Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]>C(O)C>[Cl:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 89 %

Procedure:
4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate in 80 ml of ethanol while cooling with ice and stirring. When the exothermic reaction had ceased, the mixture was stirred for another hour at room temperature, the solvent was stripped off in vacuo, and the residue was recrystallised from cyclohexane/petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (R1 =C2H5) of melting point 89° to 90° C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:15]([Sn](CC)(CC)CC)[CH3:16]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([CH2:15][CH3:16])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CC[Sn](CC)(CC)CC
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Yield: 52.5 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (1.6 g, 6.1 mmol), tetraethyltin (2.4 ml, 12.2 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuo, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 0.68 g (3.2 mmol, 53%) of 2,4-dinitro-6-ethylaniline, which was converted to the diamine (0.45 g, 95%) on hydrogenation (H2/Pd-C).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:44])[C:33]([C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.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]>[Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:38]5[CH:37]=[CH:36][C:35]([C:33]([N:32]([CH3:44])[CH3:31])=[O:34])=[N:40][CH:39]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), [6-(dimethylcarbamoyl)pyridin-3-yl]boronic acid (97 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (120 mg, 42%) as a light yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:14]=1[Cl:13])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[N:9]=[C:8]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:7]=1.Cl>CO>[CH3:20][S:17]([C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[N:9]=1)[C:5]([OH:21])=[O:4])(=[O:19])=[O:18]
Reactant: CCCN(C)c1cc(C(=O)OC)cc(S(C)(=O)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)c1cc(C(=O)O)cc(S(C)(=O)=O)n1
Reaction time: 3 h
Yield: 81.6 %

Procedure:
Add 2 N NaOH (0.95 mL) to 2-methanesulfonyl-6-(methylpropylamino)-isonicotinic acid methyl ester (0.181 g, 0.63 mmol) in methanol (5 mL). Stir 3 h, acidify to about pH=3 using 1 N HCl, extract into ethyl acetate, wash organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (0.14 g, 85%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[NH:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10][N:9]=1.[F:20][CH:21]([F:46])[C@@:22]1([C:30]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:31]=2[F:45])[C@@H:28]2[C@@H:26]([CH2:27]2)[O:25][C:24]([NH2:29])=[N:23]1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[F:46][CH:21]([F:20])[C@@:22]1([C:30]2[CH:35]=[C:34]([C:8]3[NH:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[N:10][N:9]=3)[CH:33]=[CH:32][C:31]=2[F:45])[C@@H:28]2[C@@H:26]([CH2:27]2)[O:25][C:24]([NH2:29])=[N:23]1
Reactant: CC1(C)OB(c2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)OC1(C)C
Reactant: Fc1ccc(-c2nnc(Br)[nH]2)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@](c2cc(-c3nnc(-c4ccc(F)cc4)[nH]3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with sodium carbonate (0.171 g, 1.609 mmol), 3-bromo-5-(4-fluorophenyl)-4H-1,2,4-triazole (0.078 g, 0.322 mmol, US20130184248 A1), (1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine, 1,4-dioxane (2.5 ml) and water (0.83 ml). The vessel was capped and the solution was degassed by bubbling nitrogen gas through the solution for 10 minutes. Next, 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.023 g, 0.032 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with a 9:1 mixture of aqueous saturated ammonium chloride/ammonium hydroxide, saturated aqueous sodium chloride, and then stirred with activated carbon. The solution was filtered through a pad of celite and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:40 2M NH3.MeOH in CH2CL2, and then repurified by preparative TLC by eluting with 1:30 2M NH3.MeOH in CH2CL2 to provide the titled compound as a white solid after concentration with MeOH.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([C@@H:31]([NH:33][CH2:34][C:35]([C:37]2([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38]2)=[O:36])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([N:33]([CH2:34][C:35]([C:37]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH2:39]1)=[O:36])[C@H:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:32])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CCOC(=O)C1(C(=O)CN[C@@H](C)c2ccccc2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Diethylphosphonoacetic acid (15.1 g, 76.8 mmol) was dissolved in anhydrous tetrahydrofuran (120 ml), and after adding 1,1′-carbonyldiimidazole (13.7 g, 84.5 mmol) while cooling with ice, it was stirred at room temperature for 1 hour. After adding an anhydrous tetrahydrofuran (30 ml) solution of ethyl 1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (17.6 g, 64.0 mmol) to the reaction solution while cooling with ice, it was stirred at room temperature for 1 hour. After adding 1 mol/l hydrochloric acid (100 ml) and ethyl acetate (100 ml) to the reaction solution and performing an extraction operation, the organic layer was separated. The aqueous layer was then subjected to extraction with ethyl acetate (100 ml) and the combined organic layer was washed with saturated sodium bicarbonate water (100 ml) and saturated saline solution (100 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering and then concentrating the filtrate under a reduced pressure, 28.7 g (99%) of the title compound was obtained as a yellow syrup.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=O)[CH3:2].BrBr.BrC(Br)=O.CC([O-])=O.[Na+].[NH2:24][C:25]([NH2:27])=[S:26]>CC(O)=O.C(O)C>[NH2:27][C:25]1[S:26][CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=2)[N:24]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=C(Br)Br
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)c1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-(4-Acetyl-phenyl)-ethanone (8.1 g, 5 mmol), in HOAc (50 mL) at 60° C. was treated with bromine (1 eq., 0.26 mL) dropwise over 10 minutes. After 5 more minutes the reaction was cooled, the acetic acid was removed, ethyl acetate (50 mL) was added and then removed to get drive off the remainder of the acetic acid. The crude bromo ketone was then dissolved in ethanol (30 mL) with NaOAc (1.1 g) and thiourea (1 eq., 375 mg) was added. The suspension was stirred at room temperature for 15 hours. The solvents were removed and the resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 219.1 (M+H−).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[C:11]1[C:16]([NH2:17])=[CH:15][N:14]=[CH:13][N:12]=1.[SH:18][CH2:19][CH2:20][CH2:21][OH:22].O>O1CCOCC1>[NH2:17][C:16]1[C:11]([S:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: OCCCS
Reactant: Nc1cncnc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Nc1cncnc1SCCCO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
DIEA (1.11 g, 8.61 mmol) was added to a solution of 4-bromopyrimidin-5-amine (A) (1.0 g, 5.74 mmol) and 3-mercaptopropan-1-ol (35B1) (0.53 g, 5.74 mmol) in dioxane (5 mL). The reaction mixture was heated to 50° C. under nitrogen and stirred for 30 min. The LC/MS spectrum showed that the reaction had completed. Water (50 mL) was added and a solid precipitated. The off white solid product (35C1) (913 mg, 4.93 mmol) was obtained after filtration and air drying at 25° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Sn](Cl)Cl.Cl>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
To a solution of {2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-nitro-biphenyl-3-yl}-acetic acid ethyl ester (0.70 g, 1.75 mmol) in EtOH (70 mL) was added tin (II) chloride (1.97 g, 8.75 mmol). The reaction was heated to reflux for 5 h, and then the mixture was acidified to pH 1 with concentrated HCl and diluted with EtOAc. The resulting biphasic mixture was filtered through Celite, and the organic layer was separated. The aqueous layer was neutralized to pH 7 with solid NaOH and extracted with EtOAc. The combined organic extracts were dried and filtered, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C([O:35][CH2:36][C:37]2[C:38]([C:43]3C=CC=CC=3)=[N:39]OC=2C)C=1)=O.NC1CCOC1>>[O:35]1[CH2:36][CH2:37][CH:38]([NH:39][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:43]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Agent: NC1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC2CCOC2)n(C)n1
Yield: 59 %

Procedure:
As described for example 1b, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (140 mg, 0.40 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using rac-3-aminotetrahydrofuran instead of morpholine, to the title compound (96 mg, 59%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH:8]1([C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9]1>C(O)C>[CH:8]1([C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9]1
Reactant: COC(=O)C(C)(C)C1OCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C(=O)O)C1OCCc2ccccc21
Reaction time: 8 h

Procedure:
Sodium hydroxide (1N, 12 ml) is added dropwise over several minutes, followed by a few mls of THF (to aid in solution) to a mixture of methyl 2-(isochroman-1-yl)-2-methylpropionate (LXXI, 1.833 g, 7.8 mmol) in ethanol (12 ml). The mixture is stirred overnight at 20°-25°, then at 47° for 2 hr, followed by stirring at 20°-25° over the weekend. Additional THF and sodium hydroxide (1N, 12 ml) are added and the mixture is stirred overnight at 20°-25° and then at 40° for 7 hr, followed by overnight at 20°-25°. Ethanol is then removed under reduced pressure and the resulting solids are dissolved in water. The aqueous phase is separated and washed twice with hexane to remove any unreacted starting material and the aqueous phase is then cooled in an ice/water bath and hydrochloric acid (4N, 6 ml) is added dropwise. The mixture is extracted three times with ether and the combined organic phases are backwashed with saline, dried over magnesium sulfate, and concentrated. Recrystallization from dichloromethane/hexane gives 2-(isochroman-1-yl)-2-methylpropionic acid (LXXII), mp 110.5°-115.75°.
Reaction SMILES: FC(F)(F)C(OCC)=O.O.NN.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21](Cl)[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.[F:30][C:31]([F:38])([F:37])[C:32]1[NH:36][N:35]=CN=1>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)[C:32]([C:31]([F:38])([F:37])[F:30])=[N:36][N:35]=2)=[CH:23][CH:24]=1
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ncn[nH]1
Agent: CCOC(=O)C(F)(F)F
Agent: NN
Solvent: CO
Solvent: O
Product: FC(F)(F)c1nnc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
Ethyl trifluoroacetate (2.9 g) was added to hydrazine hydrate (1.1 g, 99-100%) in methanol (20 ml) at 5°-10° and stirred for 15 min. N-(4-chlorophenyl)-4-chlorobenzimidoyl chloride (5.7 g) was added keeping the temperature below 5°for 3 hr and then at reflux for 1 hr 3,4bis 4-chlorophenyl)-5-trifluoromethyl-1,2,4-triazole crystallized on cooling (4.1 g, 57.8%) m.p. 184°. (Found: C, 50.54%; H, 2.40%; Cl, 19.6%; F, 15.8%; N, 11.54%. C15H8Cl2F3N3 requires: C, 50.30%; H, 2.25%; Cl, 19.8%; F, 15.9%; N, 11.73%) δ (CDCl3); 7.43 (m).
Reaction SMILES: BrC1C=C([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[N:15]=[CH:14][C:13]([C:20]([NH2:22])=[O:21])=[C:12]3[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)C=CC=1.[Br:32][C:33]1[CH:38]=[CH:37][C:36](S)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[N:15]=[CH:14][C:13]([C:20]([NH2:22])=[O:21])=[C:12]3[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:35][CH:34]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4cccc(Br)c4)cc23)c1
Reactant: Sc1ccc(Br)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4ccc(Br)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 59, using 4-bromothiophenol in place of 11-mercapto-1-undecanol. ES/MS calcd. for C24H21BrN3O2S+ 494.1. Found m/z=494.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)=[CH:4][CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:33])[CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(Cl)cc2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
Combine 10-((S)-3-[2-(4-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (430.9 mg, 0.99 mmol), formaldehyde (88.0 μL, 1.08 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (313.5 mg, 1.48 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 365.2 mg (82%) of the title compound as a brown foam: mp 79°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](=[S:24])[NH2:23])=[CH:18]2)(=[O:11])=[O:10].[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:24][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:23]=1)=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carbothioamide (2.3 g), ethyl but-2-ynoate (1.5 mL), tributylphosphine (1.5 mL), toluene (25 mL) and tetrahydrofuran (25 mL) was stirred for 3 hr at room temperature. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5) to give the title compound (1.23 g, yield: 41%) as a pale-brown amorphous solid.
Reaction SMILES: [F-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:15]1[C:23]2[S:22][CH:21]=[CH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1>C1COCC1.CCOCC.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].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.B(O)O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:23]3[S:22][CH:21]=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cccc2ccsc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2cccc3ccsc23)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a 50 ml round bottom flask was added Pd2(dba)3 (107 mg, 0.117 mmol), KF (2.25 g, 3.9 mmol), 4-methoxyphenylboronic acid (2.14 g, 14.1 mmol), and the flask was purged with nitrogen. Anhydrous THF (25 ml) was then added followed by 7-bromo-1-benzothiophene (2.5 g, 11.73 mmol) in 5 ml THF followed by the addition of P(Cy)3 (100 mg, 0.352 mmol). After 4 h at ambient temperature no product was observed. Heating to 60° C. overnight afforded approx. 50% completion. After the addition of another 2% Pd2(dba)3 (215 mg), 0.1 equivalent boronic acid (26 mg) and THF, the reaction was complete in 2 h. The reaction was cooled, diluted with ether, filtered through a silica plug and concentrated to 3.33 g amber oil. Purification by column chromatography (load: 5% EtOAc/hexanes to 10% EtOAc/hexanes) afforded 2.75 g (97.5%) product as a light yellow solid: mp 74–75° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.84 (3H, s), 7.11 (2H, d, J=8.7 Hz), 7.37 (1H, d, J=7.1 Hz), 7.48 (1H, t, J=7.6 Hz), 7.54 (1H, d, J=5.5 Hz), 7.67 (2H, d, J=8.7 Hz), 7.79 (1H, d, J=5.5 Hz), 7.86 (1H, dd, J=7.4 Hz, 0.8 Hz); MS (ESI) m/z 239 ([M−H]).