Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][CH2:27][C:28](O)=O)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[O:22][CH3:23])[CH2:26][CH2:27][C:28]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Product: COc1cc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc(OC)c1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(3,4,5-trimethoxyphenyl)propionic acid (241 mg; 1 mmol) as described in method 2; yield: 0.016 g (4.2%); MS m/z: 381.4 [M+H]+; 1H-NMR (CD3OD, 400 MHz): δ 3.12-3.16 (m, 2H); 3.31-3.33 (m, 2H); 3.70 (s, 3H), 3.77 (s, 6H); 6.56 (s, 2H); 7.94 (d, 1H, 3J=8.7 Hz); 8.15 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.381-8.382 (m, 1H); 9.12 (s, 1H); HPLC (METHOD [A]): rt 10.41 min (89.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:14])[CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: C1COCCO1
Reactant: OC1=CCCSc2ccc(Cl)cc21
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=S1CCC=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The solution of 6.4 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin in 65 ml of dry methanol and65 ml of dry dioxane is treated dropwise at 0° in 1 hour with the solution of 7.0 g of sodium metaperiodate in 65 ml water. The mixture is stirred at 0° for two hours after the addition period and then allowed to warm to room temperature for overnight. It is filtered and the solid rinsed with 30 ml of methanol. The combined filtrate and wash is concentrated to a smaller volume and treated with 40 ml of water. The mixture is extracted with chloroform, the extract separated, washed with water, dried and evaporated, to yield the 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1-oxide boiling at 154-157/0.25 mmHg.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:3](=[O:24])[CH:2]([NH:1][C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:34])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reaction time: 2 h

Procedure:
The amine was dissolved in anhydrous tetrahydrofuran (9 ml) under an atmosphere of nitrogen, at room temperature, and triethylamine (249 μl) was added dropwise. A solution of 4-nitrophenyl chloroformate (363 mg) in anhydrous tetrahydrofuran (9 ml) was then added, and the reaction mixture stirred for a further 2 h. After this time the undissolved solid was filtered off, washed with tetrahydrofuran, and the filtrate evaporated in vacuo. The residue was azeotroped with toluene (2×20 ml) and ether (20 ml). The resultant solid was then triturated in anhydrous ether to afford the title compound (420 mg) as a white solid. TLC (silica, petrol (60/80):ethyl acetate 2:1) Rf=0.7. 1H NMR (360 MHz, CDCl3) δ 0.77 (3H, d, J=6.6 Hz), 0.83 (3H, d, J=6.6 Hz), 1.40-1.87 (12H, m), 2.06-2.17 (1H, m), 2.98-3.02 (1H, m), 3.48 (1H, dd, J=13.8 and 5.0 Hz), 4.32 (1H, dd, J=13.8 and 9.3 Hz), 5.10 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=8.2 Hz), 7.26-7.39 (4H, m), 7.53 (1H, dd, J=8.5 and 8.5 Hz), 7.61 (1H, m), 8.21 (2H, d, J=9 Hz).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1CCN2C(=NCCC2)CC1.[CH2:16]([NH:18][C:19](=[O:21])[O-:20])[CH3:17].[OH:22][C:23]1[C:24]([I:37])=[CH:25][C:26]2[CH:27]([CH2:35]C)[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1>C(Cl)Cl.O>[CH2:16]([NH:18][C:19](=[O:20])[O-:21])[CH3:17].[CH2:1]([O:22][C:23]1[C:24]([I:37])=[CH:25][C:26]2[CH:27]([CH3:35])[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1)[CH:2]=[CH2:3]
Reactant: CCC1c2cc(I)c(O)cc2C2CNCC12
Reactant: C=CCBr
Agent: CCNC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: C=CCOc1cc2c(cc1I)C(C)C1CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Allyl bromide (52 μL, 0.6 mmol) and DBU (65 μL, 0.6 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-iodo-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (116 mg, 0.3 mmol) in CH2Cl2 (3 mL), and stirred 2 hours at room temperature. The reaction solution was diluted with H2O and filtered through an Extrelut column, The column was washed with CH2Cl2 and the filtrate was concentrated. The crude product was purified via silica plug eluting with Hexanes/EtOAc (3/1, v/v) to afford 50 mg (39%-two steps) of the subtitle compound. MS calculated for C18H221NO3+H: 428, observed: 428.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (386 mg, 2 mmol), aniline (182 μL, 2 mmol) and DIEA(419 μL, 2.4 mmol) in 3 mL dioxane was stirred in microwave at 180° C. for 10 min. After removal of the solvent, the residue was dissolved in 3 mL DCM, subjected to silica gel column purification to give 308 mg (yield 61.7%) (6-chloro-3-nitro-pyridin-2-yl)-phenyl-amine. Calculated mass=249. Observed mass=250.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[O:13][C@@:14]3([CH2:22][N:23]=2)[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]3)[N:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[O:13][C@@:14]3([CH2:22][N:23]=2)[CH:19]2[CH2:18][CH2:17][N+:16]([O-:29])([CH2:21][CH2:20]2)[CH2:15]3)[N:2]=1
Reactant: c1ccc2cc(NC3=NC[C@]4(CN5CCC4CC5)O3)ncc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: [O-][N+]12CCC(CC1)[C@@]1(CN=C(Nc3cc4ccccc4cn3)O1)C2
Yield: 83.7 %

Procedure:
By a method similar to that used in Example 1, (S)—N-(isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (108 mg, 0.350 mmol) and 3-chlorobenzoperoxoic acid (72.5 mg, 0.420 mmol) gave (R)-2-(isoquinolin-3-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (95 mg, 83% yield). 1H NMR (500 MHz, MeOD) δ ppm 9.04 (1H, s), 7.97 (1H, d, J=8.24 Hz), 7.76 (1H, d, J=8.24 Hz), 7.61-7.67 (1H, m), 7.44-7.49 (2H, m), 4.03 (1H, d, J=10.99 Hz), 3.87 (1H, d, J=10.99 Hz), 3.65-3.77 (2H, m), 3.44-3.53 (3H, m), 3.27-3.31 (1H, m), 2.43-2.55 (1H, m), 2.32 (1H, br. s.), 2.04-2.22 (3H, m). LCMS: RT=0.54 min, MH+=325.2 [ Waters Acquity SDS: 2 to 98% B, 1 min gradient; hold 98% B, 0.5 min; flow rate 0.8 mL/min; Solvent A: 100% H2O/0.05% TFA; Solvent B: 100% ACN/0.05% TFA].
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]#[N:30])=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:24][C:25]([C:29]#[N:30])=[CH:26][C:27]=2[CH3:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CNC(=O)c1cc(C#N)cc(C)c1N
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cccnc1
Solvent: CC#N
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 2003/015519 for a method of preparation) (97.4% purity, 15 g, 0.049 mol) and 2-amino-5-cyano-N,3-dimethylbenzamide (see PCT Patent Publication 2006/62978 for a method of preparation) (10.0 g, 0.0525 mol) in acetonitrile (80 mL) was added 3-picoline (13.9 g, 0.148 mol). The mixture was cooled to 15 to 20° C., and then methanesulfonyl chloride (8.2 g, 0.071 mol) was added dropwise. After 1 h, water (37.3 g) was added dropwise to the reaction mixture while maintaining the temperature at 15 to 20° C. The mixture was heated at 45 to 50° C. for 30 minutes, and then cooled to 15 to 25° C. for 1 h. The mixture was filtered, and the solid collected was washed with acetonitrile-water (approximately a 5:1 mixture, 2×10 mL) and acetonitrile (2×10 mL), and then dried under nitrogen to afford the title compound as an off-white solid (24.0 g, 93.6% corrected yield based on an assay of 91.6%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)[OH:8]>[Pd].C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]([CH:7]([C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ncsc1C(O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ncsc1C(O)c1cccc(N)c1

Procedure:
1-(4-Methyl-5-thiazolyl)-1-(3-nitrophenyl)methanol (2 g) and 10% palladium on charcoal (200 mg) in ethanol (60 ml) were shaken overnight under an atmosphere of hydrogen. The mixture was filtered and the filtrate was evaporated to dryness. The residue was converted into the hydrochloride salt, recrystallised and then reconverted into the title compound. M.p. 137°-138° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15].Cl.O>C(OCCO)C>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(N)cc1F
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: O
Solvent: CCOCCO
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 82342.5 %

Procedure:
45 g (0.28 mmol) of 2-chloro-3-nitropyridine was dissolved in 2-ethoxyethanol (300 ml), and 36 g (0.28 mmol) of 3-fluoro-4-methylaniline, 12N-hydrochloric acid and water (300 ml) were added thereto. Mixed solution was heated to reflux for 24 hours while stirring. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The solution was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue thus obtained was washed with diisopropyl ether to obtain 57 g (yield: 82%) of N-(3-fluoro-4-methylphenyl)-3-nitro-2-pyridylamine.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[N:15]1([S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)N3CCCC3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), pyrrolidine (0.701 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and made acidic with 1N hydrochloric acid (16 mL). The organic layer was then washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL). It was then purified by chromatography on silica gel eluting with methanol:dichloromethane 1:9 to give 0.432 g (27%)-5-(pyrrolidine-1-sulfonyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[N:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH2:17][CH2:16][N:6]2[C:7]=1[C:8](O)([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]2[N:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[CH2:17][CH2:16][N:6]2[C:7]=1[C:8]([CH2:12][CH2:13][CH3:14])=[CH:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCC(O)(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 25 °C

Procedure:
A mixture of 4-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol (0.0444 g, 0.000120 mol) and p-toluenesulfonic acid-H2O (15 mole %) in toluene (3 mL) was heated at reflux for 1 h. Upon cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was partitioned between ether and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the desired product in quantitative yield. LC-MS indicated the presence of two regioisomers in an approximate ratio of 2:1. LC/MS: tR=1.52 min. and 1.63 min., (MH+)=352.28.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])([OH:3])=[O:2].[CH3:17]O.S(=O)(=O)(O)O>O>[CH3:17][O:2][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])=[O:3]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 1.0 g (4.5 mmol) 1-carboxymethylquinoxaline-2,3(1H,4H)-dione, 15 ml dry methanol and 0.2 ml concentrated sulfuric acid was stirred at 80° C. for 1 h. After cooling to 25° C. the reaction mixture was poured in water and made alkaline. The precipitate was filtered off and recrystallized (acetone) to give 0.22 g (21%) 1-methoxycarbonylmethylquinoxaline-2,3(1H,4H)-dione. M.p. 269° C. 1H-NMR (DMSO-d6): 12.0 (1H, broad s), 7.1 (4H, s), 4.9 (2H, s), 3.7 (3H, s).
Reaction SMILES: O=C1[C@H:10]2[C@H:5]([C@@H:6]3C[C@H:9]2[CH:8]=[CH:7]3)[C@@H:4]([NH:12][C@@H:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]([O:16]CC2C=CC=CC=2)=[O:15])O1.[ClH:28]>O>[ClH:28].[CH2:4]([NH:12][C@H:13]([C:14]([OH:16])=[O:15])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)C[C@H](NCc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 1 g of the product of Example 2, 8 ml of demineralized water and 0.8 ml of hydrochloric acid was sitrred at 20° C. for one hour and was then heated at 60° C. for one hour and was cooled at 20° C. The mixture was diluted with 15 ml of water and was then extracted with methylene chloride. The organic phase was washed with aqueous N sodium hydroxide solution and with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of ether and a stream of hydrogen chloride was slowly bubbled therethrough. The mixture was vacuum filtered to obtain 350 mg of benzyl L-leucine hydrochloride melting at 135° C. and having a specific rotation of [α]D20 =-5.5°±1° (c=1% in 0.1N hydrochloric acid).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:22]3[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncccc1-c1nc2c(C)c(F)ccc2cc1C=O
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (8.0 g, 35.77 mmol), 2-methylpyridin-3-ylboronic acid pinacol ester (9.58 g, 39.35 mmol), tetrakis-(triphenylphosphine)palladium(0) (207 mg, 18 mmol) and Na2CO3 (5.69 g, 53.66 mmol) in water (50 mL) and DME (100 mL) was degassed and flushed three times with nitrogen gas, then heated at 90° C. for 24 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with DCM (150 mL) and washed with water (150 mL). The aqueous phase was extracted with DCM (2×100 mL) and the combined organic fractions were washed with brine (150 mL), then dried (phase separator) and evaporated in vacuo. The crude material was triturated in hexane (50 mL), then the solid was filtered off and dried under vacuum to give the title compound (9.07 g, 90%) as a pale yellow solid. δH (DMSO-d6) 9.94 (s, 1H), 9.09 (1H, s), 8.61 (dd, J 4.9, 1.7 Hz, 1H), 8.26 (dd, J 8.9, 6.4 Hz, 1H), 7.78 (dd, J 7.7, 1.7 Hz, 1H), 7.69 (t, J 9.2 Hz, 1H), 7.40 (dd, J 7.7, 4.9 Hz, 1H), 2.61 (d, J 2.4 Hz, 3H), 2.34 (s, 3H). LCMS (ES+) 281 (M+H)+, RT 2.26 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:24])([F:23])[C:15](=[O:22])[CH:16]=[C:17](SC)SC>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][C:17]2=[CH:16][C:15](=[O:22])[C:14]([F:24])([F:23])[F:13])=[CH:4][CH:3]=1
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Reactant: NCCNCc1ccc(Cl)nc1
Solvent: CC#N
Product: O=C(C=C1NCCN1Cc1ccc(Cl)nc1)C(F)(F)F
Yield: 68.9 %

Procedure:
A solution of 77 mg (0.42 mmol) of the N-((6-chloropyridin-3-yl)methyl)ethane-1,2-diamine obtained by the foregoing method in 8 mL of anhydrous acetonitrile was added to 60 mg (0.28 mmol) of 1,1,1-trifluoro-4,4-bis(methylthio)-3-buten-2-one obtained by the foregoing method, and the mixture was refluxed under heating for 40 minutes. Following reaction completion, the reaction mixture was returned to room temperature and concentrated under reduced pressure, after which ethyl acetate and water were added, and liquid-liquid extraction was carried out. The organic phase was washed with anhydrous magnesium sulfate, then concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3:1), giving 59 mg of the target compound (yield, 69%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:14]=1>>[CH:30]1([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][C:18]3[N:19]([CH3:22])[C:20]4[C:16]([N:17]=3)=[C:15]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:14]=[C:13]([N:7]3[C:6]5[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:21]=4)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C3CCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4CCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 4-(2-chloro-8-((4-cyclobutylpiperazin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine were reacted to give 444. LCMS m/z: 516.3 (MH+)
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.[O:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:17](O)=[C:14]([O:15][CH3:16])[CH:13]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[CH:11]([C:12]1[CH:20]=[CH:19][C:17]([O:8][C:7](=[O:9])[C:3]2[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=2)=[C:14]([O:15][CH3:16])[CH:13]=1)=[O:10]
Reactant: O=C(O)c1cccnc1
Reactant: COc1cc(C=O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)ccc1OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Niacin 1 (1.6 g, 13.1 mmol) in dichloromethane (10 mL) was added Vanillin 8 (2 g, 13.1 mmol), N-methyl morpholine (4.3 mL, 39 mmol) and EDCI.HCl (5 g, 26.2 mmol). The resulting mixture was stirred at ambient temp for 3 h. It was then diluted with water, extracted with dichloromethane, and the organic layer dried over anhydrous sodium sulfate and concentrated. The crude product thus obtained was then chromatographed using over a column of silica gel using petroleum ether:ethyl acetate (1:1) to afford the title compound as a off white solid (300 mg, 9%, mp (° C.): 92-94) 1H NMR (300 MHz, DMSO-D6): 10.02 (s, 1H), 9.25 (d, J=2 Hz, 1H), 8.93 (dd, J=5 & 1.5 Hz, 1H), 8.48 (dt, J=1.8 Hz & 8 Hz, 1H), 7.67 (m, 3H), 7.57 (d, J=8 Hz, 1H), 3.87 (s, 3H)); LCMS (m/z): 257.7 (M+1); HPLC: tRet: 6.486 (98.9%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:30]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:20](=[O:21])[C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:18][CH2:17]2)=[O:29])[CH2:28][CH2:27]1)(=[O:32])[CH3:31]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182(A), 0.35 g, 0.79 mmol), acetyl chloride (72.5 mg, 1.02 mmol) and triethylamine (439 μL, 3.15 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give The title compound (0.34 g, quant.) as a white powder.
Reaction SMILES: C(Cl)CCl.ClC(Cl)C(O)=O.[CH:11]1([NH:14][C:15](=[O:46])[CH:16]([OH:45])[CH:17]([NH:25][C:26](=[O:44])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:33]2[N:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[S:36][CH:37]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH:11]1([NH:14][C:15](=[O:46])[C:16](=[O:45])[CH:17]([NH:25][C:26](=[O:44])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:33]2[N:34]=[C:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[S:36][CH:37]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:12][CH2:13]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-c1csc(-c2ccccc2)n1
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CS(C)=O
Product: O=C(NC1CC1)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
EDC (700 mg, 3.65 mmol) and 2,2-dichloroacetic acid (12411, 1.46 mmol) were added to a solution of N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(2-phenylthiazol-4-yl)nicotinamide (217 mg, 0.435 mmol) in dimethyl sulfoxide (DMSO) (4 ml), and the reaction mixture stirred for 10 min at room temperature. For work up the reaction mixture was mixed with 80 ml of sat. NaHCO3-solution for 10 minutes. The resulting solid was filtered off with suction, washed with water and dried in vacuo to give 193 mg of the title product as white amorphous solid;