Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:6]2[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]2=[O:7])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1CCC(=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CCC(=O)N1S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
A flame dried flask was charged with 444 mg sodium hydride (60% wt in oil, 11.1 mmol, 1.1 equiv) under N2. The solid was washed (2×hexanes) followed by the addition of 100 mL anhydrous THF. The solution was cooled to 0° C. followed by the addition of 1 g 5-methyl-2-pyrrolidinone (10.09 mmol, 1.0 equiv). The solution was allowed to stir for 20 min, followed by the addition of 1.96 g 4-fluorobenzenesulfonyl chloride (10.09 mmol, 1.0 equiv) in 10 mL THF. After stirring for an additional 50 min, the solution was diluted with sat. NaHCO3, and the THF was removed under reduced pressure. The solution was then extracted (3×EtOAc), dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 30% EtOAc/hexanes) gave the product 1-(4-fluorobenzenesulfonyl)-5-methyl-2-pyrrolidinone as a white solid (949 mg, 3.69 mmol, 37%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[C:7]([C:11]([O:13]C)=O)[N:6]=1)=[O:4].[NH2:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][C:16]([NH:15][C:11]([C:7]1[CH:8]=[N:9][CH:10]=[C:5]([C:3]([NH:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18])=[O:4])[N:6]=1)=[O:13])([CH3:21])[CH2:19][OH:20]
Reactant: CC(N)(CO)CO
Reactant: COC(=O)c1cncc(C(=O)OC)n1
Solvent: CCO
Product: CC(CO)(CO)NC(=O)c1cncc(C(=O)NC(C)(CO)CO)n1
Temperature: 20 °C
Yield: 30.4 %

Procedure:
A solution of 500 mg of 2,6-dimethoxycarbonylpyrazine and 525 mg of 2-amino-2-methyl-1,3-propanediol in 5 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is cooled to a temperature of 20° C. and the white solid formed is then filtered off and washed with twice 5 cm3 of ethanol. 260 mg of N,N′-bis(1,3-dihydroxy-2-methyl-2-propyl)pyrazine-2,6-dicarboxamide are thus obtained in the form of a white solid melting at 169° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.34 (s, 6H: 2×CH3); 3.61 and 3.69 (2 dd, J=11 and 5.5 Hz, 8H: 4×CH2O); 4.88 (t, J=5.5 Hz, 4H: 4×OH); 8.16 (s, 2H: 2×CONH); 9.35 (s, 2H: ═CH at 3 and ═CH at 5)].
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[N:10][CH:9]=1>C(OCC)(=O)C.[Cl-].[NH4+]>[C:16]1([C:15]#[C:14][C:12]2[CH:13]=[C:8]([C:7](=[O:22])[CH3:1])[CH:9]=[N:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=O)c1cncc(C#Cc2ccccc2)c1
Reaction time: 8 h
Yield: 84 %

Procedure:
Add methylmagnesium bromide (1.25 mL, 3.7 mmol) dropwise at 0° C. to a solution of N-methoxy-N-methyl-5-phenylethynylnicotinamide, (prepared essentially as described in PREPARATION 2), (1.0 g, 3.76 mmol). Allow the mixture to warn to room temperature overnight. Dilute with ethyl acetate and saturated ammonium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 tetrahydrofuran:hexanes) to give title compound as a white solid (0.70 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[N:6][CH:5]=1>CO.[Ni]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1
Temperature: 80 °C
Yield: 76 %

Procedure:
To a suspension of 6-Amino-5-nitro-nicotinic acid methyl ester (3) (5 g, 25 mmol) in MeOH (150 ml) was added Raney Ni. The mixture was vacuum purged with H2 5 times and heated at 80° C. under H2 atmosphere for 4 h. The solution was filtered through celite and concentrated in vacuo to give the product as a brown solid (3.2 g, 19 mmol, 76%) that was used without further purification. TLC of the product in DCM/MeOH (19:1) indicated a more polar spot at Rf=0.026.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:36]=[O:37]>>[CH2:1]([O:8][C:9]1[NH:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)([CH:36]=[O:37])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(OCc2ccccc2)cc1-c1ccc2c(c1)OCCO2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1NC(OCc2ccccc2)=CC1(C=O)c1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-5-(2,3-dihydrobenzo-[1,4]dioxin-6-yl)-1-isopropyl-1H-pyrazole (1.8 g) in N,N-dimethylformamide (3 mL) was added phosphorus oxychloride (0.97 g) at 80° C., and the mixture was stirred at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, a sodium hydroxide aqueous solution (2 mol/L, 10 mL) was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=1/4-dichloromethane) to give the title compound (0.86 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]([C:19]([NH:21][C:22]2[C:26](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:20])=[CH:17][CH:16]=1.[H-].[Na+].[CH3:47]N(C)C=O.CI>O>[CH3:47][N:21]([C:19](=[O:20])[C:18]1[CH:43]=[CH:44][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)[C:22]1[C:26](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][N:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:23]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Yield: 83 %

Procedure:
To a mixture of diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil. To remove remaining trifluoroacetic acid, water was added to the oil, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-[3-(methyl{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as a colorless oil (42.5 mg, yield 83%)
Reaction SMILES: NN.C(O)COCCO.[C:10]([C:13]1[O:14][C:15]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=2[CH:17]=1)(=O)[CH3:11].[OH-].[K+]>O>[CH2:10]([C:13]1[O:14][C:15]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=2[CH:17]=1)[CH3:11]
Reactant: COc1ccc2cc(C(C)=O)oc2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCc1cc2ccc(OC)cc2o1
Temperature: 190 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
Hydrazine (4.11 g, 69.4 mmol, up to 55%, Aldrich) was added to diethylene glycol solution of 2-acetyl-6-methoxybenzofuran (3.30 g, 17.3 mmol) . The mixture was heated to a temperature of 190° C. and stirred for 10 min. After cooled down to room temperature, potassium hydroxide (2.92 g, 52.1 mmol) was added, stirred in a range of 120° C. to 130° C. for 6 hours. Following this, the reaction solution was poured into water, extracted by dichloromethane, dried over MgSO4, and was concentrated under reduced pressure. Oil residue was purified by HPLC (silica gel, CHCl3) and target product (2.98 g, 16.9 mmol, 97%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[O:23]=[S:24]1(=[O:30])[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25]1>>[O:23]=[S:24]1(=[O:30])[CH2:28][CH2:27][CH:26]([NH:29][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:19][CH:18]=2)=[O:22])[CH2:25]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC2CCS(=O)(=O)C2)s1
Yield: 37 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using 1,1-dioxidotetrahydrothien-3-ylamine instead of isopropylamine, to the title compound (37 mg, 37%) which was obtained as a brown solid MS: m/e=433.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][CH2:37][CH:38]([OH:50])[CH2:39][N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:36][CH2:37][CH:38]([OH:50])[CH2:39][N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1)=[O:9]
Reactant: Nc1ccc(F)c(C(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
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: Nc1ccc(F)c(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 17 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
The solution of 5-amino-2-fluorobenzoic acid (200 mg, 1.29 mmol) and HATU (490 mg, 1.29 mmol) in DCM (15 mL) was stirred at 17° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (265 mg, 1.29 mmol) and DIPEA (333 mg, 2.58 mmol) was added and the resulting solution was stirred at 17° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give desired product (372 mg, Yield 84%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2.[CH2:16](I)[CH:17]=[CH2:18].O>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[C:11]1=[O:15])[CH:17]=[CH2:16]
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1CCc2cc(OC)ccc2C1=O
Reaction time: 4 h
Yield: 99 %

Procedure:
To a suspension of 95% NaH (1.2 equiv) in anhydrous DMF (2 mL) was slowly added a solution of amide 42 (198 mg, 1.12 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h after which time allyl iodide (1.2 equiv) was added. The resulting mixture was stirred for 4 hours at this temperature. After addition of water and extraction with EtOAc (3×), the resulting combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography on SiO2 (Petroleum ether/EtOAc=1:1) to afford the title compound 43 as a white solid (Yield 242.3 mg, 99%).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:14]1([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)[CH2:12][CH3:13])C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]([C:14]1([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(Nc2ccc3cnccc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCC(N)C1(c2ccc(OC)cc2)CCC(Nc2ccc3cnccc3c2)CC1

Procedure:
48 mg (91.7 μmol) of {1-[4-(Isoquinolin-6-ylamino)-1-(4-methoxy-phenyl)-cyclohexyl]-propyl}-carbamic acid benzyl ester (99) were dissolved in 300 μL of dry methanol and 9.7 μg of palladium on activated charcoal (10%) were added. The mixture was stirred under a hydrogen atmosphere until conversion was complete. The catalyst was filtered off and the reaction mixture was evaporated to dryness to give the title compound. Rt=0.89 min (Method 19). Detected mass: 390.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc(NCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)C=Cc2ccc(NCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-(4-methoxyphenyl)-3-(4-phenylmethylaminophenyl)-1-oxoprop-2-ene (13.7 g, 0.04 mol) was dispersed in methanol (100 ml). Sodium borohydride (4.1 g, 0.11 mol) was added slowly at ambient temperature under vigorous stirring. After completion of the addition of sodium borohydride, the reaction mixture was kept stirred at ambient temperature for 20 hours. When the reaction was complete, the reaction mixture was poured into water (500 ml), and extracted with toluene. The toluene was removed using a rotary evaporator leaving an oily residue. The crude product was purified from petroleum ether : toluene (9:1 v/v) to give 1-(4-methoxyphenyl)-3-(4-phenylmethylaminophenyl)prop-2-en-1-ol as an amorphous solid in a yield of 12.3 g (89.1% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][CH:6]=[C:5]([O:13][CH3:14])[C:4]=1B(O)O.[CH3:18][O:19][C:20](=[O:48])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](OS(C(F)(F)F)(=O)=O)=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31]>>[CH3:18][O:19][C:20](=[O:48])[C@H:21]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:4]2[C:5]([O:13][CH3:14])=[CH:6][CH:7]=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=2[O:2][CH3:1])=[CH:38][CH:39]=1)[NH:22][C:23](=[O:32])[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COCOc1ccc(OC)c(B(O)O)c1OC
Product: COCOc1ccc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c1OC

Procedure:
2,6-Dimethoxy-3-methoxymethoxybenzeneboronic acid and N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester were coupled by a similar method as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4(2,6-dimethoxy-3-methoxymethoxyphenyl)-L-phenylalanine methyl ester.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2.[C:48]([O:54][CH2:55]I)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]>C(OCC)(=O)C.O>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48]([O:54][CH2:55][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:23])([C:24]3[N:25]=[CH:26][NH:27][CH:28]=3)[CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH:10]=1)=[O:53]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(OCOC(=O)C(C)(C)C)ccc2c1)c1c[nH]cn1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Sodium hydride (60% oil dispersion, 0.120 g) was added to DMF (15 ml), and to the mixture was slowly added 1-(6-hydroxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.397 g) under ice cooling, and the mixture was stirred for 30 min under ice cooling. To the mixture was added iodomethyl pivalate (0.83 g), and the mixture was stirred at room temperature for 6 h. To the mixture were added water and ethyl acetate, and the organic layer was washed with water and saturated solution of sodium chloride. The extract was dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=5:1→3:1). Recrystallization from hexane-ethyl acetate to give the titled compound (0.433 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][CH3:13])=[C:10]([Cl:14])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[N:7]2.[CH3:19][S:20](N)(=[O:22])=[O:21]>>[Cl:14][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[N:7]2)=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1c(Cl)cc2nc(OC)c(OC)nc2c1N
Reactant: CS(N)(=O)=O
Product: CCc1c(Cl)cc2nc(OC)c(OC)nc2c1NS(C)(=O)=O
Yield: 47 %

Procedure:
5-Amino-7-chloro-6-ethyl-2,3-dimethoxyquinoxaline was converted to the methane sulphonamide derivative by the method of step (g) above. The product was obtained in 47% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].[C:18]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([N:14]2[CH2:13][CH2:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:10][CH:9]=3)[CH2:16][CH2:15]2)=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)OC(C)(C)C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a degassed mixture of 4-(piperazin-1-yl)-benzoic acid ethyl ester (1.45 g, 6.2 mmol), 4-bromobenzoic acid tert-butyl ester (1.75 g, 6.8 mmol), cesium carbonate (3.9 g, 12 mmol) in dioxane (25 mL) was added tris(dibenzylideneacetone)dipalladium (300 mg, 5 mol %) and 2-(dicyclohexylphosphino)-2′,4′,6′-tris(isopropyl)-biphenyl (x-phos, 300 mg, 10 mol %). The mixture was heated in a sealed tube with stirring at 100° C. for 3 hrs. Solvents were evaporated and the residue was extracted with ethyl acetate and water, The organic layer was dried over sodium sulfate and solvents were evaporated. The crude material was purified through a flash column chromatography using ethyl acetate and hexanes to give the intermediate 4-[4-(4-ethoxycarbonylphenyl)-piperazin-1-yl]-benzoic acid tert-butyl ester as solid (1.3 g, 51% yield)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[N:26][OH:27])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[CH:2]=[C:1]([C:3]3[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=3)[O:27][N:26]=2)=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 3.3 %

Procedure:
To a solution of 5-ethynyl-pyridin-2-ylamine (10 mg, 85 μmol) described in Manufacturing Example 28-1-3 and 4-benzyloxy-phenyl-acetohydroximoyl chloride (70 mg, 0.25 mmol) described in Manufacturing Example 1-1-3 in tetrahydrofuran (2 mL) was added triethylamine (35 μL, 0.25 mmol) at room temperature, which was stirred for 3 hours and 40 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (1 mg, 3%) as a trifluoroacetic acid salt.
Reaction SMILES: [CH:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([NH2:13])=[O:12])[C:7]=2[N+:14]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[NH2:14][C:7]1[C:8]([C:11]([NH2:13])=[O:12])=[N:9][NH:10][C:6]=1[CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1n[nH]c(C2CCCC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1n[nH]c(C2CCCC2)c1N
Yield: 103 %

Procedure:
5-cyclopentyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.48 g, 20 mmol) and 10% palladium on carbon (800 mg) in ethanol (50 ml) were stirred under hydrogen (50 psi) at room temperature for 18 hours. The reaction mixture was filtered through arbocel and the solid was washed with ethanol (50 ml), methanol (50 ml), dichloromethane (50 ml), and ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (9:1, by volume) to give 4-amino-5-cyclopentyl-1H-pyrazol-3-carboxylic acid amide (4.0 g) as an off-white solid which was a mixture of rotamers. 1H NMR (400 MHz, DMSO-D6): δ=12.20-12.31 (0.75H, brs), 11.78-11.87 (0.25H, brs), 7.02-7.18 (1.5H, brs), 6.80-6.93 (0.5H, brs), 4.22-4.56 (2H, 2×brs), 2.92-3.02 (1.96 (2H, m), 1.48-1.78 (6H, 2×m) ppm. LRMS (electrospray): m/z [M−H]+ 193. Anal. Found C, 56.12; H, 7.39; N, 27.55. C9H14N4O. 0.2 mol acetone requires C, 56.01; H, 7.44; N, 27.22%.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([N:21]=[C:22]=[O:23])=[CH:15][C:14]=2[O:13]1>C1C=CC=CC=1>[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([NH:21][C:22]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:23])=[CH:15][C:14]=2[O:13]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(NCc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxybenzylamine (0.37 g) and 3,4-methylenedioxyphenyl isocyanate (0.4 g) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0077B (0.78 g, 98%) as a pale brown solid.