Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].[Cl-].[Li+].[Li+].CC([N-]C(C)C)C.[CH2:25](Br)[CH2:26][CH2:27][CH3:28].[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([CH2:34][CH2:30][CH2:31][CH3:32])[CH:8]=[CH:7][CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:14]
Reactant: CCOC(=O)C/C=C/CC(=O)OCC
Reactant: CCCCBr
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Product: CCCCC(C=CC(CCCC)C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 16 %

Procedure:
To a stirred solution of 2.0 g (9.99 mmol) trans-2-butene-1,4-dicarboxylic acid diethyl ester in 80 ml THF was added 2.54 g (59.9 mmol) anhydrous lithium chloride and the resulting suspension cooled to −78° C. 10.0 ml (20.0 mmol) of a 2 M solution of LDA in THF was added dropwise and stirring continued for 45 min. 2.2 ml (20.4 mmol) butyl bromide was then added and stirring continued for 15 min at −78° C., then 30 min at 0° C, and then 4 h at room temperature. The reaction was quenched by addition of saturated ammonium chloride solution and the mixture extracted three times with ether. The combined organic phases were washed successively with saturated ammonium chloride solution, water, and saturated brine, dried over sodium sulphate, and concentrated in vacuo. Successive flash chromatography (10% EtOAc in hexane for first column; then gradient: 10-100% toluene in cyclohexane for second column) afforded 509 mg (16%) of the title compound as a yellow oil. MS m/e (%): 330 ([M+NH4]+, 100).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].CN[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C:19]#[N:20].CCOCC.[CH3:26][N:27](C)C=O>O>[C:19]([CH2:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([CH2:26][NH:27][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH:10]=2)[NH:14][CH:13]=1)#[N:20]
Reactant: CNc1ccc2[nH]cc(CC#N)c2c1
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)NCc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.21 ml) was added dropwise to a stirred solution of 5-(methylamino)-1H-indole-3-acetonitrile (0.4 g) in dimethylformamide (15 ml). After 10 min. the solution was diluted with water (30 ml), stirred for 30 min. and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with 10% brine (2×100 ml), 8% sodium bicarbonate (2×100 ml) and water (2×100 ml), dried (Na2SO4) and evaporated in vacuo to yield the crude product as a brown oil. Trituration with ether gave a fawn solid (0.4 g). A sample was crystallised from ether to give the title compound as a white solid m.p. 104°-106°.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([CH3:16])[C:13](=O)[NH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([CH3:16])[C:13](=[S:20])[NH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1Oc2ccc(-c3ccccc3)cc2NC1=O
Solvent: c1ccncc1
Solvent: O
Product: CC1Oc2ccc(-c3ccccc3)cc2NC1=S
Yield: 100 %

Procedure:
1.62 g of 6-phenyl-2-methyl-1,4-benzoxazin-3-one is heated with 0.5 g of phosphorus pentasulfide in 6 ml of pyridine p.a. The product is diluted with water, extracted 3 times with ethyl acetate, the organic phase is washed with brine and dried with magnesium sulfate. It is concentrated by evaporation. The crude product corresponds to a yield of 100%. Column chromatography with a hexane/ethyl acetate mixture yields pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=2)[N:8]=1
Reactant: COC(OC)c1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc2cc(C=O)ccc2n1
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
To a solution of 6-bromo-2-(dimethoxymethyl)quinoline (1.11 g, 3.94 mmol) in tetrahydrofuran (20 mL) were added n-butyllithium (1.6 mol/L; 3.7 mL, 5.9 mmol) and dimethylformamide (0.61 mL, 7.9 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (3:1 hexane/ethyl acetate) to afford 2-dimethoxymethyl-6-quinolinecarboxaldehyde (344 mg, 38%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:29][C:28]1[O:27][C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:25][C:24]=1[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:7]2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (10.23 g), 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (14.66 g), potassium carbonate (13.09 g), and N,N-dimethylformamide (100 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (19.88 g, yield: 87%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 113˜114° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[NH:16]C(=O)C)[S:7][CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>Cl>[C:1]([NH:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[NH2:16])[S:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CS2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CSc2c(C)ccc(N)c2C1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
109 mg of the compound prepared in (1) above was added to 10 ml of 6 N hydrochloric acid, and the mixture was stirred at 90° C. for 20 minutes. After cooling, the mixture was alkalinized by the addition of sodium hydroxide and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was subjected to silica gel column chromatography using a chloroform-ethyl acetate (4:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 51 mg of the title compound. p NMR(CDCl3) δ: 2.09(3H, s), 2.16(3H, s), 2.98(1H, m), 3.60(1H, m), 4.6-5.0(1H, m), 6.33(1H, d, J=9 Hz), 7.02(1H, d, J=9 Hz).
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50]>C(Cl)Cl.CO>[CH:49]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:47][CH2:46][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1)([CH3:51])[CH3:50]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1)C(C)C

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using (2-chloroethyl)-diisopropyl-amine hydrochloride. Title compound: ES-MS: 402.0 [M+H]+; single peak at tR=6.53 min (System 1); Rf=0.50 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C([Sn](CCCC)(CCCC)/[CH:28]=[CH:29]/[CH2:30][OH:31])CCC.[Cl-].[Li+]>CN(C)C=O>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:28]=[CH:29][CH2:30][OH:31])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2c(SC)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc2c(SC)ncnc2cc1C=CCO
Temperature: 65 °C
Yield: 43.7 %

Procedure:
A suspension of 4-(methylthio)-6-methoxy-7-(trifluoromethanesulphonyloxy)quinazoline (1.1 g, 3.1 mmol), E-3-(tributylstannyl)-2-propen-1-ol (1.12 g, 3.23 mmol), bisdichloro(triphenylphosphine)palladium (44 mg, 0.06 mmol) and lithium chloride (395 mg, 9.32 mmol) in dimethylformamide (14 ml) was heated at 65° C. for 3 hours. The mixture was cooled to ambient temperature, the solid was recovered by suction filtration and washed with ether. Drying in vacuo yielded 4-(methylthio)-6-methoxy-7-(3-hydroxyprop-1-enyl)quinazoline (355 mg, 44% yield):
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[N:4]=1)#N.[OH-:16].[Na+].C(O)C.[OH2:21]>>[CH2:14]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[C:3]([C:1]([OH:21])=[O:16])=[N:4]1)[CH3:15]
Reactant: CCn1nc(C#N)c(=O)c2ccccc21
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C(=O)O)c(=O)c2ccccc21

Procedure:
A solution of 25 g 3-cyano-l-ethyl-1,4-dihydro-4-oxocinnoline, 100 g sodium hydroxide, 400 ml ethanol and 100 ml water was stirred at 70° C. for 3 hr. After the removal of ethanol by evaporation, to the mixture was added conc. hydrochloric acid to precipitate crystalline materials. Precipitates were separated by filtration, washed with water, ethyl ether/ethanol and dried to yield 25.6 g of the desired compound. Mp.=206°-208° C. 1H-NMR(DMSO-d6, δ ppm) 1.48 (3H,t), 4.76 (2H,q), 7.76 (1H,t), 8.07 (1H,m), 8.19 (1H,d), 8.33 (1H,d)
Reaction SMILES: CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][CH:36]=[O:37])=[C:31]([O:38][CH:39]([CH3:41])[CH3:40])[CH:30]=2)[CH2:25][CH2:24]1.[F:42][C:43]1[CH:44]=[CH:45][C:46]([O:66][CH3:67])=[C:47]([C:49]2[C:53]3[N:54]=[C:55](S(C)(=O)=O)[N:56]=[CH:57][C:52]=3[S:51][C:50]=2[C:62]([O:64][CH3:65])=[O:63])[CH:48]=1>CN(C=O)C>[CH:36]([N:35]([C:32]1[CH:33]=[CH:34][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]2)=[CH:30][C:31]=1[O:38][CH:39]([CH3:41])[CH3:40])[C:55]1[N:56]=[CH:57][C:52]2[S:51][C:50]([C:62]([O:64][CH3:65])=[O:63])=[C:49]([C:47]3[CH:48]=[C:43]([F:42])[CH:44]=[CH:45][C:46]=3[O:66][CH3:67])[C:53]=2[N:54]=1)=[O:37]
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1cc(F)ccc1OC
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(N(C=O)c3ccc(N4CCN(C)CC4)cc3OC(C)C)nc2c1-c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
0.7 ml of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine (BTPP) is added to a solution of 245 mg of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 5 ml of anhydrous DMF. After 10 min, a solution of 350 mg of methyl 7-(5-fluoro-2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in 6.5 ml of anhydrous DMF is added and the mixture is stirred at ambient temperature for 42 h. The mixture is then evaporated under vacuum at a temperature of 60° C., and the residue is purified on 120 g of silica, elution being carried out with 5% of methanol in dichloromethane, so as to obtain 503 mg of methyl 2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of an orangey-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1F
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2k (210 mg, 0.650 mmol), 6-mercaptopurine monohydrate (122 mg, 0.715 mmol), K2CO3 (99 mg, 0.715 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 240 mg of an off-white solid (84%), mp 244.0° C. 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.50 (s, 1H); 8.45 (s, 1H); 7.81 (t, J=8.0 Hz, 1H); 7.74 (t, J=7.7 Hz, 1H); 7.67 (d, J=8.1 Hz, 1H); 7.62 (d, J=7.7 Hz, 1H); 7.46-7.55 (m, 1H); 7.29-7.42 (m, 2H); 4.47-4.59 (m, 2H). 13C NMR (DMSO-d6) ppm: 158.4, 157.3 (d, J=249 Hz), 156.4, 153.8, 151.0, 149.1, 143.2, 135.0, 132.9, 131.8 (d, J=8.0 Hz), 130.8, 129.9, 126.7, 125.3 (d, J=3.5 Hz), 123.6 (d, J=13 Hz), 117.0, 116.2 (d, J=19 Hz), 31.7. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS: C, 54.74; H, 2.76; Cl, 8.08; N, 19.15; S, 7.31. Found: C, 54.42; H, 2.88; Cl, 8.08; N, 18.87; S, 7.08.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: CCCCCCCI
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
In 32 ml of water and 32 ml of ethanol, 27.2 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 9.0 g of sodium hydroxide were added. To this solution, 45.2 g of 1-iodoheptane was added, and the mixture was stirred at 60° C. for 2 hours. After cooling, water was added to the mixture and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/n-hexane (1:1) mixture. Thus 36.1 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained. m.p. 112°~113° C. Yield 78%.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:23])([F:22])[C:7]([CH:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([O:12]CC)=O)=O.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].CCCCCC>CCO>[CH3:26][C:25]1[NH:28][C:10](=[O:12])[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:6]([F:5])([F:22])[F:23])[N:27]=1
Reactant: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Yield: 24.1 %

Procedure:
To a solution of NaOEt (0.026 mol) in EtOH (prepared from 0.60 g of Na and 30 mL of EtOH) was added diethyl trifluoroacetylglutarate (3.70 g, 0.013 mol) and acetamidine hydrochloride (1.23 g, 0.013 mol). The reaction mixture was heated under reflux for 18 h, concentrated, and taken up in water. The mixture was acidified to pH 4 with 2N HCl and extracted with CH2Cl2. The extracts were dried (MgSO4) and concentrated to give a yellow solid. Trituration with hexane gave 0.87 g of product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]#N.[OH-:20].[K+].[OH2:22]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:22])=[O:20]
Reactant: O
Reactant: [OH-]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1F
Agent: [K+]
Solvent: CCO
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1F

Procedure:
A mixture of 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetonitrile (5 g) and potassium hydroxide (2.2 g) in ethanol (60 ml) and water (30 ml) was refluxed under heating for 20 hours, and the reaction mixture was evaporated. To the residue was added water, and the mixture was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetic acid (5.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine 2-(3-bromophenyl)-1,3-dioxolane (10.0 ml, 66.0 mmol) and tetrahydrofuran (100 ml) and cool to about −78° C. Add dropwise a solution of n-butyllithium, 1.6 M solution in hexane (44.0 ml, 66.0 mmol). After 10 min, add a solution of benzaldehyde (7.6 ml, 66.0 mmol) in tetrahydrofuran (50 ml) via cannula. After 1 hour, warm to room temperature. After 18 hours, quench into water and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 7:3 hexane:EtOAc to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)=[O:8].[OH-].[Na+].O.C(O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(F)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cc1
Yield: 86.4 %

Procedure:
A mixture of 0.60 g of ethyl 4-[(5-fluoro-2-methylbenzoyl)amino]benzoate 0.60 ml of 10 N NaOH, 25 ml of water and 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour, cooled and acidified with acetic acid. The resulting solid is filtered and dried in vacuo at 60-80° C. to give 0.47 g of the desired product as a solid, m.p. 272-275° C.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[C:40]2[C:41]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:42]=4[C:35]([C:36]=3[CH:37]=[CH:38][CH:39]=2)=[C:34]2[CH:43]=[CH:44][CH:45]=[CH:46][C:33]2=[CH:32]5)=[CH:25][CH:24]=1>O.[Cu]>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([N:7]([C:23]2[C:40]3[C:41]4[C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]6[C:42]=5[C:35]([C:36]=4[CH:37]=[CH:38][CH:39]=3)=[C:34]3[CH:43]=[CH:44][CH:45]=[CH:46][C:33]3=[CH:32]6)=[CH:25][CH:24]=2)[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc2c3cccc4cc5ccccc5c(c5cccc1c25)c43
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c4cccc5cc6ccccc6c(c6cccc2c36)c54)cc1

Procedure:
Then, di-p-tolylamine, potassium carbonate, and copper power were added to the thus obtained bromobenzo[a]perylene. This mixture stood still for reaction at 200 degrees centigrade for thirty hours. After reactant solution was diluted with water, reactant was extracted by chloroform. Thereafter, the reactant was refined in a conventional manner to thereby obtain di-p-tolylaminobenzo[a]perylene.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[Li]C(C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:16]1([CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:15]2=[N:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18]([CH2:17][C:16]3([CH2:21][CH2:22][CH:23]([O:26][CH3:27])[CH2:24][CH2:25]3)[C:15]2([NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C:1]([O:3][CH2:4][CH3:5])=[CH2:2])=[CH:19][CH:20]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Reactant: C=COCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 0 °C
Yield: 89 %

Procedure:
To solution of ethyl vinyl ether (1) (269 mg, 357 μL, 3.73 mmol, 5 eq.) in dry THF (10 mL) chilled to −78° C. under N2 was added 1.7 M t-BuLi in heptanes (1.75 mL, 2.98 mmol, 4 eq.) dropwise within 10 min. The temperature of the resulting yellow clear solution1 was allowed to warm to 0° C. slowly within 30 min. By removing dry ice and adding water to dry ice-acetone bath, finally the cooling bath was replaced with a ice water bath. The color changed from yellow to nearly colorless after being stirred ca 5 min at 0° C. Then the lithium regent solution (2) was cooled to −78° C. again and cannulated to a solution of starting material 4 (307.5 mg, 0.746 mmol) in dry THF (5 mL) at −78° C. with positive pressure. The resulting mixture was stirred at this temperature for another 30 min. The reaction was quenched with saturated aqueous NH4Cl and extracted with ether and EA, the combined organic phases were washed with water and brine, dried, and filtered. The solvent was removed under reduced pressure to generate off-white foam, which was purified by flash chromatography on silica gel 9:1 eluted with EA in hexane (0-40%) to produce the desired product 5 and its diastereomers in a ratio (321 mg, yield 89%). MS ESI+ve m/z 484 (M+H)+.
Reaction SMILES: S1C=CC=C1.[C:6]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1.[H][H]>[Pd].CO.C(O)C>[CH:6]1([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[CH2:16][CH2:17]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCC1
Reactant: [H][H]
Reactant: c1cnc(NC2CCNCC2)nc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Solvent: CCO
Product: c1cnc(NC2CCN(C3CCCC3)CC2)nc1

Procedure:
To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 2 parts of cyclopentanone, 5.5 parts of N-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 4-methyl-2-pentanone and a small amount of trichloromethane. The whole is washed twice with a diluted sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.3 parts of N-(1-cyclopentyl-4-piperidinyl)-2-pyrimidinamine; mp. 118° C.