Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]1([NH:47][C:48](=[O:72])[C@H:49]([CH2:51][S:52][C:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH2:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:50][C@@H:49]([CH2:51][S:52][C:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]([NH:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:72])=[O:20])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)Nc1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)Nc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
456 mg (0.68 mmol) of the compound from example 2A was dissolved in 8 ml dichloromethane. 300 mg (0.68 mmol) N-Phenyl-S-trityl-L-cysteinamide, 0.12 ml (0.68 mmol) N,N-diisopropylethylamine and 260 mg (0.68 mmol) HATU were added. The reaction mixture was stirred at room temperature for 4 h. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified in two portions by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 361 mg (0.37 mmol, 53% of theory) of the desired product.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:28][CH3:29])[C:23]=2Br)[CH:18]=1)(=[O:16])[CH3:15].BrC1C2C(=CC=CC=2)C=CC=1OC>>[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:28][CH3:29])[CH:23]=2)[CH:18]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: COc1ccc2ccccc2c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
51 Ml of mesitylene and 8.2 g of anhydrous aluminum chloride are added to the solution of 2-acetyl-5-bromo-6-methoxynaphthalene obtained as in example 1a), while keeping the temperature at -10° C. The reaction mixture is kept for 3 hours under stirring at 0° C. and then it is worked as in example 1 obtaining 43.2 g of product with a yield equal to 88.2% calculated on the basis of the starting material 1-bromo-2-methoxynaphthalene.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH3:14])[CH:6]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH3:14])[CH:6]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(OCCCl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene (2.1 g, 9.7 mmol), N-methylpiperazine (1.5 g, 15 mmol) and potassium carbonate (3.4 g, 0.025 mol) in N,N-dimethylformamide (15 mL) was stirred with heating at 70° C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford 1-methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine as solid (1.8 g, y. 64%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:16][OH:17]>>[Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([O:17][CH3:16])=[O:5]
Reactant: CO
Reactant: COC(=O)c1c(Cl)ccc(C(=O)Cl)c1Cl
Product: COC(=O)c1ccc(Cl)c(C(=O)OC)c1Cl

Procedure:
2,4-Dichloro-3-methoxycarbonylbenzoylchloride (34.76 g) was stirred and heated under reflux with methanol for 15 hours. After cooling, the solvent was evaporated and the residue recrystallised from cyclohexane to give dimethyl 2,4-dichloroisophthaloate (16.04 g) as a beige solid, NMR (DMSO D6) δ3.87 (3H,s), 3.94 (3H,s), 7.74 (1H,d), 7.94 (1H,d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][NH:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([C:26]2[CH:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.[F-].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][NH:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([C:26]2[CH:27]=[N:28][C:29]([C:40]3[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCC(COc1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)c1ccc(Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCC(COc1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C

Procedure:
3-{4-[2-(6-Chloro-pyridin-3-yl)-octyloxy]-benzoylamino}-propionic acid tert-butyl ester (180 mg, 0.369 mmol) is dissolved in toluene (2.5 mL), followed by palladium tetrakis triphenylphosphine (23 mg, 0.0197 mmol), 4-trifluoromethyl-phenyl boronic acid (81 mg, 0.43 mmol), and potassium fluoride (46 mg, 0.75 mmol). The reaction is purged with nitrogen and heated to reflux, then the water (2.5 mL) is added. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with EtOAc and then celite added, followed by water. This mixture is then filtered through a pad of celite. The solution is separated in a separatory funnel, then the organic layer is washed with 0.1N sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated. The product is purified by flash column chromatography (110 mg).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(O)=[O:2].S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:31][C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O
Solvent: c1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O

Procedure:
A solution of ethyl 8-carboxy-12-acetoxyheptadecanoate (12.0 g., 0.03 mole) and thionyl chloride (7.2 g., 0.06 mole) in benzene (50 ml.) is refluxed for 2.5 hours. Volatile materials are removed by using a rotary evaporator in vacuo. The residual product, ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate, is a viscous liquid weighing 12.5 g. (100%), ir (neat) 1790 cm-1 (acid chloride C=O), 1730 cm-1 (ester C=O). This material is used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[I-].[K+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2cccs2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Temperature: 80 °C
Yield: 90 %

Procedure:
To a solution of 3-ethyl-2-methoxy-6-methyl-5-(thiophen-2-yl)pyridine (6.15 g, 26.36 mmol) of the above reaction, potassium iodide (8.75 g, 52.71 mmol) and acetonitrile (80 mL) is added chlorotrimethylsilane (6.69 mL, 52.71 mmol) and the resulting cloudy mixture is heated to 80° C. for 2 hr. The reaction is cooled, poured into water and the solids collected by filtration, washed with water, with ethyl acetate and dried giving 3-ethyl-6-methyl-5-(thiophen-2-yl)-1H-pyridin-2-one as a yellow solid (90% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Cl:1])=[N:3][CH:4]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3c(Cl)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1ccc2c(Cl)nccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
1-Chloro-6-(4-toluenesulfonylamino) isoquinoline (3.323 g, Production Example 22b) was dissolved in sulfuric acid (30 ml), followed by stirring at room temperature overnight. The reaction solution was poured into ice, and basified by adding an aqueous sodium hydroxide solution and then potassium carbonate thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (1.37 g, 76.81%) as yellowish brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11]CC)[CH3:10]>C(OC(=O)C)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)ccn1
Temperature: 25 °C
Yield: 95 %

Procedure:
2-Amino4-methylpyridine (99.0 g, 91.5 mmol) in acetic anhydride (250 mL) was warmed to 70° C. for two h. The mixture was cooled to room temperature and diethyl ether (100 mL) added. The product crystallized as white needle crystals. Filtering and drying in vacuo afforded N-(4-methyl-pyridin-2-yl)-acetamide (130 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][C:34]=1[Cl:35])[O:25][C@@H:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C.CCOC(C)=O>[Cl:35][C:34]1[CH:33]=[CH:32][C:24]([O:25][C@@H:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=1[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2)[C:10]([CH3:11])=[C:2]1[CH3:1]
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cc(O[C@@H](C)C(=O)OC)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (0.34 g, 1.483 mmol) in anhydrous DMF (3 mL) at 0° C. under argon protection was added NaH (0.08 g, 2.22 mmol). The mixture was stirred at rt for 30 min and re-cooled to 0° C., and then the (S)-methyl 2-(3-(bromomethyl)-4-chlorophenoxy)propanoate (0.55 g, 1.78 mmol) was added. The reaction was stirred at rt for another 1 h. The solvent was removed to obtain the crude, which was dissolved in EtOAc, then washed with water and brine and dried over Na2SO4. The solvent was removed to obtain the crude. The crude was purified by flash chromatography (AcOEt/Hexane 0-100%) to obtain the title compound. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:6]=2)[O:3]C1.Cl.[Cl-].[Na+]>O1CCCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(Cc2ccc(C3OCCO3)cc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(Cc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4-(3-Methoxyphenylmethyl)benzaldehyde ethylene acetal (700 mg, 2.6 millimol) was dissolved in tetrahydrofuran (5 ml), and thereto was added 10% hydrochloric acid. After stirring at room temperature for 30 minutes, to the mixture was added saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed, dried over anhydrous sodium sulfate, and the solvent was distilled away to give the title compound (580 mg, 2.6 millimol, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:17]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:17])=[O:11])[CH2:7]1
Reactant: [NH4+]
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(OC2CN(C(N)=O)C2)c1
Reaction time: 18 h
Yield: 50 %

Procedure:
A stirred solution of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 1.9 g (2 ml) (0.03 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water. The oil which separated solidified on standing, (3.2 g), and was recrystallized from isopropanol, yielding 1 g (50%) of fine white crystals, m.p. 167°-168° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][S:33]([C:36]1[CH:41]=[C:40]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCCCC3)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Yield: 50.7 %

Procedure:
To a solution of (6′-chloro-3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-2′-yl)-(4-trifluoromethoxyphenyl)-amine (200 mg, 0.53 mmol) in 1,4-dioxane (8 mL) were added sodium carbonate (1N solution; 228 mg, 2.12 mmol), and tetrakis(triphenylphosphine) palladium(0) (62 mg, 0.053 mmol), followed by 3-(methanesulphonyl)-phenyl boronic acid (215 mg, 1.06 mmol). This reaction mixture was refluxed for 12 hours, after which time water was added (10 mL) to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified through column chromatography using 230-400 mesh silica gel (15% ethyl acetate in petroleum ether) to afford the desired compound as a colorless solid (132 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:14]C(=O)N)[CH2:9][C:10]([N:12]=[O:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.ClC1C=C([C@H](O)CO)C=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:14])[CH2:9][C:10]([N:12]=[O:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)O[C@@H](CC(=O)N=O)c1cccc(Cl)c1
Agent: OC[C@@H](O)c1cccc(Cl)c1
Solvent: CO
Product: O=NC(=O)C[C@H](O)c1cccc(Cl)c1
Yield: 25 %

Procedure:
(S)-(2-(3-Chlorophenyl)-2-carbamoyloxyethyl)oxocarboxamide (1.36 g, yield 25%, m.p. 117-119° C., [α]D =12.88 (c=2.30, MeOH) was prepared using the same synthetic method described in Example 20, except (S)-1-m-chlorophenyl-1,2-ethanediol was used instead of (DL)-1-m-chlorophenyl-1,2-ethanediol.
Reaction SMILES: [OH-].[Na+].C([S:6][CH2:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:10])(=O)C>CO.C(OCC)(=O)C>[SH:6][CH2:7][CH:8]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:10]
Reactant: COC(=O)CCCCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCCCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1N Sodium hydroxide (12.9 ml., 3.8 equiv.) is added dropwise over 10 minutes to a chilled solution (ice bath) of the product from part (b) (1.20 g., 3.41 mmole) dissolved in methanol (13 ml.) under a nitrogen atmosphere. The mixture is stirred at 0° for 10 minutes and then allowed to warm to room temperature and stirred for 3 hours. The mixture is concentrated to half volume in vacuo. The residue is diluted with water (40 ml.) washed with chloroform (2×20 ml.), and acidified to a pH of about 1.5 with concentrated hydrochloric acid. The resulting white suspension is extracted with ethyl acetate (3×15 ml.). These organic extracts are combined, washed with water and brine (20 ml. each), dried (Na2SO4) and concentrated to yield a white waxy solid (0.82 g.). This solid is dissolved in ethyl acetate, filtered, concentrated and the residue triturated with ether to give (±)-5-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino] pentanoic acid as white solids; m.p. 78°-79°. TLC (silica gel, 4:1 benzene/acetic acid) Rf =0.30 (slight tailing).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:12]=3[NH:11][C:10]2=[O:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[C:42]([F:45])[CH:43]=[CH:44][C:31]1=2.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:45][C:42]1[CH:43]=[CH:44][C:31]2[C:30](=[CH:29][C:16]3[CH:15]=[CH:14][C:13]4[N:9]([CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[C:10](=[O:27])[NH:11][C:12]=4[CH:17]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[CH2:34][O:33][C:32]=2[CH:41]=1
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c(=O)n3CCN2CCOCC2)OC1(C)C
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc2n1CCN1CCOCC1
Yield: 16.5 %

Procedure:
Following procedures essentially as described in Example 219, mix 1-(2-morpholin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (300 mg, 1.03 mmol), 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E isomer, 330 mg, 1.08 mmol), 2N Na2CO3 (1.4 mL), dioxane (10 mL) and (Ph3P)4Pd (44 mg, 0.038 mmol). Purify the crude product by column chromatography using 40% THF/hexane to yield 80 mg title compound as a pale yellow powder. HPLC (ISO80-10M) t=1.84 (96%), MS (ES) 472 (M+1), 470 (M−1). H NMR (DMSO-d6)10.72 (s, 1H), 7.57 (m, 2H), 7.35 (t, 1H, J=7.5 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.00 (d, 1H, J=7.5 Hz), 6.97 (s, 1H), 6.93 (d, 1H, J=8.4 Hz), 6.79 (td, 1H, J=11.9, 4.3 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.60 (m, 2H), 5.82-4.79 (m, 2H), 3.80 (t, 2H, J=6.4 Hz), 3.46 (t, 4H, J=4.4 Hz), 2.48 (m, 2H), 2.38 (s, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[C:12](=[CH2:15])[CH2:13][CH2:14][C:3]=12.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C(O)(C)C>O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[CH:12]([CH2:15][N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])[CH2:13][CH2:14][C:3]=12
Reactant: C=C1CCc2c(C)c3ccccc3n2C1=O
Reactant: Cc1ncc[nH]1
Solvent: O
Solvent: CC(C)O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cn1ccnc1C)CC2
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-methylenepyrido[1,2-a]indol-6(7H)-one (142 mg), 2-methylimidazole (180 mg), isopropyl alcohol (1 ml) and water (0.4 ml) was heated at 100° C. for 3 hours. The reaction mixture was purified by a procedure analogous to that of Example 74 to give 8,9-dihydro-10-methyl-7-[(2-methyl-1H-imidazol-1-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (60 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH2:25][OH:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1.N#N.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: N#N
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To an ice-cold solution of compound 10a (320 mg, 0.92 mmol) in dry CH2Cl2 (10 mL) in a N2 atmosphere was added Dess-Martin periodinane (DMP) (600 mg) portion wise and the reaction mixture was stirred for 3 hours at RT. The reaction mixture was quenched with solid NaHCO3 at 0° C. The product was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a 3:7 mixture of ethyl acetate and pet-ether as the eluent to afford compound 12a (220 mg) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)[C:14]([N+:27]([O-])=O)=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1.[CH2:30](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]3[N:17]([C:18]4[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=4)[CH:30]=[N:27][C:14]3=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(-n2cnc3ccc(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 20, 0.5 g) was dissolved into ethanol (20 mL) with Pd—C (60 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.29 g of the title compound. MS (electrospray): 383 (M+1) for C18H19FN8O. 1H NMR (300 MHz, CD3OD) δ ppm 8.75 (s, 2H) 8.35 (s, 1H) 7.80 (d, 1H) 6.80 (d, 1H) 6.30 (s, 1H) 5.30 (m, 1H) 4.70 (m, 1H) 1.55 (d, 3H) 1.35 (d, 6H).