, concentrated and then triturated with ethyl acetate to provide the desired product as a white solid (0.55 g, 34%). 1H NMR (DMSO-d6) δ 9.09 (s, 1H), 8.23 (d, 1H), 8.09 (d, 1H), 8.02 (s, 1H), 7.85 (m, 1H), 7.67 (d, 1H), 7.29 (m, 1H), 6.32 (d, 1H), 5.03 (m, 1H), 3.00 (m, 2H), 1.47 (s, 9H). LC/MS: 334 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:18][S:19](O)(=[O:21])=[O:20]>ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([N:5]1[CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][C:13]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:12][C:9]=2[CH2:10][CH2:11]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2CC1)C(F)(F)F
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (see WO02/40471) (20 g, 80 mmol) in dichloromethane (50 mL) was added dropwise to a solution of chlorosulfonic acid (33 mL, 240 mmol) in more dichloromethane (200 mL) at 0° C. The resulting solution was stirred for 18 h without cooling then poured onto ice (250 g). The resulting organic layer was washed with brine (100 mL), dried (MgSO4), and evaporated to give the subtitle compound as a white solid (23 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].ICC.Cl.N1CC[CH:15]([C:18]2[CH:22]=[C:21]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[S:32][C:31]([C:33]([NH2:35])=[O:34])=[C:30]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][C:43]([F:46])([F:45])[F:44])[C:28]=4[N:29]=3)[N:20]([CH:47]([CH3:49])[CH3:48])[N:19]=2)CC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:6][CH2:7][CH:15]([C:18]2[CH:22]=[C:21]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[S:32][C:31]([C:33]([NH2:35])=[O:34])=[C:30]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][C:43]([F:46])([F:44])[F:45])[C:28]=4[N:29]=3)[N:20]([CH:47]([CH3:49])[CH3:48])[N:19]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)n1nc(C2CCNCC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCC(c2cc(Nc3ncc4sc(C(N)=O)c(-c5ccccc5OC(F)(F)F)c4n3)n(C(C)C)n2)CC1
Reaction time: 4 h

Procedure:
70 microliters of triethylamine and 17 microliters of iodoethane are added, at a temperature of about 20° C., to a solution of 100 mg of 2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide hydrochloride in 2.5 ml of DMF under an argon atmosphere, and the mixture is left to stir for 4 h. 70 microliters of triethylamine and 10 microliters of iodoethane are then added and then, after stirring for 15 h, a further addition of 70 microliters of triethylamine and 10 microliters of iodoethane is carried out and the mixture is left to stir for a further 24 hours. The reaction medium is diluted with 40 ml of ethyl acetate and then the organic phase is washed three times with 15 ml of water. The aqueous phase is extracted twice with 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain a yellow solid. The crude product is purified by flash chromatography on silica gel, elution being carried out with a dichloromethane/methanol/NH4OH (96/4/0.1%) mixture, so as to obtain 57 mg of 2-{[3-(1-ethylpiperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH2:36][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2ccnnc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccnnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.05 ml, 0.54 mmol) and acetic acid (0.03 ml, 0.54 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formyl-N-4-pyridazinylbenzamide (may be prepared by Example 79; 200 mg, 0.54 mmol) in DCE (5 ml), and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (172 mg, 0.81 mmol) was then added and the mixture was stirred at 50° C. overnight. Saturated sodium hydrogencarbonate (10 ml) was added and the mixture stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml). The organics were combined and evaporated under reduced pressure. The residue was purified by MDAP to yield the title compound. 147 mg.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[O:22][CH3:23]>>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[O:22][CH3:23])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: COc1c(F)cc(F)cc1CBr
Product: Br
Product: COc1c(F)cc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N

Procedure:
According to the method of Example 172, 2-amino-5-chloronicotinamide was reacted with 1-(bromomethyl)-3,5-difluoro-2-methoxybenzene to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([C:22]([OH:24])=O)[O:3]1.Cl.[Cl:26][C:27]1[S:31][C:30]([NH2:32])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:26][C:27]1[S:31][C:30]([NH:32][C:22]([C@H:4]2[C@H:5]3[N:6]([C:7]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][C:16]5=[O:21])=[CH:11][C:8]=4[O:9][CH2:10]3)[C:2](=[O:1])[O:3]2)=[O:24])=[CH:29][CH:28]=1
Reactant: O=C(O)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: Nc1ccc(Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc(Cl)s1)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 60.3 %

Procedure:
Using compound (3R,3 aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-carboxylic acid (90 mg, 0.269 mmol), 5-chlorothiophene-2-amine hydrochloride (55 mg, 0.323 mmol), HATU (154 mg, 0.404 mmol), and TEA (95.3 mg, 0.943 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid 73 mg, yield: 60.34%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13].[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:18]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1C(F)(F)F

Procedure:
prepared by reaction of 3-chloro-3-(2-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=302.3.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O[C:13](=[O:20])[C@H:14](CC(C)C)N)C.[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26]>>[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]1[CH:6]=[CH:14][C:13]([OH:20])=[CH:22][CH:5]=1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The papain-catalyzed synthesis of leucine and HMB co-oligomers was performed. Synthesis of leucine oligomers and HMB-leucine co-oligomers was initiated with leucine ethyl ester and HMB ethyl ester as the substrates. The overall synthesis and purification approach was similar to the one used in the case of methionine and HMB-methionine. Reaction rates similar to those obtained with methionine and tyrosine were achieved. Approximate oligomer yield was 58%. The freeze-dried oligomer precipitates were solubilized in DMSO. The solution concentration was brought to approximately 2 μg/μl The solution was mixed with 1:1 acetonitrile:water mixture containing 0.1% acetic acid. The total fluid volume entering the ESI-MS was maintained at 0.2 mL min.−1 The positive mass spectrum of the leucine oligomers is shown in FIG. 33A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:13](=O)[CH3:14])[C:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[N:24][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[C:13]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)CC(C)C
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(CC(C)C)nn(-c2ccccn2)c1C
Yield: 84.9 %

Procedure:
Combine 3-acetyl-6-methyl-4-oxoheptanoic acid ethyl ester (3.0 g, 13.1 mmol) and pyridin-2-yl-hydrazine (1.72 g, 15.72 mmol) in glacial acetic acid (25 mL) and stir at room temperature for 68 hr. Concentrate to an oil and partition the residue between ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 90:10 hexanes:ethyl acetate, to give (3-isobutyl-5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-acetic acid ethyl ester (3.35 g, 85%). 1H-NMR (400 MHz, CDCl3) δ 8.38 (m, 1H), 7.77 (m, 2H), 7.13 (m, 1H), 4.12 (q, 2H), 3.41 (s, 2H), 2.98 (d, 2H), 2.27 (s, 3H), 1.82 (m, 1H), 1.22 (t, 3H), 0.80 (d, 6H).
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]Br)#[N:2].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>O>[C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: CCCCC(C#N)(CBr)c1ccc(Sc2ccccc2)cc1
Solvent: O
Product: CCCCC(C#N)(Cn1ccnc1)c1ccc(Sc2ccccc2)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 10 g (0.027 mole) of 2-cyano-2-(4-phenylthiophenyl) hexyl bromide and 8 g (0.13 mole) of imidazole is heated with stirring at 160° for four hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts were washed with water and dried over Na2SO4. The drying agent is filtered and to the filtrate is bubbled dry hydrogen chloride gas until solution is strongly acidic. The hydrochloride salt is washed with ether and back neutralized with dilute ammonium hydroxide solution to give 8 g of pure product.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1.C[N:28](C=O)C>>[O:26]=[C:20]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:21][CH:22]([NH2:28])[C:23]([OH:25])=[O:24]
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: O=C1CCC(=O)O1
Reactant: CN(C)C=O
Product: NC(CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (100 mg) in DMF (8 ml) was added succinic anhydride (79 mg). The reaction mixture was stirred at room temperature for 2.5 hr and a precipitate was collected, washed with DMF and ethanol, then dried to give the title compound (106 mg) as a beige-coloured solid: m.p. 263°-264° C.; NMR (d6 -DMSO+CF3CO2H) δ 2.68 (4H, m), 3.80 (4H, m), 4.19 (4H, m), 7.20 (2H, d), 7.56 (2H, d), 7.82 (2H, d), 8.21 (2H, d), 9.62 (1H, s); m/Z 355 (M+H)+ ; calculated for C19H22N4 O3. 0.4 H2O: C, 63.1%; H, 6.36%; N, 15.5%; found: C, 63.1%; H, 6.4%; N, 15.7%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[NH2:53][CH2:54][C@H:55]([OH:58])[CH2:56][OH:57]>CN(C=O)C.CCOCC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:53][CH2:54][C@H:55]([OH:58])[CH2:56][OH:57])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reactant: NC[C@H](O)CO
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC[C@H](O)CO)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
A solution of 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 23) (70 mg, 0.174 mmol) in DMF (2 mL) was treated with EDC (40.1 mg, 0.209 mmol), HOBT (32.0 mg, 0.209 mmol) and N-ethylmorpholine (0.066 mL, 0.523 mmol) and after 3 min with (S)-3-aminopropane-1,2-diol (15.89 mg, 0.174 mmol). The resulting mixture was stirred at room temperature for 5 h then further EDC (40.1 mg, 0.209 mmol), N-ethylmorpholine (0.066 mL, 0.523 mmol), HOBT (32.0 mg, 0.209 mmol) and (S)-3-aminopropane-1,2-diol (15.89 mg, 0.174 mmol) were added and the mixture stirred for 16 h before concentrating in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3 (×3) then brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue with Et2O gave 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N—((S)-2,3-dihydroxypropyl)benzamide (36 mg, 0.076 mmol, 43.5% yield) as a pale yellow solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:10][C:8]1([CH3:11])[O:9][CH:5]([CH2:4][NH2:1])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(CN=[N+]=[N-])O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(CN)O1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
5-(Azidomethyl)-2,2-dimethyltetrahydrofuran (22 g, 142 mmol) in THF (500 ml) was treated with Triphenylphosphine (39.0 g, 149 mmol) and t stirred for 5 mins. Water (50.0 ml) was added and the reaction mixture was heated at 80° C. for 4 hrs. The mixture was passed through Isolute® SCX-2 resin (200 g 0.67 mmol/g) eluting with MeOH (500 ml), DMSO (100 ml), 20% MeOH:DCM (500 ml), MeOH (500 ml) followed 7M ammonia in MeOH (500 ml). The ammonia layer was evaporated to dryness to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]=1[CH3:8].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([CH3:24])[C:21]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C:3]3=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]([CH3:8])=[C:2]3[N:1]=[C:2]2[CH:7]([CH3:8])[CH3:6])=[CH:13][CH:14]=1)=[O:25]
Reactant: Cc1nc(Nc2ccc(CCO)cc2)c(N)c(C)c1Br
Reactant: CC(C)C(=O)Cl
Product: Cc1nc2c(nc(C(C)C)n2-c2ccc(CCOC(=O)C(C)C)cc2)c(C)c1Br

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4) and isobutyryl chloride.
Reaction SMILES: ClCCCl.[CH:5]1([C:11]2[C:19]3[C:18](=[O:20])[NH:17][C:16]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]5)=[CH:23][C:22]=4[O:34][CH3:35])=[N:15][C:14]=3[N:13]([CH3:36])[N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:37][NH2:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[CH:5]1([C:11]2[C:19]3[C:18](=[O:20])[NH:17][C:16]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][CH:30]([NH:38][CH3:37])[CH2:31][CH2:32]5)=[CH:23][C:22]=4[O:34][CH3:35])=[N:15][C:14]=3[N:13]([CH3:36])[N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CCN(c2ccc(-c3nc4c(c(C5CCCCC5)nn4C)c(=O)[nH]3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a 4 ml 1,2-dichloroethane solution of 200 mg (0.46 mmol) of the compound obtained in Example 30, 100 μl (0.92 mmol) of methylamine (30% methanol solution), 146 mg (0.69 mmol) of sodium triacetoxyborohydride, and 26 μl of acetic acid were added, and the mixture was stirred at room temperature for 6 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/chloroform/methanol=10/10/1) to obtain 176 mg (85%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14]([O:19]CC)(=S)[C:15]([NH2:17])=O>C(O)CCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]2[C:3]=1[N:13]=[C:15]([NH2:17])[C:14](=[O:19])[NH:12]2
Reactant: CCOC(=S)C(N)=O
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Solvent: CCCCO
Product: Nc1nc2c(Br)cc(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 27.1 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 3-bromo-5-trifluoromethyl-1,2-phenylenediamine (384 mg, 1.50 mmol; Maybridge Co.) and ethyl thiooxamate (220 mg, 1.70 mmol; Aldrich Co.) in 4 mL of 1-butanol was heated to reflux. The resulting solution was stirred under reflux for 6 h. The resulting suspension was cooled to 25 ° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 125 mg (27.1%) of 5-bromo-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp dec.>267° C. 1H NMR (300 MHz, DMSO-d6) δ 7.680 (s, 1H, H-7), 7.495 (s, 1H, H-5). LRMS: 307 (M+, 100%), 280 (50%).
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[CH:29]1([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:36]2[C:35]2[CH:37]=[CH:38][C:32]([CH:29]3[CH2:31][CH2:30]3)=[CH:33][CH:34]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: Brc1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C3CC3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
The product from Example 42B (3.14 g, 5.64 mmol) and 4-cyclopropylaniline (6.01 g, 45.2 mmol) were combined in DMF (20 mL). The mixture was stirred at 50° C. under nitrogen for 3 hours. The reaction mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with brine three times, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (0.5% to 1%) to give the title compound (2.12 g, 76%) as a mixture of stereoisomers as a sticky solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:9]1)C1C=CC=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>>[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([C:34]([N:8]2[CH2:13][CH2:12][C@H:11]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C@H:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[CH2:9]2)=[O:35])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1Cl
Product: CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2Cl)CC1

Procedure:
The title compound, MS: m/e=534.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(2-chloro-phenyl)-piperidin-4-one, N-methyl-piperazine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[C:5](=[O:10])[CH2:6]1
Reactant: Cc1c(C(O)CN2CCNCC2=O)ccc2c1COC2=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 1-[2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (49 mg, 0.17 mmol) and 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (64 mg, 0.34 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 150° C. for 2 hours. LC showed formation of the product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 481 [M+1]+.