Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][OH:6].[O:7]1[CH2:12][CH2:11][O:10]CC1>O.Cl>[O:6]=[CH:5][C@H:12]([C@H:11]([C@H:12]([CH2:11][OH:10])[OH:7])[OH:10])[OH:7]
Reactant: C1COCCO1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
1-O-benzoyl-2,3-O-isopropylidene-L-ribonofuranoate (10 g) prepared in Example 6 was dissolved in a solvent mixture of methanol (30 ml) and 1.0N aqueous sodium-hydroxide solution (10 ml) and then reacted for about 3 hours. After TLC revealed the completion of reaction, the reaction solution was distilled under reduced pressure, water (10 ml) was added, and the reaction mixture was extracted two to three times with ethyl acetate. The extract was dried over magnesium sulfate and distilled under reduced pressure to give 2,3-isopropylidene-L-ribose (6.0 g). The compound thus obtained was dissolved in a solvent mixture of dioxane (12 ml) and water (12 ml), 1.0N hydrochloric acid solution (200 μl) was added, and then reaction was carried out for about 24 hours while maintaining the temperature of the reaction vessel of 40° C. After TLC revealed the completion of reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in water (30 ml) and washed with ethyl acetate. Water was removed by distillation under reduced pressure to give a compound in the form of an oil. The compound thus obtained was purified by silica gel column chromatography (eluent: chloroform/methanol=4/1, v/v) to give the title compound (4.1 g, Yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21].C(N(CC)CC)C>[Cu]I.C1COCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:19])=[CH:3][C:2]=2[F:1])[CH:15]=1)[CH3:21]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN(CC)CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 40 °C
Yield: 84.8 %

Procedure:
A stirred mixture of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (965 mg, 2.50 mmol), N,N-diethylprop-2-yn-1-amine (417 mg, 3.75 mmol), copper(I) iodide (24 mg, 0.125 mmol), triethylamine (8.7 mL, 63 mmol), and THF (20 mL) was sparged with N2 for 5 minutes, then tetrakis(triphenyl -phosphine)palladium(0) (144 mg, 0.125 mmol) was added. The sealed reaction was heated to 40° C. for 18 hours. The mixture was concentrated, and then purified by Biotage Flash 40M silica gel chromatography system, eluting with EtOAc followed by 5% MeOH in EtOAc. The product was obtained as a waxy solid (783 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.59 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.53 (m, 3H), 3.86 (br s, 2H), 3.78 (s, 2H), 2.73 (q, J=7 Hz, 4H), 1.19 (t, J=7 Hz, 6H). LRMS (ESI pos) m/e 370 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:30])=O.CN(C)C=O>CCCCCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:30])=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]2[C:11]=1[C:10](=[N:15][OH:16])[CH2:9][CH2:8]2
Reactant: COc1ccc(C)c2c1C(=O)CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C)c2c1C(=NO)CC2
Yield: 87.2 %

Procedure:
7-Methoxy-4-Methyl-1-indanon (1.0 g, 0.006 mol) was dissolved in ethanol (10 mL) and hydroxylamine hydrochloride (0.8 g, 0.012 mol) and sodium acetate (0.96 g, 0.012 mmol) were added. The reaction mixture was heated to reflux for 3 h. Then water (10 mL) was added and a precipitation formed which was filtered. The precipitate was washed with water, isolated and dried under high vacuum to yield 7-methoxy-4-methyl-indan-1-one oxime (1.0 g, 92%) as a white solid; MS: m/e=192.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#N)=[CH:13][CH:12]=1>>[C:2]1([CH3:1])[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH2:17][C:14]2[CH:15]=[N:16][C:11]([C:10]([F:21])([F:9])[F:20])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1
Yield: 50.3 %

Procedure:
In analogy to example 9, step 1, 4-methylaniline (298 mg, 2.78 mmol) was coupled to (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (750 mg, 4.03 mmol) to provide the title compound as a pale yellow oil (392 mg, 35%) MS m/e: 281.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[N:19]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:27][C:23]1[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=1)[N:18]([CH2:17][C:16]1[CH:28]=[CH:29][CH:30]=[C:14]([F:13])[CH:15]=1)[N:19]=[CH:20]3)=[N:3][CH:4]=[N:5]2
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cccc(F)c45)ccc32)c1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
A mixture of 4-chloro-5-fluoroquinazoline (1.82 g, 10 mmol), 1-(3-fluorobenzyl)-1H-indazol-5-amine (2.41 g, 10 mmol, obtained as described in WO 98/02438) and diisopropylethylamine (1.74 ml, 10 mmol) in isopropanol (20 ml) was heated at 80° C. for 45 minutes. On cooling to ambient temperature, the product was filtered off and washed with isopropanol and ether. The precipitated solid was dried under high vacuum to give 5-fluoro-N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]quinazolin-4-amine (3.2 g, 83%); NMR Spectrum (CDCl3) 5.61 (s, 2H), 6.88 (d, 1H), 6.98 (m, 2H), 7.25 (m, 2H), 7.37 (d, 1H), 7.53 (dd, 1H), 7.73 (m, 2H), 8.09 (s, 1H), 8.19 (s, 1H), 8.49 (d, 1H), 8.69 (s, 1H); Mass spectrum MH+ 388.
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.C(N)C1C=CC=CC=1.[CH2:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][N:33]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2ccccc2)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Solvent: NCc1ccccc1
Product: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 3.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (7 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)/[CH:7]=[C:21]1\[C:22](=[O:26])[NH:23][C:24]2[C:20]\1=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=2
Reactant: O=Cc1cc(Br)ccc1OCC(F)(F)F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Br)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 69.3 %

Procedure:
5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde prepared in Example 232a (11 g, 39 mmol) and 6-chlorooxindole (5.4 g, 32 mmol) were mixed in anhydrous methanol (50 mL) at room temperature. Then pyrrolidine (2.7 g, 39 mmol) was added dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-3-[5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-1,3-dihydro-indol-2-one as yellow solid (9.6 g).
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[Cl:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: Fc1ccc(N=C=S)c(Cl)c1
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccc(F)cc2Cl)c1O
Yield: 54.9 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (526 mg, 2.10 mmol) and 2-chloro-4-fluorophenylisothiocyanate (586 mg, 3.1 mmol) were coupled to form the desired thiourea (505 mg, 55%). EI-MS m/z 437.75 (M−).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: C#CC1(O)CCCCC1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC3(O)CCCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (83) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1-ethynylcyclohexanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.75 (d, J=8 Hz, 1H), 7.68 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.28 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.91 (m, 2H), 1.57-1.71 (m, 8H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 3.5 min run): tR (min)=2.66.
Reaction SMILES: CC(CC(O)C(C)(C)C=C=C)=C.[CH3:13][C:14](=[CH2:17])[CH2:15]Cl.[CH3:18][C:19]([CH3:27])([CH:22]=[C:23]=[C:24]([CH3:26])[CH3:25])[CH:20]=[O:21]>>[CH3:13][C:14]([CH2:15][CH:20]([OH:21])[C:19]([CH3:27])([CH3:18])[CH:22]=[C:23]=[C:24]([CH3:26])[CH3:25])=[CH2:17]
Reactant: C=C(C)CCl
Reactant: CC(C)=C=CC(C)(C)C=O
Agent: C=C=CC(C)(C)C(O)CC(=C)C
Product: C=C(C)CC(O)C(C)(C)C=C=C(C)C
Yield: 91.9 %

Procedure:
2,5,5,8-tetramethylnona-1,6,7-trien-4-ol (2b) was prepared as described for 2a from 8.72 g (0.36 mole) of Mg, 32.65 g (0.36 mole) of β-methylallyl chloride and 16.61 g (0.12 mole) of 1b. The work up resulted in 21.44 g (92%) of 2b. Bp. 61°-2° C./0.3 mm Hg, nD16 1.4810.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.C(CN(CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O.[OH-].[Na+]>O>[C:26]([C:25]1[CH:21]=[N:22][N:23]2[C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:19]=12)#[N:27]
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.0 gm N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl acetamide was added to a slurry of 40 ml water containing 0.83 gm of 3-amino-4-cyanopyrazole and 6.0 gm edetic acid. The reaction mass was heated to 60° C. for 3 hrs. After cooling the reaction mixture to 20° C., 15% aqueous sodium hydroxide solution was added and the pH of the reaction mixture was adjusted to between 9-10. The reaction mass was stirred for 1 hr. and filtered to give the title compound.
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:10]2[CH:11]=[CH:12][C:13]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([F:7])[CH:9]=2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: Brc1ccc[se]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1

Procedure:
A mixture of 34.2 g (0.16 mol) of 2-bromoselenophene, 40.0 g (0.16 mol) of 3-fluoro-4′-ethylbiphenyl-4-ylboronic acid, 10.0 g (8.65 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 200 ml of 2 N sodium carbonate soln. in 500 ml of toluene/ethanol (2:3) is heated at 90° C. for 2 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-selenophene is obtained as a yellow solid.
Reaction SMILES: B(O)O.S1C2C(=CC=CC=2)C=CC1.Br[C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1(C)C=CC=CC=1>CO>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:15]=1)[CH3:21]
Reactant: CCOC(=O)c1ccccc1Br
Agent: C1=Cc2ccccc2SC1
Agent: OBO
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1

Procedure:
As is shown in the reaction scheme, the (2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl) boronic acid compounds of Formula 24 (or their corresponding thiochrom-3-ene analogs) are reacted with ethyl 2-bromobenzoate in the presence of Pd(0) catalyst in an inert solvent or solvent mixture, such as toluene and methanol, to provide 2-(2,2-dialkyl-4-alkyl, aryl or heteroaryl-2H-chromen-6-yl)benzoic acid ethyl ester compounds of Formula 60. The reagent ethyl 2-bromobenzoate is available in accordance with the chemical literature, see for example J. Org. Chem. 14 (1949) 509, 512 and Helv. Chim. Acta 39 (1956) 505-511. Other examples of reagents which can be used in this reaction instead of ethyl 2-bromobenzoate are: ethyl 2-bromopyridine-3-carboxylate, ethyl 4-bromopyridine-3-carboxylate, ethyl 3-bromothiophene-2-carboxylate, ethyl 2-bromothiophene-3-carboxylate, ethyl 3-bromofuran-2-carboxylate, ethyl 2-bromofuran-3-carboxylate, ethyl cis 2-bromo-cyclopentanecarboxylate and ethyl cis 2-bromo-cyclohexanecarboxylate. However, in the ensuing desription the primary emphasis remains on the 1,2 substituted phenylene derivative actually shown in the reaction scheme.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([CH3:14])[CH2:12][OH:13].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(Cl)Cl>[C:18]([O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH:10]([O:16][CH3:17])[O:9][CH3:8])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: COC(OC)C(C)(C)CO
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(C)(C)C(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml four-neck round bottom flask equipped with a mechanical stirrer, condenser thermometer and addition funnel were added 21.24 g triethylamine, 29.8 g 3,3-dimethoxy-2,2 dimethylpropanol, and 180 ml methylene chloride. The temperature was reduced to about 0° C. to -5° C. A total of 24.6 g methacryloyl chloride was added dropwise through an addition funnel. While maintaining the temperature at about 0° to -5° C., the mixture was then allowed to warm to room temperature and stirred for 30 min, and added to an equal volume (180 ml) of ice-water. The methylene chloride layer was separated from the aqueous layer, a small amount of anhydrous magnesium sulfate (3 g) was added, the solution was filtered, and methylene chloride was stripped off to isolate the product. Purification was done by as above at 65.2° C. under 0.5 mm Hg pressure.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2ccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL, 1.9 mmol) in THF (10 mL) at 5˜10° C., was added 3-chloro-4-methyl-phenyl isocyanate (0.24 mL, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.38 min (98.4%); mp, 186-188° C.; 1HNMR (DMSO-d6) 2.15-2.23 (m, 4H, CHH and CH3Ar), 2.56-2.86 (m, 6H, CHCH2, CH3), 4.40 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz, 1H, CH2NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45, 117.66, 120.01, 123.67, 126.54, 127.39, 130.99, 132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08, 160.47, 169.47, 172.60. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.6H2O: C, 57.71; H, 4.88; N, 14.63; Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl, 7.64.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1>O>[Cl:6][C:7]1[C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][C:10]([NH2:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: O
Product: Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 99 %

Procedure:
Pyrrolidine (6 mL) was added to 4,5-dichloro-2-nitro-phenylamine (2.58 g, 12.5 mmol) in a sealed tube and the mixture heated to 100° C. for 6 h. The mixture was cooled to 23° C., poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure to afford the titled compound (3.00 g, 99%). MS (ESI/CI): mass calcd. for C10H12ClN3O2, 241.1; m/z found, 242.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.08 (s, 1H), 6.06 (s, 2H), 5.82 (s, 1H), 3.58 (ddd, J=6.6, 4.2, 2.7 Hz, 4H), 2.02-1.90 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:19]=[C:18]([CH3:29])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:29][C:18]1[CH:19]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:21]=[C:16]([CH3:15])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)[CH:31]=1
Reactant: Cc1cc(OCC2(C)COC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OCC4(C)COC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.157 g, 0.816 mmol), (2′,6′-dimethyl-4′-[(3-methyloxetan-3-yl)methoxy]biphenyl-3-yl}methanol (0.231 g, 0.741 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (0.326 g, yield 82%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:1]([NH:4][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]#[CH:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of propargylamine (6 g, 109 mmol) and triethylamine (15 mL, 109 mmol) in dichloromethane (125 mL) was added dropwise benzoyl chloride (10.5 mL, 90 mmol) at about 0° C. The ice-bath was removed and stirring was continued for about 30 min. Then the reaction mixture was concentrated under vacuum, the residue was diluted with water and was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide Example 643. MS (APCI): m/z 160 (M+H)+.