Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:28]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>ClCCl.CO>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([O:20][CH3:28])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
Boc-Lys(Cbz)-OH (25 g) was dissolved in dichloromethane/methanol=9/1 v/v (500 ml). TBTU (21.1 g) was added and the solution adjusted to pH 8 by addition of triethylamine. The reaction mixture was stirred for 1 h at room temperature. The mixture was washed successively with cold 2N hydrogen chloride solution, water, 5% sodium hydrogencarbonate, and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: ethyl acetate/heptane =1/4 v/v) to yield Boc-Lys(Cbz)-OMe (26.7 g). TLC: Rf=0.79, silica gel, ethyl acetate/heptane=3/1 v/v.
Reaction SMILES: O.[O:2]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Ca+2].O(C1C=C(C(C)C([O-])=O)C=CC=1)[C:22]1C=CC=CC=1.OS(O)(=O)=O>CO>[CH3:22][O:17][C:16](=[O:18])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=1)[CH3:19]
Reactant: CC(C(=O)[O-])c1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)c1cccc(Oc2ccccc2)c1

Procedure:
To a suspension of calcium 2-(3-phenoxy-phenyl)-propionate hydrate (5.00 g, 9.57 mmol) in methanol (150 mL) was added conc. H2SO4 (1.1 mL) and the gelatinous solution heated to reflux for 4 hrs. After cooling, the solution was filtered and evaporated to dryness, the residue dissolved in EtOAc, washed with satd. aq. NaHCO3 soln., dried (MgSO4) and evaporated to yield methyl-2-(3-phenoxy-phenyl)-propionate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.34 (2H, m), 7.26 (1H, m), 7.11 (1H, m), 6.99-7.02 (4H, m), 6.87 (1H, m), 3.70 (1H, q, J=7.2 Hz), 3.67 (3H, s), 1.58 (3H, d, J=7.2 Hz)
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[CH3:6][N:7]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)O)[CH3:8].[Cl:23][Si](C)(C)C.O>C(O)C>[ClH:3].[ClH:23].[CH3:6][N:7]([CH3:8])[CH2:9][C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=S(Cl)Cl
Reactant: CN(C)CC1CCCCC1(O)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)CC1=C(c2cccnc2)CCCC1
Temperature: 62.5 °C

Procedure:
129 ml thionyl chloride were added dropwise to 74.9 g 2-dimethylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride with vigorous evolution of gas, and the mixture was heated at 60 to 65° C. for 2.5 hours, while stirring, and was then concentrated under a water pump. After cooling, first 200 ml water and then 100 ml sodium hydroxide solution (32 per cent strength by weight) were added, the mixture was then extracted twice with 250 ml of a mixture of equal volumes of tetrahydrofuran and ethyl acetate each time, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (48.9 g) was dissolved in 350 ml absolute ethanol, and 57.4 ml chlorotrimethylsilane and 8.1 ml water were added in succession and the mixture was stirred in an ice-bath for 12 hours. The solid which had precipitated out was filtered off with suction, washed with a little absolute ethanol and dried at 90° C. in vacuo (approx. 50 mbar) for two hours. 34.7 g of crude dimethyl-(2-pyridin-3-yl-cyclohex-1-enylmethyl)amine dihydrochloride were obtained. For final purification, 168 g of crude dimethyl-(2-pyridin-3-yl-cyclohex- 1-enylmethyl)amine dihydrochloride prepared according to the above instructions were dissolved in 650 ml of boiling absolute ethanol and crystallized again by cooling in an ice-bath, while stirring. After the crystals had been stirred overnight at room temperature, they were filtered off with suction, washed with a little absolute ethanol and dried at 120° C. in vacuo (approx. 50 mbar) for 4.5 hours. 121 g dimethyl-(2-pyridin-3-yl-cyclohex- 1-enylmethyl)amine dihydrochloride with a melting point of 215 to 218° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.Cl.[F:34][C:35]1[CH:48]=[CH:47][C:38]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH:42]([CH3:46])[CH2:41]2)=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][C:38]2[CH:47]=[CH:48][C:35]([F:34])=[CH:36][CH:37]=2)[CH2:41][CH:42]1[CH3:46])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)/C=C/c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
(E)-3-(2-tert-Butyloxycarbonylamino-5chlorophenyl)-acrylic acid (1.0 g, 3.36 mmol) and EDCl.HCl (645 mg, 3.36 mmol) and racemic 1-(4-fluorobenzyl)-3-methyl-piperazine (Bolos, Jordi et al. J. Med. Chem. (1996), 39(15), 2962-2970) (770 mg, 3.7 mmol) were dissolved in CH2Cl2 (34 ml) and stirred at room temperature for 4 hours. The reaction mixture was purified via chromatography (SiO2, EtOAc/hexanes 1/1) to yield the title compound as colorless foam (1.2 g, 74%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10].O>C1C=CC=CC=1>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CO
Solvent: O
Solvent: c1ccccc1
Product: COCc1ccccc1
Yield: 93 %

Procedure:
To a solution of 1.57 g (10 mmol) of benzyl chloride in 40 ml of benzene, 5.57 g (15 mmol) of the tris(dimethylamino)[tris(dimethylamino)phosphoranilideneamino]phosphonium salt of methanol, said salt having had been synthesized in a similar manner as in Example 1, were added at 0° C., followed by a reaction at room temperature for 3 hours. Water (50 ml) was then added to the reaction mixture to terminate the reaction. An organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, and then concentrated to dryness. The resulting liquid compound was distilled, whereby benzyl methyl ether, the target compound, was obtained as a colorless liquid compound in an amount of 1.13 g. Its yield was 93%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1Br.[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:18]1[CH2:19][CH2:20][C:15]([CH3:24])([CH3:14])[CH2:16][CH:17]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: NC(=O)CCc1ccc(N)c(Br)c1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2N)CC1
Yield: 82.6 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 7, step (d) using 3-(4-amino-3-bromo-phenyl)-propionamide (as prepared in Example 7, step (c), 76.0 mg, 0.351 mmol), and 4,4-dimethylcyclohexen-1-yl boronic acid (59.5 mg, 0.387 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (79 mg, 92%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C17H24N2O, 273.2 (M+H). found 273.2.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 4-bromo-N-(4-hydroxyphenyl)benzamide in DMF (1.3 M), 2.5 eq of imidazole and 1.2 eq of TBDMSCl were added and the solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc. The organic phase was washed with aqueous HCl (1N), saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (95%); MS (ES+) m/z 406 (M+H)+, m/z 408 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B.O1CCCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][N:14]([CH3:16])[CH3:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1CCC(=O)N(C)C
Agent: B
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1CCCN(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropanamide (1.0 g, 3.0 mmol) in THF (40 mL) was added borane-tetrahydrofuran (1.0 M in THF, 8.71 mL) slowly. The reaction mixture was allowed to stir for 3 h at 50° C. The mixture was allowed to cool to rt and then concentrated to dryness. To the residue, a solution of HCl (3.0 M in water, 40 mL) was added. The resulting mixture was allowed to stir for 2 h at 80° C. The mixture was allowed to cool to rt and then was basified to pH>10 with a potassium hydroxide solution. The aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropan-1-amine (0.377 g,40%) as an oil. LCMS (FA): Rt=1.03 min, m/z=273.1 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][CH:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1.Cl>ClC=CCl>[C:5]([C:18]1[CH:17]=[CH:16][C:14]2[S:15][CH:11]([CH3:10])[CH2:12][C:13]=2[CH:19]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CC1Cc2ccccc2S1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CC(C)S2
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To 0.15M of aluminum chloride, 0.11M of propionyl chloride and 150 ml of 1,2-dichloroethylene, 0.1M of 2-methyl2,3-dihydrobenzo[b]-thiophene (prepared according to method of Petropoulos, J. Am. Chem. Soc., 75, 1130, 1953) are added slowly, temperature being maintained at ±10° C. After addition, the mixture is still stirred for 3 hours at room temperature, then a mixture of ice and HCl is added. The mixture is extracted with 1,2-dichloroethylene, dried on MgSO4 and solvent is evaporated. The oily residue as stripped in vacuum. 14 gr. of 5-propionyl-2-methyl-2,3-dihydrobenzo[b]thiophene are so obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH3:14]>C1COCC1.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:14])=[O:12]
Reactant: N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of Naphthalene-2-carbonyl chloride obtained from Step A was dissolved in THF (30 mL) and this was cooled down to 0° C. Ammonia gas was passed for approximately 1.5 hrs through the solution and the reaction was stirred at room temperature under a closed system for 4 hrs. A white solid precipitate was observed in the reaction mixture. The reaction mixture was dissolved in ethyl acetate and washed using water followed by brine solution. The organic layer was separated and dried over sodium sulphate and the volatiles were evaporated off in vacuo to afford the crude product.
Reaction SMILES: C[O:2][CH2:3][CH2:4]OC.C([Zn]CC)C.ICI.[Br:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/CO)=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:23][C@@H:4]2[CH2:3][OH:2])=[CH:18][CH:17]=1
Reactant: COCCOC
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogen atmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9 mL, 469 mmol). The product from Example 34C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10 minutes. The temperature was maintained from −5° to −10° C. throughout the additions. The product from Example 34A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 hours. It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether. The organic layers were combined and treated with NaOH (2N, 880 mL). To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes. The organic layer was separated, washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, dried and concentrated. The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+. (ee 94%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si](C)(C)N[Si](C)(C)C.[Li].C([O:27][C:28](=O)[C:29]([F:32])([F:31])[F:30])C>C(COC)OC>[O:1]=[C:2]1[CH:7]([C:28](=[O:27])[C:29]([F:32])([F:31])[F:30])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
5.0 g (25 mmol) of t-butyl 3-oxopiperidin-1-carboxylate was dissolved in dimethoxyethane, and the resulting solution was cooled to −78° C., then 30 mL (30 mmol) of lithium hexamethyldisilazane (LHMDS, 1M in THF) was dropwise added and stirred for about 1 hour, followed by dropwise addition of 3.9 mL (33 mmol) of ethyltrifluoroacetate. After stirring for 1 hour, a dryice/acetone bath was removed and then further stirred for about 2 hours and 30 minutes with the reaction solution being heated to room temperature. After the reaction solution was washed with a saturated aqueous ammonium chloride, extraction was conduced three times with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, then the residue was purified by column chromatography (20:1 dichloromethane:methanol) to give 6.0 g of the title compound in a yield of 81%.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1
Reaction time: 3 h

Procedure:
0.150 g ethyl trans-4-[4-(E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoate (0.42 mmol, 1 eq.) is dissolved in 3 mL of a 2/1 mixture of THF/methanol. At 0° C., 0.07 g of lithium hydroxide monohydrate (1.67 mmol; 4 eq.) is added with stirring. After 3 hours at room temperature, the reaction medium is evaporated and aqueous 6% sulfur dioxide solution is added. The precipitate is filtered off and washed with water to give 0.085 g of trans-4-[4-(E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][O:54][CH3:55])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:55][O:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: COCOc1ccc(OB([O-])[O-])cc1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (500 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(methoxymethoxy)phenyl borate (262 mg) and potassium carbonate (292 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was stirred 100° C. for 9 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) to give 7-(4-methoxymethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 86) (340 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][CH:20]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[I:28]Cl>C(O)(=O)C.O>[I:28][C:20]1[CH:19]=[N:18][N:12]2[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=3)=[N:10][C:11]=12
Reactant: FC(F)c1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)c1cc(-c2cccc(C(F)(F)F)c2)nc2c(I)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a stirred solution of 5-(3-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (6.35 g, 20.3 mmol) in acetic acid (30 mL) was added at room temperature sodium acetate (1.88 g, 22.9 mmol) and drop wise a solution of iodine monochloride (3.72 g, 22.9 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (300 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (8.47 g, 95%) as a yellow solid. MS (EI) 439.0 [(M)+]; mp 130° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][C:3]=1[F:29].C([Sn](CCCC)(CCCC)[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=[C:3]([F:29])[CH:4]=1)[CH3:28]
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cscn2)c(F)c1
Yield: 77.1 %

Procedure:
A mixture of 5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide (450 mg, 0.912 mmol), 4-tributylstannyl-1,3-thiazol (410 mg, 1.095 mmol), tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol), lithium chloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirred at reflux for 17 h. After cooling, the mixture was diluted with ethyl acetate, washed with water. The organic layer was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:3/1:2) to afford 350 mg (77.1%) of the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([Cl:28])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:28].[CH3:9][C:10]1[C:11]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(N2CCc3ccccc3[C@@H]2C)nc(Cl)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3[C@@H]2C)nc(Nc2ccc(F)cc2)c1C
Product: Cl
Yield: 46 %

Procedure:
After 4-fluoroaniline(0.6 ml, 6.3 mmol) was added to mixture solution of (S)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-4-chloropyrimidine(0.85 g, 3.0 mmol) prepared in Step 2 of Example 62 and dimethylformamide (10 ml), 0.55 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1.O>CS(C)=O>[C:17]1([C:8]2[N:7]=[C:6]([CH2:5][C:1]#[N:2])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1nc(-c2ccccc2)nn1-c1cccnc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)nn1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of potassium cyanide (30.7 mg, 472 μmol) and 3-(5-(bromomethyl)-3-phenyl-1H-1,2,4-triazol-1-yl)pyridine (124 mg, 393 μmol) in DMSO (3 mL) was stirred at RT for 2 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with water and brine, dried, filtrated and evaporated. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (47 mg with 80% purity, 180 μmol, 36.6%).