Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:12]([NH2:13])[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[CH:20][C:17]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[ClH:53]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[ClH:53].[ClH:53].[C:1]1([C@H:7]2[C@@H:12]([NH:13][CH2:18][C:17]3[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[CH:22]=[CH:23][C:16]=3[O:15][CH3:14])[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(-c2ccccc2C(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccccc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 10 ml of methylene chloride were suspended 176 mg of (±)-cis-2-phenylpiperidin-3-ylamine, 280 mg of 2-methoxy-5-(2-trifluoromethylphenyl)benzaldehyde, 424 mg of sodium triacetoxyborohydride and 0.2 ml of acetic acid. This reaction mixture was stirred at room temperature for 16 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give a colorless oily product. This product was dissolved in ethyl acetate, and treated with an ethyl acetate solution of 4N hydrochloric acid. The precipitated white crystals were collected by filtration and washed with ethanol, and dried under reduced pressure to give 243 mg of [(±)-cis-2-phenylpiperidin-3-yl][2-methoxy-5-(2-trifluoromethylphenyl)benzyl]amine dihydrochloride.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:23]([O:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:20])=[C:6]1[CH3:21].BrCC1C=CC([Cl:48])=C(C=1)O[C@@H](C)C(OC)=O>>[Cl:48][C:24]1[CH:25]=[CH:2][C:3]([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:12]=3)[C:7]([CH3:20])=[C:6]2[CH3:21])=[CH:22][C:23]=1[O:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C)Oc1cc(CBr)ccc1Cl
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cc(O[C@@H](C)C(=O)OC)ccc1Cl
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(Cl)c(O[C@@H](C)C(=O)OC)c1

Procedure:
The title compound was prepared following the same general protocol as described for the synthesis of the (S)-allyl 1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (Step 3, Example 26), using the (S)-methyl 2-(5-(bromomethyl)-2-chlorophenoxy)propanoate instead of the (S)-methyl 2-(3-(bromomethyl)-4-chlorophenoxy)propanoate ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=3)[CH:17]=2)[N:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56]O)[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:27]=[CH:26][C:25]([O:28][CH2:56][CH2:55][N:52]4[CH2:53][CH2:54][O:49][CH2:50][CH2:51]4)=[CH:24][N:23]=3)[CH:17]=2)[N:10]=1
Reactant: O=C(Cc1cccc(-c2ncc(O)cn2)c1)N1CCC(c2cc(Cl)ccc2Cl)=N1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1)N1CCC(c2cc(Cl)ccc2Cl)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6.2 A suspension of 108 mg (0.253 mmol) of 1-[3-(2,5-dichlorophenyl)-4,5-dihydropyrazol-1-yl]-2-[3-(5-hydroxypyrimidin-2-yl)phenyl]ethanone, 100 mg (0.38 mmol) of triphenylphosphine and 64.4 μl of 2-morpholinoethanol in 0.5 ml of THF is cooled in an ice bath, and 74 μl (0.38 mmol) of diisopropyl azodicarboxylate are slowly added dropwise. The reaction mixture is stirred at room temperature for 16 hours. The mixture is evaporated and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 1-[3-(2,5-dichlorophenyl)-4,5-dihydropyrazol-1-yl]-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]phenyl}-ethanone (“A8”) as colourless crystals; ESI 540;
Reaction SMILES: [Cl:1][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10]([CH3:12])=[CH:11][C:3]=12.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10]([CH3:12])=[C:11]([C:28](=[O:29])[CH2:27][Cl:26])[C:3]=12
Reactant: Cc1cc(C)c(-n2c(C)cc3c2=NC(C)NC=3Cl)c(C)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(-n2c(C)c(C(=O)CCl)c3c2=NC(C)NC=3Cl)c(C)c1

Procedure:
Compound (6) (11.2 g, 37.4 mmol) was added to a chloroform solution (150 ml) or 20 equivalents of aluminum chloride and 25 equivalents of chloracetyl chloride. The solution was heated at reflux for 16 hrs. The organic layer was departed and the water layer extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to yield compound (7).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[N:11]=[C:10]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1>CO>[CH3:1][O:2][C:6]1[N:11]=[C:10]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1
Reactant: CCC(CC)Nc1nc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCC(CC)Nc1nc(OC)nc(C(C)C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of sodium methylate in methanol (prepared from 1.2 g (50 m-moles) of sodium in 50 ml of methanol) is added to 14.4 g (50 m-moles) of 2-chloro-4-(3-pentylamino)-5-nitro-6-isopropyl-pyrimidine in 100 ml of methanol and the mixture is stirred for 1 hour. The solvent is distilled off and the residue is suspended in water and extracted with ether. The ethereal extracts are dried over MgSO4 and evaporated to yield 14 g of 2-methoxy-4-(3-pentylamino)-5-nitro-6-isopropyl-pyrimidine as an oil (nD20 : 1.5412).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[N:31]=[C:30]([F:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C.[F:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([NH:64][CH:65]([C:67]3[N:68]([C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)[C:69](=[O:78])[C:70]4[C:75]([CH:76]=3)=[CH:74][CH:73]=[CH:72][C:71]=4[CH3:77])[CH3:66])[N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[CH:51][N:50]=1>CCCCO>[F:32][C:30]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:31]=1.[F:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([NH:64][CH:65]([C:67]3[N:68]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)[C:69](=[O:78])[C:70]4[C:75]([CH:76]=3)=[CH:74][CH:73]=[CH:72][C:71]=4[CH3:77])[CH3:66])[N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[CH:51][N:50]=1
Reactant: Fc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: Cc1cccc2cc(C(C)N)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc(C(C)Nc3nc4cnc(F)nc4n3C3CCCCO3)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (200 mg, 0.72 mol), 6-chloro-2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound 5202) (369 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the desired product, 3-(1-(2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (167 mg, 47% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>CN(C)C=O.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>[CH2:15]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: COc1cc(Br)cc2ccoc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(OC)c2occc2c1

Procedure:
A solution of 10 g (0.044 mol) of 5-bromo-7-methoxybenzo[b]furan, 17.5 g (0.053 mol) of allyltributyltin and 1.02 g (0.00088 mol) of tetrakis(triphenylphosphine)palladium(0) in 80 ml of dimethylformamide is heated at 90° C. for 15 hours under an inert atmosphere. After returning to room temperature, the dimethylformamide is evaporated off in vacuo. The reaction mass is taken up in 200 ml of diethyl ether and washed in succession with 100 ml of water and 100 ml of a saturated sodium chloride solution. Customary treatment of the organic phase yields an oil, which is purified by chromatography on a silica column using a dichloromethane/heptane (6/4) mixture as eluant.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>>[CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=[C:32]([F:31])[CH:33]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 2-(5-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3-fluoro-5-trifluoromethylphenyl-boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[BH4-].[Na+]>>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([OH:22])[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C(CCn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Product: OC(CCn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Yield: 72 %

Procedure:
Following the procedure of Example 14, 1-(9H-fluoren-2-yl)-3-(1H-imidazol-1-yl)-1-propanone was reduced with sodium borohydride to provide a 72% yield of the title product, m.p. 143.5°-145.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC1(c2ccc(F)c(F)c2)CCCCC1
Reaction time: 6 h

Procedure:
To a solution of (E)-ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)acrylate (Int. 3-C, 550 mg, 1.869 mmol) in MeOH (20 mL) was added ˜150 mg of 10% Pd/C (wet, 50%), and the mixture was stirred under hydrogen (50 psi) for 6 hrs. The catalyst was removed by filtering through Celite and the solvent was evaporated off to give ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)propanoate as an oil. LC/MS: m/e 297.16 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][NH:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(c2ccccc2)NNC1c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the crude wet xylene solution of 3,5-diphenyl-4-methylpyrazoline (from B above), is added 1.0 g of 5% palladium on carbon catalyst. The reaction mixture is slowly heated to reflux, and the water removed by azeotropic distillation using a Dean-Stark apparatus (xylene returned to reactor). Refluxing is continued at 145° C for 4 hours. After the four-hour reflux, the reaction mixture is cooled to 25° C, and the combined 5% palladium on charcoal/3,5-diphenyl-4-methylpyrazole filtered off. The solids are slurried in warm acetone to dissolve the 3,5-diphenyl-4-methylpyrazole. The catalyst is then filtered off. Removal of the acetone in vacuo yields 1.5 g of 3,5-diphenyl-4-methylpyrazole. After recrystallization from hot xylene, pure 3,5-diphenyl-4-methylpyrazole having a melting point of 225°-226° C is obtained.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:23]([O:24]C(=O)C)[C@H:22]([O:28]C(=O)C)[CH2:21][S:20][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)(=O)C>CO>[O:10]([C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[C@@H:9]1[S:20][CH2:21][C@@H:22]([OH:28])[C@H:23]([OH:24])[C@H:8]1[OH:7]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 81.1 %

Procedure:
0.2 ml of a solution of sodium methylate in methanol (8% w/v of Na) is added under an inert atmosphere to a suspension of 1.1 g (2.6.10-3 mol) of 4-nitrophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 30 ml of methanol. After complete solubilization (2 h), the reaction mixture is neutralized by the addition of Amberlite® IR 120 H+ resin and then filtered. 620 mg (yield: 79%) of the expected product are obtained after evaporation to dryness and lyophilization.
Reaction SMILES: N#N.Br[C:4]1[S:5][C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:7][N:8]=1.[Li]CCCC.CN([CH:23]=[O:24])C.[NH4+].[Cl-]>CCOCC>[CH3:14][C:9]1([C:6]2[S:5][C:4]([CH:23]=[O:24])=[N:8][CH:7]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CN(C)C=O
Reactant: CC1(c2cnc(Br)s2)OCCO1
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1(c2cnc(C=O)s2)OCCO1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-bromo-5-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (780 mg, 3.12 mmol) in dry Et2O (10 mL) was added to a n-BuLi (1.25 mL of a 2.5M solution in hexanes, 3.13 mmol) solution in Et2O (10 mL) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before DMF (0.29 mL, 3.78 mmol) was added dropwise. The reaction mixture was allowed to warm up to −20° C. and stirred at this temperature for 20 min. Sat. aq. NH4Cl (10 mL) was added, the layers separated and the aq. layer extracted with Et2O (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (10:1 to 3:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.50. LC-MS-conditions 01: tR=0.78 min; [M+H]+=199.93.
Reaction SMILES: [C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:6])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:63][CH2:64][CH:65]([F:67])[F:66])=[C:51]([CH:62]=1)[C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)=[O:53]>C1COCC1>[F:67][CH:65]([F:66])[CH2:64][O:63][C:50]1[CH:49]=[CH:48][C:47]([NH:46][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([CH2:8][NH:7][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])[CH:10]=[CH:11][C:12]=2[C:18]([F:20])([F:19])[F:21])=[CH:62][C:51]=1[C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)=[O:53]
Reactant: Nc1ccc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(C(F)(F)F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(C(F)(F)F)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-(tert-butylcarbonylamino)methyl-2-trifluoromethyl-benzoic acid (50 mg; 0.13 mmol) HATU (53.8 mg, 0.14 mmol) and TEA (0.066 mL 0.47 mmol) in 2 mL THF was stirred for 15 min at rt. 5-Amino-N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)-benzamide (40.8 mg; 0.13 mmol) was added and it was stirred over night. The solvent was evaporated and the residue was purified by prep HPLC.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.[CH3:18][NH2:19].O>O1CCCC1.C(N(CC)C(C)C)(C)C>[I:8][C:7]1[C:2]([NH:19][CH3:18])=[N:3][C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: N#Cc1ccc(Nc2ncc(I)c(Cl)n2)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Nc2ccc(C#N)cc2)ncc1I
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 25 mg) in tetrahydrofuran (1 mL), N,N-diisopropylethylamine (37 μL) and a 2.0 mol/L solution of methylamine in tetrahydrofuran (105 μL) were added at room temperature, and the mixture was stirred at room temperature for 19 hours. To the reaction mixture, water (5 mL) was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 4-((5-iodo-4-(methylamino)pyrimidin-2-yl)amino)benzonitrile (F224, 27 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[K+].[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25](Cl)=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]([F:33])([F:19])[F:32])=[CH:23][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1Cl
Agent: C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1Oc1ccc(OCc2ccccc2)cc1

Procedure:
To a mixture of 10.01 g. of 4-(benzyloxy)phenol and 3.51 g. (0.05 mole) of potassium methoxide in 75 ml. of DMF is added 12.08 g. (0.05 mole) of 4-(trifluoromethoxy)-2-nitro-1-chlorobenzene. The mixture is heated to complete the reaction. Most of the solvent is removed at reduced pressure and the residue treated with methylene chloride and water. The methylene chloride solution is washed with saturated brine, dried, and the solvent removed, leaving 4-[4-(trifluoromethoxy)-2-nitrophenoxy]-phenyl benzyl ether.
Reaction SMILES: [C:1]1([C:7](=[N:9][OH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:12][C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][C:15]=1[OH:24].[OH-].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:24][C:15]1[CH:16]=[C:17]([O:20][CH2:21][CH2:22][O:10][N:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:18]=[CH:19][C:14]=1[C:13]([OH:25])=[O:12]
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Reactant: CC(=NO)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=NOCCOc1ccc(C(=O)O)c(O)c1)c1ccccc1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
To a solution of 1-phenyl-ethanone oxime (1.156 g, 8.55 mmol) in tetrahydrofuran (75 mL) was added 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester (2.346 g, 8.52 mmol), tetrabutylammonium iodide (0.968 g, 2.62 mmol) and 15% sodium hydroxide solution (30 mL). The reaction was heated at reflux overnight, cooled to room temperature and the layers were separated. The aqueous layer was neutralized to pH 7 by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (25/75)+1% formic acid to afford 2-hydroxy-4-[2-(1-phenyl-ethylideneaminooxy)-ethoxy]-benzoic acid (0.712 g, 27%) as a white solid. mp=149.1-150.4° C.; mass spectrum (+APCI, M+H) m/z 316. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 7.66 (m, 3H), 7.39 (m, 3H), 6.53 (m, 2H), 4.44 (t, 2H), 4.31 (t, 2H), 2.17 (s, 3H). Elemental analysis: Calcd. for C17H17NO5: C, 67.7; H, 5.43; N, 4.44, Found: C, 64.45; H, 5.32; N, 4.42.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[C:13](=[O:21])[CH2:12][C:11]2([CH3:23])[CH3:22].C(=[NH:37])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:18]([N:14]1[C:15]2[C:10](=[CH:9][C:8]([NH2:37])=[CH:17][CH:16]=2)[C:11]([CH3:23])([CH3:22])[CH2:12][C:13]1=[O:21])([CH3:20])[CH3:19]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)N1C(=O)CC(C)(C)c2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)CC(C)(C)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 25 mL round bottom flask was connected to a reflux condenser and the apparatus flame-dried under high vacuum. The vacuum was broken by the addition of dry argon, and the flask was allowed to cool to room temperature. The flask was charged with 0.135 g (1.4 mmol) of powdered sodium t-butoxide, 9.2 mg (0.01 mmol) of tris(dibenzylideneacetone)dipalladium(0) (Pd2 (dba)3), and 19 mg (0.03 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)1,1'-binaphthyl (BINAP), and the apparatus was evacuated and filled with dry argon 3 times. A solution of 6-bromo-1-isopropyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (0.296 mg, 1 mmol) available as described in U.S. Pat. No. 5,399,56, and benzophenone imine (0.218 g, 1.2 mmol) in 4 mL of dry toluene was added. The flask was immersed in an oil bath and heated to 80° C. until all of the starting material had been consumed as judged by thin layer chromatography (TLC) analysis. The solution was cooled to room temperature and diluted with 40 mL of ether. The mixture was filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (THF, 0.3 M) and 2.0 M HCl was added. The solution was stirred for 20 minutes at room temperature and partitioned between 0.5 M HCl and 2:1 hexane/ethyl acetate. The aqueous layer was made basic with 1 M NaOH and the product extracted with methylene chloride, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 33% ethyl acetate in hexanes, to produce the title compound.