Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7](C(O)=O)=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[CH:7]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCc1nc(-n2cccc2)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A suspension of 2-butyl-4-(1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid (Example 16, 50 mg) in toluene (10 mL) was heated at reflux for 1 hour. Evaporation gave a gummy solid that was redissolved in ether and evaporated again to give the title compound as a colorless powder. 1H-NMR (CDCl3) δ 7.9 (d, 1H), 7.6 (m, 2H), 7.4 (d, 2H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (s, 2H), 6.5 (s, 1H), 6.1 (s, 2H), 5.0 (s, 2H), 2.4 (t, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[S:23]>C1COCC1>[NH2:12][C:3]1[C:4]([F:11])=[C:5]([F:10])[C:6]([F:9])=[C:7]([F:8])[C:2]=1[NH:1][C:22]([NH:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[S:23]
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: Nc1c(F)c(F)c(F)c(F)c1NC(=S)Nc1c(Cl)cccc1Cl
Yield: 88.4 %

Procedure:
1-(2-Amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thiourea was obtained by boiling a mixture of 1 g of 1,2-diamino-3,4,5,6-tetrafluorobenzene with 1.13 g of 2,6-dichlorophenyl isothiocyanate in 30 ml of anhydrous THF for 4 hours. After distilling off the solvent, the thiourea was brought to crystallization under diisopropyl ether and 1.88 g of 1-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichloro-phenyl)thiourea were obtained as a crystalline solid. M.p.: >300° C.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(C)C.[CH2:33]([O:35][C:36](=[O:45])[C:37]#[C:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:33]([O:35][C:36](=[O:45])[CH:37]=[C:38]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Reaction time: 24 h
Yield: 64 %

Procedure:
A mixture of 2-[3-(1-triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridine (125 mg, 0.282 mmol), phenyl-propynoic acid ethyl ester (98.0 mg, 0.563 mmol), and tetrabutylammonium fluoride [1.0 M] 0.85 mL, 0.85 mmol) in THF (3 mL) was stirred for 24 h. After removal of the solvent, the crude reaction mixture was purified via column chromatography on silica gel with ethyl acetate/hexane (2:1) to give the title product as an E/Z isomeric mixture in 64% yield. Mass Spectrum (LCMS, ESI) calculated for C30H28N3O2 462.2 (M+H); found 462.3.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>C1COCC1.C1OCCOCCOCCOCCOC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:3][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOC(=O)C1(O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
Sodium hydride (60%, 166 mg, 4.15 mmol) was added to a solution of ethyl 1-hydroxycyclopropanecarboxylate (0.41 mL, 3.59 mmol) in THF (10 mL) at room temperature. After 15 min, 3 drops of 15-crown-5 were added followed by 4-bromo-1-fluoro-2-nitrobenzene (0.42 mL, 3.41 mmol). Mixture was stirred at room temperature for 24 hours. After diluting with 50 mL of ethyl acetate, mixture was quenched by addition of brine (25 mL) and layers were separated. Aqueous phase was extracted with ethyl acetate and combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. Resulting residue was purified via silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropanecarboxylate 7.20 (750 mg)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[O:39]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[O:39]1[CH:43]=[CH:42][C:41]([CH2:44][O:13][C:14]2[CH:38]=[CH:37][C:17]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]3)=[CH:16][CH:15]=2)=[CH:40]1
Reactant: OCc1ccoc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccoc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A toluene solution (1.04 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (699 mg), 3-furanmethanol (0.172 ml), triphenylphosphine (577 mg) and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(3-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 45%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.SC([OH:47])C.C[O-].[Na+].C(O)(=O)C>CO>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:39](=[O:47])[NH:38][CH:37]=[N:36][C:35]2=3)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: CC(O)S
Reactant: O=C(OC[C@@H]1O[C@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 1359.3 %

Procedure:
A mixture of 9 (1.05 g, 1.70 mmol), mercaptoethanol (0.48 ml, 6.9 mmol), and NaOMe in MeOH (100 ml) was refluxed for four hours. The reaction mixture was cooled, neutralized with glacial acetic acid and evaporated to dryness. The solid obtained was washed with CHCl3 and the residue was crystallized from EtOH to give pure 11 (6.198 g, 47%) as white crystals: m.p. 212°-213° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 39.4 %

Procedure:
A mixture of 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.092 g), concentrated hydrochloric acid (0.04 ml), water (0.040 ml) and ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 31) (0.10 g) as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]([CH3:16])=[CH:5][N:4]=1.S(Cl)([Cl:19])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]([CH3:16])=[CH:5][N:4]=1
Reactant: COCCCOc1c(C)cnc(CO)c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCCOc1c(C)cnc(CCl)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
4.70 g of crude 2-hydroxymethyl-4-(3-methoxypropoxy)-3,5-dimethylpyridine was dissolved in 50 ml of chloroform to obtain a solution. A solution of 2.7 g of thionyl chloride in 10 ml of chloroform was dropwise added to the above solution at 0° C. and the obtained mixture was stirred at 0° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 150 ml of chloroform twice. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The obtained residue was dried in a vacuum to obtain 4.52 g of the title compound as a crude oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2.[NH3:17].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl.O=[Mn]=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:17])=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2
Reactant: O=Cc1ccc2c(c1)CCC1(C2)OCCO1
Reactant: N
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Following the literature procedure of Lai, G. et al. (Synleft, 2001, 230-231), a stirred solution of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbaldehyde (440 mg, 2.0 mmol) in THF (2 mL) was charged with NH3 (2M solution in isopropanol, 15 mL, 30 mmol, 15 eq) and anhydrous MgSO4 (3.64 g, 30 mmol, 15 eq). After 1 hour, MnO2 (Aldrich, 85%, 3.1 g, 30 mmol, 15 eq) was added in small portions and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with CH2Cl2 (40 mL) and filtered through Celite. The filtrate was concentrated in vacuo to give 0.42 g (100%) of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbonitrile as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 1H), 7.40 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 4.03 (s, 4H), 3.02 (s, 2H), 3.00 (t, 2H, J=6.9 Hz), 1.96 (t, 2H, J=6.9 Hz). The material was sufficiently pure and it was used in the next step without further purification.
Reaction SMILES: [C:1]([N:5]([CH2:25][C:26]([OH:28])=O)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[C:1]([N:5]([CH2:25][C:26](=[O:28])[NH:32][CH3:31])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:18])([F:19])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24]2)[N:9]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)N(CC(=O)O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with a 2 M solution of methanamine (CAN 74-89-5) in MeOH in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=411.5 [MH+].
Reaction SMILES: [O:1]([C:8]([C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:21])=[O:9])[C:2]1C=CC=C[CH:3]=1.CC[O-].[Na+].C(O)(=O)C>C(O)C>[CH2:2]([O:1][C:8]([C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:21])=[O:9])[CH3:3]
Reactant: O=C(Oc1ccccc1)c1cc(O)c2ccccc2c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2ccccc2c1O

Procedure:
28 g of 2-phenoxycarbonyl-1,4-dihydroxynaphthalene was dissolved in ethanol under a nitrogen stream, and 20.4 g of sodium ethylate was added thereto, followed by refluxing for 5 hours under heating. After being cooled, the solution was made weakly acidic with acetic acid, then ethanol was distilled off. Ethyl acetate and water were added thereto to separate and extract the product. The product was purified through silica gel column chromatography with an element having the same composition as that used in the Synthesis Example 1 to obtain compound (6) as crytals. Yield: 13 g (56%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Yield: 79.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 269 μmol), morpholine (141 μl, 1.62 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 397 μl, 673 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated, the residue diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and with water. The organic layer is dried with magnesium sulfate and the solvent removed in vacuo affording 1-Methyl-4-(morpholine-4-carbonyl)-N-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (94 mg, 79.3%) as a light yellow solid. Mp.: 206-8° C. MS: m/z=441.3 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:23])=[CH:7][CH:8]=1
Reactant: CI
Reactant: CSc1ccc(Nc2nc(C)nc3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of (4-methylthio-phenyl)-(2-methyl-quinazolin-4-yl)-amine (263 mg, 0.94 mmol) in DMF (4 ml) at 0° C. was added sodium hydride (56.4 mg, 1.40 mmol, 60% oil dispersion) and followed by methyl iodide (0.09 ml, 1.40 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was diluted with EtOAc (15 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1:2 to 1:1) as eluent, yielding 120 mg of title compound (40.7%). 1H NMR (CDCl3): 7.76 (d, J=9.0 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.24-7.19 (m, 2H), 7.10-6.97 (m, 4H), 3.59 (s, 3H), 2.74 (s, 3H), 2.48 (s, 3H)
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.C(N(CC)C(C)C)(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:45]2C(=O)C[CH:48]([C:52]([F:55])([F:54])[F:53])[CH2:47][C:46]=2[OH:56])[NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)=[O:33])=[CH:26][CH:25]=1)#[N:23]>ClCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]([C:45]2[C:46](=[O:56])[CH2:47][CH:48]([C:52]([F:53])([F:55])[F:54])[CH2:12][C:11]=2[O:8][CH2:9][CH3:10])[NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)=[O:33])=[CH:28][CH:29]=1)#[N:23]
Reactant: CC[O+](CC)CC
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (1.82 g, 9.57 mmol) is added to a mixture of N,N-diisopropylethylamine (1.92 mL, 11.0 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12, 2.38 g, 4.79 mmol) in dichloromethane (30 mL). The mixture is stirred at room temperature for 1 h and washed three times with water. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 1.66 g; ESI mass spectrum [M+H]+=525, Retention time HPLC: 1.25 min (V011_S01).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([NH2:12])[S:8][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1.CN(C1C=CN=CC=1)C>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:9]2[S:8][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)cc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)cc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-amine (100 mg, 392 mmol) in THF (5 ml) with triethylamine (0.049 ml, 0.9 eq.) and DMAP (5 mg, 0.1 eq) was stirred together at 0° C. under an argon atmosphere. To this was slowly added 4-fluorobenzoyl chloride (0.038 ml, 314 mmol, 0.8 eq.) and the mixture stirred to 20° C. over 2 h. The mixture was then evaporated to dryness and chromatographed over silica gel eluting with a gradient of heptane/EtOAc (6:1 to 2:1). The product fractions were pooled and evaporated to afford the title compound (74 mg, 50% yield) as a yellow solid MS: m/e=378.3 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][C:17](=[O:19])[C:20]=2[CH:21]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g of 2-(4-methylsulfonylphenoxy)phenylacetic acid and 10 ml of polyphosophoric acid under nitrogen is stirred at 90°-100° C. for 2 hours. The reaction mixture is permitted to cool and then poured into 100 ml of an ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with methylene chloride. The combined extracts are dried and then evaporated to dryness leaving an oil. The oil is chromatographed through a silica gel/methylene chloride column with 2% methanol in methylene chloride. The chromatographed solution is evaporated to dryness leaving an oil which solidifies on standing. The solid is triturated with pentane to provide 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]oxepin, mp 105°-106° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1)[CH:23]=[CH2:22]
Reactant: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(Br)ccc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(C)cc(Oc3ccc(C#N)cc3)nc2c1

Procedure:
6.8 g (0.02 mol) of 4-[(7-bromo-4-methyl-quinolin-2-yl)-oxy]-benzonitrile, 6.8 g (5.9 mmol) of tetrakis-(triphenylphosphine)-palladium (0) and 6.8 ml (0.022 mol) of allyltributyltin are refluxed in 50 ml toluene under a nitrogen atmosphere for 2 hours. The toluene is distilled off, the residue triturated with ether and suction filtered. The mother liquor is combined with silica gel and evaporated down. Then the mixture is chromatographed on silica gel and eluted with cyclohexane/ethyl acetate (95:5 and 9:1). The desired fractions are combined and evaporated down.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:68](O)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.6 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (200 mg, 0.52 mmol), DCC (129 mg, 0.62 mmol) and DMAP (6 mg, 0.052 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine (183 mg, 0.52 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (210 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 120 mg (47%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][CH2:5][C:4]([CH3:7])=[C:3]1[CH:8]=[CH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[OH:16]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:16][C:4]1([CH3:7])[CH2:5][CH2:6][C:2]([CH3:1])([CH3:15])[CH:3]1[CH:8]=[CH:9][CH:10]([OH:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)C=CC1=C(C)CCC1(C)C
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCCC(O)C=CC1C(C)(C)CCC1(C)O

Procedure:
The entitled compound was obtained from 1-(2,2,5-trimethylcyclopent-5-enyl)hex-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).