Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].CI.[CH2:27]1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[C:5]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 gm, 3 mmol) (example 9), methyl iodide (1 ml, excess) and 18-Crown-6 (500 mg) in acetone (250 ml), K2CO3 (10 gm, excess) was added and the reaction mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexanes to afford 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield 1.0 g, 98%; MS: 349 (M+H)+.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:26][CH2:27]1)[OH:32]
Reactant: O=CC1CCN(CCc2ccc(F)cc2)CC1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of veratrole (0.93 g, 6.7 mmol) in THF (20 mL) under argon at 0° C. was added n-BuLi (2.7 mL of a 2.5 M solution in hexane, 6.75 mmol). After stirring 2.5 h, the solution was cooled to −78° C. and treated with 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde (1.30 g/ 5.5 mmol) in THF (25 mL) via an addition funnel. The cooling bath was removed and the solution was allowed to stir for 2 hours. Water was added, the layers separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a white solid. The solid was recrystallized from hexane to afford racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as shiny white needles, m.p. 126-127° C. Anal. Calcd for C22H28FNO3: C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[C:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>ClC(Cl)C>[C:25]1([CH2:31][CH2:32][NH:33][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: NCCC1=CCCCC1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: O[C@H](CNCCC1=CCCCC1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-(1-cyclohexenyl)ethylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS-80%, [M+H]+=411.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19][CH3:20])[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:17][O:16][C:14]1[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19][CH3:20])[C:5](=[O:21])[C:4]=2[CH:3]=[C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(N)cc1C2=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc2c1C(=O)c1c(OC)cc(NS(C)(=O)=O)cc1C2=O
Temperature: 90 °C

Procedure:
2-Amino-9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene (1.5 g) was dissolved in dry pyridine (30 ml) and freshly distilled methanesulphonyl chloride (0.61 g) slowly added. The mixture was heated to 90° C. for 3 hours under an atmosphere of nitrogen before being allowed to cool to room temperature. The mixture was then poured into water (150 ml), generating a brown precipitate. The solid was collected by filtration and dried in vacuo over silica gel to yield N-(4,5-dimethoxy-9,10-dihydro-9,10-dioxoanthracen-2-yl)methanesulphonamide at 94% purity (HPLC) as brown lustrous crystals. To improve purity, the crystals were dissolved in 2N sodium hydroxide solution, washed with CHCl3, and filtered to remove any remaining solid residue.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:19]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[C:19]=3[CH3:28])[C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cn2c(CF)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Into a 250 ml of round bottom flask with 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (3 g, 10.95 mmol) in N,N-Dimethylformamide (DMF) (50 mL) was added 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (4.16 g, 16.42 mmol) and potassium carbonate (4.54 g, 32.8 mmol). The resulting reaction mixture was stirred 1 h at 80° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 6.84 mmol, 62.4% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (s, 3H) 5.54-5.78 (m, 4H) 6.51 (d, J=7.83 Hz, 1H) 7.18 (t, J=7.83 Hz, 1H) 7.64 (d, J=7.83 Hz, 1H) 8.13 (d, J=1.77 Hz, 1H) 8.44 (d, 1H); LC/MS: MS (ES+) m/e 447 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.C[Si]([N:31]=[C:32]=[O:33])(C)C.C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:32]([NH2:31])=[O:33])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), (trimethyl)silyl isocyanate (78 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and THF, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (39.5 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10]C2CCC(=O)CC2)=[N:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]1[CH:4]1[CH2:9][CH2:8][CH:7]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:6][CH2:5]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2noc3ccccc23)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3oc4ccccc4c3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[d]isoxazol-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=O.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:22]\[OH:23])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: NO
Reactant: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2cc(F)ccc2F)c(O)c1Cl

Procedure:
A mixture of 28 g of 3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone and 26 g of hydroxylamine HCl in 250 ml pyridine is refluxed for three hours. Pyridine is evaporated and the residue partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a solid product as a mixture of isomers. The solid is heated at 200°-210° C. for approximately 30-45 minutes and recrystallized from toluene giving E-3-chloro-2',5'-difluro-2-hydroxy-4-methoxybenzophenone oxime, mp 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(P(CCCC)(CCCC)=CC#N)CCC.[CH3:49][C:50]([O:53][C:54]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:55])([CH3:52])[CH3:51]>C1(C)C=CC=CC=1>[C:60]([O:59][C:57]([N:56]([C:54]([O:53][C:50]([CH3:52])([CH3:51])[CH3:49])=[O:55])[CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][C@@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])=[O:58])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC[C@@H](CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (282 mg, 0.589 mmol; Example 186, Step A), 2-(tributylphosphoranylidene)acetonitrile (171 mg, 0.707 mmol) and di-tert-butyl iminodicarbonate (256 mg, 1.179 mmol) in toluene (3 mL) under argon was stirred at 110° C. for 2 h. Flash column purification on silica gel (0 to 60% EtOAc in hexanes) gave the title compound. Mass Spectrum (ESI) m/z=677 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(O)(=O)=O>>[CH2:7]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCO
Reactant: N#CCC(=O)O
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCOC(=O)CC#N

Procedure:
Cyanoacetic acid (20.85 g, 0.245 mol) was added to decanol (47 mL, 0.25 mol) and methane sulfonic acid (0.5 mL, 7.8 mmol), followed by heating under reduced pressure while removing the water by-product through the use of a dean stark trap. The reaction was cooled upon completion, providing the title compound in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[N:14][C:13]([CH3:18])=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([F:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(Br)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(C)nc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 110 mg (0.352 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 106.1 mg (0.423 mmol) of 2-bromo-6-bromomethyl-pyridine, 16.9 mg (0.423 mmol, 60% dispersion in oil), and 2 mL of N,N dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3-fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C23H17BrFN3O3 [M+H]: 482.04 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.6 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH:9]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:38])=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:38])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH:9]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2Cc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: FC(F)(F)c1nc(Cl)c2c(n1)C(Cc1ccccc1)N(Cc1ccccc1)CC2
Temperature: 150 °C
Yield: 66 %

Procedure:
A mixture of 669 mg (1.68 mmol) of 7,8-dibenzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol and 1.2 mL of phenylphosphonic dichloride was heated in a sealed tube at 150° C. for 2.5 h. The mixture was cooled to ˜100° C., then poured into crushed ice, washing with ethyl acetate. The resultant biphasic mixture was neutralized with solid sodium bicarbonate to ˜pH 8 with vigorous stirring. The ethyl acetate layer was removed. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried, and concentrated to give a red, viscous oil. Purification by Biotage chromatography (silica gel, 5% ethyl acetate/hexane) gave 464 mg (66%) of the title compound as a yellow solid. LC-MS 418.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=O.O>ClCCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:7][C:13]([C:12]([OH:17])=[O:16])=[CH2:15])=[O:6]
Reactant: COc1ccccc1C(N)=O
Reactant: CC(=O)C(=O)O
Solvent: O
Solvent: ClCCCl
Product: C=C(NC(=O)c1ccccc1OC)C(=O)O
Yield: 8.5 %

Procedure:
A suspension of 2-methoxybenzamide in 1,2-di-chloroethane (24.5 ml/g) is brought to reflux in the presence of 3 equivalents of freshly distilled pyruvic acid in a round-bottomed flask surmounted by a system which makes it possible to remove the water formed during the reaction. When the formation of water has finished 15 (approximately 7 hours), the reaction mixture is left at room temperature. After filtering off the insoluble materials, the filtrate is extracted with an aqueous sodium bicarbonate solution. The combined aqueous phases are extracted with dichloromethane and then acidified with hydrochloric acid. The precipitate formed is filtered off, dried and then taken up in ethyl acetate. After filtering off the insoluble material, the filtrate is concentrated under vacuum, dissolved in dichloromethane and then precipitated with heptane, thus providing pure N-(2-methoxybenzoyl)dehydroalanine. (Nonoptimized yield 8.5%).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]2[C:32]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[N:33][O:34][C:30]=2[CH:29]=1>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:32]1[C:31]2[CH:46]=[CH:47][C:28]([NH:27][C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:16]=4[CH:17]=[CH:18][C:19](=[O:25])[NH:20]5)[C:10]3=[O:26])=[CH:29][C:30]=2[O:34][N:33]=1
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2cccc3[nH]c(=O)ccc23)C1=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1)[C@H]1OCCN(c2cccc3[nH]c(=O)ccc23)C1=O

Procedure:
According to the Step 15-1 in the synthetic method for Example aa15, (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetic acid (compound aa16-4) and 6-amino-3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(1R)-2-[[3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]ethyl]acetate (compound ap3-1), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap3.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH3:13])(=O)=O)=CC=1.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:12]([CH3:13])[CH2:11][N:39]2[CH2:40][CH2:41][N:36]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)=[CH:19][CH:18]=1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)c2ccc(C(=O)c3ccccc3)cc2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Product: CC(CN1CCN(Cc2ccccc2)CC1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
Reaction of 2-(4-benzoylphenyl)propyl p-toluenesulfonate with 1-benzylpiperazine in acetonitrile and isolation of the product in the form of the free base affords 1-[2-(4-benzoylphenyl)propyl]-4-benzylpiperazine. Conversion of the latter to the ethylene glycol ketal, catalytic reduction of the latter over palladium-on-charcoal at a hydrogen pressure of 50 p.s.i. in order to effect catalytic debenzylation thereof using the manipulative procedure described in Example 10 above, cleavage of the ketal with aqueous hydrochloric acid, and isolation of the product in the form of the dihydrochloric salt affords 1-[2-(4-benzoylphenyl)propyl]piperazine dihydrochloride m.p. 243°-245° C. (from ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][C:10](=S)[N:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[NH2:23][NH2:24]>CCO>[CH3:18][CH:12]1[C:13](=[O:14])[NH:24][N:23]=[C:10]2[CH2:9][S:8][C:7]3[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:11]12
Reactant: CCOC(=O)C(C)N1C(=S)CSc2ccc([N+](=O)[O-])cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2CSc3ccc([N+](=O)[O-])cc3N21
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(6-nitro-3-thioxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.475 g, 1.455 mmol) in EtOH (30 mL) was added hydrazine hydrate (0.364 g, 7.28 mmol) and the mixture was then heated at reflux for 16 h. After cooling to ambient temperature gradually, the precipitate was collected by filtration to give 1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]-triazin-2(1H)-one (0.312 g, 77%), which was used in the next step directly without further purification. TLC (eluting with 33% EtOAc in petroleum ether) Rf=0.3.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][CH:61]([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][CH:61]([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)F)C4CC4)c23)c(C)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (112.9 mg, 0.283 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (142.8 mg, 0.566 mmol) and tributylphosphine (141.0 μL, 0.566 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (179.2 μL, 2.830 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (62.0 mg, 0.134 mmol, 47%).
Reaction SMILES: [Na][Na].N[C:4]1C=C[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[C:13](O)=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=O>>[CH3:4][C:5]1[C:13](=[O:14])[N:16]([C:17]2[CH:18]=[C:19]3[C:26](=[O:27])[O:28][C:21](=[O:23])[C:20]3=[CH:24][CH:25]=2)[C:7](=[O:8])[C:6]=1[CH3:10]
Reactant: Nc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Agent: [Na][Na]
Product: CC1=C(C)C(=O)N(c2ccc3c(c2)C(=O)OC3=O)C1=O

Procedure:
If instead of 22.5 g of the disodium salt of 3-aminophthalic acid, an equivalent amount of the disodium salt of 4-aminophthalic acid is employed and in other respects the procedure indicated in the above example is followed, 4-(dimethylmaleinimidyl)-phthalic anhydride of melting point 197°C is obtained.