Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)=[CH:9][C:8]2=[O:24].[OH-].[Na+]>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[CH:9][C:8]2=[O:24]
Reactant: O=c1cc(-c2ccc([N+](=O)[O-])cc2)oc2ccc(Br)cc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
Tin(II) chloride (275 mg, 1.45 mmol) was slowly added to an ethanol solution (7 ml) that contained compound 4 (100 mg, 0.289 mmol), while stirring. The obtained mixture was heated to reflux for 1 hour. After completion of the reaction, a 1 N sodium hydroxide aqueous solution (50 ml) was added to the reaction solution, and the obtained mixture was then extracted with 50 ml (25 ml×2) of ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain a product of interest, 6-bromo-4′-aminoflavone (compound 5) in the form of a yellow crystal. Yield: 77 mg (yield constant: 84.3%) 1H NMR (300 MHz, CDCl3) δ8.36 (s, 1H), 7.72-7.76 (m, 3H), 7.44 (d, J=9.0 Hz, 1H), 6.72 (d, J=8.7 Hz, 2H), 6.70 (s, 1H), 4.15 (s, 2H). MS m/z 317 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([OH:28])[C:12]3[C:13]([F:27])=[C:14]([NH:19][S:20]([CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:12]3[C:13]([F:27])=[C:14]([NH:19][S:20]([CH2:23][CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])=[O:28])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CC(C)CS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
In a round bottom flask, 2-methyl-propane-1-sulfonic acid {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-amide (68, 618 mg, 1.30 mmol) was dissolved in 20 mL of tetrahydrofuran, and Dess-Martin periodinane (555 mg, 1.31 mmol) was added. The reaction was stirred at room temperature for 30 minutes, then quenched with water and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, water, and brine, then dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with dichloromethane and methanol. Appropriate fractions were collected and concentrated under vacuum to provide the desired compound (69, 257 mg). MS (ESI) [M−H+]−=469.9, 471.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl>O.C(OCC)C>[CH3:16][C:13]([CH3:17])([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:2]1[CH2:11][C:10]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:14][OH:15]
Reactant: CC(C)(CO)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(CO)n1c(Cc2ccccc2)nc2cnc3ccccc3c21
Temperature: 130 °C

Procedure:
A mixture of 26.7 g (0.115 mole) of 2-[(3-amino-4-quinolinyl)amino]-2,2-dimethyl-1-ethanol and 42.8 g (0.180 mole) of triethyl orthophenylacetate was heated at 130° C. for four hours. The mixture was diluted with water, acidified to pH 5 with 6N hydrochloric acid and diluted with diethyl ether. The solid which precipitated was separated by filtration, rinsed with diethyl ether and slurried in saturated sodium bicarbonate solution. The solid was separated by filtration and dried to provide beta,beta-dimethyl-2-phenylmethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH2:11]([C:13]([C:20]([F:23])([F:22])[F:21])([C:17](F)=[O:18])[C:14](F)=[O:15])[CH3:12]>C(COC)OC>[CH2:11]([C:13]1([C:20]([F:21])([F:22])[F:23])[C:14](=[O:15])[NH:4][C:2](=[O:3])[NH:1][C:17]1=[O:18])[CH3:12]
Reactant: NC(N)=O
Reactant: CCC(C(=O)F)(C(=O)F)C(F)(F)F
Solvent: COCCOC
Solvent: c1ccncc1
Product: CCC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A mixture of 1.70 g (0.028 mol) of urea, 4.4 g (0.056 mol) of pyridine and 30 ml of glyme was stirred at 25°C while a solution of 5.7 g (0.028 mol) of ethyltrifluoromethylmalonyl fluoride in 20 ml of glyme was added rapidly. The mixture was stirred overnight, solvent was removed under vacuum, and the residue was stirred with 15 ml of water. Filtration provided a solid which was recrystallized from water to give 3.8 g of 5-ethyl-5-trifluoromethylbarbituric acid, mp 210°-211°C. A second crop, 0.2 g, mp 208°-209°C, raised the total to 4.0 g (64%). A sample was recrystallized twice from water for analysis, mp 211°C; ir (KBr): 3.05 and 3.18 (NH), 3.49 (satd. CH), 5.72 and 5.82 (C=O), and 8-8.5 μ (CF); nmr ((CD3)2CO): 1H at ca. 8.5 (very broad (partly exchanged into acetone-d6), 2, NH), 2.37 (quartet with fine structure, JHH = 7.5 Hz, 2, CH2); and 0.94 ppm (triplet, JHH = 7.5 Hz, 3, CH3); 19F at -69.3 ppm (singlet with fine structure, CF3).
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1([C:14]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]3[CH2:34][O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[S:19][CH:20]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO>[ClH:1].[ClH:1].[O:11]1[CH2:12][CH2:13][N:8]([C:14]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[CH2:34][O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[S:19][CH:20]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)N3CCOCC3)cs2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1csc(N2CCNCC2COc2cccnc2)n1)N1CCOCC1
Reaction time: 8 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(morpholine-4-carbonyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (35.4 mg, 0.0723 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 33.2 mg (99%) of the title compound. LC-MS: RT=2.33 min, (M+H)+=390.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[I:18]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:18][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc21
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCc2cc(OC)c(I)cc21
Temperature: 25 °C

Procedure:
Ethyl (5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate (472 mg, 2.015 mmol) was dissolved in ethanol (20 mL). Iodine (511 mg, 2.015 mmol) and silver sulfate (628 mg, 2.015 mmol) were added and the reaction was stirred vigorously at room temperature, protected from light, for 1 hour. The reaction was diluted with ethyl acetate (75 mL) and filtered to remove solids. The filtrate was washed with sodium bisulfite (2×50 mL), water (70 mL), and brine (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes. Further purification by SFC on a chiral AD column with 15% IPA/heptanes removed a minor regioisomer and separated the two enantiomers of ethyl (6-iodo-5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate. 1H NMR (CDCl3, 500 MHz) δ 7.55 (s, 1H), 6.72 (s, 1H), 4.17 (m, 2H), 3.85 (s, 3H), 3.53 (m, 1H), 2.95-2.65 (m, 3H), 2.60-2.42 (m, 2H), 1.78 (m, 1H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([N+:16]([O-])=O)[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[OH:20][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH3:19])[CH2:7][C:2](=[O:1])[C:3]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A solution of 3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)-2-butyrylcyclohex-2-en-1-one (3.3 g, 0.01 mole) and sodium hydroxide (38 g) in 50% aqueous ethanol (120 ml) was stirred and heated under reflux. Sodium dithionite (9.6 g, 0.05 mole) was added in portions over a period of 30 minutes to the solution and refluxing was continued for 1 hour. The reaction mixture was filtered while still hot and the filtrate was diluted with water (100 ml), neutralized with hydrochloric acid and finally extracted with dichloromethane (2×100 ml). Evaporation of the dichloromethane layer gave 3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)-2-butyrylcyclohex-2-en-1-one (0.96 g, 32%) as an orange oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm); 1.00 (3H, t); 1.5 (2H, m); 2.14 (3H, s); 2.22 (3H, s); 2.30 (3H, s); 2.4-4.0 (7H, m); 6.78 (1H, s); exchangeable protons not observed.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:27]CCl>C(O)C>[ClH:27].[C:18]1([CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCl
Reactant: CCOC(=O)C1CCCN(CCOCCCc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(CCOCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (3.2 g, 10 mmol) was dissolved in ethanol (10 ml) and 12N sodium hydroxide (2.5 ml) was added. The mixture was stirred at ambient temperature for 3 h. Excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The mixture was dried (Na2SO4) and the solvent was evaporated in vacuo to give a residue which was re-evaporated twice with acetone. Crystallisation of the residue from a mixture of acetone and ethyl acetate followed by recrystallisation from acetone gave 1.1 g of the title compound as a solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:28])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21](Cl)[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:29][C:30]1[CH:35]=[C:34]([Sn](CCCC)(CCCC)CCCC)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:28])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(C#N)c(Cl)c3)nc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(C#N)c(-c4ccnc(C)c4)c3)nc2)CC1
Temperature: 118 °C
Reaction time: 8 h

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-chloro-4-cyanophenyl)acetamide as solid 237-3 (17 mg, 0.043 mmol), 2-methyl-4-(tributylstannyl)pyridine (24.5 mg, 0.064 mmol), Pd(PPh3)4 (5 mg, 0.0043 mmol) in DMF (0.6 ml) was stirred at 118° C. under argon overnight. After cooled to room temperature, it was filtered through celite while washed and diluted with ethyl acetate (30 ml). Then it was washed with water (40 ml) and extected with 0.5 N HCl (30 ml). After the aqueous extraction was treated with Na2CO3 to have the pH adjusted to around 9, the aqueous phase was extracted with ethyl acetate (30 ml×2). The combined organic phases were dried over Na2SO4, concentrated by rotary evaporation and the residue subjected to silica gel column chromatography with MeOH in ethyl acetate (0 to 5%) as eluent to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-cyano-3-(2-methylpyridin-4-yl)phenyl)acetamide as solid 237. MS m/z 455.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.62 (d, 1 H), 8.08 (d, 1 H), 8.02 (bs, 1 H), 7.91 (d, 1 H), 7.79 (d, 1 H), 7.53-7.47 (m, 2 H), 7.34 (bs, 1 H), 7.31-7.26 (m, 2 H), 3.82 (s, 2 H), 3.80-3.75 (m, 2 H), 3.65-3.60 (m, 2 H), 3.16-3.08 (m, 4 H), 2.64 (s, 3 H), 2.14 (s, 3 H).
Reaction SMILES: C([O:5][CH2:6][C@H:7]([CH3:20])[C@H:8]([O:18][CH3:19])[C@@H:9]([CH3:17])[C@@H:10]([O:15][CH3:16])/[CH:11]=[CH:12]/[CH:13]=[CH2:14])(C)(C)C.C[O-].[Na+]>CO>[CH3:19][O:18][C@H:8]([C@@H:9]([CH3:17])[C@@H:10]([O:15][CH3:16])/[CH:11]=[CH:12]/[CH:13]=[CH2:14])[C@@H:7]([CH3:20])[CH2:6][OH:5]
Reactant: C=C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO
Reaction time: 8 h

Procedure:
To (E)-(5S,6S,7S,8S)-9-tert-Butoxy-5,7-dimethoxy-6,8-dimethyl-nona-1,3-diene (1.3 g, 4.2 mmol) in anhydrous methanol (10 ml) at room temperature and under an atmosphere of nitrogen was added sodium methoxide (30% wt in MeOH, 3.7 ml, 20.8 mmol). The reaction was stirred overnight. A further amount of sodium methoxide (30% wt in MeOH, 3.7 ml, 20.8 mmol) was added and the reaction was stirred for a further 1 hour. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane (3×). The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 10:1 then 2:1) to afford 2.0 g (100%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 6.40 (dt, J=16.8 Hz, 10.4 Hz, 10.2 Hz, 1H), 6.23 (dd, J=15.2 Hz, 10.4 Hz, 1H), 5.46 (dd, J=15.2 Hz, 8.4 Hz, 1H), 5.26 (dd, J=17.0 Hz, 1.6 Hz, 1H), 5.14 (dd, J=10.2 Hz, 1.6 Hz, 1H), 3.77-3.53 (m, 3H), 3.51 (s, 3H), 3.42 (t, J=9.3 Hz, 1H), 3.27 (s, 3H), 2.75 (dd, J=8.4 Hz, 3.1 Hz, 1H), 1.91 (m, 1H), 1.72 (m, 1H), 0.85 (d, J=7.1 Hz, 3H), 0.80 (d, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[CH2:4][CH2:5][C:6]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([NH:16][C:17](=[O:19])[CH3:18])[CH:10]=[CH:9][C:8]=2[CH:7]=1.CCN=C=NCCCN(C)C.[C:32]1([C:41]2[CH:46]=[CH:45]C=[CH:43][CH:42]=2)[CH:37]=[CH:36][C:35](C(O)=O)=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[CH3:20][N:3]([CH3:2])[CH2:4][CH2:5][C:6]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([NH:16][C:17]([C:18]3[CH:43]=[CH:42][C:41]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:46][CH:45]=3)=[O:19])[CH:10]=[CH:9][C:8]=2[CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN(C)C)=C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCC1=Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Concentrated hydrochloric acid (1.5 ml) was added to N-[6-[2-(dimethylamino)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (57.5 mg, 0.223 mmol) obtained in Reference Example 104, which was stirred at 100° C. for 1 hour. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (29.2 mg, 0.139 mmol) was added to a dimethylformamide solution (0.7 ml) of the resulting oily substance (30 mg, 0.139 mmol), [1,1′-biphenyl]-4-carboxylic acid (30.2 mg, 0.139 mmol) and DMAP (16.9 mg, 0.139 mmol) under ice-cooling, which was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (12.4 mg).
Reaction SMILES: [OH:1][CH2:2][C:3](O)=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:22]([O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27])[CH3:23].N1C=CN=C1>C(#N)C.C1(C)C=CC=CC=1>[CH2:22]([O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH:27][C:2](=[O:1])[CH2:3][OH:4])[CH3:23]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)[C@H](C)NC(=O)CO
Temperature: 25 °C
Yield: 61 %

Procedure:
One equivalent each of hydroxyacetic acid (10.0 g), dicyclohexylcarbodiimide, (L)-alanine ethyl ester hydrochloride and imidazole was stirred in 500 mL acetonitrile. The reaction mixture, initially at 0° C. was allowed to warm to room temperature overnight and then heated at 65° C. for 2 hours. After the addition of an equal volume of toluene, the reaction mixture was filtered and the solvent removed by rotovaping from the filtrate to give crude product. An aliquot of the crude product was chromatographed on silica gel to give N-(hydroxyacetyl)alanine ethyl ester (61% yield). 1H NMR (300 MHz, DMSO-d6 /TMS): δ1.19 (t , 3H, J=7.1 Hz), δ1.31 (d, 3H, J=7.2 Hz), δ3.83 (s, 2H), δ4.09 (d×q, 2H, J=1.2 and 7.1 Hz, irradiation in the methyl region eliminates the smaller coupling constant), δ4.32 (d×q, 1H, J=7.3 and 7.3), and δ 8.31 (br d, 1H, J=7.2 Hz). 13C NMR (75 MHz, CDCl3 /TMS): 13.59, 17.54, 47.31, 61.02, 61.48, and 172.17. [α]25D =-4.1°±0.4° (c=1.99, CHCl3). HRMS: calcd for C7H14NO4 (M+H)+, 176.0923; found, 176.0921.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[N:4][C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[Cl:16][C:3]1[N:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:7][N:2]=1
Reactant: Cn1cc(-c2ccccn2)cnc1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1ncc(-c2ccccn2)cn1
Temperature: 120 °C

Procedure:
A mixture of 1-methyl-5-(2-pyridinyl)-2(1H)pyrimidone (8.994 g, 0.048 mole), phosphorus pentachloride (2.156 g, 0.0104 mole), and phosphorus oxychloride (24 mL) was refluxed at 120° C. for 8 h. POCl3 was distilled out under reduced pressure. The residue was cooled to room temperature and ice-water was added. The mixture was extracted with EtOAc, the organic layer was washed with 15% NaCl solution, brine and dried over MgSO4. Solvent was distilled out under reduced pressure to yield a solid. The water layer was adjusted to pH 6-7 by using saturated Na2CO3, then extracted with EtOAc. The organic layer was washed with 15% NaCl, brine, dried over MgSO4. Solvent was distilled out under reduced pressure to give a solid. After trituration with MeOH, additional product was obtained.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:9]>N1C=CC=CC=1>[C:12]1([C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:9])=[O:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(C(=O)c1ccccc1O)c1ccccc1
Solvent: c1ccncc1
Product: O=C(C(=O)c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
10 gm of commercially available monofunctional hydroxyl terminated polypropylene oxide having Mn of 5000 was dissolved in 25 ml of 20% phosgene in toluene. The mixture was heated to 60° C. for 2 hours and then the phosgene and toluene were removed by a stream of nitrogen. The resulting chloroformate end-capped oligomer was dissolved in 50 ml of methylene chloride. To this mixture was added 0.43 g (0.0019 mole) of hydroxy benzil and 5 g of pyridine at 0° C. to form a benzil end cap polypropylene oxide having Mn of about 5000. The product was isolated by an aqueous workup and the methylene chloride was removed under reduced pressure to give 8.2 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:7]([C:13]#[N:14])[C:8](=[NH:12])[O:9]2)=[CH:4][C:3]=1[Cl:21].CC1C(Cl)=CC(C(C2C=CC=CC=2)=O)=C(O)C=1.C(#N)CC#N.N1CCCCC1>C(O)C>[NH2:12][C:8]1[O:9][C:10]2[C:5]([CH:6]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=1[C:13]#[N:14])=[CH:4][C:3]([Cl:21])=[C:2]([CH3:1])[CH:11]=2
Reactant: Cc1cc2oc(=N)c(C#N)c(-c3ccccc3)c2cc1Cl
Agent: Cc1cc(O)c(C(=O)c2ccccc2)cc1Cl
Solvent: C1CCNCC1
Solvent: N#CCC#N
Solvent: CCO
Product: Cc1cc2c(cc1Cl)C(c1ccccc1)C(C#N)=C(N)O2
Yield: 17 %

Procedure:
7-Methyl-6-chloro-3-cyano-2-imino-4-phenyl-2H-chromene. To a mixture of 4-methyl-5-chloro-2-hydroxybenzophenone (500 mg, 2 mmol) and malononitrile (132 mg, 2 mmol) in ethanol (15 mL) was added piperidine (0.1 mL, 1.0 mmol). The mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 100 mg (17%) of the title compound.
Reaction SMILES: C(OC(OCC)C[CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH:14][C:15](=[O:17])[CH3:16])=[N:9][C:8]=1[N:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20])C.O.C(OCC)(=O)C.C1C=CC=CC=1>CCO>[C:15]([NH:14][C:10]1[NH:11][C:12](=[O:13])[C:7]2[CH2:6][CH2:20][CH:19]([OH:21])[N:18]([C:22](=[O:24])[CH3:23])[C:8]=2[N:9]=1)(=[O:17])[CH3:16]
Reactant: CCOC(CCc1c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c1=O)OCC
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1nc2c(c(=O)[nH]1)CCC(O)N2C(C)=O

Procedure:
3-(2-Acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde diethyl acetal (25.0 g, 0.66 mol) was heated with 100 ml of water on a steam bath for 4 hours. The solution was filtered hot to remove an insoluble by-product, and the filtrates were spin evaporated in vacuo to a thick syrup. This syrup was successively dissolved in ethanol and then ethylacetate followed by spin evaporation each time to give a solid which was digested with ethyl acetate. The solids were collected and dried; yield, 15.1 g (76%), mp 199°-201° of a cream colored solid which was used without further purification. Recrystallization of a portion from 2-propanol gave the analytical sample, mp 202°-205° ; TLC (C6H6 :EtOH/10:1): NMR (DMSO-d6)δ11.75 (br s, 1H, NH), 11.30 (br s, 1H, NH, W1/2=5 Hz), 6.15 (d, 1H, J=5.0 Hz, OH), 6.06 (m, 1H, J= 2.7 Hz when D2O exchange removed OH CH), 2.43 (s, 3H, CH3), 2.40-2.10 (m, 2H, pyrimidine-CH2), 2.02-1.42 (m, 2H, CH2CH2CH); 13C-FT nmr (DMSO-d6) ppm: 15.7, 23.9, 27.2, 72.8, 102.2, 147.2, 152.4, 160.4, 171.0, 173.4; MS m/e 266, 248.
Reaction SMILES: [Na].[C:2](OCC)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.Cl>O.C(O)C>[C:21]([CH:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)[CH2:2][C:3]1[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=1)#[N:22]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(Cc1ccncc1)c1ccc(F)cc1

Procedure:
250 ml of dry ethanol were added dropwise to metallic sodium (17.3 g/0.7 mol). Ethyl isonicotinate (75.8 g/0.5 mol) and 4-fluorophenylacetonitrile (67.6 g/0.5 mol) were then added dropwise, and the mixture was subsequently heated under reflux for 15 min. After cooling, 600 ml of distilled water were added to the mixture. When the mixture was acidified to pH 1 using concentrated hydrochloric acid (HCl), the desired compound 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethane precipitated as a yellow precipitate. The precipitate was filtered off, washed with distilled water and dried under reduced pressure over phosphorus pentoxide (P2O5). The yield was 85.0 g (62%).