Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH2:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:27](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])=[N-:28]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)CC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of allyl acetoacetate (226.5 g, 1.594 mole) in 3 l acetonitrile and triethylamine (243.4 ml, 1.753 mole), there was added p-toluenesulfonyl azide (345.3 ml, 1.753 mole) over a 1 hour period while keeping the temperature at ~20° C. with a cooling bath. The reaction mixture became yellow. The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 18 hours. The mixture was concentrated on a rotary evaporator. The residue was dissolved in diethyl ether (2.6 l) and 1M aqueous KOH (800 ml). The organic phase was washed five times with 1M KOH (500 ml) and once with brine (400 ml). After drying over MgSO4 and concentration on a rotary evaporator (temp. ≤30° C.), there was obtained 260.2 g (97%) of the title product.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[N:3]=1>CO.[Pd]>[O:1]=[C:2]1[NH:3][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[NH:7]1
Reactant: COC(=O)c1cc(C(=O)OC)nc(O)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CC(C(=O)OC)NC(=O)N1
Yield: 87.7 %

Procedure:
Dimethyl 2-hydroxypyrimidine-4,6-dicarboxylate (1.42 g. 6.7 mmol) was dissolved in methanol (300 ml) and hydrogenated over 10% Pd/C catalyst. The reaction mixture was filtered and the methanol removed under reduced pressure. The crude product was recrystalized from methanol/ether to yield (4R*, 6R*)-dimethyl 2-oxo-hexahydropyrimidine-4,6-dicarboxylate (1.27 g, 88%) as colourless needles m.p. 178°-179°.
Reaction SMILES: [CH2:1]([O:19][CH2:20][C:21]([CH2:58][O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])([CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:37])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:78][C:79]1[CH:84]=[CH:83][C:82]([Mg]Br)=[CH:81][CH:80]=1>C1COCC1>[CH2:40]([O:39][CH2:38][C:21]([CH2:58][O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:82]3[CH:83]=[CH:84][C:79]([Cl:78])=[CH:80][CH:81]=3)([OH:37])[C:26]=2[CH:25]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc2c(c1)C(O)(c1ccc(Cl)cc1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Under a nitrogen atmosphere, 2-(3-octadecyloxy-2,2-bis-octadecyloxymethyl-propoxy)-9-fluorenone (75 mg, 73 μmol) was suspended in THF (1 ml) to allow dissolution at 50° C. 4-Chlorophenylmagnesium bromide solution (0.15 ml, 0.15 mmol) was added dropwise, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with chloroform (3 ml), and washed 3 times with 1N hydrochloric acid (1 ml), 3 times with 5% NaHCO3 solution (1 ml) and once with 20% NaCl solution (1 ml). The organic layer was dried over Na2SO4, the solvent of the filtrate was evaporated, and the obtained residue was separated and purified by silica gel column chromatography and crystallized from methanol (1 ml) to give 2-(3-octadecyloxy-2,2-bis-octadecyloxymethyl-propoxy)-9-(4-chlorophenyl)-9-fluorenol (66 mg, 56μ mmol, 77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([Br:34])=[CH:24][N:25]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc2ncc(Br)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A solution of [6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (543 mg, 1.38 mmol) in DMF (5 mL) was cooled to 0° C., treated with NBS (222 mg, 1.25 mmol), and stirred at 0° C. for 1 h. The reaction mixture was diluted in AcOEt and washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→6:4) to yield the title compound (435 mg, 0.92 mmol, 67%) as a beige foam. MS: 472 [M+1]+; HPLC: AtRet=1.93; TLC: RF 0.50 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)C>CN(C=O)C>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=1)[CH3:13]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Nc1nc(OCOC(=O)C(C)(C)C)ncc1F
Yield: 9.3 %

Procedure:
N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and chloromethyl pivalate (90 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was treated with diethyl ether (3-4 mL) to produce a solid. The solid was removed and the ether solution was placed onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 14 mg, 0.05 mmol (9%) of the title compound as a white solid: mp 86-88° C.; 1H NMR (CDCl3) δ 8.73 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 6.04 (s, 2H), 3.20 (s, 3H), 3.18 (s, 3H), 1.16 (s, 9H); HPLC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: FC1C2C(=CC=CC=2)C=CC=1.[K].[CH3:13][N:14]([CH2:16][CH2:17][CH:18]([O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)C.ClC(OC1C=CC=CC=1)=O.ClC(OCC(Cl)(Cl)Cl)=O.C(=O)([O-])N>[Zn].C(O)=O>[CH3:13][NH:14][CH2:16][CH2:17][CH:18]([O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: Fc1cccc2ccccc12
Agent: NC(=O)[O-]
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O=CO
Product: CNCCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.
Reaction SMILES: [OH-].[Na+].BrBr.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15](=[O:17])C.[O-:18]S([O-])=O.[Na+].[Na+].Cl>O.O1CCOCC1>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]([OH:17])=[O:18]
Reactant: O=S([O-])[O-]
Reactant: COc1cc(SC)ccc1C(C)=O
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(SC)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Sodiumhydroxide (11.0 g, 275 mmol) was dissolved in water (70 ml) and cooled to 0° C. Bromine (3.5 ml, 68.7 mmol) was added, and after 15 min a cold solution of 1-[2-methoxy-4-(methylthio)phenyl]ethanone in dioxane (140 ml) was added dropwise during 20 min. The reaction mixture was stirred at 0° C. for 2.5 h. Na2SO3 (10 g dissolved in 50 ml water) was added and after 10 min the reaction mixture was acidified with an aqueous HCl (10%). The aqueous phase was extracted with EtOAc and the combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give an oil (5.7 g) of the title compound. Some sulfoxide and sulfonyl compound are also observed. 1H-NMR (400 MHz, MeOH): δ 7.77 (1H, d, J 8.4 Hz), δ 6.91 (1H, s), δ 6.84 (1H, dd, J1 8.0 Hz, J2 1.2 Hz), δ 3.96 (3H, s), δ 2.53 (3H, s).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]([OH:31])[CH2:14][N:15]2[CH2:20][CH:19]=[C:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.OC1C=CC(C(O)C[N:46]2CCC(N3C4C=CC=CC=4NC3=O)CC2)=CC=1C(OC)=O>>[ClH:1].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]([OH:31])[CH2:14][N:15]2[CH2:20][CH:19]=[C:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:9][C:4]=1[C:5]([NH2:46])=[O:7]
Reactant: COC(=O)c1cc(C(O)CN2CC=C(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Reactant: COC(=O)c1cc(C(O)CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Agent: Cl
Product: NC(=O)c1cc(C(O)CN2CC=C(n3c(=O)[nH]c4ccccc43)CC2)ccc1O

Procedure:
Following essentially the same procedure but substituting methyl 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]benzoate hydrochloride for the methyl 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)piperidino]ethyl]benzoate hydrochloride above results in the formation of 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]benzamide hydrochloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: BrCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A solution of 6-bromohexanoyl chloride (49.7 g, 0.233 mol) in dry dichloromethane (40 ml) was added dropwise over 5 minutes to a suspension of aluminium chloride (31.0 g, 0.233 mol) in dry dichloromethane (100 ml), keeping the temperature between 20° C.-23° C. The mixture was stirred for 30 minutes at room temperature to give a yellow solution. Benzene (18.2 g, 0.233 mol) in dry dichloromethane (30 ml) was added and stirred for 20 hours at room temperature. Triethylsilane (59.9 g, 0.515 mol) was added over 10 minutes, maintaining the temperature between 25° C.-35° C. The solution was stirred for 60 minutes at room temperature. This was then poured onto ice/water (200 g). A partial separation was achieved and the organic layer was washed with brine and water several times until the pH of the solution was neutral. The organic solution was dried (MgSO4) and evaporated under reduced pressure to a yellow oil. This was distilled under reduced pressure at 90° C.-110° C./0.5 mbar to give colourless oils. The relevant fractions were combined and purified by flash chromatography on silica gel using hexane to give 6-bromo-1-phenylhexane as a colourless oil (18.33 g, 33%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:24][C:25]([F:30])([F:29])[CH:26]([NH2:28])[CH3:27]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(N)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C(F)(F)F)cn1
Yield: 47 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2,2,2-trifluoro-1-methyl-ethylamine (ABCR FO7820EFA) instead of methylamine, to the title compound (66 mg, 47%) which was obtained as a light yellow solid. MS: m/e=404.5 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:17]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1Oc1ccccc1-c1ccccc1
Temperature: 70 °C
Yield: 89 %

Procedure:
A suspension of 5-bromo-2-fluorobenzonitrile (6.48 g, 32.4 mmol), 2-phenylphenol (5.79 g, 34 mmol) and potassium carbonate (4.92 g, 35.6 mmol) in DMF (50 ml) was heated at 70° C. for 3 hours. The reaction was cooled and quenched by the addition of water (200 ml) followed by extraction with tBuOMe. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Heptane 5:95 to 15:85) to furnish 10.1 g of the desired compound. LCMS Rt=1.78 min MS m/z 349 [M]+ 1HNMR (d6-DMSO): δ 6.6 (m, 1H), 7.2-7.6 (m, 9H), 7.65 (m, 1H), 8.0 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:14][C:12]([O:11][CH3:10])=[O:13]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (2.44 g) in toluene (25 ml) was added methoxycarbonylmethylene-triphenylphosphorane (6.68 g) and the mixture was stirred for 3 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluting with ethyl acetate - n-hexane (1:1)] to give methyl 3-(2-hydroxyphenyl)acrylate (2.47 g).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[N:14][C:13]([C:18]2[C:19]([CH3:26])=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:12]([CH2:27][CH3:28])[N:11]=1)[CH3:2].Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.CC(C)([O-])C.[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.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]>[CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:6][C@H:5]1[NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[N:14][C:13]([C:18]2[C:19]([CH3:26])=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:12]([CH2:27][CH3:28])[N:11]=1)[CH3:2]
Reactant: Brc1ncccn1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Solvent: C1COCCO1
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Temperature: 100 °C
Yield: 52 %

Procedure:
To a solution of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine (112 mg) in dioxane (1.45 ml) was added 2-bromo-pyrimidine (69 mg, 1.5 eq.), 1,3 Bis(2,6-di-i-propylphenyl)imidazolium chloride (20 mg, 0.16 eq.), Tris(dibenzylideneacetone)dipalladium (21 mg, 0.8 eq.) and potassium t-butoxide (49 mg, 1.5 eq.). The reaction mixture was heated at 100° C. for 16 h, poured into saturated sodium bicarbonate (50 ml), extracted 2×50 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Purification via MPLC chromatography eluting with 20–50% ethyl acetate/heptane provided the title compound as an amorphous solid (70 mg, 52%):
Reaction SMILES: CSC.B.[F:5][C:6]([F:14])([F:13])[C:7]1([C:10](O)=[O:11])[CH2:9][CH2:8]1>C1COCC1>[F:5][C:6]([F:14])([F:13])[C:7]1([CH2:10][OH:11])[CH2:9][CH2:8]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCC1(C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
50 mL of borane dimethylsulfide 2M in THF were added dropwise at RT via an addition funnel to a solution of 1-trifluormethyl-cyclopropanecarboxylic acid (10 g, 64.90 mmol) in 100 mL of THF. The resulting clear solution was stirred at 40° C. for 24 hours before being cooled to 0° C. and quenched by slow addition of aqueous saturated NH4Cl. The biphasic slurry was filtered through celite. The organic layer was separated, and the aqueous layer was back extracted twice with AcOEt. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 7 g of (1-trifluoromethyl-cyclopropyl)-methanol (77% yield). Used as in the next step.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1>>[NH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 96.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.89 min, m/z=445.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[Br:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](Cl)=[O:43]>CCCCCC>[Br:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:6][CH:7]=1)=[O:43]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a 200 mL three-neck flask was added 5.0 g (12 mmol) of 9-(4-bromophenyl)-10-phenylanthracene. The air in the flask was replaced with nitrogen. Then, 65 mL of tetrahydrofuran was added thereto, and the temperature of the mixture was set to −80° C. Into this solution was dripped 8.1 mL (13 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) with a syringe. After that, this solution was stirred at the same temperature for 1 hour. Then, 2.8 g (13 mmol) of 3-bromobenzoyl chloride was added to this solution, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. Then, an organic substance was extracted from the aqueous layer of this mixture with ethyl acetate, and the solution of the extract and the organic layer were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The obtained filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (with a developing solvent of hexane and toluene in a 5:1 ratio) to give 1.8 g of a light-yellow solid in a yield of 28%. A reaction scheme of the above synthesis method is illustrated in the following (H-1).
Reaction SMILES: CC([Si](C)(C)[O:6]C1CC(CCC2C3C(=CC(C)CC3O)C=CC2C)OC(=O)C1)(C)C.[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1>[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38]([OH:6])=[O:39])=[CH:34][CH:33]=1
Reactant: CC1C=C2C=CC(C)C(CCC3CC(O[Si](C)(C)C(C)(C)C)CC(=O)O3)C2C(O)C1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (1S-(1α(4R*,6R*),2α,6β,8β,8aα]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one in an amount of 1.00 g (2.29 mmol), 18.6 ml of dry pyridine, 1.40 g (1.15 mmol) 4-N,N-dimethylaminopyridine and 5.34 g (22.9 mmol) of 2-(4-chlorophenoxy)-2-methylpropionyl chloride was heated at 50° C. for 63/4 hour, then stirred overnight at room temperature. Ice chips were then added, and after 30 min the mixture was poured into ice water and extracted four times with diethylether. The combined ether layers were washed with water, then washed with 0.1M H2SO4 and then dried over a conventional drying agent, preferably anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure (i.e. below atmospheric pressure, preferably around 30 mm). The residue was dissolved in diethylether, washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure to leave 1.6 of 2-(4-chlorophenoxy)-2-methylpropionic acid-[1S-[1α,3α,7β,8β(2R*,4R*),8aβ]]-8-[2[tetrahydro-4 -[[(1,1-dimethylethyl)dimethylsilyl]oxy]6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester as a brown oil which was used directly without further purification.