Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:17]=[C:16](SC)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.FC1C=CC(C2CCN(C3C(C#N)=C(OCC(F)(F)F)N=C(S(C)(=O)=O)N=3)CC2)=CC=1.[N:72]1[CH:77]=[CH:76][CH:75]=[C:74]([CH2:78][NH2:79])[CH:73]=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]([NH:79][CH2:78][C:74]4[CH:73]=[N:72][CH:77]=[CH:76][CH:75]=4)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Reactant: NCc1cccnc1
Agent: CS(=O)(=O)c1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(OCC(F)(F)F)nc(NCc2cccnc2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 57c, the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile was oxidized by 3-chloro-perbenzoic acid to 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile which was then treated with 3-picolylamine in dioxane at 40° C. during 18 hours to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-[(pyridin-3-ylmethyl)-amino]-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=487.
Reaction SMILES: [OH-].[K+].BrC(Br)(F)F.[C:8]1([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C(O)CCC>[C:8]1([CH2:14][C@H:15]([NH2:17])/[CH:16]=[CH:14]\[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)Cc1ccccc1
Agent: FC(F)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: N[C@H](/C=C\c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
552.7 mg (9.85 mmol) potassium hydroxide was dissolved in methanol, absorbed onto 1.1 g aluminum oxide and then dried in a high vacuum. At 5-10° C., 307 μL (3.3 mmol) dibromodifluoromethane was added by drops to a solution of 240 mg (0.82 mmol) (2S)-1-benzylsulfonyl)-3-phenylpropan-2-amine and 1.56 g of the potassium hydroxide prepared in this way on aluminum oxide in 6.2 mL n-butanol. The reaction mixture was stirred for two hours at RT, then filtered through Celite, and the residue was rewashed well with dichloromethane. The filtrate was concentrated and the resulting residue was dried in vacuo. The resulting raw produce was purified by preparative HPLC, yielding 98 mg (35% of the theoretical) of the title compound with an E/Z diasteromer ratio of 4:1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+].[C:15]1([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:33]=2[CH2:34][CH2:35][CH2:36][NH:37]3)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][C:12]([N:37]2[C:38]3[C:33](=[C:32]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=[CH:17][CH:16]=4)[CH:41]=[CH:40][CH:39]=3)[CH2:34][CH2:35][CH2:36]2)=[S:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1cc2c(c(OCCCCCOc3cccc4ccccc34)c1)CCCN2
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(NC(=S)N1CCCc2c(OCCCCCOc3cccc4ccccc34)cccc21)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a stirred solution of 4-fluorobenzoyl chloride (38 mg, 0.24 mmol) in acetone (2.0 mL) was added ammonium thiocyanate (51 mg, 0.66 mmol). The resulting mixture was stirred for 1 h at room temperature followed by the addition of the above-obtained tetrahydroquinoline compound (80 mg, 0.22 mmol). After stirred overnight at room temperature, the reaction mixture was quenched with excess saturated ammonium chloride (20 mL) followed by extraction with ethyl acetate (3×20 L). The organic layers were combined, washed with brine, and then concentrated under vacuum. The residue was purified by silica gel chromatography to give 4-fluoro-N-{5-[5-(naphthalen-1-yloxy)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carbothioyl}-benzamide (83 mg, 0.15 mmol, 70%) as a white solid. MS (EI): m/z 543 (M+H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:11]([OH:15])(=[O:14])[CH:12]=[O:13]>CC(C)=O>[C:1]([NH:9][CH:12]([OH:13])[C:11]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(O)C(=O)O)c1ccccc1
Yield: 100 %

Procedure:
The titled compound 65 was prepared according to a procedure described by Zoller et al., 209 A mixture of benzamide 35 (5.00 g, 41.3 mmol) and glyoxylic acid monohydrate 41 (4.32 g, 46.9 mmol) in anhydrous acetone (70 mL) was heated at reflux for 19 h. The reaction mixture was evaporated under reduced pressure to afford the desired product 65 as a colourless solid (8.06 g, 100%), m.p. 198-200° C. (lit.209 200-201° C. (dec)) Spectroscopic data indicated the crude product 65 did not require purification and was used directly in the subsequent reaction (Section 7.11.4). νmax (KBr): 3310bs, 3058w, 1728s, 1646s, 1602w, 1582w, 1535s, 1491w, 1452w, 1315m, 1292w, 1254m, 1161m, 1097s, 1040m, 1002w, 957m, 805w, 770w, 728m, 692m, 654m, 609w, 515m, 483w cm−1. 1H n.m.r. (300 MHz, D6-DMSO): δ 5.60 (d, J=7.8 Hz, 1H, H2), 7.41-7.49 (m, 2H, H3′, 5′), 7.55 (m, 1H, H4′), 7.86-7.92 (m, 2H, H2′, 6′), 9.26 (d, J=7.8 Hz, 1H, NH), two exchangeable OH protons not observed. 13C n.m.r. (75 MHz, D6-DMSO): δ 71.7 (C2), 127.6, 128.3, 131.7 (Arom CH), 133.7 (C1′), 166.0, 171.5 (C1, CONH). Mass Spectrum (ESI+, MeOH): m/z 218.2 (M+Na)+, C9H9NNaO4 requires 218.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH:24][C:25]([C:27]2([CH3:30])[CH2:29][O:28]2)=[O:26])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>>[OH:28][C:27]([CH3:30])([CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1)[C:25]([NH:24][C:17]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH3:14])[CH:16]=1)=[O:26]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: COc1ccc(NCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1C(F)(F)F

Procedure:
2-Hydroxy-3-(4-methoxy-3-trifluoromethylphenylamino)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 3-amino-6-methoxybenzotrifluoride and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.5% methanol). 1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.12 (1H, dd, J=13.0 Hz, J=4.8 Hz), 3.45 (1H, dd, J=13.0 Hz, J=7.7 Hz), 3.71 (3H, s), 5.42 (1H, m), 6.00 (1H, s), 6.88 (1H, dd, J=8.9 Hz, J=2.7 Hz), 6.92 (1H, d, J=2.7 Hz), 6.97 (1H, d, J=8.9 Hz), 7.78 (1H, dd, J=8.9 Hz, J=2.3 Hz), 7.81 (1H, d, J=1.9 Hz), 8.00 (1H, d, J=8.9 Hz), 9.98 (1H, s).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23]C)=O)[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:26]>CO>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21](=[O:23])[NH2:26])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reactant: N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1

Procedure:
A solution of methyl 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]imidazole-4-carboxylate (10 g.) in methanol (100 ml.) is reacted in a bomb with ammonia (44 g.) at 100° C. for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel. The product is eluted with chloroform that is washed with concentrated aqueous ammonia (90%) and methanol (10%) and is recrystallized from acetonitrile to yield the 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-carbamoylimidazole as a white solid, m.p. 149°-154° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.[CH3:22][O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35]Cl>>[CH3:22][O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35][N:19]1[CH2:18][CH2:17][CH:16]([C:9]2[C:10]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[N:7]([CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:8]=2)[CH2:21][CH2:20]1
Reactant: c1cc2c(C3CCNCC3)cn(Cc3ccoc3)c2cn1
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Product: COC(=O)c1ccc(OC)cc1OCCN1CCC(c2cn(Cc3ccoc3)c3cnccc23)CC1
Yield: 37 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 1.50 g (5.25 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridine and 1.55 g (6.3 mmol) of 2-(2-chloroethoxy)-4-methoxybenzoic acid methyl ester. After standard work-up and purification, 0.95 g (36% yield) of 2-{2-[4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-4-methoxy-benzoic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[N:8][N:9](CC2C=CC=CC=2)[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C(O)=O>[C].[Pd].C(O)C>[C:11]1([C:10]2[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])=[CH:7][NH:8][N:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Yield: 90.1 %

Procedure:
A mixture of ethyl(1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetate (3.60 g), 5% palladium-carbon (7.00 g), formic acid (40 ml), and ethanol (150 ml) was refluxed for 2 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain ethyl (3-phenyl-1H-pyrazol-4-yl)acetate (2.33 g, yield: 90%) as a colorless oily substance.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])=[CH:13][C:12]=2[Cl:31])[CH:7]=[CH:6][N:5]=1)(=O)N.O.[N:33]1C=CC=CC=1.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O>CN(C=O)C>[ClH:31].[NH2:33][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])=[CH:13][C:12]=2[Cl:31])[CH:7]=[CH:6][N:5]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2Cl)ccn1
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2Cl)ccn1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-(2-carbamoylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (Example 90, 27 mg, 0.06 mmol) in DMF (1.0 mL) were added H2O (2.2 mg, 0.12 mmol), pyridine (0.04 mL) and bis(trifluoroacetoxy)iodobenzene (Aldrich, 39 mg, 0.09 mmol) at room temperature. The solution was allowed to stir overnight and then it was purified on prep HPLC to give the desired product, which was further converted to 1-(4-(2-aminopyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea hydrochloride (19 mg, 70% yield) by the addition of 1N HCl solution (0.5 mL). 1H NMR (DMSO-d6) δ 13.50 (s, 1H), 11.02 (s, 1H), 10.57 (s, 1H), 7.80-7.95 (m, 4H), 7.55 (m, 1H), 7.37 (m, 1H), 7.30 (m, 2H), 7.11 (m, 2H), 6.60 (m, 1H), 6.00 (s, 1H), 3.70 (s, 2H); MS (ESI+): m/z 415.16 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]2[C:8](=[O:20])[C:9]3[NH:10][CH:11]=[N:12][C:13]=3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]2=[N:5][N:4]=1.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:20])[N:7]3[C:3]([S:2][CH3:1])=[N:4][N:5]=[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]=2[N:12]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(SC)nnc12

Procedure:
A solution of 3-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (111 mg, 0.380 mmol), N-bromosuccinimide (81.1 mg, 0.456 mmol) in THF (3 ml) was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H16BrN6OS (M+H) 371.0. found: 371.0, 373.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:11]=[C:12]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:13]2[S:18][C:17]([O:19]C)=[N:16][C:14]=2[N:15]=1.O.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:11]=[C:12]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:13]2[S:18][C:17](=[O:19])[NH:16][C:14]=2[N:15]=1
Reactant: COc1nc2nc(SCc3ccccc3F)nc(N[C@H](C)CO)c2s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2[nH]c(=O)sc12

Procedure:
The product of example 32 step e) was dissolved in 1,4-dioxane (50 ml), H2O (1 ml) and concentrated HCl solution (0.5 ml) and stirred for 20 h at 40° C. The volatiles were removed under reduced-pressure and the crude product purified by preparative HPLC to afford the subtitle compound as a white solid (21 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35])[CH:28]=[CH:27]2>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([NH:37][C@H:38]([C:46]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Reactant: CCOC(=O)C1CCCCN1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2piperidinecarboxylate. For analysis of the product, a portion of the product was converted to the flavianate, M.P. 192°-3° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([Sn](CCCC)(CCCC)CC=C)[CH2:22][CH2:23]C.C(OCC)(=O)C.O>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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:23][CH:22]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 68.8 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.62 g, 1.744 mmol), tributyl(2-propen-1-yl)stannane (0.924 g, 2.79 mmol) and Pd(PPh3)4 (0.201 g, 0.174 mmol) in N,N-Dimethylformamide (DMF) (14 ml) was heated in a microwave reactor at 120° C. for 30 min. The vessel was cooled to RT and ethyl acetate (200 mL) and water (200 mL) were added. The organic layer was separated, washed with brine (200 mL), dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (hexanes/ethyl acetate) to give 0.38 g of a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile and Bu3SnBr. The material was used without further purification. N4011-30-100. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.29 (m, 2H), 7.17 (s, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 5.78-5.96 (m, 1H), 5.01-5.18 (m, 2H), 3.91 (s, 2H), 3.37 (d, 2H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][O:36][C:35]2=[O:44])[CH2:30][CH2:29]1)[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(=O)C>C(O)(=O)C.CN(C)C=O.O>[CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][O:36][C:35]2=[O:44])[CH2:32][CH2:33]1)[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(N)c1
Agent: CC=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCNc1cc(C(=O)NC(C)C)ccc1N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (0.1 g) was added to a solution of the product from example 160 (0.1 g), acetaldehyde (0.015 ml), acetic acid (1 drop) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with ethyl acetate, dried, and evaporated under reduced pressure. Yield 0.035 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(Br)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N,N′-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50%) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99%) was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[C:5](Br)=[C:4]([CH3:20])[N:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[C:5](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@H]2CC[C@@H](OCCO)CC2)c1Br
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@@H](OCCO)CC1
Temperature: 130 °C
Yield: 41.9 %

Procedure:
In a sealed tube a solution of 2-(cis-4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol (695 mg, 4.03 mmol) and ethyl acrylate (438 uL, 4.03 mmol) in triethylamine (10 mL) was bubbled with argon for ˜5 minutes. Tetrakis(triphenylphosphin)-palladium (0) (232 mg, 0.201 mmol) was added, the vial was sealed and the mixture was bubbled again with argon (5 minutes). The reaction was heated to 130° C. overnight, cooled to room temperature and concentrated. The residue was dissolved in chloroform (500 mL) and washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-4%) to afford the title compound (615 mg, 84%).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C@@:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH:14]1([C@:11]([OH:13])([CH3:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=3)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15]1
Reactant: C[C@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: C[C@](O)(CNC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((R)-2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 531.0 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]Br.N1C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:34][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Reactant: Oc1ccccc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(Oc4ccccc4)cc3)nc12
Temperature: 130 °C
Yield: 49.2 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (35 mg, 0.074 mmol), phenol (14 mg, 0.15 mmol), copper(I) bromide (2 mg, 0.014 mmol), cesium carbonate (49 mg, 0.15 mmol) and pyridine (1 mL) was heated at 130° C. under nitrogen overnight, and then was cooled to room temperature, quenched with saturated sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-phenoxyphenyl)benzoxazole-4-carboxamide (16 mg, 50%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.66 (d, J=7.0 Hz, 1H), 8.20-8.17 (m, 3H), 7.70 (dd, J=8.0, 1.0 Hz, 1H), 7.47-7.42 (m, 3H), 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 4H), 4.35-4.28 (m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.09-2.81 (m, 5H), 2.17-2.07 (m, 2H), 1.80-1.62 (m, 3H); MS (ESI+) m/z 440 (M+H); HPLC>99% (AUC), tR=13.81 min.