Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cccc(C)c3C)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(/C=C/c2ccc(C(=O)O)c(NC(=O)c3cccc(C)c3C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2,3-dimethylbenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 15 mg of 2-(2,3-dimethylbenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic acid as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].O>CN(C)C=O>[CH3:27][N:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21](=[O:22])[N:16]([C:13]2[CH:14]=[CH:15][C:10]3[S:9][N:8]=[C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[O:1][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:11]=3[CH:12]=2)[C:17]1=[O:28]
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4O)c3c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccsc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a mixture of 3-[3-(3-hydroxy-2-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.580 g, 1.36 mmol) in dimethylformamide is added potassium carbonate (0.230 g, 1.66 mmol). The resultant mixture is stirred 30 minutes and treated with methyl bromoacetate (0.230 g, 1.50 mmol). The mixture is stirred over a weekend at room temperature and poured into water. Filtration and drying affords the title compound as an off-white solid (0.550 g, 81.4%, mp 73-79° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45](OC)OC)=[CH:41][CH:40]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:12]1[C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:11][CH:45]1[C:42]1[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)=[O:14])([CH3:18])([CH3:17])[CH3:19]
Reactant: CCOC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Yield: 53 %

Procedure:
A solution of 2.07 g of ethyl (2R,3S)-3-cyclopropyl-3-tert -butoxycarbonylamino-2-hydroxypropionate and 213 mg of pyridinium p-toluenesulfonate in 125 ml of toluene is refluxed under heating. To the mixture is added dropwise a solution of 2.76 g of p-anisaldehydedimethylacetal in 25 ml of toluene for 20 minutes. The reaction mixture is evaporated to remove the generated methanol. The mixture is stirred under heating for 1.5 hours and cooled. After the reaction mixture is condensed under reduced pressure, ethyl acetate and water are added to the residue. The ethyl acetate layer is obtained by separation. The aqueous layer is extracted with ethyl acetate. The extract is washed with water and brine, dried and condensed under reduced pressure. The residue is purified by silica gel column chromatography (solvent; toluene:ethyl acetate=40:1) to give 1.572 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:15]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Nc3ccc(F)cc3)n2)cc(OC)c1OC
Yield: 28 %

Procedure:
Using Method R, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 4-fluoroaniline, 72 mg of title compound were obtained. Yield: 28%. 1H NMR (250 MHz, DMSO-d6) δ 3.62 (s, 9H), 6.83 (s, 2H), 7.06 (t, 2H, J=9.0 Hz), 7.51 (s, 1H), 7.57 (d, 2H, J=9.1 Hz), 9.05 (s, 1H), 9.14 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 55.56, 60.12, 97.01, 114.94, 115.29, 120.38, 120.50, 121.62, 121.83, 132.29, 137.19, 137.22, 150.15, 152.84. m/z 371.2 [(M+H)+ calcd for C19H19FN4O3 370.1].
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:28]([NH2:30])=[O:29])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][C@@H:16]([NH2:26])[CH2:17][O:18]CC3C=CC=CC=3)[C:7]=2[N:27]=1.I[Si](C)(C)C.Cl>C(Cl)(Cl)Cl.CO>[NH2:2][C:3]1[C:4]([C:28]([NH2:30])=[O:29])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][C@@H:16]([NH2:26])[CH2:17][OH:18])[C:7]=2[N:27]=1
Reactant: NC(=O)c1cc2c3ccccc3n(C[C@@H](N)COCc3ccccc3)c2nc1N
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1cc2c3ccccc3n(C[C@@H](N)CO)c2nc1N
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a cooled (0° C.) solution of 2-amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamide (61, 81 mg, 0.160 mmol) in chloroform (2 mL) was added iodotrimethylsilane (140 uL, 0.990 mmol). The reaction was stirred under argon, allowed to warm slowly to room temperature and then stirred an additional 16 h. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by reverse phase HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to provide the product which was then converted to the hydrochloride salt by stirring with a solution of excess hydrochloric acid in methanol to afford 2-amino-9-[(2R)-2-amino-3-hydroxypropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (65, 24 mg, 45%). NH4OAc standard conditions. DAD Retention time=4.76 min. M+H=300. 1H NMR (300 MHz, MeOD-d4): 8.97 (s, 1H), 8.01 (d, J=7.0 Hz, 1H) 7.67 (d, J=7.4 Hz, 1H), 7.52 (t, J=6.9, 1H), 7.38 (t, J=6.9 Hz, 1H), 4.75-4.69 (m, 2H), 3.96-3.81 (m, 2H), 3.71-3.62 (m, 1H).
Reaction SMILES: C([O:4][CH:5]([C:8]1[C:13]2[N:14]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C:15]3=[N:16][C:12]=2[C:11]([Cl:29])=[CH:10][CH:9]=1)[CH2:6][CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:29][C:11]1[C:12]2[N:16]=[C:15]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:14]3[C:13]=2[C:8]([CH:5]([OH:4])[CH2:6][CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.8 %

Procedure:
To a solution of (+)-1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl acetate (80.6 mg, 0.178 mmol) in methanol (1.5 mL) was added potassium carbonate (36.9 mg, 0.267 mmol). The reaction mixture was stirred at room temperature for 1.5 hrs. After the mixture was concentrated, the residue was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (51.6 mg, 0.126 mmol, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:23])[C:16]([OH:18])=[O:17])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)OC(C)(C)C)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
46 mg (0.12 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 54 mg (purity 90%, quant.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([CH3:34])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 3-(5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-2-oxopyridin-1(2H)-yl)propanoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI−): m/z=515.3 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]O.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH:28]([CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]3[CH2:43][CH:42]3[C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[CH:50]=[C:49]([C:54]#[N:55])[CH:48]=[CH:47]4)[CH:39]=2)[CH2:34][CH2:33][NH:32]1)([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O>[CH:28]([CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]3[CH2:43][CH:42]3[C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[CH:50]=[C:49]([C:54]#[N:55])[CH:48]=[CH:47]4)[CH:39]=2)[CH2:34][CH2:33][N:32]1[CH2:3][C:2]([F:6])([F:5])[F:1])([CH3:30])[CH3:29]
Reactant: CC(C)C1NCCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc21
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)C1c2cc(C3CC3c3ccc4cc(C#N)ccc4c3)ccc2CCN1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,2-trifluoroethanol (0.88 mL, 12 mmol) and pyridine (0.9 mL, 12 mmol)in dichloromethane (10 mL) at 0° C. was treated dropwise with trifluoromethanesulfonic anhydride (2.0 mL, 12 mmol), stirred for 15 minutes, warmed to room temperature, and stirred for 18 hours. The solution (0.7 mL, 0.84 mmol) was added dropwise to a mixture of Example 20A (150 mg, 0.41 mmol) and K2CO3 (172 mg, 1.2 mmol) in DMF (1.1 mL), stirred for 24 hours, treated with water, and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel using 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:28].N1C=CC=CC=1.Cl>C(Cl)(Cl)(Cl)Cl>[CH2:30]([O:29][C:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCOC(=O)Cl
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1cnc(-c2ccc(OC(=O)OCCCCCCCCC)cc2)nc1
Reaction time: 8 h

Procedure:
2-(4-Hydroxyphenyl)-5-dodecylpyrimidine (G) (1.0 g) was dissolved in 50 ml of carbon tetrachloride, 0.8 ml of nonyl chlorocarboxylate and 5 ml of pyridine were added, and the mixture was stirred for a while and allowed to stand overnight. 1N Hydrochloric acid was added, and the carbon tetrachloride layer was taken and concentrated. The residue was purified by repeated recrystallization from methanol to obtain (H).
Reaction SMILES: C(=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][Cl:19])[CH2:14][S:15][C@H:10]12)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CO>[NH2:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][Cl:19])[CH2:14][S:15][C@H:10]12
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CCCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCCl)CS[C@H]12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of XVII from Preparation No. 7 (180 mg, 0.34 mmole) in ethyl acetate (10 ml) was added to a solution of Girard Reagent T [(carboxymethyl)trimethylammonium chloride hydrazide] (251 mg, 1.5 mmole) in CH3OH (10 ml) containing acetic acid (0.25 ml), at 5° C. After stirring for 30 minutes at 5° C., the mixture was concentrated to remove the CH3OH and then ethyl acetate (20 ml) was added. The ethyl acetate solution was washed with H2O (2×5 ml), saturated aqueous NaHCO3 (5 ml) and brine (5 ml), successively and dried over MgSO4. Evaporation of the solvent gave 145 mg (97%) of the title compound XVIII (Z isomer) as a yellow powder. M.p. >100° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33][CH2:34][CH3:35])=[CH2:32])CCC>O1CCOCC1>[CH2:34]([O:33][C:31]([C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)=[CH2:32])[CH3:35]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.0 g, 2.88 mmol) was added 1,4-dioxane (15 mL) and the resulting solution degassed with nitrogen. Pd(TPP)2Cl2 (0.202 g, 0.288 mmol) and tributyl(1-ethoxyvinyl)stannane (5.2 g, 14 mmol) were added under a nitrogen stream and the reaction mixture was heated to 90° C. where it stirred for 16 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by neutral alumina column chromatography (20% ethyl acetate, hexane) to yield 2-(1-ethoxyvinyl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (940 mg, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.23 (d, 1H, J=4.4 Hz), 7.75-7.85 (m, 2H), 7.70 (dt, 1H, J=2, 7.6 Hz), 7.45-7.58 (m, 5H), 7.20-7.30 (m, 3H), 6.61 (br s, 1H), 4.61 (s, 1H), 4.60 (d, 2H, J=4 Hz), 3.94 (q, 2H, J=6.8 Hz), 1.40 (t, 3H, J=6.8 Hz). LCMS Method Y: retention time 1.952 min, [M+1]=383.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([CH3:35])[CH2:32][C@H:31]([NH:36]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:36][C@H:31]1[CH2:32][C@@H:33]([CH3:35])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
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: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (13.7 mg, 0.0541 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (15.9 mg, 0.0456 mmol), and HATU (59.1 mg, 0.155 mmol), DMF (1.0 mL) was added followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (8.5 mg, 38%). LCMS calc. for C25H25F3N5O2 (M+H)+: m/z=484.2. found 484.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OB(O)c1ccoc1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC(Nc2ccc3ncc(-c4ccnc(-c5ccoc5)c4)n3c2)CC1

Procedure:
To [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 100 mg, 0.29 mmol), 3-furyl boronic acid (1.05 eq, 0.3 mmol, 34 mg), Na2CO3 (2 eq, 0.58 mmol, 62 mg) in ethanol (2 ml) and H2O (0.7 ml), under inert atmosphere is added tetakis(triphenylphosphine)palladium (0.1 eq, 0.029 mmol, 21 mg). The reaction is heated in using microwave radiation at 80° C. for 2 hours. The mixture is diluted with H2O (5 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-2.5% methanol in EtOAc to afford the title compound; [M+H]+375
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:29]>C(O)C>[IH:29].[IH:29].[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CCCCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCO
Product: CCCCCn1c(N2CCCNCC2)nc2ccccc21

Procedure:
Hydrolyze 4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.70 g, 1.81 mmol) by refluxing an ethanol solution of the compound with hydroiodic acid (57%, 5 mL) as described in Example 111 to provide 2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.85 g).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([F:30])[CH:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5]C=1)[CH3:2].C(C1OC(CCN)=NC=1)C.CC1N=C(CCN)OC=1.Cl.C(C1OC(CCN)=NC=1)C.NCC(O)CC.NC(C)CO>>[F:30][C:22]1[CH:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[O:7][CH:3]=[C:1]([CH3:2])[N:5]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)o1
Agent: CC(N)CO
Agent: CCC(O)CN
Agent: CCc1cnc(CCN)o1
Product: Cc1coc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)n1

Procedure:
The title compound is prepared by the same procedure as 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(4-methyl-oxazol-2-yl)ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 2-amino-1-propanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH2:1]([O:8][C:9](=[O:12])[CH2:10][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(CBr)OCc1ccccc1
Product: CCOP(=O)(CC(=O)OCc1ccccc1)OCC
Yield: 80.3 %

Procedure:
The mixture of bromo-acetic acid benzyl ester (229 g, 1.0 mol) and phosphorous acid triethyl ester (166 g, 1.0 mol) was stirred at reflux for 10 hrs and the solvent was evaporated in vacuo to give crude (diethoxy-phosphoryl)-acetic acid benzyl ester (230 g) which was directly used for next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:16][O:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:14][O:15][CH2:16]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2COC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)ccc1OC1COC1
Reaction time: 1 h

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (498 mg, 3 mmol) was added DMF (3 mL) and sodium hydride (240 mg, 6.0 mmol) followed by oxetan-3-ol (445 mg, 6 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled and quenched with brine solution and extracted with EtOAc (3×10 mL). The organic layer was separated and dried over sodium sulfate and evaporated to give methyl 3-methyl-4-(oxetan-3-yloxy)benzoate. To methyl 3-methyl-4-(oxetan-3-yloxy)benzoate was added sodium hydroxide (3 mL of 1 M NaOH, 3 mmol) solution and the reaction mixture was stirred for 1 hour. The reaction was acidified with 1 M HCl solution to pH 3 and extracted with EtOAc. The organics were separated and dried and concentrated in vacuo to give 3-methyl-4-(oxetan-3-yloxy)benzoic acid. ESI-MS m/z calc. 208.1. Found 209.3 (M+1)+; Retention time: 1.04 minutes (3 min run).