Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:28](=[O:30])[NH2:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[NH2:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1)[C:28]([NH2:29])=[O:30]
Reactant: CC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)COc1ccc(C[C@H](N)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of {(S)-1-carbamoyl-2-[4-(2-oxopropoxy)phenyl]ethyl}carbamic acid tert-butyl ester (2.65 g, 7.88 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. The latter procedure was repeated once. The crude product was purified by C-18 reversed phase chromatography on a HPLC, using a gradient of 13-33% acetonitrile in water in a buffer of trifluoroacetic acid (0.1%) to give 460 mg of (S)-2-amino-3-[4-(2-oxopropoxy)phenyl]propionamide.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.[I:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35][NH2:36])[CH:30]=1>C(Cl)Cl>[I:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35]/[N:36]=[CH:1]/[C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[C:6]([N:13]4[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:17][CH2:18]4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Reactant: NNc1cc(I)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(/C=N/Nc4cc(I)ccn4)nc23)CC1
Reaction time: 1 h

Procedure:
To tert-butyl (1-(2-formylquinolin-8-yl)piperidin-4-yl)methylcarbamate (112 mg, 0.303 mmol) in DCM (20 mL) was added 1-(4-iodopyridin-2-yl)hydrazine (78.4 mg, 0.333 mmol). The reaction mixture was stirred for 1 hour and then taken on to directly to the next step.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH2:37][CH:36]([N:35]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:32])[F:33])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH3:34])[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and tert-butyl 4-(methylamino)piperidine-1-carboxylate following General Procedure B.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[O:24])[C:5]1=[O:32].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][C:27]([CH3:30])([CH3:31])[CH2:28][OH:29])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as a white solid: ES+ MS: 556 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1C(C)=O
Yield: 67.6 %

Procedure:
A mixture of 136 g of o-hydroxyacetophenone, 167 g of ethyl bromoacetate and 205 g of potassium carbonate was refluxed in 3 l of acetone for 6 hours under heating with stirring. The insoluble materials were filtered from the reaction mixture and the acetone was evaporated from the filtrate. Further, the mixture was distilled to obtain a fraction having a boiling point of 132° C/2 mmHg which was then recrystallized from ligroin to obtain 150 g of the product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]=[CH:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:4]=4)[CH:33]=[N:34][CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CBr)cc1OCC(F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCC(F)(F)F
Temperature: 60 °C

Procedure:
4-Bromomethyl-2-(2,2,2-trifluoro-ethoxy)-benzonitrile from Step 3 (200 mg, 0.68 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (360 mg, 0.68 mmol) were dissolved in CH3CN (3.5 ml) and heated to 60° C. for 4 hours. The solvent was removed in vacuo and redissolved in MeOH (3.5 ml). The reaction mixture was heated to 60° C. for 3 more hours. The solvent was removed in vacuo and the crude residue purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [OH-].[K+].C([O:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[NH:15][C:13]1=[O:14])(=O)C.Cl>CO.O>[OH:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[NH:15][C:13]1=[O:14]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)[nH]c2ncn(C)c2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)[nH]c2ncn(C)c2c1=O
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Potassium hydroxide (1.0 g, 17.8 mmol) was added to a solution of (R)-1-(5-acetoxyhexyl)-7-methylxanthine (prepared as described for CT12460) (3.8 g, 12.3 mmol) in methanol-water (1:1, 100 ml). After stirring for 3 hours, the pH of the solution was adjusted to 7 by the slow addition of 1 N hydrochloric acid. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 15% methanol-ethyl acetate to provide (R)-1-(5-hydroxyhexyl)-7-methylxanthine (2.5 g).
Reaction SMILES: C[O-].[Na+].[CH:4]([C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH:15]=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[N:17]([CH2:20][C:21]([O:23][CH2:24]C)=[O:22])=[N+:18]=[N-:19]>CO>[N:17](/[C:20](=[CH:15]\[CH:14]=[CH:13]\[C:10]1[CH:9]=[CH:8][C:7]([CH:4]([CH3:5])[CH3:6])=[CH:12][CH:11]=1)/[C:21]([O:23][CH3:24])=[O:22])=[N+:18]=[N-:19]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CC(C)c1ccc(/C=C/C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C/C=C/c1ccc(C(C)C)cc1)N=[N+]=[N-]

Procedure:
Following General Procedure I, a 1.34 M solution of NaOMe in methanol (30 ml), (E)-3-(4-isopropylphenyl)acrylaldehyde (Compound 110, 1.4 g, 8.0 mmol) and ethyl azidoacetate (12 ml, 40.2 mmol) in MeOH (20 ml) were reacted to produce the title compound as a solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[OH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[OH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(O)cc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (543 mg), 450 mg 6-hydroxy-2-oxindole, and 450 μL piperidine in 10 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give a brown solid.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12]C)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Br:25])[C:18]([O:20][CH3:21])=[O:19].O1CCOCC1>O>[Br:25][C:24]1[C:15]2[NH:14][C:2]3[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[CH2:4][C:3]=3[C:10](=[O:12])[C:16]=2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(Br)c(N)c1
Reactant: COC(=O)C1=C(O)CCC(C)(C)C1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Temperature: 130 °C
Yield: 26.7 %

Procedure:
A mixture of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (26 g, 0.141 mol), methyl 3-amino-4-bromobenzoate (25 g, 0.109 mol), polyphosphoric acid (220 g) and dioxane (220 mL) was heated at 130° C. for 5 hours. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (400 mL), and TMSCl (90 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (250 mL). The organic layer was separated, concentrated and recrystallized with methanol to afford desired compound (10.6 g, 27%). 1H NMR (DMSO-d6) δ 10.32 (s, 1H), 7.98 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 3.80 (s, 3H), 2.90 (t, 2H, J=6.6 Hz), 2.22 (s, 2H), 1.56 (t, 2H, J=6.6 Hz), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+364.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[O:15][C:14]([F:13])([F:24])[F:25])[C:4]=2[CH:3]=1
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1ccccc1OC(F)(F)F
Yield: 61 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (942 mg) was reacted with 2-(trifluoromethoxy)benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (61% yield). m.p.=235° C., LCMS: m/z=449.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.29 (2H, s), 4.89 (1H, s), 5.16 (2H, s), 7.09 (2H, m), 7.24 (1H, m), 7.34 (2H, m), 7.92 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C:10]([CH2:12][C:13](O)=[O:14])=[CH2:11]>O>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([N:1]2[C:13](=[O:14])[CH2:12][CH:10]([C:9]([OH:17])=[O:16])[CH2:11]2)=[CH:3][CH:4]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Cc1ccc(N)cc1
Solvent: O
Product: Cc1ccc(N2CC(C(=O)O)CC2=O)cc1
Temperature: 130 °C
Yield: 97 %

Procedure:
p-Toluidine (23.05 g) and itaconic acid (28.0 g) are mixed and heated at 130° C. for 1 hour to melt and then allowed to cool. Water (200 ml) is added thereto and the reaction mixture is crushed. The resulting precipitate is collected by filtration, washed with water and recrystallized from a mixed solvent (about 300 ml) of ethyl acetate and hexane [1:3 (v/v)] to give the desired product (45.73 g), m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:33][O:34][CH:35]=[CH:36][C:37](Cl)=[O:38]>C1C=CC=CC=1>[CH3:33][O:34][CH:35]=[CH:36][C:37]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:38]
Reactant: COC=CC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)cc3)CC2)cc1OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC=CC(=O)Nc1ccc(N2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)cc1
Yield: 72.9 %

Procedure:
A solution of 11 g of p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline in 100 ml of benzene was added 4.56 ml of triethylamine and refluxed while adding dropwise a solution of 3.94 g of β-methoxyacryloyl chloride in 20 ml of benzene. After completion of addition, the mixture was refluxed for 1 hour. After completion of reaction, the reaction mixture was washed with water and dried. The solvent was distilled off and the residue was purified through silica gel column chromatography to give 10 g of N-(β-methoxyacryloyl)-p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)N1CCC(CO)CC1

Procedure:
To a solution of 5.76 g (0.05 mol) of 4-piperidinemethanol and 4.75 g (0.06 mol) of pyridine in 50 mL of methylene chloride cooled to 0° add dropwise a solution of 10.4 g (0.055 mol) of 4-chlorobenzeneacetyl chloride in 25 mL of methylene chloride. When the addition is complete stir the reaction overnight at room temperature. After this time add 25 mL of 2N hydrochloric acid. Separate the layers and wash the methylene chloride layer with two 50 mL portions of saturated sodium bicarbonate solution and 25 mL of saturated sodium chloride solution then dry the methylene chloride layer over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][CH:10]2[CH:15]([N:16]=1)[CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11]2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)C1=CC2N=C(N3CCC[C@@H]3C)C(=O)NC2C=C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-((S)-2-methylpyrrolidin-1-yl)-2-oxo-1,2,4a,8a-tetrahydroquinoxaline-6-carboxylate (140.0 mg, 0.48 mmol) in dichloromethane (50 mL) was added pyridine (152 mg, 1.92 mmol) and Tf2O (271 mg, 0.96 mmol), and the reaction mixture was stirred overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3×15 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (195 mg, crude), which was used in the next step directly.
Reaction SMILES: [CH3:1][NH:2][C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[NH2:14][C:13]1[C:10]([C:11]#[N:12])=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]([CH3:1])[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CNC(=C(C#N)C#N)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(N)c(C#N)c(-c2ccccc2)n1C
Temperature: 25 °C
Yield: 56 %

Procedure:
[(Methylamino)phenylmethylene]methane-1,1-dicarbonitrile (3.00 g) and anhydrous potassium carbonate (4.51 g) were added to acetonitrile (200 mL). A solution of methyl bromoacetate (3.09 mL) in acetonitrile (10 mL) was added thereto, and the mixture was heated to reflux for 3 hours. After cooling the mixture to room temperature, it was allowed to stand, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The concentrated residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized (hexane/ethyl acetate=1/1) to obtain the title compound (1.15 g) as a white solid. The recrystallized residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→2/1) to obtain the title compound (1.21 g, (total of 2.36 g with the recrystallized portion), yield: 56%) as a white solid. The NMR and ESI/MS data for this compound are shown below.
Reaction SMILES: [OH-].[K+].[CH:3]([C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])([CH3:5])[CH3:4]>CO.O>[CH:3]([C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=1)[C:11]([OH:13])=[O:12])([CH3:5])[CH3:4]
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.2 ml) was added to a suspension of methyl 5-isopropyl-2,4-dimethoxybenzoate (330 mg, 1.39 mmol) in methanol (5 ml) and water (2 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were evaporated in vacuo to afford 5-isopropyl-2,4-dimethoxybenzoic acid (305 mg, 98%) as an off-white solid. 1H NMR (DMSO-d6) 12.07 (1H, br s), 7.57 (1H, s), 6.64 (1H, s), 3.90 (3H, s), 3.85 (3H, s), 3.13 (1H, m), 1.14 (6H, d). MS: [M+H]+ 225.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16](=[CH2:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:25])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:25][CH2:22]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: C=C(C(=O)OCC)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1([C@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 852 mg (2.8 mmol) of ethyl 2-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)acrylate and 5 mg (0.02 mmol) of palladium acetate was added 100 ml of diethyl ether, followed by dropwise addition of a solution of excess (10 equivalents) diazomethane in diethyl ether while ice cooling. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was evaporated and the resulting residue was applied to a silica gel column chromatography to yield 890 mg (quantitative) of the title compound as an oily substance from the eluate of n-hexane:ethyl acetate=3:1.
Reaction SMILES: [I-].CO[N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N+:6]([CH3:13])=[CH:5]1.[CH3:14][NH2:15]>>[CH3:13][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]=[C:5]1[NH:15][CH3:14]
Reactant: COn1c[n+](C)c2ccccc21
Reactant: CN
Agent: [I-]
Product: CNc1nc2ccccc2n1C
Yield: 20 %

Procedure:
3-N-Alkoxyimidazolium salts are also known. For example, 3-N-methoxy-1-N-methylbenzimidazolium iodide has been shown to react with methylamine to afford 1-methyl-2-methylaminobezimidazole in approximately 20% yield (S. Takahashi et al., Chem. Pharm. Bull. 14(4):375-385 (1966)). While this reaction was reported to proceed under relatively mild conditions (i.e., 20°-25° C. for 1 hour), the difficulty in obtaining large quantities of 3-N-oxide starting material renders this approach to 2-substituted imidazoles particularly undesirable.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[N:23]=[C:22]([NH2:24])[CH:21]=[N:20][CH:19]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[N:23]=[C:22]([NH:24][S:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(=[O:33])=[O:32])[CH:21]=[N:20][CH:19]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
To a solution of 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis(boc-amino))pyrazine (Intermediate 10) (0.845 g, 1.61 mmol) in DCM (8.05 ml) was slowly added TFA (2.48 ml, 32.2 mmol) at 0° C. After stirring for 4 hours at room temperature, the reaction mixture was quenched with 1N NaOH, and extracted with DCM. The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine (0.27 g, 52%) as a yellow solid. To a solution of 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine (0.1 g, 0.308 mmol) in pyridine (1.542 ml) was slowly added benzenesulfonyl chloride (0.050 ml, 0.385 mmol) at 0° C. After stirring for 6 hours at room temperature, the reaction mixture was diluted with DCM and quenched with 1N aq. HCl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc and the resulting solid was collected by filtration to give N-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-yl)benzenesulfonamide (0.02 g, 14%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.82-1.90 (2H, m), 2.14-2.17 (2H, m), 3.57-3.62 (2H, m), 3.92-4.06 (2H, m), 5.59-5.63 (1H, m), 7.63-7.65 (3H, m), 8.10 (2H, dd, J=2.0, 7.6 Hz), 8.43 (1H, s), 8.49 (1H, d, J=8.8 Hz), 8.55 (1H, d, J=8.8 Hz), 8.89 (1H, s), 9.21 (1H, s), 11.96 (1H, s). m/z=465.0 [M+1]+.