Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]([C:16]([NH:18][CH:19]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:20]([OH:33])[C:21]([F:32])([F:31])[CH:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[C:41]([CH2:45][C:46](Cl)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>ClCCl>[C:41]([CH2:45][C:46]([NH:30][CH:22]([C:21]([F:32])([F:31])[CH:20]([OH:33])[CH:19]([NH:18][C:16](=[O:17])[C@:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(N)Cc1ccccc1)(c1ccccn1)C(C)C
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(Cc1ccccc1)NC(=O)CC(C)(C)C)(c1ccccn1)C(C)C
Yield: 77 %

Procedure:
Reaction of the resultant compound from Example 269 with t-butylacetyl chloride in dichloromethane and 1.1 equivalent of triethylamine provided the desired compound in 77% yield. Mass spectrum: (M+H)+ =653. 1H NMR (CDCl3): 80.80 (s, 9H), 0.82 (d, 3H), 0.93 (d, 3H), 1.83 (q, 2H), 2.12 (m, 1H), 2.70-3.20 (m, 4H), 3.80 (m, 1H), 3.95 (m, 1H), 4.55 (m, 1H), 4.80 (m, 1H), 5.20 (s,0.2H), 5.35 (br d, 1H), 6.50 (br d, 1H), 7.10-7.35 (m, 13H), 7.70 (m, 1H), 8.60 (br d, 1H).
Reaction SMILES: COC1C=CC=CC=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15]C(C)(C)C=C2CSC(=O)C.Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[CH:36]=2)[NH:31][C:30]([CH3:47])([CH3:46])[CH:29]=1.C(O)(=S)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:47])([CH3:46])[CH:29]=[C:28]2[CH2:27][NH:15][C:16]1[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSC(C)=O)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: CC(O)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
Thioacetic acid S-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl] ester 776 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline in 16 mL of methylene chloride was treated with 155 μL of thioacetic acid and 303 μL of triethylamine to give 100 mg of the title compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC1C=NC=C(C=1)C(O)=O>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: O=C(O)c1cncc(F)c1
Product: O=C(O)c1cc(F)cnc1Cl
Yield: 26 %

Procedure:
Into a 200 mL round bottomed flask, 2,6-dichloro-5-fluoronicotinic acid (1 g), methanol (10 mL), triethylamine (0.96 g) and 5% Pd/calcium carbonate (one poisoned by lead) (107 mg) were charged under cooling with ice and stirred at room temperature for one hour in a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated to obtain a crude product (1.3 g). The concentrated filtrate was analyzed by HPLC and found to be a mixture comprising 26% of the title compound, 57% of 2,6-dichloro-5-fluoronicotinic acid and 17% of 5-fluoronicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2=[N:12][N:13]([CH2:23][CH2:24][CH3:25])[C:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH2:26](I)[CH3:27].[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2=[N:12][N:13]([CH2:23][CH2:24][CH3:25])[C:14]([N:15]([CH2:26][CH3:27])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1NC(=O)OC(C)(C)C
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCn1nc2c(Cl)nc3ccccc3c2c1N(CC)C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
To a solution of tert-butyl 4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-ylcarbamate (722 mg, 2.00 mmol) in THF (5 mL) was added ethyl iodide (624 mg, 4.0 mmol). Sodium hydride (120 mg of a 60 wt % dispersion in mineral oil, 3.00 mmol) was added, and after 40 min, more ethyl iodide (624 mg, 2.00 mmol) was added, and the reaction was stirred overnight. Saturated ammonium chloride was added, and the aqueous layer was extracted with methyl tert-butyl ether (3×). The combined organic layers were dried (magnesium sulfate), filtered, concentrated, and purified by prep HPLC (silica cartridge, eluting with ethyl acetate in hexane) to afford 718 mg of tert-butyl 4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl(ethyl)carbamate as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:34][CH2:35][CH3:36])[N:32]=[CH:33][C:22]=4[C:21]3=[O:37])[CH:17]=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(O)C>C(O)C>[CH2:35]([NH:34][C:31]1[N:32]=[CH:33][C:22]2[C:21](=[O:37])[N:20]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=3)[CH2:29][C@H:28]3[N:24]([CH2:25][CH2:26][CH2:27]3)[C:23]=2[N:30]=1)[CH3:36]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Agent: Cl
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCNCC3)c1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
(S)-5-[5-(4-Tert-butoxycarbonylpiperazine-1-yl)pyridin-3-yl]-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (104 mg, 0.204 mmol) obtained in Step 1 was dissolved in ethanol (2 mL), and the mixture was stirred at room temperature for 1.5 hours after adding 4 mol/L hydrochloric acid-ethanol (3 mL). After concentrating the mixture, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (S)-9-ethylamino-5-[5-(piperazine-1-yl)pyridin-3-yl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (56.1 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH2:41])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH2:41])[C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:27][CH2:26][CH2:25][C@H:8]4[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C@:7]4([CH3:28])[C:6]=3[CH:29]=2)=[O:38])=[N:35][CH:36]=1
Reactant: C=Cc1cc(Cl)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.080 g, 0.19 mmol) in DCM (2.0 ml) were added 5-chloro-3-vinylpicolinic acid (0.036 g, 0.20 mmol), triethylamine (0.053 ml, 0.38 mmol) and HATU (0.079 g, 0.21 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 60% EtOAc in hexane, to provide tert-butyl ((4aR,11bR)-10-(5-chloro-3-vinylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.11 g, 0.19 mmol, 99% yield) as a white solid. m/z (ESI) 589.0 (M+H)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=C1C=C(O)C(=Cc2ccc(Cl)cc2Cl)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccc(Cl)cc2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2,4-dichlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2,4-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 55%, with a melting point of 180° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:18])[CH2:14][C:13](=[CH2:15])[CH2:12][C:11]([CH3:17])([CH3:16])[NH:10]1.B1C2CCCC1CCC2.[Cl:28][C:29]1[N:30]=[N:31][CH:32]=[C:33](Cl)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:28][C:29]1[N:30]=[N:31][C:32]([CH2:15][CH:13]2[CH2:12][C:11]([CH3:17])([CH3:16])[NH:10][C:9]([CH3:18])([CH3:8])[CH2:14]2)=[CH:33][CH:34]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: C=C1CC(C)(C)NC(C)(C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(Cc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 65 °C
Yield: 99.7 %

Procedure:
To 50 mL flask was added 2,2,6,6-tetramethyl-4-methylenepiperidine 2,2,2-trifluoroacetate (1.1 g, 4.12 mmol) and 9-BBN (0.5 M in THF) (16.5 mL, 8.23 mmol) and the reaction mixture was heated at 65° C. for 1 h. The reaction was cooled to RT and 3,5-dichloropyridazine (0.61 g, 4.12 mmol), K2CO3 (1.7 g, 12.35 mmol), and PdCl2(dppf).CH2Cl2 (0.17 g, 0.21 mmol) in 1,4-dioxane (8.5 mL)/H2O (1.7 mL) were added and heated at 60° C. overnight. The reaction mixture was cooled to RT, diluted with EtOAc, filtered through celite and concentrated in vacuo. The crude material was adjusted to pH 3 using 12 M HCl aqueous solution and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (1.1 g) MS [M+H+]=268.2.
Reaction SMILES: [CH2:1]([OH:9])[CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:10]([O:12]COCC)C.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:10][O:12][O:9][CH2:1]1
Reactant: CCOCOCC
Reactant: OCCCCC(O)CO
Agent: Cc1ccccc1S(=O)(=O)O
Product: OCCCCC1COOC1

Procedure:
13.4 g of commercial 1,2,6-hexanetriol are added to 12.4 ml of diethoxymethane and the mixture is refluxed in the presence of 500 mg of toluenesulfonic acid acting as a transacetalisation catalyst. The ethanol is evaporated at 80° C. and the 4-(4-hydroxybutyl)-1,2-dioxolane obtained is purified by distillation. 7.3 g of this product and 4.6 g of epichlorhydrine are reacted in the presence of 2.8 g of potassium hydroxide (powder) and tetrabutylammonium chloride, to form the monomer 4-[(4-glycidyloxy)-butyl]-1,3-dioxolane
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C@@:19]1([CH2:22][OH:23])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([C:39]5[CH:40]=[N:41][NH:42][CH:43]=5)=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[N:12][N:13]=[C:14]2[CH2:20]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5cn[nH]c5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A solution of the compound (500 mg, 0.98 mmol) obtained in Example 52-1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210 mg, 1.08 mmol), tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.10 mmol), and potassium carbonate (272 mg, 1.97 mmol) in 1,2-dimethoxyethane (6 mL) and water (3 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (10 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was partially purified by silica gel chromatography (ethyl acetate:methanol=40:60). A solution of the residue and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 N aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was partially purified by silica gel chromatography (ethyl acetate/methanol=40:60). The residue was dissolved in a solution (8 mL) of ethyl acetate/methanol=3:1, and diisopropyl ether (20 mL) was gradually added to the mixture with stirring at room temperature to prepare a suspension. The suspension was stirred at 60° C. for 1 h and stirred for 1 h with cooling to room temperature. The colorless precipitate was collected by filtration and washed with diisopropyl ether. The solid was dried under reduced pressure to obtain the title compound (46 mg, 12%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](SC(=O)N(C)C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[OH-].[K+].Cl.[OH:23]S(O)(=O)=O>CO.C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:23])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(SC(=O)N(C)C)ccc2o1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc2cc(O)ccc2o1
Yield: 95 %

Procedure:
A solution of 5-dimethylcarbamoylsulfanyl-benzofuran-2-carboxylic acid methyl ester (0.5 g, 1.8 mmol) and potassium hydroxide (0.5 g, 12.5 mmol) in 25 ml 2:1 ethanol/water was heated at reflux for 18 hours. The reaction was then cooled, acidified with 2 M HCl, extracted 2×25 mL EtOAc, dried (Na2SO4) and the solvent removed in vacuo to give 350 mg of the crude product. The crude mixture was then refluxed overnight in 25 mL MeOH and catalytic H2SO4. The reaction was then cooled, concentrated in vacuo, taken up in EtOAc and washed with brine. The organic layer was then dried (Na2SO4) and concentrated in vacuo to give 330 mg (95%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 7.66 (s, 1H), 7.62 (s, 1H), 7.57(d, 1H, J=9.0 Hz), 7.37 (d, 1H, J=9.0 Hz), 5.49 (s(br), 1H), 3.85 (s, 3H). Preparation of 5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylic acid methyl ester (Compound 6E)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:35][C:11]3[C:12](=[O:34])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23]5)=[C:18]([O:32][CH3:33])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:35][C:11]3[C:12](=[O:34])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@H:24]([N:37]([CH3:38])[CH3:36])[CH2:23]5)=[C:18]([O:32][CH3:33])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](OS(C)(=O)=O)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@H](N(C)C)C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Dissolve methanesulfonic acid (R)-1-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-pyrrolidin-3-yl ester (0.504 g, 0.952 mmol) in 2 M dimethylamine in THF (10 mL). Stir the mixture at 75° C. overnight in a sealed pressure tube. Dilute the mixture with EtOAc (50 mL) and wash with saturated NaHCO3 (2×20 mL) and brine (20 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material by chromatograghy, eluting with 2% NH3—H2O/50% CH3OH/EtOAc to give 0.293 g (64%) of 2-(4-chloro-phenyl)-6-[4-((S)-3-dimethylamino-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[CH2:3]1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.[Cu]I.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>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:9][CH:10]=2)[N:5]([CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[CH2:3]1
Reactant: CC(C)N1C(=O)CC(C)(C)c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)N1C(=O)CC(C)(C)c2ccc(C#C[Si](C)(C)C)cc21
Temperature: 50 °C

Procedure:
To a solution of 0.40 g (1.36 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-iso-propyl-7-bromoquinoline (Compound 24) in 5.0 ml of triethylamine which was degassed under argon for 15 min in a sealable tube, were added successively 0.069 g (0.36 mmol) of copper(I)iodide, (1.0 ml, 7.1 mmol) of (trimethylsilyl)acetylene, and 0.147 g (0.21 mmol) of bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was degassed for an additional 5 min. The tube was sealed and the reaction mixture was heated at 50° C. for 72 h. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as an oil. PNMR (CDCl3) d 0.25 (9H, s), 1.26 (6H, s), 1.54 (6H, d, J=7.1 Hz), 2.39 (2H, s), 4.60 (1H, p, J=7.1 Hz), 7.17 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:27])[C:22]#[C:23][CH2:24][O:25][CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:28]#[N:29])[CH:5]=[CH:6][C:7]=1[F:8]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:27])/[CH:22]=[CH:23]\[CH2:24][O:25][CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:28]#[N:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COC/C=C\C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Reaction time: 5.5 h
Yield: 0.7 %

Procedure:
A mixture of 0.05 g (0.1 18 mmol) N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-quinolinyl}-4-methoxy-2-butynamide and 6 mg of Lindlar catalyst in 15 mL of methanol was hydrogenated at room temperature for 5.5 hrs. The mixture was filtered through a pad of Celite. The solvent was removed to give 0.05 g (99.7%) yellow solid; HRMS m/z 410.0928 (M+.).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].COC1C=CC(N2CCNCC2)=CC=1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:54][C@H:51]3[CH2:52][CH2:53][C@H:48]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([N+:38]([O-:40])=[O:39])=[C:42]([C:55]([F:56])([F:57])[F:58])[CH:43]=4)[CH2:49][CH2:50]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(N2CCN(C(=O)CCl)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: COc1ccc(N2CCNCC2)cc1
Agent: O=C(Cl)CCl
Product: COc1ccc(N2CCN(C(=O)CO[C@H]3CC[C@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
1-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-methoxy-phenyl)-piperazine (also known as 2-chloro-1-[4-(4-methoxy-phenyl)-piperazin-1-yl)-ethanone) was prepared with a 78% yield from 1-(4-methoxy-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-methoxy-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-methoxy-phenyl)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (24% yield). The structure was confirmed using Protocol II-A. Calculated mass=537; observed mass=537; HPLC retention time=4.05 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)O)([O-:3])=[O:2].CC(C)[O-:14].[Ti+4:16].CC(C)[O-:19].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:7]=[C:6]([O-:11])[C:5]=1[O-:14])([O-:3])=[O:2].[Ti+4:16].[N+:1]([C:4]1[CH:10]=[CH:9][CH:7]=[C:6]([O-:11])[C:5]=1[O-:19])([O-:3])=[O:2]
Reactant: CC(C)[O-]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [Ti+4]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc([O-])c1[O-]
Temperature: 100 °C

Procedure:
A solution of 4-nitrocatechol (10 g, 64.5 mmol) and toluene (220 ml) was dehydrated by distilling 20 mL of the solution. Thereafter, 9.15 g (32.2 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (4-nitrocatechol-titanium complex) was brown in color. The yield amount was 11.0 g (31.1 mmol), and the yield percentage was 97%. 3.54 g of 4-nitrocatechol-titanium complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.