Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]3[N:24]([C:55]4[N:56]=[CH:57][N:58]=[C:59]([NH2:62])[C:60]=4[N:61]=3)[C@@H:25]3[O:54][C@H:44]([CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C@@H:35]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:26]3[O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Si:28]([O:27][C@@H:26]1[C@H:35]([O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38])[C@@H:44]([CH2:45][O:46][Si:47]([C:50]([CH3:51])([CH3:52])[CH3:53])([CH3:48])[CH3:49])[O:54][C@H:25]1[N:24]1[C:55]2[N:56]=[CH:57][N:58]=[C:59]([NH2:62])[C:60]=2[N:61]=[C:23]1[NH:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)=[CH:20][CH:19]=1)([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:29])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4cccc(OCc5ccccc5)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4cccc(O)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.9 %

Procedure:
A mixture of 8-(3′-benzyloxybiphenyl-4-ylmethyl-amino)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)adenosine (0.713 g) and 10% palladium on carbon (55.4 wt % H2O, 0.480 g) in ethyl acetate (11 mL) was stirred at room temperature for 23 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give the title compound (0.615 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[C:7]#N.C(O)=[O:17]>[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=[O:17]
Reactant: O=CO
Reactant: N#Cc1cc(Cl)ccc1OCC(F)(F)F
Agent: [Ni]
Product: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask equipped with a refluxcondenser were placed 400 mg (1.7 mmol) of the above nitrile and 10 ml of formic acid. To the system were added ca. 500 mg of Raney nickel and the mixture was heated at reflux for 6 hours and stirred at room temperature overnight. The mixture was filtered through a pad of a diatomaceous earth,and the pad was rinsed with water and CHCl3. The layers were separatedand the aqueous phase was extracted with three portions of CHCl3. The combined organic fractions were dried and concentrated to obtain 270 mg ofthe title compound.
Reaction SMILES: [NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([O:25]CC)=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:28])[C:3]=1[F:29].OS(O)(=O)=O>CC(O)=O.O>[NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:28])[C:3]=1[F:29]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC[C@@H]2Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](Cc1ccccc1)CO2
Temperature: 0 °C
Yield: 94.5 %

Procedure:
To a suspension of ethyl (3S)-8-amino-9,10-difluoro-2,3-dihydro-7-oxo-3-phenylmethyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (100 mg, 0.250 mmol) in a mixture of AcOH (0.6 mL) and water (0.5 mL), was added H2SO4 (0.1 mL), the whole mixture was heated under reflux for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were suspended in water, filtered, and dried in vacuo to give (3S)-8-amino-9,10-difluoro-2,3-dihydro-7-oxo-3-phenylmethyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (88.0 mg, 95%) as a yellow powder.
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:2][CH3:1])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) was added 4-fluorophenylacetyl chloride (518 mg, 3.0 mmol) at −78° C. The reaction mixture was stirred from −78° C. to room temperature for 1 h. The solution was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtration, followed by concentration, provided the title compound (490 mg, 98%). MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:7]2([C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[CH2:6][C:5]([NH2:8])=[CH:4][N:3]([C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[C:2]2([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[NH2:1])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccc(N)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=CN(c2ccc([N+](=O)[O-])cc2)C(N)(c2ccc([N+](=O)[O-])cc2)C(c2ccc([N+](=O)[O-])cc2)(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 96 h

Procedure:
0.1 mole of 2,5-diaminopyridine, 0.43 mole of p-nitrochlorobenzene, 0.23 mol of anhydrous potassium carbonate, and 2 parts by weight of powdery copper in 130 parts of dimethylformamide was refluxed with stirring for 4 days. After the reaction, the reaction mixture was filtered. The filtered matter was washed with dimethyformamide, water, and acetone, and was dried to obtain 26 parts of tetrakis(p-nitrophenyl)-2,5-diaminopyridine.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:27]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1ccccc1)C(=O)O
Yield: 39 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with L-phenylalanine to provide the title compound in 39% yield as yellow needles (recrystallization from EtOH).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1.C([Li])CCC.[I-:15].Cl>C1COCC1>[I:15][C:5]1[S:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: [I-]
Reactant: Cc1nscc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nsc(I)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylic acid (E-4) (3.9 g, 27.3 mmol) in anhydrous THF (150 mL) at −78° C. under argon, n-butyl lithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at −78° C. for 1 h. To this mixture, a solution of iodide (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HCl to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2SO3 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3-methylisothiazole-4-carboxylic acid (E-5).
Reaction SMILES: FC(F)[O:3][C:4]1[CH:26]=[CH:25][C:7]2NC(C3C(NC(N4CCCCC4)=O)=CNN=3)=NC=2C=1.[NH:28]1[C:39]2[C:31](=[CH:32][C:33]3[CH2:34][CH2:35][CH2:36][C:37]=3[CH:38]=2)[N:30]=[C:29]1[C:40]1[C:44]([NH2:45])=[CH:43][NH:42][N:41]=1.C(N(CC)CC)C.C1(C(Cl)=O)CC1.[OH-].[K+].[Cl-].[NH4+]>O1CCCC1>[NH:30]1[C:31]2[C:39](=[CH:38][C:37]3[CH2:36][CH2:35][CH2:34][C:33]=3[CH:32]=2)[N:28]=[C:29]1[C:40]1[C:44]([NH:45][C:4]([CH:26]2[CH2:7][CH2:25]2)=[O:3])=[CH:43][NH:42][N:41]=1
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(OC(F)F)ccc2[nH]1)N1CCCCC1
Reactant: Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)CCC3
Agent: O=C(Cl)C1CC1
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)CCC3)C1CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
By proceeding in a similar manner to Example 258(a) above but (i) treating a solution of 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine [310 mg, Example 256(b)] and triethylamine (4 eq) in tetrahydrofuran (15 mL) with cyclopropanecarbonyl chloride (4 eq), (ii) stirring the reaction mixture at 60° C. for 2 hours, (iii) treating the resulting bis-acylated product with methanolic potassium hydroxide (20 mL, 10.05 g KOH) at 40° C. for 1 hour followed by treatment with aqueous ammonium chloride (200 mL), (iii) extracting this mixture three times with ethyl acetate (100 mL), (iv) evaporating the combined extracts and (v) chromatographing the residue on silica gel (ethyl acetate/gradient of 50-0% heptane) there was prepared cyclopropanecarboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide (50 mg) as a yellow solid. LC-MS (Method E) RT=2.05 minutes, 308 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[SH:16].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([S:16][C:12]2[NH:11][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:8]=[O:9]
Reactant: Sc1ncc[nH]1
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cncc1Sc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
A mixture of 3,5-dichloro-pyridine-4-carbaldehyde (600 mg, 3.41 mmol), 1H-imidazole-2-thiol (341 mg, 3.41 mmol) and Cs2CO3 (1.33 g, 4.09 mmol) in THF (10 mL) was stirred at RT for 8.5 h. The solvent was removed in vacuo and the residue was partitioned between EA (30 mL) and brine (30 mL). After extraction of the aqueous layer with EA (2×30 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 240.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.Cl.[CH3:21][O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH:25][C@H:24]([C:23]([O:22][CH3:21])=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 87 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and (L)-phenylalanine methyl ester hydrochloride (215 mg, 1.0 mmol) to give 390 mg of a diastereomeric mixture of the title compound (87%): mp 170°~174° C. The mixture (300 mg) was separated by preparative thin layer silica gel chromatography with 1% acetic acid/ethyl acetate to give 110 mg of the less polar product and 120 mg of the more polar product. Less polar product: 1H NMR (270 MHz, DMSO-d6) δ12.12 (s, 1H), 8.59 (d, 1H, J=7.6 Hz), 7.06~7.26 (m, 7H), 5.14~5.22 (m, 1H), 4.40~4.51 (m, 1H), 3.58 (s, 3H), 3.03 (dd, 1H, J=13.5, 4.5 Hz), 2.89 (dd, 1H, J=13.5, 9 Hz), 2.64 (dm, 1H, J=16.8 Hz), 2.37 (dm, 1H, J=12.6 Hz), 2.14~2.28 (m, 1H), 1.78~1.93 (m, 1H). More polar product: 1H NMR (270 MHz, DMSO-d6) δ12.14 (s, 1H), 8.77 (d, 1H, J=7.6 Hz), 7.19~7.34 (m, 5H), 7.15 (d, 1H, J=2 Hz), 7.06 (d, 1H, J=2Hz), 5.13~5.18 (m, 1H), 4.47~4.58 (m, 1H), 3.63 (s, 3H), 3.10 (dd, 1H, J=13.5, 5.4 Hz), 2.85 (dd, 1H, J =13.5, 9.9 Hz), 2.44~2.56 (m, 1H), 2.10 (dm, 1H, J=12.6 Hz), 1.75~2.02 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[C:17]([C:25]4[NH:33][C:32]5[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=5[CH:26]=4)[CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][C:23]1[C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[C:25]2[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=2)[N:22]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
Prepared according to Example 53, using (R)-tert-butyl-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)pyrrolidine-1-carboxylate (Ex. 48, 150 mg, 0.506 mmol), and TFA (940 μl, 12.66 mmol) in DCM (20 mL), stirring at 25° C. for 1.5 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided (R)-2-(2-methyl-3-(pyrrolidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (140 mg, 76%). 1H NMR (DMSO-d6) δ: 12.20 (s, 1H), 7.85-7.92 (m, 1H), 7.54-7.61 (m, 1H), 7.28-7.37 (m, 1H), 7.12 (s, 1H), 6.95 (s, 2H), 4.40-4.52 (m, 1H), 3.40-3.51 (m, 3H), 3.09-3.14 (m, 1H), 2.94-3.07 (m, 2H), 2.88 (s, 3H), 2.58-2.69 (m, 1H), 2.11-2.23 (m, 1H), 1.81-1.95 (m, 1H). m/z (ESI, +ve) 363.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][CH2:24][C:25](OC)=[O:26])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][CH2:24][CH2:25][OH:26])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2oc(CCCO)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
A solution containing 100 mg (0.239 mmol) of 3-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]propanoic acid, methyl ester in 10 mL of tetrahydrofuran was cooled to 0° C. with stirring under a nitrogen atmosphere as 0.53 mL of diisobutylaluminum hydride (1M in toluene, 0.523 mmol) was added dropwise over 5 minutes. The reaction was allowed to warm to 25° C. and poured into 100 mL of a saturated solution of sodium potassium tartarate. Ethyl acetate (100 mL) was added and the mixture was stirred until the layers separated (approx. 1 hour). The organic layer was separated and dried over sodium sulfate. Concentration in vacuo gave an oily solid, which was recrystallized from 50% ethyl acetate-isooctane to give 75 mg of a white crystalline solid (mp 123°-124° C.) which was characterized on the basis of its spectral characteristics: 1H-NMR (CDCl3, 300 MHz) ∂ 2.10 (m, 2H), 2.56 (bs, 1H), 3.01 (t, 2H, J=7.0 Hz), 3.07 (s, 3H), 3.80 (t, 2H, J=5.9 Hz), 7.09 (t, 2H, J=8.5 Hz), 7.57 (dd, 2H, J=8.5 and 5.5 Hz), 7.73 (d, 2H, J=8.5 Hz) and 7.89 (d, 2H, J=8.5 Hz). 19F-NMR (CDCl3, 280 MHz) ∂-111.97. LRMS m/z 376 (M+H)+. HRMS calc. for C19H18NO4FS: 376.1019. Observed: 376.1026. Analysis calc. for C19H18NO4FS-C: 60.79, H: 4.83, N: 3.73. Observed-C: 60.53, H: 4.85, N: 3.66.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]1[CH:6]=[C:7]([CH2:25][OH:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:2][CH3:3].C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:6]=[C:7]([CH:25]=[O:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:28][CH3:29]
Reactant: CCCN(CCC)c1cc(CO)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCN(CCC)c1cc(C=O)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1-(Dipropylamino)-3-(hydroxymethyl)-6-mesityl-4H-quinolizin-4-one (0.60 g, 1.53 mmol) was dissolved in dichloromethane (20 mL) and acetonitrile (4 mL). 0.5 g of crushed sieves (4 angstroms) was added followed by N-methylmorpholine N-oxide (NMO) (0.27 g, 2.3 mmol). Tetrapropylammonium perruthenate (TPAP) (0.081 g, 0.23 mmol) was added last. The reaction stirred for 0.5 h. The solution was filtered and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.436 g (73% yield) of the title compound as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C@@H:24]([NH:29][C:30]([N:32]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39](=O)[CH2:40][CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:42][CH:41]([CH3:43])[CH2:40][CH3:39])[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C@@H:24]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(C)CN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 169.3 %

Procedure:
(S)-Azepane-1-carboxylic acid {1-[4-(4-benzyloxy-phenylamino)-piperidine-1-carbonyl]-3-methyl-butyl}-amide (Example 28) (0.30 g, 0.28 mmol) was dissolved in CH2Cl2 (5 mL) and treated with isovaleraldehyde (62 μL, 0.58 mmol). The reaction was stirred for 30 minutes at RT, then cooled to 0° C., treated with NaBH(OAc)3, allowed to warm to room temperature as the ice melted and stir overnight. The reaction was then diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 3:2 hexane/EtOAc to give 0.28 g (82%) of the desired product.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][CH2:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>ClCCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[S:13][CH2:14][CH3:15])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCSc1nc2ccccc2c(=O)n1N
Solvent: ClCCCl
Product: CCSc1nc2ccccc2c(=O)n1NC(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 3-amino-2-ethylthio-4-quinazolone (0.60 g, 2.71 mmol) and 4-chlorophenyl isocyanate (0.48 g, 3.13 mmol) in 1,2-dichloroethane is heated at reflux for 63 hours, cooled to 0° C. and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 0.84 g (83%) mp 234°-235° C.
Reaction SMILES: O=O.[Br:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][C:7](=O)[CH2:8][O:9]2.BrC1C=C(O)C=CC=1.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>>[Br:3][C:4]1[CH:5]=[C:10]([O:9][CH2:8][CH:7]=[CH2:6])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COc2cccc(Br)c2C1
Agent: O=C([O-])[O-]
Agent: O=O
Agent: Oc1cccc(Br)c1
Solvent: C=CCBr
Product: C=CCOc1cccc(Br)c1

Procedure:
The compounds of this invention in which X is oxygen are available by reductive amination and bromo replacement as in the foregoing, but using 5-bromo-3-chromanone. The latter can be produced by a sequence of reactions beginning with m-bromophenol. Briefly, m-bromophenol is treated with allyl bromide in the presence of potassium carbonate to produce allyl 3-bromophenyl ether. The ether is converted to 2-allyl-3-bromophenol upon heating it in the presence of N,N-dimethylaniline. The phenol, upon reaction with ethyl chloroacetate, is converted to the ethyl ester of 2-allyl-3-(carboxymethoxy)bromobenzene. Upon oxidation using ozone followed by reductive work up, the allyl group is converted to a formylmethyl substituent which is then further oxidized using Jones' Reagent to the carboxymethyl substituent, the resulting product being the ethyl ester of (2-carboxymethyl-3-bromo)phenoxyacetic acid. The partial ester is converted to the diethyl ester using ethanol and gaseous hydrogen chloride. In the presence of potassium t-butoxide, the diester is cyclized to a mixture of 4-ethoxycarbonyl-5-bromo-3-chromanone and 2-ethoxycarbonyl-5-bromo-3-chromanone. Upon heating in the presence of acid, the latter is converted to 5-bromo-3-chromanone.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[C:11]=1[CH3:18])(=O)C>O.C(O)C>[OH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:6])[C:11]=1[CH3:18]
Reactant: COc1cccc(OC(C)=O)c1C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: COc1cccc(O)c1C
Temperature: 120 °C
Reaction time: 0.6 h
Yield: 87.7 %

Procedure:
A solution of 18.0 mL of concentrated sulfuric acid in 90 mL water was added to a solution of 4.69 g (26.0 mmol) of 2-acetoxy-6-methoxytoluene in 360 mL ethanol and heated and stirred on a 120° C. oil bath for 36 minutes. The reaction mixture which had been allowed to stand at room temperature overnight was transferred to a separatory funnel, extracted with 50 mL and 20 mL of toluene, and after the combined organic layers were washed with 30 mL of water, 30 mL of 5% sodium hydrogen carbonate aqueous solution and 30 mL of water twice, the solvent was evaporated to obtain 3.15 g of title compound.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[C:26](=[O:27])[O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)CCN1CCCc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: CN(CCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.4 %

Procedure:
A solution of N,N-dimethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanamine (500 mg, 2.01 mmol) in 10 mL CH2Cl2 was treated dropwise with phenylchloroformate (378 μL, 3.01 mmol). The reaction was stirred at room temperature for 17 hours then partitioned between CH2Cl2 100 mL and 1N NaOH (20 mL). After extraction, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a yellow residue. This residue was subjected to flash chromatography on silica gel using 20% EtOAc/CH2Cl2 to give a yellow residue (610 mg, 85.4%). 1H-NMR (CDCl3) δ 7.99-7.92 (m, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.39-7.33 (m, 2H), 7.23-7.19 (m, 1H), 7.06-7.01 (m, 2H), 6.69 (m, 1H), 3.67-3.52 (m, 4H), 3.48 (t, J=5.7 Hz, 2H), 3.14 and 3.07 (2×s, 3H), 2.79 (t, J=6.3 Hz, 2H), 1.99-1.96 (m, 2H). MS (ESI): 356.2 (M+1).