Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][C:9]2[S:10][C:11]([C:14]([NH:16][NH2:17])=O)=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([N:20](CC)CC)[CH3:19].[ClH:25].C(=N)(OCC)C.[Cl-].[NH4+]>C(O)C>[ClH:25].[ClH:25].[CH3:19][C:18]1[NH:17][N:16]=[C:14]([C:11]2[S:10][C:9]([CH2:8][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][CH:12]=2)[N:20]=1
Reactant: CCN(CC)CC
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: CCOC(C)=N
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: Cc1nc(-c2ccc(CN3CCCCCC3)s2)n[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.3 %

Procedure:
To 5 ml of ethanol solution containing 1.01 g (4.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide was added 2.8 ml (20 mmol) of triethylamine and 2.48 g (20 mmol) of ethyl acetoimidate hydrochloride, and the mixture was stirred at room temperature for 21 hours. Then, 1.2 g of ammonium chloride was added and the mixture was stirred at 80° C. for 4 hours. The reaction solution was concentrated, 28% aqueous ammonia and chloroform were added to the resulting residue, and then the resulting organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (80:1) to give 814 mg of the title compound in its free form. By subjecting this compound to salt formation using 4 N HCl/ethyl acetate, 593 mg of the title compound was obtained.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:7])C>CO>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:6]([OH:7])=[O:5])=[C:16]2[CH3:17]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2N NaOH (20 mL) was added to a suspension of 5-chloro-3-methyl-1H-indole-2-carboxylic acid ethyl ester (7.0 g, 29.4 mmol) in methanol (50 mL) and the resulting mixture stirred at 25° C. for 18 hours. Tetrahydroturan (100 mL) was added and the resulting solution heated at reflux for 30 minutes and concentrated. The residue was dissolved in water and the resulting solution extracted twice with ethyl acetate. The aqueous layer was acidified and the precipitate collected by filtration and washed with water (5.24 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (3.28 g, 14.00 mmol) was dissolved in THF (23.34 mL), water (11.67 mL) was added, followed by lithium hydroxide monohydrate (1.763 g, 42.0 mmol), and the mixture stirred at room temperature for 30 minutes. After this time the THF was removed under reduced pressure and the pH of the water layer was adjusted to ˜5 with 2 M HCl while the solution was cooled in an ice bath. The precipitate that formed was dissolved in ethyl acetate (125 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL) and then dried over magnesium sulfate. Evaporation of the solvent yielded 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (2.952 g, 94% yield) as an off white powder. 1H NMR (400 MHz, DMSO-d6): δ 13.06 (broad s, 1H), 10.56 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s, 4H); MS (ESI) m/z: 224.1 (M+H+).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[N:44]=[C:43]2[C:39]([N:40]=[C:41]([CH:46]=[O:47])[N:42]2[CH3:45])=[C:38]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[N:37]=1.[CH2:54]([C:56]1[NH:60][C:59]2[CH:61]=[CH:62][CH:63]=[CH:64][C:58]=2[N:57]=1)[CH3:55].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:54]([C:56]1[N:57]([C:36]2[N:44]=[C:43]3[C:39]([N:40]=[C:41]([CH:46]=[O:47])[N:42]3[CH3:45])=[C:38]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[N:37]=2)[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1)[CH3:55]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1

Procedure:
A mixture of Pd2(dba)3 (458 mg, 0.5 mmol), Xphos (954 mg, 2 0 mmol), 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (5.64 g, 20 0 mmol), 2-ethyl-1H-benzoimidazole (3.21 g, 22.0 mmol), cesium carbonate (9.78 g, 30.0 mmol) in dioxane (80 mL) was degassed for 5 min and heated at reflux for 18 h. The reaction mixture was filtered through a pad of celite while still hot, and the pad was washed with hot dioxane. The combined filtrate was concentrated under reduced pressure to give a residue which was triturated in Et2O (ca 100 mL), filtered and dried at 50° C. under vacuum to give 2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde as a yellow solid (4.5 g). LCMS (Method H): RT 3.63 min; [M+MeOH]+ 424
Reaction SMILES: [CH2:1]([S:17][CH2:18][C:19]1([CH2:24]O)[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(SCC(OC)C[NH2:46])CCCCCCCCCCCCCCC>>[NH2:46][CH2:24][C:19]1([CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCSCC1(CO)CCCO1
Product: CCCCCCCCCCCCCCCCSCC1(CN)CCCO1

Procedure:
2-Hexadecylthiomethyl-2-hydroxymethyltetrahydrofuran IVb1 is allowed to react and worked by the same procedure as described in (3), the summary of the experimental condition and the physical data of the prodcut are listed in the Tables 5 and 6.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15](O)[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:5][C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][Cl:1])[CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1ccccc1
Reaction time: 72 h
Yield: 71.9 %

Procedure:
(S)-α-(2-Chloroethyl)benzenemethanol (170 mg, 1.0 mmol), 4-chloro-2-hydroxybenzonitrile (154 mg, 1.0 mmol.) and triphenylphosphine (260 mg, 1.0 mmol.) in dry tetrahydrofuran (5 ml) were stirred in an ice bath under nitrogen whilst diethyl azodicarboxylate (0.16 ml, 1.0 mmol.) was added. The reaction mixture was allowed to warn to room temperature and stirred for 3 days. The solvent was evaporated and the residue dissolved in toluene, added to the top of a flash chromatography column and eluted with 10% ether/isohexane to give the product (220 mg, 72%) as a viscous oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:23]3[C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[S:26][CH:27]=3)[OH:22])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[S:26]1[CH:27]=[C:23]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:16][CH2:17]2)=[O:22])[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]1=2
Reactant: OC(c1csc2ccccc12)C1CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1csc2ccccc12)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dissolve oxalyl chloride (4.22 g, 33.28 mmol) in methylene chloride (200 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, dimethylsulfoxide (5.42 g, 69.33 mmol) and stir at -78° C. for 15 minutes. Add, by dropwise addition, a solution of α-[1-(2-phenylethyl)-4-piperidinyl]-3-benzo[b]thiophenemethanol (9.75 g, 27.73 mmol) in dimethylsulfoxide (150 mL). Stir at -78° C. for 30 minutes, add triethylamine (15.18 g, 0.150 mol) and stir at -78° C. for 1 hour. Remove the ice bath and stir for an additional 1.5 hours. Evaporate the solvent in vacuo and recrystallize (isopropanol) to give the title compound as a tan powder; mp 110°-112° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([F:11])[C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][O:17][C:18]([C:20]1[C:29]([OH:30])=[CH:28][CH:27]2[CH:22]([CH2:23][CH2:24][CH2:25][C:26]2=O)[CH:21]=1)=[O:19]>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[CH3:16][O:17][C:18]([C:20]1[C:29]([OH:30])=[CH:28][C:27]2[C:26]3[NH:9][C:6]4[C:7]([C:25]=3[CH2:24][CH2:23][C:22]=2[CH:21]=1)=[CH:8][C:3]([Br:2])=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]=4[F:11])=[O:19]
Reactant: NNc1ccc(Br)c(C(F)(F)F)c1F
Reactant: COC(=O)C1=CC2CCCC(=O)C2C=C1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1O)-c1[nH]c3c(F)c(C(F)(F)F)c(Br)cc3c1CC2
Temperature: 105 °C
Yield: 65.9 %

Procedure:
A sample of (4-Bromo-2-fluoro-3-trifluoromethyl-phenyl)-hydrazine hydrochloride (199 mg, 642 μmol) and 3-hydroxy-5-oxo-4a,5,6,7,8,8a-hexahydro-naphthalene-2-carboxylic acid methyl ester (141 mg, 642 μmol) are treated with anhydrous ZnCl2 (219 mg, 1.60 mmol) and acetic acid (8 mL). The reaction is heated to 105° C. overnight. After cooling to room temperature, the solvent is removed by rotary evaporation. The reaction is then treated with ethyl acetate and extracted with 1 M HCl twice. The organics are then dried over MgSO4 and filtered. The residue is then crystallized from methanol to afford 194 mg of the title compound as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.56 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 3.92 (s, 3H), 3.00-2.88 (m, 4H); ESIMS m/z for (M++H+) calculated 458.0, found 458.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[OH2:21]>>[NH2:20][C:19]([CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:21]
Reactant: O
Reactant: CCOC(=O)C(C#N)CCCCCc1ccc(Cl)cc1
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(N)=O
Yield: 78 %

Procedure:
12 g (41 mmol) of ethyl 7-(4-chlorophenyl)-2-cyanoheptanoate and 96 g of polyphosphoric acid are heated for 3 hours at 100° C. with stirring. Then the mixture is diluted with 200 ml of water and extracted thrice with methylene chloride. The combined extracts are washed with water, dried and concentrated. 10 g (78% of theory) of ethyl 2-(aminocarbonyl)-7-(4-chlorophenyl)heptanoate is obtained, M.P. 110°-111° C.
Reaction SMILES: [O-]Cl.[Na+].[OH-].[Na+].[F:6][C:7]([F:22])([F:21])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:18]=[N:19][OH:20])=[CH:15][C:16]=1[CH3:17])=[O:11].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1>C1COCC1.C(OCC)C>[F:22][C:7]([F:6])([F:21])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([C:18]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:20][N:19]=2)=[CH:15][C:16]=1[CH3:17])=[O:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C=NO)sc1C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)NCC(F)(F)F
Reaction time: 21 h
Yield: 15.7 %

Procedure:
Chlorox (4%, 1.02 ml) and NaOH (1N, 0.1 ml) are premixed and then added to a solution of 5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (200 mg) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (170 mg, example 1, Step A) in THF (3 ml) and diethyl ether (3 ml) at 5° C. The cold bath is then removed. After 21 hours, water is added and the reaction mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (56 mg) as light yellow oil. MS (HPLC/MS): 505 (MH+). Retention time: 4.38 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:30])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[NH:29][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]=12.[CH3:31][S:32]([OH:35])(=[O:34])=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:30])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[NH:29][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]=12.[CH3:31][S:32]([O-:35])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Product: CS(=O)(=O)[O-]
Reaction time: 10.5 h

Procedure:
Carvedilol was suspended in an aqueous solution of methanesulfonic acid, with the acid being present at a 1:1 molar ratio. The suspension is vortexed during the addition of carvedilol powder. After storage of the suspension for 6-15 hrs, the suspension is filtered and the solid residue is dried.
Reaction SMILES: OC(C)(C)CNC(N)=N.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][C:28]([OH:51])([CH3:50])[CH2:29][NH:30][C:31]1[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([C:41]2[CH:46]=[CH:45][N:44]=[C:43](S(C)=O)[N:42]=2)=[CH:33][N:32]=1>C1COCC1>[CH3:50][C:28]([OH:51])([CH3:27])[CH2:29][NH:30][C:31]1[N:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[C:34]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:42]=2)=[CH:33][N:32]=1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2C(F)(F)F)n1
Reactant: Nc1ccncc1
Agent: CC(C)(O)CNC(=N)N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
This compound was synthesized in an analogous manner to 22 utilizing 1-(2-hydroxy-2-methylpropyl)guanidine in step 3. To a solution of 4-aminopyridine (80 mg, 0.852 mmol) in THF (426 μl) cooled at −78° C. under nitrogen, LiHMDS (852 μl, 0.852 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 2-methyl-1-(2-(methylsulfinyl)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol (80 mg, 0.213 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for 1 hour. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a pale yellow solid (25.7 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (s, 6 H) 3.40 (br. s., 2 H) 4.51 (s, 1 H) 7.13 (d, J=5.05 Hz, 1 H) 7.76 (s, 2 H) 8.01 (br. s., 1 H) 8.34 (d, J=5.56 Hz, 2 H) 8.66 (d, J=4.93 Hz, 1 H) 10.19 (s, 1 H). HRMS (ES+) for C18H18F3N7O.H+ [MH+]: calcd, 406.1603. found, 406.1612. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.95 minutes over 7.75 minutes.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27][CH3:28])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCOC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), n-propyl salicylate (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (104 mg, yield 57%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:18][N:15]1[CH:16]=[CH:17][C:13]([NH:12][C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:35])=[O:36])[CH:30]=[N:31][CH:32]=2)=[CH:3][CH:4]=3)=[N:14]1
Reactant: Cn1ccc(Nc2cnc3ccc(Br)cc3n2)n1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1ccc(Nc2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)n1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A slurry of 7-bromo-N-(1-methyl-1H-pyrazol-3-yl)-2-quinoxalinamine (0.37 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.55 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 2 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (10% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (81 mg, 32%) as a pale green solid. MS(ES)+ m/e 458.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([NH:32][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (made by Ullmann reaction as described in Example 1, 42.0 mg, 0.14 mmol), benzylamine hydrochloride (23.4 mg, 0.16 mmol), EDCI (31.2 mg, 0.16 mmol), HOBT (22.0 mg, 0.16 mmol), and triethylamine (0.066 mL, 0.48 mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography of the residue over silica gel, using 20% ethyl acetate/hexane, gave the title compound (16.1 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.14 (t, 1H), 7.57 (d, 1H), 7.38-7.51 (m, 4H), 7.16-7.36 (m, 7H), 6.96-7.06 (m, 2H), 6.15 (s, 1H), 4.37 (d, 2H), 3.70 (s, 3H); ES-MS m/z 399.1 (MH+), HPLC RT (min) 3.72.
Reaction SMILES: [OH:1][C:2]1([C:17]#[C:18]/[C:19](/[CH2:26][CH2:27][CH3:28])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:15])([CH3:14])[CH2:12][C:5]2([O:9][CH:8]([CH3:10])[CH:7]([CH3:11])[O:6]2)[CH:4]=[C:3]1[CH3:16].ClCCl.C(O[SiH](OCC)OCC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N.CC#N.CC#N.[CH]1[CH][CH][CH][CH]1.F[P-](F)(F)(F)(F)F.[Ru+].[Cu]I.O.O1CCCC1.C(OCC)C>[OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[CH2:26][CH2:27][CH3:28])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:14])([CH3:15])[CH2:12][C:5]2([O:9][CH:8]([CH3:10])[CH:7]([CH3:11])[O:6]2)[CH:4]=[C:3]1[CH3:16]
Reactant: CCC/C(C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)=C/C(=O)OCC
Agent: [Cu]I
Agent: [Ru+]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCC(=C/C(=O)OCC)/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, ethyl (2Z)-3-[(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)ethynyl]-hex-2-enoate (340 mg, 0.87 mmol) was dissolved in a round-bottom flask in abs. dichloromethane (4 ml), and triethoxysilane (172 mg, 1.05 mmol) was added. The reaction solution was then cooled to 0° C., tris(acetonitrile)cyclopentadienylruthenium(II) hexafluorophosphate (18 mg, 0.04 mmol) was added and the mixture was stirred at room temperature for 2 h. Diethyl ether was then added, and the reaction mixture was concentrated under reduced pressure. The residue that remained was dissolved in abs. tetrahydrofuran (4 ml), copper(I) iodide (16 mg, 0.09 mmol) and tetra-n-butylammonium fluoride (289 mg, 1.11 mmol) were added, the mixture was stirred at room temperature for 4 h, and water was then added. The aqueous phase was repeatedly extracted thoroughly with dichloromethane. The combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the resulting crude product by column chromatography (ethyl acetate/heptane gradient) gave ethyl (2Z)-3-[(E)-2-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]-dec-6-en-8-yl)vinyl]hex-2-enoate (140 mg, 41% of theory) in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.68 (d, 1H), 6.09 (d, 1H), 5.97 (s, 1H), 5.48 (s, 1H), 4.19 (m, 3H), 3.61 (m, 1H), 2.29 (m, 1H), 2.22 (m, 2H), 2.02 (m, 1H), 1.92 (m, 3H), 1.67 (m, 2H), 1.62 (m, 1H), 1.28 (m, 6H), 1.20-1.08 (m, 9H), 0.91 (t, 3H).
Reaction SMILES: [O:1]1[C@H:9]2[C@@H:10]3[C@@H:14]([C@@H:2]1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=12)[C@@H:13]([CH3:15])[O:12][C:11]3=[O:16]>C(O)C.[C].[Pd]>[O:1]1[C@H:9]2[C@@H:10]3[C@@H:14]([C@@H:2]1[C@H:3]1[C@@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[C@@H:13]([CH3:15])[O:12][C:11]3=[O:16]
Reactant: C[C@H]1OC(=O)[C@H]2[C@H]1[C@H]1O[C@@H]2C2=C1CCCC2
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1OC(=O)[C@@H]2[C@@H]3O[C@@H]([C@@H]4CCCC[C@@H]43)[C@H]21
Yield: 61.2 %

Procedure:
Similarly to Example 2, 0.22 g(10% by weight) of 10% palladium-carbon were added to 2.20 g(9.99 mmol) of (3R,3aR,4R,9S,9aS)-4,9-epoxy-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one in 5 ml of ethanol solution and catalytic reduction was conducted at ambient temperature under 98.1 Kpa to obtain 1.36 g of (3R,3aR,4S,4aR,8aS,9R,9aS)-4,9-epoxy-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one(yield 61%).