Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH:36]([C:38](=[O:48])[CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[NH2:37]>O1CCCC1>[C:43]([O:42][C:41](=[O:47])[NH:40][CH2:39][C:38]([NH:36][NH:37][C:18]([CH:13]1[CH2:12][CH2:11][CH:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:48])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)C1CCC2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NNC(=O)C1CCC2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (153 mg, 0.554 mmol) in tetrahydrofuran (3 mL) were added triethylamine (0.232 mL) and isobutyl chloroformate (89.1 μl) under ice-cooling, followed by agitating at 0° C. for 45 minutes. To the reaction solution was added a solution of tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (129 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6) in tetrahydrofuran (3 mL) at 0° C., followed by stirring at room temperature for 2.5 hours and concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10) to afford 179 mg of the title compound (yield 72%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:25][C@H:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:25][C@H:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:27](=[O:28])[N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:15])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
A 10 mL round-bottomed flask was charged with 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.12 g, 0.36 mmol), (R)-2-amino-3,3-dimethyl-1-(pyrrolidin-1-yl)butan-1-one hydrochloride (137 mg, 0.53 mmol), HOBt (61 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol). Then added DMF (1.6 mL) followed by N,N-diisopropylethylamine (0.16 mL, 0.92 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×50 mL). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 8 g SiO2 with EtOAc/hexanes (gradient: 0-60% EtOAc) to afford 195 mg of (R)-2-cyclopropyl-N-(3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a viscous yellow oil.
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:29]=[N:28][CH:27]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CO>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:29]=[N:28][CH:27]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 71.8 %

Procedure:
Following a procedure similar to that described in Example 151, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}piperidine hydrochloride (560 mg) was treated with potassium carbonate in methanol and the concentrated extract was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 30/70, v/v) to afford the title compound (370 mg, yield: 72%) as a yellow amorphous solid.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:13])[CH:6]=1.[CH3:14][N:15]1[CH2:24][C:23](=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1>CCOCC>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:23]2([OH:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][N:15]([CH3:14])[CH2:24]2)=[C:7]([F:13])[CH:6]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: CN1CC(=O)c2ccccc2C1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CN1Cc2ccccc2C(O)(Cc2ccc(Cl)cc2F)C1
Yield: 82.2 %

Procedure:
To a suspension of magnesium shavings (15.7 g) and a few crystals of iodine in anhydrous ether (200 ml) is slowly dropped 4-chloro-2-fluorobenzylbromide (146.0 g) in anhydrous ether (200 ml) at such a rate so as to maintain the ether reflux. After the addition is complete, the reaction mixture is heated under reflux for two hours. A solution of 2-methyl-2,3-dihydro-4(1H)-isoquinolone (70.2 g) in anhydrous ether (200 ml) is slowly added dropwise. After the addition is complete, the reaction mixture is heated under reflux for three hours. The reaction mixture, after cooling, is stirred in 1.5 l. saturated ammonium chloride and extracted with ether. The combined ether extracts are washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield a solid, which upon trituration with petroleum ether, yields the product (109.5 g, 82%), mp 113°-116°. An analytical sample is recrystallized from anhydrous ether to yield needles, mp 116°-117°.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][N:25](C)C=O>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.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>[C:24]([C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)#[N:25]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C#N)ccc1-2
Yield: 71.3 %

Procedure:
8-Bromo-2-isopropyl-2H-1,2,4-triazol-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (330 mg, 0.84 mmol) and degassed dimethylformamide (4.2 mL) were added to a CEM microwave vial. The mixture was thoroughly purged with nitrogen. Zinc cyanide (99.0 mg, 0.84 mmol, 1.0 equiv.) and Pd(PPh3)4 (48.7 mg, 0.04 mmol, 0.05 equiv.) were added to the reaction mixture in one portion and the vial was sealed immediately. The reaction was submitted to MW irradiation at 60 W for 15 minutes (T=175° C.). The mixture was diluted with methylene chloride, filtered through celite, and washed with saturated NH4Cl. The organic layers were combined, dried with MgSO4 and concentrated. The crude mixture was loaded onto silica gel and purified by flash chromatography (0-100% EtOAc in hexanes) to give 202 mg (71.3% yield) of 8-cyano-2-isopropyl-2H-1,2,4-triazol-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:20][C:19]4[CH2:18][NH:17][CH2:16][C:15]=4[CH2:14]3)=[N:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][N:30]=1>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][C:15]4[CH2:16][N:17]([C:29]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]=[CH:31][N:30]=5)[CH2:18][C:19]=4[CH2:20]3)=[N:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: Clc1ncnc2ccccc12
Reactant: O=C(NCC1CC1)c1cnc(N2CC3=C(CNC3)C2)s1
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCC1CC1)c1cnc(N2CC3=C(C2)CN(c2ncnc4ccccc24)C3)s1

Procedure:
N-(Cyclopropylmethyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (106 mg, 0.26 mmol) was reacted with 4-chloroquinazoline analogously to example 5. M+H+: 419.15.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][N:13]=1>N1C=CC=CC=1.CCOC(C)=O>[C:18]1([C:15]2[N:16]=[CH:17][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc(-c2ccccc2)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Phenyl chloroformate (0.64 mL, 5.1 mmol) was added to a vigorously stirred solution of 2-amino-5-phenylpyrazine 1-1 (794 mg, 4.64 mmol) in pyridine (10 mL) at room temperature. After being stirred at room temperature overnight, the mixture was diluted with EtOAc to give a suspension, in which the desired compound precipitated out. The suspension was successively washed with 1 N KHSO4, brine and dist. water. The precipitate was collected by filtration and dried to give phenyl N-(5-phenyl-2-pyrazinyl)carbamate 1-2 (847 mg, 63%). The filtrate was concentrated under reduced pressure to produce precipitate, which was collected and dried to give the second crop (340 mg, 25%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][CH:17]=[N:16][C:15]=2[C:19](OC)=[O:20])=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:18][CH:17]=[N:16][C:15]=2[CH2:19][OH:20])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ncoc1-c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ncoc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
166 mg (4.38 mmol) of lithium aluminum hydride are initially charged in 10 ml of dry THF and cooled to 0° C. A solution of 260 mg (1.09 mmol) of the compound from Example 37A in 10 ml of dry THF is added dropwise. After the addition has ended, the reaction solution is slowly warmed to RT and stirred at this temperature for 1 h. With stirring, the mixture is then heated at reflux for 2 h. The mixture is then cooled again to 0° C., 0.4 ml of water and 0.8 ml of 1 N aqueous sodium hydroxide solution are added carefully and the mixture is stirred at RT for 3 h. The precipitate formed is filtered off, and the filtrate is freed from the solvent on a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[CH:8][CH2:7][CH2:6][N:5]2[C:18]=1[CH3:19]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[CH:8][CH:7]=[CH:6][N:5]2[C:18]=1[CH3:19]
Reactant: Cc1nc2n(c1C)CCC=C2c1ccc(Cl)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc2c(-c3ccc(Cl)cc3Cl)cccn2c1C

Procedure:
2,3-Dimethyl-8-(2,4-dichlorophenyl)-5,6-dihydroimidazo[1,2-a]pyridine (3) (29.3 g, 0.1 mol) is dissolved in methylene chloride (1L) and activated manganese dioxide (120 g) is added. The mixture is heated at reflux for 16 hours with stirring. The catalyst is removed by filtration of the reaction through a Celite pad and the filtrate is evaporated to a solid (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:11][O:10][C:9]=2[C:20]([NH:22][NH2:23])=[O:21])=[CH:4][CH:3]=1.CN([CH:27]=[O:28])C>C(OCC)(=O)C>[C:20]([C:9]1[CH:8]=[C:12]([CH:13]=[CH:14][C:27]=1[OH:28])[C:11]([NH:23][NH:22][C:20]([C:9]1[O:10][CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:21])=[O:10])#[N:22]
Reactant: NNC(=O)c1occ(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccc(Cl)cc3)c2-c2ccc(Cl)cc2)ccc1O

Procedure:
A mixture of 3,4-bis(4-chlorophenyl)-2-furancarboxylic acid hydrazide (compound of Reference Example 36, 0.092 g) and the compound of Reference Example 63 (0.11 g) in DMF (5 ml) was stirred overnight at 70° C. The reaction solution was diluted with ethyl acetate, washed with water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 1:20 methanol/chloroform), and recrystallized from ethyl acetate/hexane, thereby giving 0.054 g of the desired compound. Melting point: 190-191° C. (Recrystallized from ethyl acetate)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([OH:10])=O)=[N:5][S:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15]>>[NH2:2][C:3]1[C:4]([C:8]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([F:19])=[C:12]([Br:11])[CH:13]=2)=[O:10])=[N:5][S:6][CH:7]=1
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Nc1csnc1C(=O)O
Agent: Cl
Product: Nc1csnc1C(=O)Nc1ccc(F)c(Br)c1

Procedure:
This compound was prepared according to the procedure of Example 44, Step 1, using 4-aminoisothiazole-3-carboxylic acid hydrochloride and 3-bromo-4-fluoroaniline as the starting materials. LCMS for C10H8BrFN3OS (M+H)+: m/z=315.9, 317.9.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.Br[CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].[Na+].C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C=O)C.O>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28])[CH2:21][CH2:20][C:6]1=2
Reactant: O=S(=O)([O-])CCBr
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CCS(=O)(=O)O)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol (200 mg, 0.652 mmol) and sodium 2-bromoethanesulfonate (164 mg, 0.78 mmol) in DMF (3 mL) and water (0.5 mL), were added sodium bicarbonate (164 mg, 1.95 mmol) and potassium iodide (128 mg, 0.78 mmol) and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was diluted with water and extracted with DCM. The aqueous layer was neutralized with aq HCl and the solid obtained was recrystallized from MeOH to yield 2-(3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)ethanesulfonic acid as a white solid (80 mg). 1H NMR (CD3OD, Free base) δ (ppm): 8.45 (d, 2H), 7.40 (d, 2H), 7.26 (s, 1H), 7.23 (d, 1H), 7.00 (s, 1H), 5.06 (t, 1H), 4.59 (m, 2H), 4.29 (m, 2H), 3.71 (t, 4H), 3.55 (m, 2H), 3.0 (d, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers II-97a-b.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][N:54]4[CH:59]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][N:54]4[CH:59]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 213 from 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium hydroxide solution in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:10]([CH3:24])[NH:9]2)=[CH:4][CH:3]=1.F[C:26](F)(F)S(OC)(=O)=O>ClCCl>[CH2:17]([O:16][C:14]([C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]([CH3:26])[C:10]=1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1[nH]n(-c2ccc(F)cc2)c(=O)c1C(=O)OCc1ccccc1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccc(F)cc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
To a solution of benzyl 2-(4-fluorophenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (8.0 g, 0.024 mol) in dichloromethane (80 mL), methyl trifluoromethanesulfonate (4.8 g, 0.029 mol) was added and stirred at room temperature for 24 hours. The resulting mixture was extracted with dichloromethane and saturated baryta water. After phase separation, the aqueous layer was extracted again with dichloromethane. All the organic layers were collected, dried with Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=4:1) to give the target compound (2.69 g, 32% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>O.C(#N)C>[C:34]1(=[O:43])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: CCCCOc1cc(C(N)CC(=O)OC)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-butoxy-4-methoxyphenyl)propionate hydrochloride (0.95 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 1.1 g (89%) of methyl 3-phthalimido-3-(3-butoxy-4-methoxyphenyl)propionate as a white solid: mp 54°-55° C.; 1H NMR (CDCl3) δ5 7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.85-6.76 (m, 1H), 5.76 (dd, J=5.9, 10 Hz, 1H), 4.02 (t, J=6.7 Hz, 3.86-3.71 (m, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.24 (dd, J=5.9, 16.5 Hz, 1H), 1.89-1.73 (m, 2H), 1.59-1.41 (m, 2H), 1.04-0.89 (m, 3H); 13C NMR (CDCl3) δ5 171.1, 168.1, 149.2, 148.5, 133.9, 131.8, 130.9, 123.3, 120.2, 112.7, 111.4, 68.6, 55.9, 51.9, 50.7, 35.9, 31.1, 19.2, 13.9; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 6.5 min, 100%, Anal. Calcd. for C23H2 NO6. Theoretical: C, 67.14; H, 6.12; N, 3.40. Found: C, 66.89; H, 6.15; N, 3.31.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:9]([C:10](=[O:12])[CH3:11])=[CH:8][C:7]([F:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].[Li+].[OH-].Cl>C1COCC1.O>[C:10]([C:9]1[C:4]([C:3]([OH:23])=[O:2])=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:6]([F:14])=[C:7]([F:13])[CH:8]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)c1c(C(C)=O)cc(F)c(F)c1Nc1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(F)c(F)c(Nc2ccccc2Cl)c1C(=O)O
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of 6-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (200 mg, 0.59 mmol) in THF-water (2 mL/0.5 mL) was added 1 M aqueous LiOH (1.21 mL, 1.21 mmol) at room temperature. The reaction mixture was stirred for 30 minutes, acidified to pH 1 with 1 N aqueous HCl, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the desired acid (166 mg, 86%) that was used directly without further purification.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36]C)=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:33][O:32][C:31]1[C:3](=[O:2])[C:4]([CH3:38])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[C:29](=[O:36])[C:30]=1[O:34][CH3:35]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 61.9 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoyl]morpholine (0.460 g, 0.885 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (5 ml) and after adding thereto CAN (1.21 g, 2.21 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.270 g, 0.548 mmol, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To a vial with 6-aminobenzo[d]oxazol-2(3H)-one (1.0 g, 6.7 mmol) and 2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol), solvents MeOH (20 mL) and H2O (5 mL) were added. The turbid mixture was stirred at room temperature for 2 days. Precipitate from the reaction mixture was collected by filtration, washing with H2O (3 mL×2) and EtOAc (3 mL×2), and was further drying in vacuo. 6-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as a light tan color solid: 1.59 g (86% yield); 1H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=8.3, 1H), 7.06 (d, J=8.3, 1H), 2.14 (s, 3H).