Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1>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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CC(O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 10 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 64 mg, 70%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C.CCOCC>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:5][C:4]3[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=3)[CH:1]=[O:10])=[N:19]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C

Procedure:
A solution of isophthalaldehyde (4.0 g) and 7-chloroquinaldine (5.39 g) in acetic anhydride was heated at 125° C. in an oil bath for 48 hours. The reaction was cooled to room temperature, diluted with ether (30 mL) and the resulting suspension was stirred vigorously. The solid title compound was collected by filtration and was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:30])=[N:28][N:27]([CH3:31])[C:15]2=[N:16][C:17]=1[N:18]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:8]([NH2:10])=[O:9]>C(O)(C)(C)C>[F:40][C:2]([F:39])([F:1])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:30])=[N:28][N:27]([CH3:31])[C:15]2=[N:16][C:17]=1[N:18]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:8]1[O:9][CH:34]=[C:3]([C:2]([F:40])([F:39])[F:1])[N:10]=1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O)c(C)nn2C
Solvent: CC(C)(C)O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nc(C(F)(F)F)co1)c(C)nn2C
Temperature: 25 °C
Yield: 20 %

Procedure:
To a stirred solution of 1-(3,5-bis-trifluoromethyl-benzyl)-1-[6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl]-urea (0.250 g, 0.430 mmol) in tert-butanol (10 mL) was added 1,1,1-trifluoromethyl acetyl bromide (0.20 g, 0.480 mmol). This mixture was refluxed for 3 h and then cooled to RT. After concentration in vacuo, water (10 mL) was added to the residue, and the product was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the crude residue, which was purified by column chromatography over 100-200 mesh silica gel using 5% ethyl acetate and petroleum ether, to yield the title compound as a white solid (20%), mp: 139° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[N:19]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:20]1[C:21](=[O:23])[NH:22][C:18]([CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:33])=[O:3])=[CH:14][CH:13]=2)=[N:19]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3cccc(OC)c3)c(=O)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(Cn2nc(CCCc3ccc(OC(C)(C)C(=O)O)cc3)[nH]c2=O)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
2-(4-{3-[1-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (1.55 g, 3.42 mmol) was dissolved in a mixture of ethanol (7.5 mL) and water (7.5 mL). Solid sodium hydroxide (0.36 g, 8.73 mmol) was added in one portion and the solution was warmed to 70° C. and stirred for 1 h. The solution was cooled to rt and the pH adjusted to 7 with 6N HCl. The solution was concentrated to an oil, which was partitioned between 1N HCl (10 mL) and ethyl acetate (15 mL). The aqueous layer was then reextracted with ethyl acetate (15 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo at 50° C. to afford the title compound as an oil (1.41 g, 97.0%). 1H NMR (DMSO-d6) δ 13.0 (broad s, 1 H), 11.47 (s, 1 H), 7.23 (t, 1 H, J=8 Hz), 7.03 (d, 2 H, J=8 Hz), 6.82 (d, 1 H, J=2 Hz), 6.75 (m, 5 H), 4.73 (s, 2 H), 3.70 (s, 3 H), 3.35 (broad s, 1 H), 2.48 (t, 2 H, J=8 Hz), 2.36 (t, 2 H, J=8 Hz), 1.80 (quint, 2 H, J=7 Hz), 1.46 (s, 6 H); 13C NMR (DMSO-d6, 20° C.) δ 175.8, 160.0, 155.0, 154.1, 146.8, 139.8, 135.0, 130.3, 129.7, 120.1, 119.1, 113.8, 113.2, 78.9, 55.6, 47.8, 40.6, 40.5, 34.0, 28.4, 27.5, 26.2, 25.7; IR (CHCl3) 1707, 1603, 1509, 1159 cm−1; Anal. Calcd. for C23H27N3O5: C, 64.93; H, 6.40; N, 9.88. Found: C, 65.02; H, 6.65; N, 9.57.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([OH:24])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:24][C:17]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(Cl)c2c1CCCC2
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution containing 39.96 g of 4,5-dichloro-2-nitrotoluene and 39.30 g of 4-chloro-5,6,7,8-tetrahydro-1-naphthol in 250 ml of DMF under an atmosphere of nitrogen and at room temperature was added 3.87 g of anhydrous potassium carbonate. The resulting mixture was then heated to 110° C. After 20 hrs at 110° C., the reaction mixture was cooled to room temperature. The DMF was removed in vacuo. The residue was dissolved in 500 ml of warm toluene and filtered through celite. The filter cake was thoroughly washed with toluene. The solvents from the combined filtrates were removed to afford 67.04 g of tan powder. This material was recrystallized from a hexane-ethyl acetate mixture to afford 49.46 g of the desired product as light tan crystals. mp 139°-140° C. NMR (CDCl3): 1.6-1.9 (m, 4H), 2.4-2.9 (m, 7H, contains singlet at 2.45), 6.51 (s, 1H), 6.73 (d, J-8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11](=[O:20])[CH:10]1[CH3:21])=[O:8])(C)(C)C.CN1CCOCC1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH:33]=[CH:34]C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:29][C:30]1[CH:31]=[C:32](/[CH:33]=[CH:34]/[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11](=[O:20])[CH:10]2[CH3:21])=[O:8])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: C=CCCCN1CCN(C(=O)OC(C)(C)C)C(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: C=CCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)C(C)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.1 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 8 ml) was added to a solution of 2-methyl-3-oxo-4-pent-4-enyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 3.5 h, then volatile material was removed by rotary evaporation. The residue was taken up in dichlormethane (10 ml), treated with 4-methylmorpholine (358 mg, 3.54 mmol), and the mixture obtained concentrated in vacuo. The residue was taken up in N,N-dimethylformamide (8 ml), then 4-methylmorpholine (358 mg, 3.54 mmol), 3,4-dichlorocinnamic acid (161 mg, 0.71 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (404 mg, 1.06 mmol) were added. The solution was stirred at room temperature for 48 h, then the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (233 mg, 86%). Light yellow oil, MS (ISP)=381.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.OO.C(=O)([O-])[O-].[Na+].[Na+].[BrH:17]>>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:17])=[CH:4][N:3]=1
Reactant: Br
Reactant: Cc1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1cc(N)ncc1Br
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
2-Amino-4-methylpyridine (110 g, 1.02 mol) in hydrobromic acid (1 L, 48%) was stirred at 70° C. and a solution of hydrogen peroxide (300 mL, 15%) was added dropwise over a one h at such a rate that the temperature of the reaction mixture remained at 70-80° C. The mixture was stirred for 90 min at 70° C. and poured onto crushed ice. The pH was adjusted to 4-5 with sodium carbonate and the precipitated solid (containing mostly dibrominated products) was filtered off and discarded. The pH was subsequently raised to 9 and the precipitated product collected by filtration. Recrystallization from toluene gave 2-Amino-5-bromo-4-methylpyridine (76.3 g, 40%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[C:29]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30]1.Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCCC(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (500 mg, 1.54 mmol) was dissolved in mixture of THF (6 mL) and first portion of K2CO3 (3 mmol) and the resulting solution was cooled to 5° C. with vigorous stirring. To this stirred solution glutaric anhydride (263 mg, 2.30 mmol) was added slowly while maintaining the pH at 9.0-9.5 with another portion of K2CO3 (3 mmol). The mixture was stirred at RT for 3 h, TLC showed completion of the reaction. The pH of the reaction mixture then adjusted to 2.0 by the addition of 2 N hydrochloric acid. The acidic solution was extracted with ethyl acetate (10 mL×3). The combined organic extract was washed with water, brine and dried over Na2SO4, the solvent was removed on rotary evaporator to afford crude Compound E, which was further purified by preparative HPLC (459 mg, 68%) to yield Compound E. 1H-NMR (500 MHz, CD3OD): δ 1.60 (s, 6H), 1.70 (s, 3H), 1.72 (s, 3H), 2.02-1.95 (m, 4H), 2.15-2.05 (m, 4H), 2.32 (t, 2H), 2.40 (t, 2H), 2.75 (m, 2H), 3.05 (dd, 1H), 3.15 (dd, 1H), 3.30 (d, 2H), 4.60 (dd, 1H), 5.14 (t, 2H), 5.25 (t, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.1, 17.7, 18.4, 22.2, 26.3, 27.4, 27.7, 35.7, 40.6, 53.3, 121.5, 125.2, 125.4, 131.8, 136.1, 140.1, 173.7, 175.3, 177.6; ES-MS: mass calcd for Chemical Formula: C23H32NO5S 439.6. Found (M+Na) m/z 462.3.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19]>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:18]=[O:19])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: O=Cc1ccccc1B(O)O
Product: Nc1ncc(-c2ccccc2C=O)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-formylphenyl-boronic acid gives “A66”; method 1: HPLC/MS: 1.23 min, [M+H]=319;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH3:13])#[CH:2].[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19](Cl)[CH:20]=1.C(N(CC)CC)C>CN(C=O)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>[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=2[CH3:13])[CH:20]=1
Reactant: C#Cc1ccc(OCOC)cc1C
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (8) (1.0 equiv.), 3,5-dichloropicolinonitrile (9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60° C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2×). The combined organic layers were washed with 10% aq NH4OH (2×), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (10) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)ccc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (150 g, 458 mmol) in dichloromethane (1500 ml) was added DMF (2.0 ml) followed by oxalylchloride (58.2 ml, 688 mmol) at 0° C. in drop wise fashion over the period of 30 min. After complete addition, the reaction mixture was stirred at room temperature for 3 h. Volatiles were evaporated under reduced pressure to give 2-bromo-5-iodo-benzoyl chloride (−158 g). The crude product was used for the next step immediately. (Note: The product should not be exposed to air).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].Cl>C(OCC)C.CCCCCC>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-trifluoromethoxyiodobenzene (39.28 g.) in anhydrous diethyl ether (200 ml.) was added dropwise at -70° C. to n-butyl-lithium (96 ml. of a 1.6M solution in hexane) over 25 minutes. The solution was stirred for 30 minutes, and then dimethylformamide (14.83 g.) and anhydrous ether (50 ml.) were added over 15 minutes. After 1 hour, the solution was allowed to warm to -20° and was then hydrolysed by the addition of 3N hydrochloric acid (150 ml.). The organic layer was separated, and the aqueous layer was extracted twice with diethyl ether. The ether extracts were combined, washed with water, dried over magnesium sulphate and filtered, and the solvent was evaporated to give a yellow oil. Distillation of this oil gave 4-trifluoromethoxy benzaldehyde, b.p. 75°-7°/8 mm. of mercury, pressure.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1cccc(Br)n1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)n1
Yield: 98 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 2-bromo-6-methoxypyridine, the title compound was formed in 98% yield [ ] as a white solid, mp 193°-195° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 7.57 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 5H), 6.63 (d, J=8.0 Hz, 1H), 4.75 (s, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.49 (s, 2H), 2.94 (m, 2H), 2.77 (m, 2H), 2.64 (d, J=1.2 Hz, 2H), 2.04 (m, 2H), 1.63 (m, 2H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (18) hydrochloride salt:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid ethyl ester (481 mg, 1.42 mmol) in THF (12 mL) was added a solution of lithium hydroxide monohydrate (418 mg, 9.8 mmol) in water (6 mL) and the resulting mixture stirred at room temperature overnight. The mixture was acidified with HCl (1 N, 10 mL) and evaporation afforded the title compound (335 mg, 70%) which was obtained as a light yellow solid. MS: m/e=309.0 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[CH3:9][S:10]([O:7][CH2:6][C:2]([CH3:8])([CH3:1])[C:3](=[O:5])[CH3:4])(=[O:12])=[O:11]
Reactant: CC(=O)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(C)(C)COS(C)(=O)=O
Reaction time: 12 h
Yield: 85.5 %

Procedure:
232 g (2 mols) of 3,3-dimethyl-4-hydroxy-2-butanone (for the preparation, see Beilstein H 1, E III, 3239, IV 4030 and Bull. Soc. Chim. France 1954, 2849) in 700 ml of absolute pyridine were reacted with 229 g (2 mols) of methanesulphonyl chloride at 0° to 5° C. After leaving the mixture to stand at 20° C. for 12 hours, it was diluted with methylene chloride and extracted by shaking with ice-water. The organic phase was dried and freed from the solvent in vacuo and the residue was fractionated over a column. 332 g (86% of theory) of 2,2-dimethyl-3-oxo-butyl methanesulphonate of boiling point 106°-120° C./0.12 mm Hg were obtained. ##STR79##
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][CH2:34][NH2:35]>>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:34][CH2:33][C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: NCCc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: c1cc(NC2CCNCC2)cc(-c2ccnc(NCCc3cccs3)n2)c1

Procedure:
Intermediate 7 was coupled with 2-thiophen-2-yl-ethylamine by procedure F and the resulting product deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 380. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.28 (d, 1H) 6.8-7.5 (m, 8H) 4.85 (m, 1H) 3.9 (m, 2H) 3.7 (m, 2H) 3.1-3.5 (m, 4H) 2.2-2.3 (m, 2H) 2.28 (m, 2H) 1.6-1.8 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:13]2[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35](O)=[O:36]>>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([CH:29]=1)[CH2:23][N:12]([C:13]1[CH:22]=[CH:21][C:16]2[O:17][CH2:18][CH2:19][O:20][C:15]=2[CH:14]=1)[CH:9]1[CH2:8][CH2:7][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]2[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:33]=2[CH3:32])[CH2:11][CH2:10]1
Reactant: CC(CCN)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc3c(c2)OCCO3)CC1
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc3c(c2)OCCO3)CC1
Yield: 85.3 %

Procedure:
Using general procedure E, [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (see EXAMPLE 215) (86 mg, 0.19 mmol) and 2,6-dimethyl-benzoic acid (40 mg, 0.27 mmol) gave COMPOUND 216 as a white foam (94 mg, 84%). 1H NMR (CDCl3) δ 0.83-1.14 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.47-1.57 (m, 1H), 1.66-1.81 (m, 3H), 2.06-2.17 (m, 1H), 2.30 (s, 6H), 2.46-2.57 (m, 1H), 2.69-2.90 (m, 3H), 3.22-3.33 (m, 1H), 3.36-3.47 (m, 1H), 3.75 (s, 2H), 3.81-3.93 (m, 1H), 4.12-4.23 (m, 4H), 6.07-6.17 (m, 2H), 6.66 (d, 1H, J=8.7 Hz), 6.87-7.04 (m, 4H), 7.10-7.18 (m, 2H), 8.36 (s, 1H). 13C NMR (CDCl3) δ 13.25, 18.99, 28.82, 30.02, 30.90, 39.54, 42.59 (d, J=3.8 Hz), 43.57, 52.01, 57.47, 60.23, 64.04, 64.56, 103.36, 107.81, 116.24 (d, J=23.2 Hz), 117.28, 127.13, 127.77 (d, J=8.1 Hz), 128.32 (d, J=5.5 Hz), 128.35, 129.20 (d, J=3.2 Hz), 129.35 (d, J=15.3 Hz), 133.61, 135.82, 138.27, 143.27, 143.66, 158.57 (d, J=245 Hz), 169.89. ESI-MS m/z 580 (MH)+, 582 (MH+2)+. Anal. Calcd. for C33H39ClFN3O3.0.3H2O.0.2CH2Cl2: C, 66.55; H, 6.72; N, 7.02; Cl, 7.70. Found: C, 66.44; H, 6.60; N, 7.12; Cl, 7.74.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:4]N1C(=O)C2=CC=CC=C2C1=O)[CH3:2].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[C:23]1([S:29][S:4][N:3]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:1][CH3:2])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1ccccc1
Reactant: CCN(Cc1ccccc1)SN1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: CCN(Cc1ccccc1)SSc1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
N-(N-ethylbenzylaminothio)-phthalimide (6.24 grams, 20 millimoles) was stirred in 100 milliliters of benzene and 2.2 grams (20 millimoles) of benzenethiol was added. The mixture was refluxed one hour, then cooled to room temperature and filtered to remove phthalimide. The filtrate was washed with 10 percent NaOH, then with water, dried (Na2SO4) and concentrated under reduced pressure to afford 5.2 grams (94.5%) of N-(phenyldithio)-N-ethylbenzylamine as a pale yellow liquid.