Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
2-methoxy-5-nitrophenol (254 mg, 1.5 mmol, 1 eq.) was placed in dimethylformamide (3 mL) with 4-(2-chloro-ethyl)morpholine hydrochloride (837 mg, 4.5 mmol, 3 eq.), Cs2CO3 (3.4 g, 10.7 mmol, 7 eq.), KI (547 mg, 3.3 mmol, 2.2 eq.). The reaction mixture was heated at 80° C. and stirred for 20 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1% NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-(2-(2-methoxy-5-nitrophenoxy)ethyl)morpholine (386 mg, 91%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1>C1COCC1>[F:7][C:8]([F:20])([F:21])[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)CCc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
590 mg (15.4 mmol) of LiAlH4 were added in portions at 0° C. to a solution of 2.2 g (10.3 mmol) of 4-(3-(trifluoromethyl)phenyl)but-3-en-2-one in THF (20 ml), and stirring was then carried out for 1 h at RT. The mixture was then quenched at 0° C. with a sat. aq. Na2SO4 sol. and the reaction solution was filtered over kieselguhr. The filtrate was extracted with EA (3×60 ml) and the combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. There were obtained as residue 2.0 g (9.2 mmol, 89%) of 4-(3-(trifluoromethyl)phenyl)-butan-2-ol, which was reacted further without additional purification.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[C:10]([N+:15]([O-])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[CH3:1][NH:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1ccccc1)c1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1cccnc1N
Yield: 86.6 %

Procedure:
A mixture of N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) and 10% Pd—C (0.569 g) in EtOH (50 mL) was hydrogenated under balloon pressure at room temperature over weekend. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give N3-methylpyridine-2,3-diamine (1.14 g) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([Cl:18])[CH:3]=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Cl.[I-].[K+]>C(O)C>[Cl:18][C:4]1[CH:3]=[C:2]([N:1]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][C:10](=[O:17])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: ClCCOCCCl
Reactant: Cc1cc(N)cc(Cl)c1NC(=O)CC1CCCC1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N2CCOCC2)cc(Cl)c1NC(=O)CC1CCCC1
Temperature: 170 °C
Yield: 41 %

Procedure:
N-(4-Amino-2-chloro-6-methyl-phenyl)-2-cyclopentyl-acetamide (830 mg), bis-(2-chloroethyl)ether (3.35 mL) and potassium iodide (470 mg) were mixed in absolute ethanol (33 mL) and heated to 170° C. for 1 hour in a sealed microwave process vial. The crude mixture was concentrated in mow and purified by flash chromatography to furnish 390 mg (41%) of the title compound as a white solid. LC-MS (m/z) 337 (MH+); tR=2.61, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.22 (m, 2H), 1.51 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 3H), 2.25 (m, 1H), 2.26 (m, 2H), 3.10 (m, 4H), 3.71 (m, 4H), 6.80 (d, 1H), 6.84 (d, 1H), 9.18 (s,
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([SH:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:34]([O:36][CH:37]([O:42][CH2:43][CH3:44])[CH2:38][CH2:39][CH2:40][NH2:41])[CH3:35]>C(Cl)Cl>[CH2:43]([O:42][CH:37]([O:36][CH2:34][CH3:35])[CH2:38][CH2:39][CH2:40][NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([SH:19])([CH3:18])[CH3:17])[CH3:44]
Reactant: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(CCCN)OCC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(CCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a round bottom flask was added (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (4.68 g, 16.52 mmol), HOBT (2.53 g, 16.52 mmol), EDC (3.17 g, 16.52 mmol), DCM (50 mL), TEA (2.302 mL, 16.52 mmol) and 4,4-diethoxybutan-1-amine (2.66 g, 16.52 mmol). The reaction was stirred at rt overnight. The reaction was diluted with DCM (150 mL). The organics was washed with water (2×150 mL), saturated aqueous NaCl (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-benzyl 1-(4,4-diethoxybutylamino)-3-mercapto-3-methyl-1-oxobutan-2-ylcarbamate (6.90 gm, 16.2 mmol, 98% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[C@@H:12]([CH3:29])[CH2:11]2)(=[O:9])=[O:8])=[N:4][N:3]=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[NH2:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C@@:22]([OH:28])([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:18][CH:17]=3)[C@@H:12]([CH3:29])[CH2:11]2)(=[O:8])=[O:9])=[N:4][N:3]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2nnc(N)s2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@H]1CN(S(=O)(=O)c2nnc(N)s2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1

Procedure:
(2R)-2-(4-((2S)-4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-methyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.47 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 4.10-4.03 (m, 1H), 3.80-3.74 (m, 1H), 3.57-3.51 (m, 1H), 3.42-3.36 (m, 1H), 3.29-3.17 (m, 2H), 3.15-3.07 (m, 1H), 1.68 (s, 3H), 1.10-1.06 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 452.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.04 μM; GK-GKRP EC50 (LC MS/MS)=5.62 μM.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[C:26]([OH:39])(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[C:35]([O:37][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)=[C:2]([OH:1])[CH:21]=1)(=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[C:2]([OH:1])[CH:21]=1)=[O:39]
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Reactant: O=C(O)CCCCCCCCC(=O)O
Product: O=C(CCCCCCCCC(=O)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
Following the general procedure of Example 13 or Example 17, the title compound is prepared by reacting an equivalent amount of the alcohol compound of Example 7 with a half equivalent amount of sebacic acid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27](O)[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)=[CH:13][CH:12]=1.O>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27]([F:7])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h
Yield: 45 %

Procedure:
At −78° C., a solution of 51 μl (380 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 170 mg (350 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 21A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −20° C. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from cyclohexane/ethyl acetate (10:1) gives 77 mg of the target product. Column chromatography of the concentrated mother liquor on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1) gives a further 60 mg of the target compound.
Reaction SMILES: [CH3:1][CH2:2][C@:3]1([OH:60])[C@H:25]([C:26]([O:28][CH3:29])=[O:27])[C:7]2[CH:8]=[C:9]3[C:21](=[O:22])[C:20]4[C:19]([OH:23])=[CH:18][CH:17]=[C:16]([OH:24])[C:15]=4[C:13](=[O:14])[C:10]3=[C:11]([OH:12])[C:6]=2[C@@H:5]([O:30][C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@@H](O)[C@@H](O)C4)[C@@H](O)C3)[C@@H](N(C)C)C2)[CH2:4]1>Cl>[CH3:1][CH2:2][C@:3]1([OH:60])[C@H:25]([C:26]([O:28][CH3:29])=[O:27])[C:7]2[CH:8]=[C:9]3[C:21](=[O:22])[C:20]4[C:15](=[C:16]([OH:24])[CH:17]=[CH:18][C:19]=4[OH:23])[C:13](=[O:14])[C:10]3=[C:11]([OH:12])[C:6]=2[C@@H:5]([OH:30])[CH2:4]1
Reactant: CC[C@@]1(O)C[C@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]3C[C@H](O)[C@H](O[C@H]4C[C@H](O)[C@H](O)[C@H](C)O4)[C@H](C)O3)[C@H](C)O2)c2c(cc3c(c2O)C(=O)c2c(O)ccc(O)c2C3=O)[C@H]1C(=O)OC
Agent: Cl
Product: CC[C@@]1(O)C[C@H](O)c2c(cc3c(c2O)C(=O)c2c(O)ccc(O)c2C3=O)[C@H]1C(=O)OC
Reaction time: 2 h

Procedure:
The drug (75 mg) is refluxed in methanolic HCl (25 mL, 0.1N) for two hours. At the end of this Marcellomycin (75 mg, 0.175 mmol) is dissolved in methanolic HCl (25 mL, 0.1N) and refuxed at 50° C. for two hours. At the end of this time the reaction mixture is concentrated under vacuum and purified by preparative thin layer chromatography (15% methanol-chloroform). The aglycone ε-pyrromycinone is isolated as a bright red solid (21 mg, 54% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:13][C:14](O)=[O:15].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:13][C:14]([Cl:24])=[O:15]
Reactant: O=C(O)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid (270 mg, 0.94 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.16 mL, 1.88 mmol), followed by N,N-dimethylformamide (1 drop). After the gas ceased to produce, the reaction mixture was stirred at room temperature for 2 hours. After the mixture was concentrated in vacuo, the residue was diluted with dichloromethane and concentrated in vacuo again to afford 280 mg of the product (yield was 90%), which was used for next step without purification.
Reaction SMILES: [C:1]1([C:7]2([OH:21])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:23][C:24](=[O:47])[C@@H:25]([C@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[C:1]1([C:7]2([O:21][C@@H:44]([CH3:46])[C@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C)O
Reactant: OC1(c2ccccc2)c2ccccc2Oc2ccccc21
Product: C[C@H](OC1(c2ccccc2)c2ccccc2Oc2ccccc21)[C@@H](N)C(=O)O

Procedure:
from 9-phenyl-9H-xanthen-9-ol (Example 1f) and Nα -(9-fluorenylmethoxycarbonyl)-D-threonine methyl ester;
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:18][CH2:17]1>C1COCC1>[C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:18][CH2:17]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Solvent: C1CCOC1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(P(=O)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3.4 ml (17.3 mmol) diphenylphosphinic acid chloride are dissolved in 100 ml absolute THF and cooled to ca. 0° C. under moisture exclusion. 5.0 g, (17.3 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 4.8 ml (34.6 mmol) TEA are dissolved in 50 ml absolute THF and added dropwise under ice cooling. The mixture is stirred for three days at RT without further cooling. Subsequently, the solvent is removed under vacuum to a large extent and the residue is taken up in 100 ml 10% sodium hydroxide solution and extracted twice, each with 150 ml CHCl3. The combined organic phases are Bashed with saturated NaCl-solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10) and crystallized from diisopropyl ether after drawing off the solvent. Colorless crystals with an MP of 134-135° C.; yield 5.3 g (62%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH3:38]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and ethyl chloroformate by using the same method as in Example 107.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:12]#[C:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(C#N)cc1
Reaction time: 4 h
Yield: 45 %

Procedure:
3.65 g of p-iodobenzonitrile, 6.25 g of ethyl propiolate, 220 mg of dichlorobis(triphenylphosphine)palladium, 120 mg CuI, and 4.42 g potassium carbonate were combined in a round-bottom flask along with 50 mL freshly distilled THF. This mixture was refluxed while magnetically stirring for 4 hrs. THF was then removed in vacuo. The reaction mixture was extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with H2O (2×100 mL) and brine (1×100 mL), dried over MgSO4, and concentrated to give a brown/black oily solid as a crude product. Purification by automated flash chromatography (silica gel, ethyl acetate/hexanes) gave the intermediate product ethyl (4-cyano)phenylpropiolate as a white solid in 45% yield. This intermediate product was analyzed by 1HNMR (CDCl3) δ1.36 (t, 3 H, J=7.2 Hz), 4.31 (q, 2 H, J=7.2 Hz), 7.67 (s, 4 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]([CH3:25])[C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:34]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]([CH3:25])[C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:17]=3)=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[S:8][C:7]=2[CH:34]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(N(C)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1

Procedure:
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate (25.5 mg, 0.05 mmol) in DCM (1.5 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.215 mL, 0.21 mmol) dropwise. After 4 h at 0° C. the reaction was quenched with sat. aq. NaHCO3 and extracted with 5% MeOH/EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to afford crude (E)-ethyl 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate which was used without further purification. LC/MS (m/z, MH+): 446.5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[N:40]=[CH:39][C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([CH3:50])[CH:42]=2)=[CH:37][C:36]=1[C:51]1[N:52]=[N:53][N:54]([CH:56]([CH3:58])[CH3:57])[CH:55]=1.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C>[NH2:34][C:35]1[N:40]=[CH:39][C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:46])=[C:43]([CH3:50])[CH:42]=2)=[CH:37][C:36]=1[C:51]1[N:52]=[N:53][N:54]([CH:56]([CH3:58])[CH3:57])[CH:55]=1
Reactant: C1COCCN1
Reactant: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
HATU (336 mg, 0.88 mmol) and DIPEA (0.30 mL, 1.77 mmol) were added to a solution of 4-(6-amino-5-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-methylbenzoic acid (200 mg, 0.59 mmol) in DMF (10.0 mL) at room temperature, after 5 min, morpholine (0.06 mL, 0.71 mmol) was added, stirred at RT for 18 h. The reaction mixture was poured into ice cold water, extracted with EtOAc (2×50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude product was purified by washing with ether to afford 148 mg of (Yield: 61.4%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][NH:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][N:20]([C:24]5[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: Cc1cccc(B(O)O)c1
Reactant: c1nc2c(c(Nc3ccc4c(c3)OCCO4)n1)CNCC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc5c(c4)OCCO5)c3C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4 A molecular seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[O:15][C:11]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2ccc(O)cc2o1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
To a stirred solution of 266 (1.2 g, 4.26 mmol) in methanol (20 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen gas for 1 minute and then the reaction was stirred under a hydrogen atmosphere for 15 hours. The palladium was filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 267 as a white solid (700 mg, 86%). 1H NMR: (DMSO) δ 10.07 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 3.84 (s, 3H).
Reaction SMILES: C[C:2]1(C)[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH:11][C:12]3[C:13](=[O:28])[N:14]([CH3:27])[CH:15]=[C:16](B4OC(C)(C)C(C)(C)O4)[CH:17]=3)=[N:10][N:4]2[CH2:3]1.[Br:30]C1C(=O)N(C)C=C(Br)C=1>>[Br:30][C:16]1[CH:17]=[C:12]([NH:11][C:9]2[CH:8]=[C:5]([CH2:6][O:7][CH3:2])[N:4]([CH3:3])[N:10]=2)[C:13](=[O:28])[N:14]([CH3:27])[CH:15]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Yield: 71.3 %

Procedure:
Following the procedure in Example 335a, and starting with 335b (1.7 g, 12 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.2 g, 12 mmol) afforded 336c as a yellow solid (2.8 g, 71%). MS-ESI: [M+H]+ 327. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5 Hz, 1H), 7.38 (s, 1H), 6.88 (d, J=2.5 Hz, 1H), 5.86 (s, 1H), 4.41 (s, 2H), 3.82 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)#[CH:29]>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:29]#[C:28][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1ccncc1
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccncc3)ccc12

Procedure:
2-isoquinolin-3-yl-7-(pyridin-4-yl)ethynyl-chromen-4-one oxime was prepared in 6% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 4-ethynylpyridine. The title compound was isolated as a yellow solid and as a 95/5 mixture of Z/E oxime isomers.