Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1Br)[CH:2]=[CH2:3].[Li][CH2:24]CCC.C[Si](C)(C)[O:30][C@@H:31]1[C@@H:36]([O:37][Si](C)(C)C)[C@H:35]([O:42][Si](C)(C)C)[C@@H:34]([CH2:47][O:48][Si](C)(C)C)[O:33][C:32]1=[O:53].CS(O)(=O)=O>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C@@:32]1([O:53][CH3:24])[C@H:31]([OH:30])[C@@H:36]([OH:37])[C@H:35]([OH:42])[C@@H:34]([CH2:47][OH:48])[O:33]1)[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: [Li]CCCC
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@]1(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
To a solution of 1-(allyloxymethyl)-2-bromo-5-chloro-4-(4-ethylbenzyl)benzene in dry THF:toluene (1:2, 2.4 mL) was added n-BuLi (0.3 mL, 2.5 M in hexane) dropwise under argon. After it was stirred for 1 h, a cooled solution (−70° C.) of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one in dry toluene (1.8 mL) was added dropwise to the reaction mixture. After being stirred for 3 h, the reaction was quenched by addition of ice water and extracted with EtOAc. The combined organic layers were washed 2× with water, 2× with brine, and then dried over Na2SO4. Concentration gave a yellow oil, which was dissolved in 20 mL of methanol, and methanesulfonic acid in 5 mL of methanol was added. The reaction mixture was stirred over 50 h under argon prior to being quenched by addition of satd NaHCO3 to pH 7.5. Concentration gave a residue, which was purified by preparative TLC to yield 14 mg of title compound as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.03 (s, 4H), 5.93-5.87 (m, 1H), 5.24 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.11 (dd, J=1.6 Hz, 10.4 Hz, 1H), 4.70 (m, 3H), 4.06-3.89 (m, 4H), 3.82 (dd, J=2.4 Hz, 12.4 Hz, 1H), 3.71-3.62 (m, 2H), 3.50-3.46 (m, 1H), 3.26-3.22 (m, 1H), 3.00 (s, 3H), 2.78-2.74 (m, 1H), 1.12 (d, J=7.2 Hz, 6H); LC-MS (m/z) 493 [(M+1)+].
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[CH3:11][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (14.7 mmol, 2.12 g), K2CO3 (17.6 mmol, 2.44 g) in DMF (15 mL) is added iodomethane (17.6 mmol, 1.10 mL). After stirring for 2 hours, the mixture is diluted with EtOAc. The mixture is washed with H2O and brine, dried over Na2SO4 and concentrated. The obtained residue is used to next reaction without further purification (1.62 g, 70%); 1H-NMR (400 MHz, CDCl3): 1.24-1.33 (m, 2H), 1.45-1.53 (m, 2H), 1.98-2.28 (m, 4H), 2.21-2.29 (m, 1H), 3.57-3.64 (m, 1H), 3.67 (s, 3H).
Reaction SMILES: C(C([CH:9]=[CH:10][C:11]([C:17]#[N:18])=[C:12](O)[C:13]([OH:15])=[O:14])=C(O)C(O)=O)#N.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C1(C)C=CC=CC=1>O>[C:17]([C:11]1[CH:10]=[CH:9][N:23]([C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)[C:12]=1[C:13]([OH:15])=[O:14])#[N:18]
Reactant: Nc1cccc(Cl)c1
Reactant: N#CC(C=CC(C#N)=C(O)C(=O)O)=C(O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccn(-c2cccc(Cl)c2)c1C(=O)O

Procedure:
A mixture of 9.2 g of the diethyl ester of 3,6-dicyano-2,7-dihydroxy-2,4,6-octatrienedioic acid, 7.0 g of 3-chloroaniline and 75 ml of dry toluene was stirred at reflux for 3 hours, water of reaction being distilled from the mixture as it was formed. The resulting mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 35 ml of hot ethanol and the solution was chilled in a freezer. The resulting solid was filtered and dried under vacuum to give the ethyl ester of 3-cyano-1-(3-chlorophenyl)-1H-pyrrole-2-carboxylic acid (5A), m.p.: 113°-116° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:31]([O:33]C)=O)=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[C:27]([F:30])([F:29])[F:28])[CH2:17][CH2:18][CH2:19][N:12]21.O1C[CH2:38][CH2:37][CH2:36]1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[C:27]([F:29])([F:28])[F:30])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:31]([OH:33])([CH2:36][CH2:37][CH3:38])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: CCC[Mg]Br
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Product: CCCC(O)(CCC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
n-Propylmagnesium bromide (2.0 M solution in tetrahydrofuran, 3.9 mL, 7.8 mmol) was added to a stirred solution of methyl 9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (700 mg, 1.58 mmol) in tetrahydrofuran (5.0 mL), and the mixture was stirred at 60° C. for 6 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (129 mg, 0.258 mmol, 16%).
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:29])[NH:20][O:21]CC3C=CC=CC=3)[CH:17]=2)[NH:12][C:11](=[O:30])[C:10]1=[O:31])C1C=CC=CC=1.O.[OH-].[Na+]>C(O)C.[Pd]>[OH:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:29])[NH:20][OH:21])[CH:17]=2)[NH:12][C:11](=[O:30])[C:10]1=[O:31]
Reactant: O=C(NOCc1ccccc1)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NO)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 76.6 %

Procedure:
A suspension of 1-Benzyloxy-7-(benzyloxycarbamoyl)quinoxaline-2,3(1H,4H)-dione (250 mg, 0.6 mmol) in 50 ml of ethanol was hydrogenated at atmospheric pressure and room temperature for 1 h in the presence of 50 mg of 5% palladium on carbon. Water (20 ml) and 4 ml of 2N sodium hydroxide was added to dissolve the product and the catalyst was removed by filtration. The filtrate was acidified with 4 ml of 4M hydrochloric acid, evaporated to about 10 ml and filtered to give a white solid. Washing with a small amount of cold water and ethanol yielded 109 mg (70%) of the title compound. 1H-NMR (DMSO-d6): 7.21 (d, J=8 Hz,1H, ArH), 7.60 (dd, J=8 Hz, 2 Hz, 1H, ArH), 7.90 (d, J=2 Hz, 1H, ArH), 9.05 (br.s, 1H, exchangeable), 11.35 (br.s, 1H, exchangeable), 11.82 (br.s, 1H, exchangeable), 12.35 (br.s, 1H, exchangeable).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].ClCCl.C(=O)(O)[O-].[Na+].C[N+](C)(C)C.Cl[I-:24]Cl>O.CO>[I:24][C:7]1[C:6]([CH3:9])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: Cl[I-]Cl
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(I)c(C)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 2,5-dimethylaniline (20 g, 165 mmol) in a 1:1 mixture of dichloromethane and methanol (400 mL) was added sodium bicarbonate (20.8 g, 250 mmol) and tetramethylammonium dichloroiodate(I) (44.7 g, 165 mmol). The resulting mixture was stirred at room temperature for 1 hour and then water was added (500 mL). The organic layer was removed and washed with 5% aqueous sodium thiosulfate (500 mL) and brine (500 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 4-iodo-2,5-dimethylphenylamine (39.6 g, 98% yield). The product was used without further purification.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[OH-].[Na+]>O1CCOCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C(NCc1ccccc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 18.1 %

Procedure:
To a stirred solution of (3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-N-benzylcarboxamide (0.232 g, 0.322 mmol) was added dioxane (10.0 mL) and aqueous 6 N hydrochloric acid (10.0 mL) and the mixture heated at 50° C. for 24 h. The mixture was cooled and aqueous 6 N sodium hydroxide (20 mL). Neutralization of the aqueous layer to pH=7 with aqueous 6 N hydrochloric acid followed by extraction with ethyl acetate, drying of the organic extracts over anhydrous sodium sulfate, filtration and evaporation gave crude product. Purification by preparative HPLC (15-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0230 g, 18% yield). 1HNMR(CD3OD) δ 8.78 (s, 1H), 8.49 (t, 1H), 8.21 (dt, 1H), 8.11 (brd, 1H), 7.93 (dt, 1H), 7.69 (t, 1H), 7.65 (d, 1H), 7.40 (dd, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 4.64 (s, 2H). ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[N:13][C:12](Cl)=[N:11][C:10]=2[C:9]([CH2:24][NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:8]1.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>CS(C)=O>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:1][C:2]([F:32])([F:31])[CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[N:13][C:12]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:11][C:10]=2[C:9]([CH2:24][NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:8]1
Reactant: FC(F)(F)CNCc1nn(CCOCC(F)(F)F)c2c(Nc3ccncn3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: FC(F)(F)CNCc1nn(CCOCC(F)(F)F)c2c(Nc3ccncn3)nc(N3CCNCC3)nc12
Temperature: 120 °C

Procedure:
1-(2-(2,2,2-trifluoroethoxy)ethyl)-3-((2,2,2-trifluoroethylamino)methyl)-5-chloro-N-(pyrimidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (213 mg, 0.41 mmol) prepared in Step 1 and piperazine (152 mg, 1.8 mmol) were mixed in dimethyl sulfoxide (3.0 ml) in a reaction vial. The reaction mixture was heated at 120° C. for 10 hours. The reaction was cooled to room temperature and brought to acidic condition by adding trifluoroacetic acid. The crude reaction mixture was purified by reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) and lyophilized to give the title compound as a dark yellow solid (70 mg).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7](Cl)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[C:21]([O:25][C:26]([NH:28][CH2:29][CH:30]1[C:35]2[S:36][C:37](B(O)O)=[CH:38][C:34]=2[CH2:33][CH2:32][N:31]1[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[C:21]([O:25][C:26](=[O:27])[NH:28][CH2:29][CH:30]1[C:35]2[S:36][C:37]([C:7]3[S:6](=[O:13])(=[O:12])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9](=[O:10])[CH:8]=3)=[CH:38][C:34]=2[CH2:33][CH2:32][N:31]1[CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc(CN2CCc3cc(B(O)O)sc3C2CNC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCc3cc(C4=CC(=O)N(C(C)(C)C)S4(=O)=O)sc3C2CNC(=O)OC(C)(C)C)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 9-A and 4.11-C as the starting materials. 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.46 (s, 1H), 4.75–4.65 (m, 1H), 4.58–4.50 (m, 1H), (m, 1H), 4.08–4.00 (m, 1H), 3.83 (s, 3H), 3.80–3.65 (m, 3H), 3.55–3.48 (m, 1H), 3.18–3.10 (m, 2H), 1.75 (s, 9H), 1.36 (s, 9H); LCMS found for C28H38N3O6S2 (M+H)+: m/z=576.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([OH:21])=O)[CH2:14]2)=[CH:9][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:38][NH:39][O:40][CH3:41].N1C=CC=CC=1.Cl>CN(C)C=O.O>[CH3:41][O:40][N:39]([CH3:38])[C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH2:14]1)=[O:21]
Reactant: CNOC
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (0.200 g, 0.001 mol) was dissolved in dry N,N-dimethylformamide (1 ml) under argon and the solution cooled to 0° C. 1,1′-Carbonyl-diimidazole (0.108 g, 0.001 mol) was added to the mixture and the reaction stirred for one hour while the temperature rose from 0° C. to room temperature. After the addition of N,O-dimethylhydroxylamine hydrochloride (0.063 g, 0.001 mol) and pyridine (0.053 ml, 0.001 mmol), the reaction was stirred for two hours at room temperature. Water (10 ml) and hydrochloric acid (0.1 N) was added and the mixture extracted with ethyl acetate. The organic phase was washed with a solution of sodium carbonate (1 M) and extracted again with ethyl acetate to yield 0.225 g (99% of theory). The crude product obtained in this way was used in the next step without further purification. MS: m/e=373.4(M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]([NH2:18])=O)=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)C(C)C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]#[N:18])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Cc1nc(CNC(=O)OC(C)(C)C)sc1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CNC(=O)OC(C)(C)C)sc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(N-BOC-Aminomethyl)-4-methylthiazole-5-carboxamide [sic] (11.13 g, 41.02 mmol) was suspended in dichloromethane (75 ml) and cooled to 0° C. At this temperature, ethyldiisopropylamine (17.86 ml, 102.55 mmol) was first added, and then, slowly, a solution of trifluoroacetic anhydride (6.56 ml, 47.17 mmol) in dichloromethane (20 ml). After stirring for 1 hour, the mixture was diluted with dichloromethane and washed with 5% strength citric acid solution. After drying (MgSO4), the solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[C:5]([CH3:12])[C:4]=1[OH:13].[CH3:14]C(C)([O-])C.[K+].CI.Cl>C1COCC1.O>[CH3:12][C:5]1[C:4]([O:13][CH3:14])=[C:3]([C:8]([CH:9]([CH3:10])[CH3:11])=[CH:7][CH:6]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(C(C)C)c(CO)c1O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C)ccc(C(C)C)c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
2-Hydroxymethyl-6-methyl-3-(1-methylethyl)phenol (37.3 g, 207 mmol) was dissolved in THF (350 ml), and then potassium tert-butoxide (22.1 g, 197 mmol) was added. To the mixture was added methyl iodide (19.7 ml, 311 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mixture was combined with water, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and purified by column chromatography on a small amount of silica gel which was eluted with ethyl acetate. The solvent was concentrated under reduced pressure, and the residue was crystallized from hexane to obtain 21.7 g of the title compound.
Reaction SMILES: [Na].[CH3:2][C:3]1[NH:4][O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].I[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH3:2][C:3]1[N:4]([CH2:15][CH2:16][CH3:17])[O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)[nH]oc1=O
Reactant: CCCI
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCn1oc(=O)c(C(=O)OCC)c1C
Temperature: 120 °C
Yield: 13.5 %

Procedure:
To a stirred solution of ethyl 3-methyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate sodium salt [prepared according G. Doleschall, Tetrahedron Lett. 1987, 28, 2993-2994] (3.5 g, 18.1 mmol) in DMF (20 mL) was added 1-iodopropane (1.70 g, 18.1 mmol). The resulting mixture was heated to 120° C. for 1 hr. When cooled down, it was poured into ice-water (30 mL), and extracted with dichloromethane (2×50 mL). The organic layer was washed with water (2×50 mL), dried over sodium sulfate, concentrated and purified by flash chromatography with ethyl acetate/hexanes (1/1) to provide a solid product (0.52 g, 13% yield). 1H NMR (CDCl3) δ ppm 4.33 (q, 2H, J=7.1 Hz), 3.86 (t, 2H, J=6.8 Hz), 2.57 (s, 3H), 1.81-1.88 (m, 2H), 1.37 (t, 3H, J=7.1 Hz), 0.98 (t, 3H, J=7.6 Hz). LCMS (APCI, M+H+): 214.1.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[Cl:1][CH2:2][CH:3]=[N:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: O=CCCl
Solvent: O
Product: ClCC=NCc1ccccc1

Procedure:
A solution of 4 ml of chloroacetaldehyde in 20 ml of demineralized water was cooled and a solution of 2.14 g of benzylamine in 10 ml of water was added thereto with stirring. After stirring for 5 minutes at 10° to 15° C., a gum was obtained and a turbid solution which was extracted with 30 ml and then with 20 ml of benzene. The organic solution was dried, filtered, rinsed and the filtrate was evaporated to dryness under vacuum to obtain 3.34 g of 2-chloro-N-benzylethanimine which was used as is for the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].BrBr.[Br:23]C1C(=O)C(Br)=C(C)N(C)C=1C1C=CC=CC=1>CO>[Br:23][C:9]1[C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]([CH3:1])[C:10]=1[CH3:11]
Reactant: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Reactant: Cc1c(Br)c(=O)c(Br)c(-c2ccccc2)n1C
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Br)c(=O)c(C(=O)O)c(-c2ccccc2)n1C

Procedure:
6.0 gms of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid is suspended in 200 mls of methanol. 1.0 gms of sodium hydroxide is added. As soon as the acid dissolves a solution of 5.52 gms of Br2 in 50 mls of methanol is slowly added with stirring. The pH of the reaction mixture is maintained at 8-9 by the addition of extra sodium hydroxide as required. A precipitate of 3,5-dibromo-1,6-dimethyl-2-phenyl-pyrid-4-one forms. This material is collected by filtration and discarded. Acidification of the clear filtrate yields 3.4 gms of 5-bromo-1,6-dimethyl-2-phenyl-4-oxonicotinic acid as a white solid. mp=252°-3° (acetonitrile).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)O1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([C:36]#[N:37])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[NH:23]1[CH:24]=[C:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:27]4[CH:32]=[CH:31][C:30]([C:33]5([C:36]#[N:37])[CH2:34][CH2:35]5)=[CH:29][CH:28]=4)[N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH:21]=[N:22]1
Reactant: Nc1nc2c(Cl)nccn2n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC1(c2ccc(Cl)cc2)CC1
Product: N#CC1(c2ccc(Nc3nc4c(-c5cn[nH]c5)nccn4n3)cc2)CC1

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine is reacted first with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using general procedure 1 and then with 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile following general procedure 2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:2]1.[NH2:15][C:16]([NH2:18])=[S:17].II.[NH4+].[OH-].CN([CH:26]=[O:27])C>O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:17][C:16]([NH:18][CH:26]=[O:27])=[N:15][C:7]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2]1
Reactant: NC(N)=S
Reactant: CN(C)C=O
Reactant: O=C(Cc1ccoc1)c1ccccc1
Agent: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=CNc1nc(-c2ccccc2)c(-c2ccoc2)s1
Temperature: 100 °C

Procedure:
To a solution of 2-furan-3-yl-1-phenyl-ethanone (5.7 g, 31 mmol) and thiourea (4.7 g, 61 mmol) in DMF (57 mL) was and added iodine (7.8 g, 31 mmol). The reaction mixture was heated at 100° C. overnight, then it was diluted with water and made alkaline with saturated aqueous NH4OH, and extracted with ether. The organic phases were washed with water, dried over sodium sulfate, concentrated and purified on neutral Al2O3 using 50% ethyl acetate in hexane as eluent. Yield: 5.7 g, 69%.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1.C([O-])(O)=O.[Na+].CN1CCOCC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[N:41][C:42]#[N:43])OC2C=CC=CC=2)[CH:27]=1>C(O)CC.CCOC(C)=O>[C:42]([N:41]=[C:33]([NH:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:5]=[CH:6][CH2:7]1)[NH:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)#[N:43]
Reactant: NC1(c2ccccc2)CC=CC1
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCCO
Product: N#CN=C(Nc1cccnc1)NC1(c2ccccc2)CC=CC1

Procedure:
A stirred mixture of the product from Step 4 (0.537 g, 2.74 mmol) and EtOAc was mixed with enough aqueous NaHCO3 to give a solution and the aqueous layer was extracted with EtOAc; the EtOAc extract was dried (MgSO4) and concentrated. A solution of the residue in -propanol (25 ml) was treated with N-methylmorpholine (0.75 ml, 6.86 mmol) and N-(3- pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (0.98 g, 4.12 mmol) and refluxed under N2 for 16.75 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel with 1.5% MeOH--0.15% NH4OH--CH2Cl2. The product was crystallized from EtOAc to give 3 which had m.p. 155.5°-157° C.