Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10]([O:12][N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.8 %

Procedure:
To a suspension of Fmoc-Phe (1.9442 g, 5.0186 mmol, 1.0 eq) and N-hydroxysuccinimide (0.6095 g, 5.2959 mmol, 1.06 eq) in methylene chloride (50 ml) cooled in an ice bath, was added DCC (1.0880 g, 5.2731 mmol, 1.05 eq). The mixture was stirred at room temperature overnight. The resulting DCU was removed by filtration and the filtrate was condensed and dried in vacuo to give 2.7664 g of white foam.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13]>C(O)(=O)C>[CH:9](=[C:2]1/[C:1](=[O:6])[CH2:5][CH2:4][CH2:3]/1)\[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCC/C=C1\CCCC1=O
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A stirred solution of 42.0 grams (g) (0.5 mole) of cyclopentanone in 80 milliliters (ml) of 1 percent (%) NaOH was treated with 21.5 g (0.25 mole) of n-pentanal at about 30 degrees Celsius (°C.). After stirring for about 2 hours, the solution was neutralized with 36% acetic acid, then extracted with three 30 ml portions of benzene. Then 1.0 ml of phosphoric acid was added to the combined extracts. After the resulting mixture was refluxed through a condenser equipped with a Dean-Stark trap for about 2 hours, the solvent was removed on a rotary evaporator to give an oil residue, which was subjected to distillation to give 28.5 g of 2-(E)-pentylidene cyclopentanone as a yellowish liquid. The boiling point of this intermediate compound was determined to be 98°-102° C. at a pressure of 6 millimeters (mm) mercury (Hg).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1>C(O)CCC.C(N(CC)CC)C>[NH:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4nc5ccccc5[nH]4)CC3)nc(N)c2cc1OC
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To 5.14 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride in 100 ml butanol, 11 ml of triethylamine was added. The mixture was stirred for 15 min and 2.65 g of 2-chloro-1H-benzimidazole was added. The mixture was refluxed for 18 hr and evaporated. Water was added to the residue and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate and evaporated. The residue was crystallized from methanol to give 3.5 g of the title compound, which was recrystallized from methanol: mp>250° C.; ir (nujol mull) 3360 and 3180 cm-1 ; uv max (MeOH) 341 (ε=6,300), 284 (ε=28,500) and 251 nm (ε=66,800); nmr (DMSO-d6) δ 3.5 (m, 4H), 3.8 (m, 4H), 3.8 (s, 3H), 3.84 (s, 3H), 7.1 (m, 8H) and 10.7 (s, 1H); and Anal. Calcd for C21H23N7O2. H2O: C, 60.86% H, 5.79% N, 23.67% and Found: C, 60.87% H, 5.98% N, 23.65%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([N:23]5[CH2:25][CH:24]5[CH3:26])=[O:22])=[CH:19][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(#N)C.Cl.[C:39]([CH:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)#[N:40].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C.O>[C:39]([CH:41]1[CH2:45][CH2:44][N:43]([CH2:25][CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:19]=2)=[O:22])[CH3:26])[CH2:42]1)#[N:40]
Reactant: CC1CN1C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Reactant: N#CC1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(CN1CCC(C#N)C1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 120 °C
Yield: 25.3 %

Procedure:
[2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(2-methyl-aziridin-1-yl)-methanone (70 mg, 0.14 mmol) was dissolved in 1:1 THF: acetonitrile (1.5 ml). 3-Cyanopyrrolidine hydrochloride (28 mg, 0.21 mmol) and N,N-diisopropylethylamine (37 ul, 0.21 mmol) were added and the reaction was heated in a microwave reactor at 120° C. for 2 h. An additional 0.5 eq of 3-cyanopyrrolidine hydrochloride and N,N-diisopropylethylamine were added and the heating was repeated twice more. Water and ethyl acetate were then added to the cooled solution. The aqueous layer was extracted twice more with ethyl acetate and the combined organics were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of solvent the crude residue was purified by silica gel chromatography (ethyl acetate/dichloromethane) to give 21 mg (25%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-(3-cyano-pyrrolidin-1-yl)-1-methyl-ethyl]-amide. (M+H)+=593.
Reaction SMILES: CC(C1C=CC(OC)=CC=1)=O.COC1C=CC(NC2N=CC=CC=2C=O)=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:43]([CH:44]=[CH:45][C:46]([C:48]3[CH:53]=[C:52](OC)[C:51]([O:56][CH3:57])=[C:50](OC)[CH:49]=3)=[O:47])=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:33][CH:32]=1.Cl>CO>[CH3:57][O:56][C:51]1[CH:52]=[CH:53][C:48]([C:46](=[O:47])[CH:45]=[CH:44][C:43]2[C:38]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: COc1ccc(C(C)=O)cc1
Agent: COc1ccc(Nc2ncccc2C=O)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Nc2ncccc2C=CC(=O)c2ccc(OC)cc2)cc1
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To a solution of 4-methoxyacetophenone (65.72 mg, 0.438 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 2-(4-methoxyphenylamino)nicotinaldehyde (100 mg, 0.438 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture was acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6l) (145 mg, 92% yield).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[NH:13]1[CH:17]=[CH:16][N:15]=[N:14]1>>[F:1][C:2]1[C:3]([N:14]2[N:15]=[CH:16][CH:17]=[N:13]2)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1I
Reactant: c1c[nH]nn1
Product: O=C(O)c1cc(F)cc(F)c1-n1nccn1

Procedure:
The title compound was prepared using the methods described herein, using 3,5-difluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 226 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26](C)(C)C)=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(#N)C.C(N(CC)C(C)C)(C)C.ClC(OC)=O>O1CCOCC1>[C:1]([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-{4-[1-(tert-butoxycarbonyl)cyclopropyl]phenyl}piperazine-1-carboxylate (16.0 mg, 0.0000397 mol) was treated with hydrogen chloride in 1,4-dioxane (4.0 M, 0.20 mL) at rt for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile (1.0 mL, 0.019 mol) and was treated with N,N-diisopropylethylamine (20.0 μL, 0.000115 mol) and methyl chloroformate (5.0 μL μL, 0.000065 mol). After 30 min, the solvent was evaporated under reduced pressure and the residue was the desired product, which was directly used in the next step without further purification. LC/MS: 361.2 (M+H+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])[CH3:14].[CH2:23]=[O:24].[Cl-].[NH4+].Cl>C1COCC1>[CH2:13]([C:15]([CH2:23][OH:24])([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])[CH3:14]
Reactant: CCCCC(CC)C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(CC)(CO)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
27 ml (72.9 mmol) of n-butyllithium (2.7 M in heptane) are added dropwise at 0° C. to a solution of 10.9 ml of diisopropylamine (77.5 mmol) in 60 ml of THF, and the mixture is stirred at 0° C. for 30 min. Within 10 min, 5 g (34.7 mmol) of 2-ethylhexanoic acid are added dropwise at 0° C. and the reaction mixture is heated at 50° C. for 1.5 h. The clear solution is cooled to −20° C. and admixed with 3.1 g (103 mmol) of paraformaldehyde. After 10 min at −20° C., the mixture is stirred at RT for 2 h. The mixture is admixed with saturated aqueous solution of ammonium chloride and adjusted to pH=1-2 with 6N HCl. The organic phase is removed, the aqueous phase is re-extracted once with MTBE and the combined organic phases are concentrated on a rotary evaporator. The crude product (85% yield (GC)) can be purified further by distillation (b.p.: 121° C., 0.2 mbar). Alternatively, it is also possible to crystallize the sodium salt of the product from aqueous solution in pure form. The pure product of the free 2-ethyl-2-hydroxymethylhexanoic acid, which is typically obtained as a viscous oil, crystallizes slowly at RT (melting point: 45-46° C.). Alternatively, the product can also be crystallized from a suitable solvent, for example pentane, hexane, heptane or petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:11][C:12]=1[S:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:40]
Reactant: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(S(=O)c2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl ({4-(2-fluorophenyl)-5-[(3-methoxyphenyl)thio]-2-thienyl}methyl)methylcarbamate (277 mg) in ethyl acetate (5 mL) was added 3-chloroperbenzoic acid (144 mg) and the mixture was stirred for 6 hr. The reaction mixture was treated with aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorless oil (yield 231 mg, yield 81%).
Reaction SMILES: O1CCCC1.CC1C=CC(C(C)C)=CC=1.[F:16][C:17]([F:28])([F:27])[C:18](=[O:26])[CH2:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21]>C(N(CC)CC)C.C(O)=O>[F:16][C:17]([F:27])([F:28])[CH:18]([OH:26])[CH2:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)OC(=O)CC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)CC(O)C(F)(F)F
Temperature: 35 °C
Reaction time: 15 h

Procedure:
Into 6 mL of tetrahydrofuran were dissolved 6.4 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 1.0 g of isopropyl 4,4,4-trifluoro-3-oxobutanoate, and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active isopropyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 96.2% e.e. and 100%, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[F:13][C:14]1([F:30])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26](OC)=[O:27])[CH2:15]1>C1COCC1>[F:30][C:14]1([F:13])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26](=[O:27])[NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:15]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Reactant: Nc1cnccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)Nc1cnccn1
Reaction time: 0.25 h

Procedure:
To a stirred solution of pyrazin-2-amine (4.30 g, 45.2 mmol) in 50 mL of THF was added isopropylmagnesium chloride (16.96 mL, 33.9 mmol) dropwise under nitrogen atmosphere. A solid precipitated from the solution. After 15 min, a solution of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate 116A (3 g, 11.31 mmol) in 50 mL of THF was added and stirred for 2 hr. The solvent was evaporated to dryness at the reduced pressure. The residue was suspended in ethyl acetate, washed with water, brined and dried. Evaporation of the solvent furnished a solid, which was chromatographed (20% ethyl acetate, CH2Cl2) to give 116B. LC/MS [M+H]+: 329; Ret time (Method F): 2.42 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:25][C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:4]2[C:3]([CH2:2][O:33][C:31]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:32])=[C:12]3[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: COc1ccc(F)cc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)cc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)NC(=O)C(C)(C)N2
Yield: 85 %

Procedure:
8-Chloromethyl-7-(5-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 4-2, 50.9 mg, 0.14 mmol), 5-methyl-2-thiophenecarboxylic acid (62.5 mg, 0.44 mmol), and potassium carbonate (79.9 mg, 0.58 mmol) were suspended in anhydrous. N,N-dimethylformamide (1.5 mL) and stirred at 80° C. for 4.5 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (55.0 mg) as a colorless solid. (Yield 85%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:34]([CH3:35])[CH3:33])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (29 μL, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes, dimethylamine was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by dimethylamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide (26 mg, 0.059 mmol, 37%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc(C(F)(F)F)ccn2)CCN1c1cnccc1C1CC1
Yield: 71 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 150 mg, 0.738 mmol) was reacted with 2-bromo-4-(trifluoromethyl)pyridine (200.3 mg, 0.88 mmol), 1,4-dioxane (5 mL), copper iodide (14.03 mg, 0.073 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (10.49 mg, 0.073 mmol) and potassium phosphate (469.9 mg, 2.21 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 182.5 mg of the product (71% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[NH:35][C:36](=[NH:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:44]=[C:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N=C(Cc1ccccn1)NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccccn2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 25.9 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15 ml) was treated sequentially with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg, 1.00 mmol), 4-(dimethylamino)pyridine (125 mg, 1.02 mmol) and N-hydroxy-2-(2-pyridinyl)ethanimidamide (Chem.Pharm.Bull.; 21; 10; 1973; 2146-2160) (152 mg, 1.00 mmol). The resulting mixture was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1). The residue was further purified by column chromatography on silica gel eluting with ethyl acetate:pentane (30:70) to afford the title compound as an oil (107 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[CH:40][N:39]=1>CS(C)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][C:38]3[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:27][C:21]=2[S:20](=[O:29])(=[O:30])[N:19]=1
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(Oc4ncccc4[N+](=O)[O-])ccc3N2)c(O)c2ccccc21
Temperature: 110 °C
Yield: 78.1 %

Procedure:
A mixture the product of Example 321C (10.0 mg, 0.02 mmol), cesium carbonate (27.7 mg, 0.09 mmol), and 2-bromo-3-nitropyridine (8.4 mg, 0.04 mmol) in dimethylsulfoxide (0.3 mL) was stirred while heating at 110° C. in a microwave reactor for 20 minutes. After cooling to 25° C., the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a 0-100% dichloromethane in hexane step gradient to give the title compound as a yellow solid (8.6 mg, 68%). MS (ESI−) m/z 549 (M−H)−. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, J=6.62 Hz, 6 H) 2.00 (m, 1 H) 2.81 (m, 2 H) 5.73 (m, 1 H) 7.23 (m, 1 H) 7.40 (m, 2 H) 7.50 (dd, J=8.82, 2.57 Hz, 1 H) 7.82 (m, 2 H) 7.97 (m, 1 H) 8.27 (dd, J=8.09, 1.10 Hz, 1 H) 8.35 (dd, J=4.78, 1.84 Hz, 1 H) 8.42 (dd, J=8.09, 1.84 Hz, 1 H) 14.39 (s, 1 H) 15.02 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH2:8][CH:7]=[C:6]2[C:13]#[N:14].[H][H]>[Pd].[Pt].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH:6]2[C:13]#[N:14])=[CH:10][C:11]=1[CH3:12]
Reactant: [H][H]
Reactant: COc1cc2c(cc1C)CC=C2C#N
Agent: [Pd]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C)CCC2C#N
Reaction time: 0.75 h
Yield: 91.6 %

Procedure:
Under a nitrogen atmosphere, 0.1 gram (catalyst) of 10% palladium on carbon and 0.05 gram (catalyst) of 5% platinum on carbon were placed in a 250 mL Parr hydrogenation bottle, followed by a solution of 2.5 grams (0.014 mole) of 5-methoxy-6-methylinden-3-carbonitrile (iii) in 100 mL of ethyl acetate. The mixture was hydrogenated in a Parr hydrogenation apparatus for about 45 minutes, during which time the theoretical amount of hydrogen was taken up by the reaction. The reaction mixture was then washed through a pad of diatomaceous earth with methylene chloride. The methylene chloride wash was concentrated under reduced pressure, yielding 2.4 grams of subject compound. The NMR spectrum was consistent with the proposed structure.