Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@@H:33]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1.[CH3:60][C:61]([C:63]1[CH:64]=[CH:65][CH:66]=[C:67](O)[CH:68]=1)=[O:62]>C1COCC1>[C:61]([C:63]1[CH:68]=[C:67]([CH:66]=[CH:65][CH:64]=1)[O:32][C@H:33]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1)(=[O:62])[CH3:60]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-hydroxyacetophenone (100 mg) and THF (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 hrs). The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the desired product (2.73 mg, 39.9%) as a thick oil: 1H NMR (CDCl3) δ 7.70–7.64 (m, 2H), 7.54 (m, 2H), 7.49–7.44 (m, 6H), 7.25 (m, 1H), 7.05 (d, 1H, J=8.3 Hz), 6.96 (apparent d, 1H, J=7.7 Hz), 5.34 (apparent dd, 1H, J=4.8, 8.2 Hz), 3.15 (m, 2H), 2.67 (m, 2H), 2.52 (s, 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30–2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 499.4 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.CCN(C(C)C)C(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>C(Cl)Cl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH2:7][C@@H:8]2[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]2)=[CH:31][CH:30]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reactant: Fc1ccc(S)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)S[C@@H]1CO[C@@H](CSc2ccc(F)cc2)C1

Procedure:
The title compound is prepared by the procedure of Example 23 using 0.308 g of product from Example 22 in 1 ml of methylene chloride, 107 microliter of 4-fluorothiophenol, and 174 microliter of Hunig's base to give 0.236 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[C:26]([C:33](O)=[O:34])[CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cnn2ccccc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnn3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Pyrazolo[1,5-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=492.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[N:11][C:4]=2[NH:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[CH:20]2>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([S:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:12]([C:10]3[CH:9]=[CH:8][C:5]4[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=4[N:11]=3)=[O:14])[CH2:32][CH2:31]1)=[CH:20]2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(n4)NC(=O)CS5)CC3)cc2c1

Procedure:
The title compound is prepared as a light yellow solid (64 mg, 30% yield) following Scheme 3 and in analogy to Example 53 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (19 mg, 0.09 mmol, 1.0 eq) and 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[O:18][N:17]=[C:16]([CH3:27])[C:15]=3[CH:13]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]=3)[OH:14])=[CH:21][CH:22]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4ccccc4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.Cl.[CH3:24][O:25][NH2:26]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[N:26][O:25][CH3:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: CON
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1cccc(C(C)c2nc(N)no2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 105.2 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.60 g, 2.0 mmol) in pyridine (10 ml) was added methoxyamine hydrochloride (0.224 g, 2.7 mol). After reflux with stirring for 18 h, the mixture was poured upon ice water, extracted with ethylacetate. The extracts were washed with water, dried and anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(α-methoxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.678 g, quantitive yield) as oily substance: NMR(CDCl3)δ1.70 (d, 3H), 3.97(s, 3H), 4.24(q, 1H), 4.48(broad singlet, 2H), 7.21-7.58(m, 9H) ppm; IR(neat) 3310, 3220, 1625, 1585, 1410, 1050 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
A solution 3-tert-butyl-trimethylsilanylethynyl benzene (Intermediate 102, 0.47 g, 2.04 mmol) in methanol (20 mL) was treated with potassium carbonate (2.8 g, 20.2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title compound as a light yellow oil (0.125 g, 39%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>O>[Cl:5][C:6]1[C:11]([N:12]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cccnc1Cl
Solvent: O
Solvent: CC(=O)O
Product: Clc1ncccc1-n1cccc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To 30 ml of acetic acid were added 5.0 g of 2-chloro-3-pyridinylamine and 5.6 g of 2,5-dimethoxytetrahydrofuran, and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 6.5 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole of the formula:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1cc(C)cc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cc(C)cc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>C1COCC1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 18 h
Yield: 59 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methoxyphenylacetate (2.15 g, 9.04 mmol), 2,6-dichlorophenyl isocyanate (1.70 g, 9.04 mmol) in THF (40 ml) was added Et3 N (0.25 ml, 9.04 mmol) at room temperature. After 18 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 59%) as a colorless powder. mp 177–181° C. (dec.); 1H-NMR (CDCl3) δ 1.43 (s, 9H), 3.74 (s, 2H), 3.83 (s, 3H), 6.34 (s, 1H), 6.81 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 7.06 (br, 1H), 7.27 (t, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.3 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[NH2:9][OH:10].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[N:9][OH:10])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=CC1CCOCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=CC1CCOCC1
Temperature: 90 °C
Yield: 50.2 %

Procedure:
To a suspension of tetrahydro-pyran-4-carbaldehyde (36.9 g, 259 mmol) and hydroxylamine (27.2 g, 388 mmol) in ethanol (246 mL) and water (246 mL) was added sodium acetate) 42.9 g, 517 mmol) and the resulting mixture heated at 90° C. overnight. After cooling to room temperature the resulting mixture was then evaporated and extracted with diethylether and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1) afforded the title compound (16.8 g, 50%) which was obtained as a yellow liquid. MS: m/e=129.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:44][CH3:45])[C:7]([C:31]2[CH2:32][CH2:33][N:34](C(OC(C)(C)C)=O)[CH2:35][CH:36]=2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([CH3:30])[CH:12]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCCl>[CH2:44]([C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[CH2:21][CH2:22]3)=[C:13]([CH3:30])[CH:12]=2)=[N:8][C:7]=1[C:31]1[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=1)[CH3:45]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a mixture of tert-butyl 4-[5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate (600 mg) and 1,2-dichloroethane (6 mL) was added trifluoroacetic acid (742 μL), followed by stirring at room temperature for 3 hours. The mixture was subjected to liquid separation by the addition of a 5% aqueous potassium carbonate solution and chloroform. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxamide (460 mg) as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Li+].CC([N-]C(C)C)C.Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[C:31](=[O:34])[O:32][CH2:33][C:29]=2[C:28]=1[CH3:37])=[O:26]>C1COCC1>[CH3:37][C:28]1[C:29]2[CH2:33][O:32][C:31](=[O:34])[C:30]=2[CH:35]=[CH:36][C:27]=1[C:25](=[O:26])[CH2:24][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1]
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc2c1COC2=O
Reaction time: 0.25 h

Procedure:
To a THF solution of tert-Butyl 3-oxopiperazine-1-carboxylate (164 mg, 0.82 mmol) was dropped LDA (0.37 ml, 0.74 mmol) at −78° C. After stirring the solution for 15 minutes, a THF solution of 5-(bromoacetyl)-4-methyl-2-benzofuran-1(3H)-one (200 mg, 0.74 mmol) was added into the reaction. TLC showed formation of a new spot right away. LC confirmed the desired alkylation product. The product was purified by MPLC to afford tert-Butyl 4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]-3-oxopiperazine-1-carboxylate. LC-MS (IE, m/z): 389 [M+1]+. The resulting solid was further treated with TFA to remove the BOC group. The crude material was dissolved in aqueous sodium bicarbonate, extracted with Chloroform-IPA (3:1) three times, dried over sodium sulfate, and concentrated to furnish the free base of 1-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]piperazin-2-one.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.[Cl:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][N:30]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:8][C:9]=3[O:16][CH3:17])=[O:13])[CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 106.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (266 mg) described in Preparation Example 19 and 1-(3,5-dichloropyridin-2-yl)piperazine (227 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (507 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OCC)(=O)C>CC#N>[N:28]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCCCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 43 %

Procedure:
To a slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) and K2CO3 (56 mg, 0.403 mmol) in MeCN (5 mL), piperidine (35 μL, 0.353 mmol) was added and the reaction mixture was stirred at reflux for 18 hrs. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (Flash Master, Isolute 5 g silica, gradient 0-5 min, 100% hexane and then 0-100% ethyl acetate over 40 min) to afford 2-(piperidin-1-yl)-N-[3-(quinoxalin-2-yl)phenyl]acetamide (50 mg, 42% yield). LCMS calculated for C21H22N4O (M+H): 347.18. found 347. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.88 (1H, br. s), 9.48 (1H, s), 8.54 (1H, m), 8.12-8.10 (2H, m), 7.98 (1H, d, J=7 Hz), 7.91-7.81 (3H, m), 7.52 (1H, m), 3.12 (2H, s), 2.55-2.53 (4H, m), 1.61-1.55 (4H, m), 1.42-1.36 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][C:18]([NH2:23])=[N:17][C:16]=2[N:15]([CH2:24][C:25]2[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=2)[CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][C:18]([NH2:23])=[N:17][C:16]=2[N:15]([CH2:24][C:25]2[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=2)[CH:14]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCCCNC(=O)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCCCN)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of {5-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethy)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-pent-4-ynyl}-carbamic acid tert-butyl ester (see previous example, 33 mg) in DCM (1.0 mL) was treated with TFA (0.2 mL) at rt for 10 min. The reaction mixture was concentrated, taken in water (1.5 mL), washed with EtOAc (1.5 mL), made alkaline with sat. aq. NH4OH (0.5 mL), and back-extracted into EtOAc (25 mL). Washing (NH4OH 1M), drying (Na2SO4) and concentration afforded the title compound. tR=4.37 min. 1H NMR (CDCl3) δ 8.15 (s, 1H), 6.97 (s, 1H), 5.25 (s, 2H), 3.72 (s, 3H), 2.94 (m, 2H), 2.48 (t, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 1.80 (quint., 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(N)=O)cc2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (76 mg, 0.209 mmol) in DMF (2 mL) was added CDI (41 mg, 0.251 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (330 μL, 2.09 mmol) was added and reaction mixture was stirred for 1 h and then evaporated. Purification by crystallization afforded the title compound (64 mg, 84%) as a white solid. MS: m/e=363.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([CH3:23])[C:19](=O)[CH2:20]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([C:19]1[N:7]=[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]2[CH:20]=1)[CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)CBr
Reactant: Nc1cnccn1
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)c1cn2ccncc2n1
Temperature: 25 °C

Procedure:
A mixture of pyrazin-2-ylamine (3 g, 31.5 mmol) and (3-bromo-1-methyl-2-oxopropyl)-carbamic acid benzyl ester (12 g, 41.05 mmol) in EtOH (20 mL) was heated to reflux overnight. After completion, the reaction mixture was cooled to rt. EtOH was removed in vacuo. The residue was dissolved in EtOAc and washed with satd. sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide (1-imidazo[1,2-a]pyrazin-2-yl-ethyl)-carbamic acid benzyl ester: LC-MS (ESI) m/z 297.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][O:24][C:23]=1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])=[O:29]
Reactant: COC(=O)c1ccoc1CBr
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2occc2C(=O)OC)c(=O)[nH]c1=O
Yield: 38 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (150 mg, yield: 38.0%).