Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:36]=[CH:35][C:34]2[C:33](=[O:37])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:38])[C:25]=2[CH:24]=1>>[CH:24]1[C:25]2[C:26](=[O:38])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33](=[O:37])[C:34]=2[CH:35]=[CH:36][C:23]=1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c1
Yield: 31.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (155 mg, yield: 31.2%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][OH:14])[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[O:4]1)[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Cl.[H-].[Na+]>>[CH2:1]([C:3]1([CH2:13][O:14][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[O:4]1)[CH3:2]
Reactant: CCC1(CO)CCC2(CCCOC2)O1
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2ccccn2)CCC2(CCCOC2)O1

Procedure:
Following procedures similar to Embodiments I-V above, 2-ethyl-1,7-dioxaspiro[4.5]decane-2-methanol was treated with 2-picolinyl chloride in the presence of sodium hydride to yield the desired product as a pale amber oil, b.p. 123° C. (0.006 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester (example 24 c]) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (examples 5 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1ccc(C=O)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cn1nccc1-c1ccc(/C=C/C=O)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-5-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A stirred solution of 4.5 g (0.015 mol) of 3-[2-fluoro-5-(trifluoromethyl)phenoxyl]-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4.0 g (0.05 mol) of 40% aqueous monomethylamine. After stirring for 16 h the reaction mixture was diluted with 200 mL of water and the oil which separated slowly solidified. The solids were collected by filtration (3.9 g) and recrystallized from benzene/ligroin, yielding 3.5 g (79.8%) of white crystals, mp 93.5°-95° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[O:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B>C1COCC1.C(OCC)C>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)c1cccc(OC)c1OC
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCNCc1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
N-Heptyl-2,3-dimethoxybenzamide (6.47 g, 23.2 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (29 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL) and washed with aqueous 2 M K2CO3 (3×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (160 g) with ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol in ethyl acetate as the eluent yielded 3.40 g (55%) of a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Cl>>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccccc1Cl
Product: Clc1ccc(-c2nn(Cc3ccccc3Cl)c3c2CCNCC3)cc1
Yield: 13.4 %

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-chlorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C17H22ClN3O, 371.10. found, m/z 372.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.43-7.41 (m, 2H), 7.32-7.30 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.23 (s, 2H), 2.94-2.91 (br m, 4H), 2.79-7.77 (br m, 2H), 2.73-7.71 (br m, 2H).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=2[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[C:14]([N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]3)[CH:13]=[CH:12][C:11]=2[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Yield: 30.5 %

Procedure:
1-(2-(1-Phenylethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (150 mg, 0.48 mmol), t-butyl piperazine-1-carboxylate (98.7 mg, 0.53 mmol), N,N-diisopropylethylamine (124 mg, 0.96 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 21 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (70 mg, 30% yield). 1H NMR (400 MHz, CDCl3): δ 9.36 (d, 1H), 7.60 (d, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.13 (d, 1H), 5.61 (s, 1H), 4.55 (m, 1H), 3.41 (m, 4H), 3.25 (m, 2H), 3.14 (m, 2H), 1.61 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C25H30F3N3O3: 477.22; Observed: 500.3 (M++Na).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]([OH:37])[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:37])[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)N(Cc1ccccc1C(C)O)c1ccccc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
A solution of 0.22 ml of oxalyl chloride in 13.5 ml of dichloromethane was cooled to −70° C. or below on dry-ice-acetone, and a solution of 0.24 ml of dimethyl sulfoxide in 0.9 ml of dichloromethane was added dropwise, followed by stirring for 10 minutes. To this was added dropwise a solution of 0.48 g of N-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline in 4.5 ml of dichloromethane, and the temperature of the reaction solution was gradually raised to −45° C., followed by stirring at the same temperature for an hour. To the reaction solution was added dropwise 1.34 ml of triethylamine at −40° C. or below, followed by stirring at 0° C. for 20 minutes. The reaction solution, after addition of a saturated aqueous ammonium chloride solution, was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:1) and recrystallized from ethyl acetate-hexane to give 0.41 g of N-acetyl-N-(2-acetylbenzyl)-2-phenoxyaniline.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([NH:22][C:23]1[C:32]([C:33]2[CH:37]=[CH:36][O:35][C:34]=2[CH2:38][O:39][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=[C:29]([NH:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:21])[CH3:20]>C1COCC1>[C:19]([NH:22][C:23]1[C:32]([C:33]2[CH:37]=[CH:36][O:35][C:34]=2[CH2:38][OH:39])=[CH:31][CH:30]=[C:29]([NH:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:21])[CH3:20]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1NC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO)c1NC(C)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.2 %

Procedure:
Tetrabutylammonium fluoride (1M solution in THF, 1.1 mL) was added to a stirred, cooled solution of methyl 2-acetylamino-3-[2-(tert-butyldimethylsilanyloxymethyl)-furan-3-yl]-6-(2,2-dimethylpropionylamino)benzoate (Intermediate 34, 0.43 g) in THF (10 mL) at 0° C. and the mixture was stirred at 0° C. for 40 minutes then evaporated to dryness. The residue was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and ethyl acetate with a gradient of 0-2% to give methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(2-hydroxymethylfuran-3-yl)benzoate (0.2 g) as a gum.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1.[O:16]=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C.[Li+].[Br-]>C1COCC1>[C:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH:18]([C:17](=[O:16])[CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:5]=1)#[N:15]
Reactant: N#Cc1ccsc1-c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2sccc2C#N)cc1)C(=O)OCC
Yield: 97.7 %

Procedure:
A mixture of 50 g of 2-(4-bromomethylphenyl)-3-cyanothiophene, prepared above, 40 g of ethyl 3-oxohexanoate, prepared in Example 1, 300 ml of THF, 62 ml of diisopropylethylamine and 15.6 g of LiBr is refluxed for 15 h. It is concentrated under vacuum, a dilute solution of hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with water, dried and evaporated to give 62.4 g of ethyl 2-[4-(3-cyano-2-thienyl)benzyl]-3-oxohexanoate in the form of an oil, which is used without further purification.
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.C(N(CC)CC)C>CO>[F:25][C:20]1[CH:19]=[C:18]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9]2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: COC(=O)C(C)(C)CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate from Step E (300 mg, 0.800 mmol) in MeOH (16 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 30 seconds, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (16 mL), triethylamine (323 mg, 3.2 mmol) was introduced and the mixture was heated to 65° C. for 16 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (50 mL) and 1 N HCl (50 mL). The organics were washed with additional 1 N HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=240 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[C@H:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21](=[O:23])[NH:41][C@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: N[C@@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
Anhydrous DMF (20 ml) is added to a 100 ml round bottom flask containing compound 4 (325 mg, 1.014 mmol) under N2. After ten minutes diisopropylamine (0.88 ml, 5.07 mmol) is added to the flask. It is then stirred at room temperature for 1.5 hrs. (R)-1,2,3,4-Tetrahydro-1-napthylamine (149.3 mg, 1.014 mmol) is then added to the flask and stirred for 1 hr. HBTU (423.07 mg, 1.115 mmol) is added to the reaction followed by HOBT (152.1 mg, 1.126 mmol). The reaction mixture is then stirred at room temperature under N2 overnight at which point LCMS shows completion of the reaction. It is then diluted with EtOAc and washed subsequently with 1.0 M citric acid, brine, saturated sodiumbicarbonate, brine, water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound is flash column purified using hexane and ethylacetate gradient solvent system to yield 423 mg (93%) of the desired product 6. HPLC shows this compound to be greater than 99% pure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[N:26]=[C:25]3[C:20]([CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31])[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]2[N:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][NH:24]3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](CNC(=O)c1ccc(C=Cc2ccc3cccnc3n2)cc1)NS(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CNC(=O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1)NS(=O)(=O)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 33-2 (1.3 g, 2.45 mmol), 10% Pd/C (650 mg) and ethanol (100 ml) was stirred under a hydrogen atmosphere (1 atm) for 18 hr. Filtration followed by concentration gave a yellow foam which was purified by flash chromatography (silica, 49:1 EtOAc/EtOH.NH3) to provide 33-3 as a pale yellow solid.
Reaction SMILES: C[O:2][CH2:3][CH2:4]OC.Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:21]=[C:20]([C:31]3C=C[N:34]=[C:33](F)[CH:32]=3)[N:19]=2)[CH3:16])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[N:19]=[C:20]([C:31]3[CH:32]=[CH:33][N:34]=[C:3]([OH:2])[CH:4]=3)[CH:21]=[C:22]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:23]=2)[CH3:16])=[CH:13][CH:14]=1
Reactant: COCCOC
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccnc(F)c2)n1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccnc(O)c2)n1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1 ml of 1,2-dimethoxyethane and 10% hydrochloric acid were added to 80 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, and the mixture was stirred at 85° C. for 2 hours. 0.5 ml of 10% hydrochloric acid was added thereto, and the mixture was further stirred for 2 hours. The reaction solution was diluted with ethyl acetate and alkalified with a saturated aqueous solution of sodium bicarbonate. The mixture was subjected to extraction, and the obtained organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained solid was washed with diethyl ether and filtrated, and then dried under reduced pressure to obtain 54 mg of the objective compound as white powder.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[C:19]([NH:21][C:22](=[O:33])[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20])C1C=CC=CC=1.Cl.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[C:19]([NH:21][C:22](=[O:33])[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccc(OCc4ccccc4)cc23)=C1c1c[nH]c2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1NC(=O)C(c2c[nH]c3ccc(O)cc23)=C1c1c[nH]c2ccccc12
Temperature: 0 °C

Procedure:
0.15 g (0.34 mmol) 2-(5-benzyloxy-1H-indol-3-yl)-3-(1H-indol-3-yl)-maleinimide and 4.0 g (34 mmol) pyridinium hydrochloride are heated under an atmosphere of nitrogen for 1 hour at 150° C. After cooling, the reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic phase is washed out with water and evaporated to dryness. The solid residue is triturated with a little water, filtered off with suction and dried in a vacuum at 0.1 Torr and 80° C. There are obtained 85 mg (73% of theory) of dark red product; m.p. 200°-205° C.; RF=0.29 (toluene/ethanol 10:2 v/v).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:12]([CH2:13][CH2:14][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)#[N:15]
Reactant: c1c[nH]c(Cn2ccnc2)c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#CCCn1cccc1Cn1ccnc1
Reaction time: 18 h

Procedure:
2-(Imidazol-1-ylmethyl)pyrrole (4.41 g) and acrylonitrile (6.0 ml) were dissolved in dioxan (75 ml) and benzyltrimethylammonium hydroxide (1.5 ml of 40% solution in methanol) was added. The mixture was warmed to 55° for 1 hour and then allowed to stand at room temperature for 18 hours. It was then poured into water and the mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave 1-(2-cyanoethyl)-2-(imidazol-1-ylmethyl)pyrrole (5.0 g) as an oil.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (300 mg, 0.76 mmol) is coupled to 4-bromobenzonitrile (167 mg, 0.92 mmol) using Method B to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:27]O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:27])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc([N+](=O)[O-])cc3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc([N+](=O)[O-])cc3)ccc2[nH]1

Procedure:
Prepared analogous to Examples 123 from 6-[4-(4-nitrophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.