Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[O:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH:14]=[C:13]1[C:21]([OH:23])=O.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([SH:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([S:37][C:21]([C:13]2[O:12][C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[CH:14]=2)=[O:23])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: O=C(O)c1cc2cnccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(SC(=O)c2cc3cnccc3o2)CC1
Reaction time: 1 h

Procedure:
A solution of EDCI (66 mg, 0.35 mmol) in anhydrous DMF (2 mL) was added to a stirred solution of furo[3,2-c]pyridine-2-carboxylic acid (45 mg, 0.28 mmol) in anhydrous DMF (1 mL). After 1 h, the mixture was treated with a solution of DMAP (6 mg, 0.05 mmol) and 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.23 mmol), before being stirred for an additional 16 h. The DMF was removed under reduced pressure, then the residue was purified by flash chromatography (IH-EtOAc, 1:1 to 3:7) to furnish the title compound: RT=3.34 min; m/z (ES+)=363.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)O.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[Cl:24]
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(-c2ccccc2)cc1)c1ccccc1Cl
Solvent: c1ccccc1
Product: Clc1ccccc1C(Cl)c1ccc(-c2ccccc2)cc1

Procedure:
290 g (0.985 mol) of 2-chlorophenyl-(biphenyl-4-yl)-carbinol are dissolved in 1,000 ml of benzene and a solution of 144 ml (2 mols) of thionyl chloride in 400 ml of benzene is added slowly at 40° C. with stirring. The reaction mixture is heated under reflux for 15 hours. The solvent is distilled off in vacuo and the residue is stirred with 500 ml of petroleum ether. The crystals produced are filtered off and purified by recrystallization from ethanol. 36 g (89% of theory) of (2-chlorophenyl)-(biphenyl-4-yl)-chloromethane [alternatively named as α-(biphenyl-4-yl)-2l -chlorobenzyl chloride] of melting point 80° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[CH2:6][CH2:5][C:4](=[O:16])[NH:3]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Na+].[Cl-]>C1COCC1.CO.O.CCOC(C)=O>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]2[C:2]([CH3:17])([CH3:1])[NH:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]=2[CH:12]=1
Reactant: CC1(C)NC(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)NC(=O)CCc2cc(N)ccc21
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
A solution of 1,1-dimethyl-7-nitro-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (1.75 g) in THF (175 mL) and MeOH (20 mL) was treated with an solution of Na2S2O4 (5 g) and sodium bicarbonate (5 g) in water (200 mL). After 15 minutes, 250 mL of EtOAc and 250 mL saturated NaCl was added and the organic layer was separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were washed again with brine. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo to provide 400 mg of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one: 1H NMR (300 MHz, CDCl3) δ 7.1 (d, 1H, C9-H), 6.5 (dd, 1H, C8-H), 6.4 (d, 1H, C6-H), 3.0 (m, 2H), 2.6 (m, 2H), 1.6 (s, 6H).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:29]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 0.8), 251(18), 250 (100), 163 (5), 121 (19), 114 (7), 110 (5), 107 (7), 91 (6).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:22][CH3:23])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C(O)CO.[Cu](Cl)Cl>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:22][CH3:23])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c1c(n2Cc2ccccc2)CCCC1=O
Agent: Cl[Cu]Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c1c(O)cccc1n2Cc1ccccc1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a mixture of 9-benzyl-6-methoxy-1,2,3,9-tetrahydro-4H-carbazol-4-one (4.23 g, 13.85 mmol) in ethylene glycol: p-dioxane ((1:1) 150 mL) is added copper (II) chloride (9.31 g, 69.26 mmol). The mixture is heated at 80° C. for 30 minutes. The mixture is partitioned between water and Et2O. The layers are separated and the organic layer washed with water (100 mL). The ether layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is dissolved in DMF (50 mL) to which is added lithium bromide (2.45 g, 28.3 mmol) and lithium carbonate (2.09 g, 28.3 mnmol). The mixture is heated at 120° C. for 5 h. The mixture is partitioned between water and ethyl acetate. The layers are separated and the organic layer washed twice with water (200 mL). Column chromatography (250 mL) silica gel using ethyl acetate/ hexanes (20/80) gave 2.5 g (73%) of the title compound; IR (drift) 3471, 1482, 1469, 1450, 1328, 1198, 1171, 1144, 805, 799, 780, 745, 724, 717, 701 cm−1. 1H NMR (DMSO-d6) δ3.82, 5.54, 6.56, 6.97), 7.14, 7.23, 7.43, 7.72; Anal. Calcd for C20H17NO2: C, 79.18; H, 5.65; N, 4.62. Found: C, 78.99; H, 5.75; N, 4.63.
Reaction SMILES: [OH-].[Li+].[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]([O:16]C)=[O:15])[CH2:9][CH2:8]1)(=[O:6])=[O:5]>O1CCCC1.O>[CH3:3][S:4]([N:7]1[CH2:8][CH2:9][N:10]([C@@H:13]([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:14]([OH:16])=[O:15])[CH2:11][CH2:12]1)(=[O:5])=[O:6]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(OC)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
1 ml (1 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N is added to a solution of 260 mg (0.7 mmol) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-(4-methoxybenzoyl-amino)propanoate in 8 ml of tetrahydrofuran and 1 ml of water. The reaction medium is stirred at ambient temperature for 20 h. The solvents are concentrated under vacuum, the reaction medium is brought to pH=6 with an aqueous solution of acetic acid having a concentration of 1N. The product precipitates and the residue is taken up in 10 ml of water and stirred for 1 h. The solid is filtered, rinsed with water and with diethyl ether then dried. 190 mg (76%) of (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-(4-methoxybenzoyl-amino)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (302 mg, 1.32 mmol) in anhydrous THF (10 mL) was cooled to 0° C., and NaH (60% dispersion in oil, 63 mg, 1.58 mmol, 1.2 equiv.) was added all at once. Alkoxide formation was effected by stirring at room temperature for 2 h under N2, then 4-(trifluoromethyl)benzyl bromide (378 mg, 1.58 mmol, 1.2 equiv.) was added. The mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl solution was added, and the product was extracted into EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by CC (SiO2, EtOAc/hexane 1:4) to afford the ether (496 mg, 97%) after evaporation. 1H NMR (CDCl3, 400 MHz) δ 7.59 (d, 2H, J=8.4 Hz), 7.43 (d, 2H, J=8.0 Hz), 4.54 (s, 2H), 4.06 (d, 2H, J=13.2 Hz), 5.31 (t, 2H, J=6.4 Hz), 2.68 (t, 2H, J=12.8 Hz), 1.58 (m, 5H), 0.89 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:23]([C:17]1[CH:18]=[CH:19][C:20]([O:22][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:21][C:16]=1[OH:15])(=[O:24])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)c2ccccc2)c(O)c1
Yield: 58 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (46.10 g), (2,4-dihydroxyphenyl)(phenyl)methanone (50.14 g), potassium carbonate (48.51 g) and acetone (700 mL) was heated under reflux for 20 hrs. The reaction mixture was concentrated, water was poured into the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-(4-benzoyl-3-hydroxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole as colorless crystals (49.6 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 26.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.100 g, 0.194 mmol) obtained in step 2 and ethanesulfonamide (0.105 g, 0.969 mmol), the title compound (0.031 g, 27%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21]C)=[CH:20][C:15]=3[O:14][C:13]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:10])[CH2:5][CH2:4]1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][N:2]([CH3:33])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][C:13]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:10])[CH2:7][CH2:8]1
Reactant: COc1ccc2c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c(C(=O)Nc3ccc(Cl)cn3)oc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(O)ccc23)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-methoxy-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (473 mg) obtained in Example 23 in dichloromethane (20 ml) is added dropwise boron tribromide (3.5 g) over 2 minutes at −78° C. The mixture is stirred at room temperature for 4 days, and the reaction solution is poured into ice-water, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is suspended in chloroform/diethyl ether, and the precipitates are collected by filtration, and dried to give trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (335 mg). This product (48 mg) is suspended in methanol and treated with 4N hydrogen chloride in dioxane to give the title compound (54 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:35][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][C:31]=3[F:36])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of the crude 7-benzyloxy-4-chloro-6-methoxyquinazoline, potassium carbonate (50 g, 362 mmol) and 4-chloro-2-fluorophenol (8.8 ml, 83 mmol) in DMF (500 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (21) and was stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane and filtered through diatomaceous earth. The filtrate was treated with decolourising charcoal, boiled for a few minutes then filtered through diatomaceous earth. The filtrate was filtered through phase separating paper and then evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2 g, 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20](O)=[O:21])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]3)=[O:21])[CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: OCC1CCCNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of 3-piperidinemethanol (5.0 g, 43.4 mmol), 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid (9.14 g, 43.4 mmol), and diisopropylethylamine (11.22 g, 86.8 mmol) in dichloromethane (100 mL) at 0° C. was added PyBroP® (22.26 g, 47.8 mmol). The reaction was stirred at 0° C. for 1 h and then at room temperature for 4 h. The reaction mixture was washed successively with water, 1 N HCl, water, sat. sodium bicarbonate solution, and water (100 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol (96:4) to give 5.8 g of the amide 1 as a thick gum.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N+:29]([O-:31])=[O:30])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3[N+](=O)[O-])C2=O)cn1
Yield: 22 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-nitrobenzene. Yield 22%. MS M+H calculated 411.1; found 411.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 uM.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([OH:26])[CH:28]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: Cc1ccc(N)cc1O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccccc1
Yield: 65.9 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.18 g, 18.4 mmol), (prepared as described for the starting material in Example 4), DMF (1 ml) and thionyl chloride (70 ml) was heated at reflux under argon for 2 hours. The mixture was allowed to cool, excess thionyl chloride was removed by evaporation and the residue azeotroped to dryness with toluene. The resulting crude 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride was suspended in isopropanol (50 ml) and 3-hydroxy4-methylaniline (2.60 g, 21.1 mmol) added. The mixture was heated at reflux for 3 hours and then allowed to cool. The precipitated product was collected by filtration, washed with isopropanol and dried to give 7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazoline (4.7 g, 60%).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]([NH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([CH2:23][NH:24]/[C:25](=[N:34]/[C:35]([C:37]2[C:38]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]=C)=[CH:45][CH:44]=3)=[N:39][O:40][C:41]=2[CH3:42])=[O:36])/[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:18][C:17]=1[Cl:53])=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:30]([O:29][C:27]([NH:26][C:25]1[NH:24][CH2:23][C:19]2[CH:18]=[C:17]([Cl:53])[C:16](=[C:21]([Cl:22])[CH:20]=2)[NH:15][C:13](=[O:14])[CH2:12][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[CH2:1][CH:2]=[CH:51][CH2:50][O:49][C:46]2[CH:45]=[CH:44][C:43](=[CH:48][CH:47]=2)[C:38]2[C:37](=[C:41]([CH3:42])[O:40][N:39]=2)[C:35](=[O:36])[N:34]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: C=CCOc1ccc(-c2noc(C)c2C(=O)/N=C(/NCc2cc(Cl)c(NC(=O)CN(CC=C)C(=O)OC(C)(C)C)c(Cl)c2)NC(=O)OC(C)(C)C)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Product: Cc1onc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CC=CCOc1ccc-2cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
The intermediate (170 mg, 0.216 mmol) from Step 1(B) was dissolved in 35 mL of 1,2-dichloroethane, followed by the addition of Grubbs Catalyst 2nd Generation (40 mg, 0.047 mmol) with 2 mL of 1,2-dichloroethane. The resulted reaction mixture was stirred at 45° C. for 2 hrs. Solvent was evaporated in vacuo to give a crude product, which was purified by flash chromatography (15% EtOAc/DCM, Rf 0.37) to give 85 mg (53%, theoretical yield 161 mg).
Reaction SMILES: I[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28].O>C(O)(=O)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:27]([O-:32])=[O:28])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Cc1cccc2c(-c3ccccc3)c(I)oc12
Agent: O=C(O)C1CC=CCC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
To a stirred solution of 5.0 g (0.015 mole) of 2-iodo-7-methyl-3-phenylbenzofuran from Example 9 in 100 ml of acetic acid is added 2.8 g (0.022 mole) of cyclohexene-4-carboxylic acid, then dropwise 2.0 g (0.022 mole) of dinitrogen tetroxide in 10 ml of acetic acid. The mixture is poured into cold water, then extracted with diethyl ether. The ether extracts are washed with water, 5% sodium hydroxide solution, water and saturated sodium chloride solution and dried. The extracts are then concentrated to provide a solid residue which is recrystallized from aqueous ethanol to provide yellow crystals of 7-methyl-2-nitro-3-phenylbenzofuran, m.p. 122°-127° C., which is shown to be identical to the product of Example 2 by its infrared spectrum.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:24]=1)[NH2:23]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([NH:23][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Cc1ccc(Cl)cc1Nc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 78.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 5-chloro-2-methylaniline (80 mg, 0.56 mmol) to provide 206 (113 mg, 78% yield) as a white solid. LC-MS (M+H=336, obsd.=336).
Reaction SMILES: I[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:7]([CH:8]=[O:9])=[CH:6][N:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(I)c(C=O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Yield: 67 %

Procedure:
4-Iodo-6-methoxynicotinaldehyde (0.41 g, 1.6 mmol), trimethylsilylacetylene (0.35 mL, 2.8 mmol), PdCl2(PPh3)2 (catalytic amount), CuI (catalytic amount), TEA (2 mL) and THF (10 mL) were stirred at 60° C. for 2 h. The volatiles were evaporated and the residue was taken up in water and extracted with ether. The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:3) as eluent gave 0.25 g (68% yield) of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde.