Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N+:9]=2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+]>O1CCCC1.O>[CH3:25][C:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C[N+]2=C(c3ccccc3)c3ccccc3CC2)cc1
Reactant: C[Mg]Br
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)c2ccccc2CCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 1-phenyl-2-benzyl-3,4-dihydroisoquinolinium bromide (353.1 g) in tetrahydrofuran (3.5 l) was added 2.0M tetrahydrofuran solution of methylmagnesium bromide (700 ml) for 1.5 hours with stirring at room temperature. After additional stirring for 1.5 hours, the mixture was poured into a solution of ammonium chloride (300 g) in water (650 ml) under ice cooling. After separation, the aqueous layer was extracted with ethyl acetate (3.5 l). The combined organic layers were washed with water (1 l), sodium chloride aqueous solution (1 l) and dried over magnesium sulfate (125 g) and evaporated in vacuo. The residue was crystallized from ethanol (500 ml) to give 1-methyl-1-phenyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline (254.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)CC)C.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl)acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid. 1H NMR (CD3OΔ) δ (ppm) 7.43-8.33 (m, 8H), 7.30 (d, 1H, J=6.6 Hz), 5-0.64 (s, 2H), 5.14 (bs, 1H), 3.68 (t, 2H, J=8:0 Hz), 2.81 (s, 3H), 1.59-1.64 (m, 3H), 0.94 (m, 2H), 0.32 (s, 9H), −0.09 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14]Cl)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: O=C(CCl)c1cn(-c2cccc(Br)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cccnc1)c1cn(-c2cccc(Br)c2)cn1
Yield: 24.6 %

Procedure:
1-[1-(3-Bromo-phenyl)-1H-imidazol-4-yl]-2-chloro-ethanone 4 (60 mg; 0.17 mmol) was dissolved in acetone (5 mL). 3-Hydroxypyridine (22 mg; 0.23 mmol) and K2CO3 (117 mg; 0.85 mmol) were added and heated to reflux for 16 h. The mixture was partitioned between EtOAc and water. The organic phase was then washed with 2N NaOH, saturated aqueous NaCl and was dried over Na2SO4. Concentration of the organic layer afforded 15 mg (25%) of 5. HRMS (ESI+): m/z=358.1938 [M+H]
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[Br:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([C:18]4[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=4)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([C:18]4[N:19]([CH:1]([CH3:3])[CH3:2])[CH:20]=[C:21]([CH3:23])[N:22]=4)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: Cc1c[nH]c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Isopropyl iodide (165 uL, 1.65 mmol) was added to a mixture of 417 mg (1.21 mmol) of 9-bromo-2-(4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and cesium carbonate (538 mg, 1.65 mmol) in 3 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours, mixed with water and extracted with ethyl acetate. The organic extract was washed with water, brine, dried over MgSO4, concentrated, and purified on 4 g silica column eluting with 4-5% methanol in DCM to give 210 mg of 9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. MS: 387.1.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].Cl>C(OCC)(OCC)OCC.C(OCC)(=O)C>[CH3:26][C:23]([C:20]1[CH:19]=[C:18]([S:27][CH2:28][CH2:29][C:30]2[O:31][CH:1]=[N:33][N:32]=2)[CH:17]=[C:16]([C:13]([CH3:12])([CH3:14])[CH3:15])[C:21]=1[OH:22])([CH3:24])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(SCCc2nnco2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 679.6 %

Procedure:
A catalytic amount of p-toluenesulfonic acid (25 mg) is added to a stirred solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (0.50 g, 1.54 mmol) in triethyl orthoformate (10 mL). After 30 minutes, 10 mL of 1N hydrochloric acid is added and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate, twice with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is chromatographed on a column of silica with ethyl acetate/hexane (1/9 then 1/4) to afford 0.33 g (64%) of 2,6-bis(1,1-dimethylethyl)-4-[[2-(1,3,4-oxadiazol-2-yl)ethyl]thio]phenol, mp 87.5°-89.0° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH3:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:28]([O:32][C:33](Cl)=[O:34])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([O:32][C:33]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([C:18](=[O:20])[CH3:19])=[C:12]([NH:11][C:8]3[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:34])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
A mixture of 1-[4-(6-methanesulfonyl-pyridin-3-ylamino)-6-(piperidin-4-yloxy)-pyrimidin-5-yl]-ethanone (48 mg, 0.11 mmol), isobutylchloroformate (14.0 μL, 0.11 mmol), and triethylamine (45 μL, 0.34 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 3 minutes at 80° C. The crude mixture was purified by HPLC to provide Compound A60 as a white solid (35 mg, 65%). 1H NMR (CDCl3, 400 MHz) δ 0.97 (d, 6H), 1.82-1.92 (m, 2H), 2.10-2.19 (m, 2H), 2.70 (s, 3H), 3.22 (s, 3H), 3.37 (m, 2H), 3.89-3.96 (m, 5H), 5.59 (h, 1H), 8.10 (d, 1H), 8.49-8.57 (m, 2H), 8.92 (d, 2H). Exact mass calculated for C22H29N5O6S 491.18, found 492.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(CC)CC.[BH4-].[Na+]>CO>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH2:18][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)CCNCc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 50 °C
Yield: 43.9 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde(23 mg, 0.05 mmol) in 3 mL MeOH, β-alanine (8.7mg, 0.1 mmol) and catalytic amount Et3N are added. The suspension is heated to 50° C. for 0.5 hours, followed by the addition of 2 mg of NaBH4. After Pre-LC-MS, 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-6-ylmethyl]-amino}-propionic acid is obtained as a white solid. MS m/z 456[M+1]+. 1H NMR (MeOD-d4): δ 8.22 (d, 1H), 7.93 (m, 2H), 7.86 (d, 1H), 7.81 (s, 1H), 7.40 (m, 1H), 7.34 (d, 1H), 7.28 (m, 3H), 7.24 (m, 2H), 4.26 (s, 2H), 3.15 (t, 2H), 2.52 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(F)cn1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(F)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 39-3), using 5-fluoro-2-pyridinecarboxylic acid and t-butylamine.
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:9]1[O:13][C:12](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(C=O)o1
Reactant: O=C(O)CC(=O)O
Product: CCCCCCC#Cc1ccc(/C=C/C(=O)O)o1
Yield: 88.2 %

Procedure:
Reaction of 5-(1-octynyl)furan-2-carboxaldehyde (0.72 g, 3.5 mmole from example 8) with malonic acid (0.73 g, 7 mmole) as described in Example 2 gave 0.76 g (88%) of the title compound, mp(Hexane) 100°-100.5° C. νmax (mull) 2650 (broad), 1695, 1630, 1565, 1510, 1410, 1300, 1235, 1210 cm-1 ; δ(CDCl3) 0.90(3H, t, 6.8 Hz), 1.32(4H, m), 1.44(2H, m), 1.62(2H, m), 2.47(2H, t, J=6.5 Hz), 6.38(1H, d, J=15 Hz), 6.54(1H, d, J=3 Hz), 6.64(1H, d, J=3 Hz), 7.48(1H, d, J=15 Hz), 10.53 (1H, broad).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:7]2[C:8]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[C:5]3[C@H:16]4[NH:17][C@@H:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:21][CH:20]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1ccc(Cl)cc1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C[C@H]2CCC[C@@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (226 mg, 1.0 mmol; Example 118A) and 1-chloro-4-vinylbenzene (277 mg, 1.99 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.03-1.17 (m, 1H), 1.28-1.43 (m, 2H), 1.65 (d, J=13 Hz, 1H), 1.76-1.94 (m, 2H), 1.98 (d, J=17 Hz, 1H), 2.40 (s, 3H), 2.90 (dd, J=17, 8 Hz, 1H), 2.97-3.15 (m, 2H), 3.47-3.54 (m, 1H), 4.15-4.27 (m, 1H), 4.31-4.44 (m, 2H), 6.93-6.99 (m, 2H), 7.15 (s, 1H), 7.18 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 365 367 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH2:14])=[N:11][N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]3)(=O)=O)=CC=1>CN(C=O)C.O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([NH:14][CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]4)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)CCC(=O)N3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(OCCNc3nnc(-c4ccc(C(F)(F)F)cc4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.5 %

Procedure:
To a solution of 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (0.047 g, 0.207 mmol) in DMF (2 mL) was added potassium carbonate (0.052 g, 0.376 mmol) and 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethyl 4-methylbenzenesulfonate (0.068 g, 0.188 mmol) and the reaction stirred at room temperature for 15 h. The temperature was then increased to 60° C. for 15 h. After cooling to room temperature, the mixture was diluted with water (5 mL), extracted with EtOAC (20 mL), dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC on a X— Terra column (10×150 mm, 5 μm) with 0-100% AcCN in 10 mM aq. NH4OAc. Solvents were evaporated under vacuum to yield 6-(2-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-ylamino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (4.3 mg, 5.5%). 1H NMR: 400 MHz, DMSO-d6: δ 2.53 (dd, J=7.60, 8.40 Hz, 2H), 2.91 (t, J=8.00 Hz, 2H), 3.76 (t, J=5.20 Hz, 2H), 4.20 (t, J=5.20 Hz, 2H), 6.80-6.84 (m, 3H), 7.83 (d, J=8.40 Hz, 2H), 8.07 (d, J=8.00 Hz, 2H). LCMS: RT 1.79 min. LCMS (ES-API), m/z 419.0 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39](=[O:53])[NH:40][CH2:41][CH2:42][C@H:43]([NH2:52])[C:44]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:45])([CH3:37])([CH3:36])[CH3:35].[C:54]([O:58][C:59](=[O:81])[C:60]1[CH:65]=[C:64]([C:66]2[CH:71]=[C:70]([S:72][CH2:73][CH2:74][C:75](O)=[O:76])[N:69]=[C:68]([NH2:78])[N:67]=2)[C:63]([CH3:79])=[CH:62][C:61]=1[CH3:80])([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[C:54]([O:58][C:59](=[O:81])[C:60]1[CH:65]=[C:64]([C:66]2[CH:71]=[C:70]([S:72][CH2:73][CH2:74][C:75](=[O:76])[NH:52][C@H:43]([C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[O:45])[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:53])[N:69]=[C:68]([NH2:78])[N:67]=2)[C:63]([CH3:79])=[CH:62][C:61]=1[CH3:80])([CH3:57])([CH3:56])[CH3:55]
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)O)nc(N)n2)cc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cc(SCCC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N3CCOCC3)nc(N)n2)cc1C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (58 mg, 0.149 mmol), and diisopropylethylamine (43 μl, 0.247 mmol) were added at room temperature to an N,N-dimethylformamide solution (1.0 ml) of ((S)-3-amino-4-morpholin-4-yl-4-oxobutyl)carbamic acid tert-butyl ester (44 mg) obtained in Step 2 above and 5-[2-amino-6-(2-carboxyethylsulfanyl)pyrimidin-4-yl]-2,4-dimethyl-benzoic acid tert-butyl ester (50.3 mg) obtained in Step 1 of Example 2-1. The reaction solution was stirred for 16 hours, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=30:1) to yield 5-(2-amino-6-{2-[(S)-3-tert-butoxycarbonylamino-1-(morpholine-4-carbonyl)propylcarbamoyl]ethylsulfanyl}pyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (84 mg) as a pale yellow oily material.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc(F)cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-fluorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 275 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.O>CN(C)C=O>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:18]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzotrifluoride (4 g) in N,N-dimethylformamide (40 mL) was added trans-4-aminocyclohexanol (6.61 g), and the mixture was stirred at 90° C. for 4 hours under nitrogen atmosphere. After cooling to room temperature, water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzotrifluoride (5.4 g) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.C1(C[OH:42])CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][OH:42])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: OCC1CCCCC1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: OCc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (25 mg, 0.051 mmol), cyclohexylmethanol (17.48 mg, 0.153 mmol) and potassium carbonate (21.16 mg, 0.153 mmol) were placed in N-methyl-2-pyrrolidone (1 ml) and the mixture heated under microwave irradiation at 100° C. for 20 mins. Additional cyclohexylmethanol (17.48 mg, 0.153 mmol) was added and the mixture heated at 110° C. for 20 mins, followed by 110° C. for a further 20 mins. The solvent was removed and the residue purified by Mass Directed Automated Preparative HPLC to give the title compound as a white solid (5 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1>>[CH3:25][C:23]1[CH:22]=[CH:21][C:20]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=2)=[C:19]([NH:18][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:24]=1
Reactant: Cc1ccc(Sc2ccc(CO)cc2)c(N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(CO)cc3)ccnc2n1

Procedure:
The product from Example 2g as a 3.15M solution in ethanol (0.08 mL, 0.25 mmol) was reacted with the product from Example 115b (0.061 g, 0.25 mmol) for 18.5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0195 g, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.75-1.93 (m, 2H) 2.31-2.42 (s, 3H) 2.91-3.08 (m, 2H) 4.42 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 7.11-7.42 (m, 7H) 7.81 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.98 (d, J=8.82 Hz, 1H) 11.01 (s, 1H); MS (ESI+) m/z 416.2 (M+H)+, (ESI−) m/z 414.3 (M−H)−.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2]([OH:1])([CH3:12])[CH3:11])[CH:5]=1)\[CH3:19])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: CC(C)(O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(CC(C)(C)O)c1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
A mixture of 3-(2-hydroxy-2-methyl-propyl)-phenol (1.00 g, 6.01 mmol), ethyl-2-butynoate (4.00 g, 36.06 mol) and potassium carbonate (0.830 g, 6.01 mmol) in tetrahydrofuran (20 mL) in a sealed tube was heated to 80° C. for 3.75 h. The reaction mixture was then cooled and filtered. The solids were washed with a small amount of tetrahydrofuran and the combined filtrate was collected and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) to afford (E)-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (1.41 g, 84%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)#[N:2].[C:11]([O-])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C>[Ni]>[C:11]([NH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: COc1cccc(C#N)n1
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(CNC(C)=O)n1
Reaction time: 5.5 h

Procedure:
A mixture of 1.0 g (7.46 mmole) of 2-cyano-6-methoxypyridine, 0.37 g (4.48 mmole) of sodium acetate, 25 ml of acetic anhydride and about 1.0 g of Raney nickel was hydrogenated on a Parr apparatus for about 5.5 hours. The mixture was filtered, and then evaporated with warming in vacuo to provide 2-acetamidomethyl-6-methoxypyridine. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: [C:1]1([C:7]2[C:11]([OH: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.C[O-].[Na+].CO.Br[CH2:25][CH2:26][CH3:27]>O>[CH2:25]([O:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:26][CH3:27]
Reactant: Oc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Reactant: CCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3,5-diphenyl-4-pyrazolol (10 g, 0.042 mole), sodium methoxide (2.27 g, 0.042 mole) and methanol (60 ml) is heated at 60° C for 2 hours. Then 1-bromopropane (5.17 g, 0.042 mole) is added slowly (5 minutes) at 60° C. The reaction mixture is then held at 60° C until the reaction is complete by tlc. The mixture is poured into water and the solid formed is isolated by filtration. Recrystallization of the solid from acetonitrile affords white crystals, 7.4 g (63%), melting point 142°-142.5° C.