Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccccc2n2c(C(F)(F)F)nnc12

Procedure:
A mixture consisting of 700 mg. (0.0025 mole) of 4-chloro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline (prepared as described above) and 560 mg. (0.0075 mole) of diethylamine (0.8 ml.) in 10 ml. of N,N-dimethylformamide was stirred at room temperature overnight and then poured over ice. The resulting mixture was then filtered and the recovered solid product washed with water and then dissolved in ethyl acetate. The latter organic solution was next washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was ultimately obtained a light yellow solid which after recrystallization from diethyl ether gave pure 4-diethylamino-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline. The yield of the first crop melting at 155°-157° C. amounted to 260 mg. (34%), while the yield of the second crop melting at 153°-156° C. amounted to 170 mg. (22%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[N:18][N:17]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:16]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CC(=O)OC(C)(C)C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (500 mg) and tert-butyl bromoacetate (225 mg) in N,N-dimethylformamide (7.5 ml) was added potassium carbonate (390 mg), and the mixture was stirred at 60° C. for 7 hours. Water was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane (1:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(tert-butoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[F:21].[C:22](=[O:24])=[O:23]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Fc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:8][CH:7]=2)=[O:15])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Anhydrous aluminum chloride (80.0 g, 0.60 mol) was added to a stirred solution of terephthaloyl chloride (50.8 g, 0.25 mol) dissolved in fluorobenzene (235 ml, 2.5 mol) over a 10-15 minute period. The mixture was stirred at room temperature for one hour and then maintained at 70°-80° C. for four hours. After cooling, the reaction mixture was poured onto approximately 1000 g of ice containing 100 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 100° C. The crude solid was recrystallized from approximately 2000 ml of toluene to afford 70.7 g (88% yield) of 1,4-bis(4-fluorobenzoyl)-benzene; mp 218.5°-219.5° C.; Anal. Calcd for C20H12F2O2 : C, 74.53%; H, 3.75%; F, 11.179%. Found: C, 74.60%; H, 3.80%; F, 11.83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(#N)C>[CH:24]1([CH2:23][N:13]2[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]2=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc(=O)n(CC3CCCCC3)c2)cc1
Yield: 31.4 %

Procedure:
According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 0.35 mmol, 70 mg, Example 7 Step 1) in acetonitrile (2 mL) were added K2CO3 (10 eq, 3.50 mmol, 0.48 g) and (bromomethyl)cyclohexane (10 eq, 3.50 mmol, 0.49 mL). The reaction was microwaved for 10 minutes at 180° C. The reaction was allowed to cool. The reaction was then filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using CH2Cl2/AcOEt (80/20, Rf=0.3). The product was further purified by reverse phase C18 column using water/acetonitrile 60/40 to afford 1-(cyclohexylmethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.11 mmol, 32 mg, 31%) as a colorless oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].C([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13][C:14]1[C:15](Cl)=[N:16][C:17]([CH3:21])=[N:18][C:19]=1[Cl:20])(=O)C>CO>[Cl:20][C:19]1[C:14]([N:13]=[C:9]2[NH:8][CH2:12][CH2:11][NH:10]2)=[C:15]([O:2][CH3:1])[N:16]=[C:17]([CH3:21])[N:18]=1
Reactant: C[O-]
Reactant: CC(=O)N1CCNC1=Nc1c(Cl)nc(C)nc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc(C)nc(Cl)c1N=C1NCCN1

Procedure:
The final product, 4-chloro-N-(imidazolin-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine is synthesized by first preparing sodium methoxide in situ from anhydrous methanol and sodium. The fifth intermediate, N-(1-acetylimidazolin-2-ylidene)-4,6-dichloro-2-methyl-5-pyrimidinamine, is added and the reaction mixture brought to a boil. From 15 minutes to 1 hour after the reaction mixture is brought to a boil, further sodium methoxide is added and the reaction mixture is maintained at a boil for from 15 minutes to 1 hour to afford 4-chloro-N-(imidazolin-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20]([C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:15])[F:16])[C@H:10]([O:17][C:27]2[N:26]=[N:25][C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[C:29]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(F)F)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a stirred solution of (±)-trans-4-difluoromethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.52 mmol, 0.13 g) in anhydrous THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (1.08 mmol, 0.043 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.43 mmol, 0.15 g) in anhydrous THF (1 mL). After completion of addition, the reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction was quenched with water (2 mL). The reaction was then extracted with ethyl acetate (5 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to give (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-4-difluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (0.18 g). LCMS: m/z 561 [M+1].
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCC1CC1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCC1CC1
Temperature: 80 °C

Procedure:
2-bromo-pyridin-3-ol Compound 1a (6.4 g, 36.8 mmol) was dissolved into DMF (100 mL), then bromomethyl-cyclopropane Compound 1b (5.0 g, 37 mmol) and K2CO3 (7.5 g, 54.3 mmol) were added. The mixture was stirred and heated at 80° C. for 2 hrs. Excess DMF was removed on a rotary evaporator. The brown residue was mixed with Et2O (150 mL), then washed with H2O and dried over Na2SO4. The solvent was evaporated from the dry solution to provide 2-bromo-3-cyclopropylmethoxy-pyridine Compound 1c (7.04 g, yield 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=2)[N:7]=1)[CH:9]1[CH2:25][CH2:24][C:12]2([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a suspension of tert-butyl 8-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.30 g, 0.79 mmol) in n-BuOH (4.0 mL) were added 1-methyl-1H-pyrazol-4-amine hydrochloride (0.21 g, 1.58 mmol) and DIPEA (0.41 g, 3.15 mmol). The mixture was stirred in a sealed tube at 150° C. overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a yellow solid (0.22 g, 63%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C(Cl)Cl>[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CC(C)(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of ethyl 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]butanoate (15.4 g, 0.0347 mol) in THF (151 mL) at −78° C. was added 1.00 M diisobutylaluminum hydride in DCM (84.5 mL) dropwise. The reaction was stirred for 2 hours with slow warming to −10° C. The mixture was quenched with water, then was treated with potassium sodium tartrate tetrahydrate and water. The mixture was stirred for 1 hour, then was extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (13.8 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=O)[CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[S:50])[CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=S)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Temperature: 50 °C

Procedure:
(S)-N-[1-(tert-Butoxycarbonyl)pyrrolidin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]acetamide, as described above in Step C, (1.27 g, 2.37 mmol) was dissolved in toluene (20 mL), Lawesson's Reagent (478 mg, 1.18 mmol) was added and the reaction mixture was heated to 50° C. for 5 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 5% MeOH—0.1% to 0.5% NH4OH, to yield the above-titled compound.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])=[O:6].Cl>C1COCC1.CCOC(C)=O>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[NH:7][C:5](=[O:6])[CH2:4][NH:2][CH3:1]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCC(=O)Nc1c(C)cccc1C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, methylamine (600 mmols) in 300 mL THF was cooled to 0° C. A solution of 2-chloro-N-(2′,6′-dimethylphenyl)acetamide (100 mmols) was dissolved in 200 mL THF, and slowly dripped into the cold methylamine solution. The reaction was stirred overnight. The reaction was filtered, and the filtrate evaporated to yield an oily residue. This was dissolved in EtOAc (100 mL) and treated with 1N HCl (200 mL). The aqueous layer was washed with EtOAc, then basified to Ph 10-12 with 6 N NaOH. The product was extracted into EtOAc (2×50 mL), the organic phase was dried, and the solvent was evaporated to yield N-(2,6-dimethyl-phenyl)-2-methylamino-acetamide (compound (23)) as an oil (12.8 gm; 67% yield).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.9 %

Procedure:
Add triethylamine (28.6 mL, 205 mmol) dropwise to a mixture of 2-fluoro-5-methylphenol (5.18 g, 41.1 mmol), copper(II) acetate (7.46 g, 41.1 mmol), phenylboronic acid (10.0 g, 82.1 mmol), powdered 4 Å sieves (7 g), and methylene chloride (400 mL). Stir at ambient temperature. After 22 h, filter and concentrate the filtrate. Purify the residue by silica gel chromatography (50% methylene chloride/hexanes), concentrate and purify again by silica gel chromatography (100% hexanes) to give 2.4 g (29%) of the title compound: MS(m/e): 202 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[CH3:20][CH2:21]N(CC)CC>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].CCO>[F:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([CH:20]=[CH2:21])[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cc2F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Product: C=Cc1cc(C(=O)OC)cc(-c2ccc(C)cc2F)c1
Temperature: 140 °C
Yield: 693.3 %

Procedure:
To Biotage Advancer MW reactor was charged methyl 5-bromo-2′-fluoro-4′-methylbiphenyl-3-carboxylate (20 g, 61.9 mmol), PdCl2(dppf) (0.20 g, 0.273 mmol), potassium vinyl trifluoroborate (12.4 g, 93 mmol), Et3N (13.0 ml, 93 mmol) and EtOH (150 ml). The reactor was sealed and heated at 140° C. for 10 min followed by flash cooling. Removed mixture from the cooling reservoir via vacuum and reaction repeated 5× (120 g, 371 mmol processed). All runs were combined and concentrated to dryness. The crude was partitioned between water and dichloromethane. The layers were separated and the aqueous extracted 2× w/DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated via rotary evaporation to give 116 g amber oil. The crude was purified by automated silica gel chromatography (750 g SiO2, EtOAc/hexanes) to give nearly colorless oil which solidified to white solid upon cooling (99.7 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(5-(4-Bromophenyl)thien-2-yl)-3-(2,3-dichloro-4-hydroxyphenyl)prop-2-en-1-one is dissolved in dichloromethane (0.7 g, 1.5 mol/L). Triethylsilane (2.1 eq.) and trifluoroacetic acid (8 eq.) are successively added dropwise. After stirring for 16 hours at room temperature, the reaction mixture is washed with water and then the dichloromethane is removed by evaporation under reduced pressure. The evaporation residue is purified by silica-gel chromatography
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([S:18][C@@H:16]([CH3:17])[C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:29])[CH3:28]
Reactant: C[C@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)S[C@@H](C)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dichloromethane (1 ml) was added (2S,3S)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (3 mg), followed by addition of a dichloromethane solution of triethylamine (10%, 16 μl) with ice-cooling. Then, a dichloromethane solution of acetyl chloride (10%, 8.2 μl) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (1×1 cm) using ethyl acetate-hexane (2:1) as the eluent. The desired fraction was concentrated to give (2S,3S)-3-acetylthio-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 44:1.2 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Product: CCC(CC)(c1ccc(NS(=O)(=O)C(F)(F)F)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1

Procedure:
The title compound is prepared from 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one and trifluoromethane sulfonyl chloride using a procedure analogoues to Example 17 (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:19]([O:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3,5-dichlorophenol (1.63 g, 10 mmol) and imidazole (1.50 g, 22 mmol) in DMF (10 mL) was cooled to 0° C. then TBDMSCl (1.66 g, 11 mmol) was added. After the addition, the solution was warmed up to ambient temperature and stirred for 10 min. The solution was re-cooled to 0° C. and the mixture was quenched with water. The aqueous layer was extracted with Et2O and the combined organic layers were washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (15:1) as eluent to give tert-butyl-(3,5-dichlorophenoxy)-dimethylsilane as a pale yellow solid.