Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:20])[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][N:12]([C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-[N-methyl-N-(3-picolyl)-amino]-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 154°-156° C.) and piperazine.
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=O.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:5](=[O:7])[CH2:4][CH:3]([OH:2])[CH3:8])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(O)CC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CC(O)CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 29.7 %

Procedure:
Proceeding as in Example 1, but substituting 3-hydroxybutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 118, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-hydroxybutanoyl)pyrrolidine-2-carboxamide (8.5 mg, 29.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.93 (s, 1H), 7.55-7.60 (m, 2H), 7.28-7.35 (m, 2H), 7.17-7.24 (m, 5H), 6.94-7.02 (m, 4H), 4.67 (m, 1H), 4.47-4.50 (m, 1H), 3.90 (m, 1H), 3.68-3.70 (m, 1H), 3.25-3.30 (m, 1H), 2.63-2.73 (m, 3H), 2.35-2.47 (m, 1H), 2.70-2.30 (m, 1H), 1.86-1.96 (m, 2H), 1.01-1.13 (m, 3H). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][S:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:27][CH2:28][S:29](=[O:43])[CH2:30][CH2:31]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCSCC6)c45)ccc32)c1
Solvent: ClC(Cl)Cl
Product: O=S1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A solution of [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-[5-(thiomorpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine (46 mg, 0.096 mmole) in chloroform (2 mL) was cooled in an ice bath and m-chloroperbenzoic acid (26 mg, 65%, 1 equiv) was added in portions over 12 min. After 1 hr, the reaction was then diluted with chloroform, washed with 6% aq. NaHSO3 solution, sat. aq. NaHCO3 solution and dried (Na2SO4). The solvent was removed and purification by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 0 to 5% MeOH) afforded the title compound as an oil (13 mg, 27%). MS: 490 (M+H)+; HPLC Ret Time: 1.62 min (YMC S5 C18, 4.60×50 mm column, 3 min gradient, 4 mL/min).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH3:21])[N:8]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:3][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH3:21])[N:8]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(O)nc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)OC)c(Cl)nc1C
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (4.11 mL) was added to a mixture of dimethyl 2-hydroxy-6-methylpyridine-3,5-dicarboxylate (4.96 g) and acetonitrile (30 mL), and the resultant mixture was stirred overnight at 90° C. in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and then, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.97 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][N:9]=1)=[O:6].[OH-].[K+]>C(O)C.O>[CH3:14][C:13]([C:11]1[O:10][N:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]2=[O:6])[CH:12]=1)([CH3:16])[CH3:15]
Reactant: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1CCN(c2cc(C(C)(C)C)on2)C1=O

Procedure:
To a solution of 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide in 10 ml of ethanol was added 2 g of powdered potassium hydroxide in 5 ml water and 5 ml ethanol. The mixture was refluxed for 30 minutes, cooled and poured into 40 ml water. A gummy solid was collected by filtration and recrystallized from pentane to afford 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methyl-2-pyrrolidinone as a solid. mp 89°-90° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.[ClH:26].[H][H]>[C].[Pd].CO>[ClH:26].[O:24]=[C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1
Reactant: [H][H]
Reactant: O=C1Oc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1Oc2ccccc2CN1C1CCNCC1

Procedure:
In this reference example, 16.0 g of 1-benzyl-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine and 4.0 g of 10% palladium carbon are added to a mixture of 150 ml of water, 50 ml of 1 N hydrochloric acid and 300 ml of methanol. While the resultant mixture is stirred, hydrogen gas is passed therethrough overnight. Then, the reaction mixture is filtered and the filtrate is concentrated. The white crystals as a residue are mixed with methanol and separated by filtration to obtain 11.4 g of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[N:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.O>[N:10]([CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[N:7]=1)=[N+:11]=[N-:12]
Reactant: N#Cc1csc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1csc(CN=[N+]=[N-])n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
2-Bromomethyl-thiazole-4-carbonitrile (1.6 g, 7.8 mmol) was dissolved in 20 mL DMF and sodium azide (0.768 g, 11.8 mmol) was added. The reaction was allowed to stir for 16 h at room temperature and then diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were washed again with 75 ml of brine, dried with anhydrous sodium sulfate and concentrated in vacuo to yield 1.20 g (92%) of the title compound as a gummy material which was used in next step with out further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[N:24]1([CH2:29][CH2:30]O)[CH:28]=[CH:27][N:26]=[CH:25]1>>[N:24]1([CH2:29][CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: OCCn1ccnc1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCCn3ccnc3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-imidazol-1-yl-ethanol.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:19][CH2:20][CH2:21][C:22](=O)[CH2:23][C:24]([O:26][CH3:27])=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]3[C:20]([OH:19])=[CH:21][C:22]([CH2:23][CH2:24][O:26][CH3:27])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCC(=O)CC(=O)OC
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: COCCc1cc(O)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Yield: 61 %

Procedure:
A solution of 2.69 g (10 mmol) of) 4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine and 1.6 g (10 mmol) of methyl 5-methoxy-3-oxo-valerate in 10 ml of acetic acid was heated at reflux for 4 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 80 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 20:1) yielded 2.40 g (61%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]1[O:17][C@H:16]1[CH2:18][OH:19]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:15][C@@H:16]([OH:17])[CH2:18][OH:19])[N:5]=1)([O-:3])=[O:2]
Reactant: OC[C@H]1CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(C[C@@H](O)CO)n1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared as in Example 5, 3.00 g, 26.55 mmol) in N,N-dimethylformamide (15 mL) was treated with solid potassium carbonate (5.50 g, 39.82 mmol) and (S)-(−)-glycidol (3.93 g, 53.10 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the N,N-dimethylformamide was removed in vacuo. Purification by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) afforded (R)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (3.17 g, 64%) as a yellow oil: LR-ES-MS m/z calculated for C6H9N3O4 [M]+ 187, observed [M+H]+ 188.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH3:25][CH2:26][N:27]([CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[CH:39][CH:40]=1)=[O:34])[CH2:28][CH3:29].[ClH:42].CS(C)=O>CC(C)=O>[ClH:42].[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:41][C:38]3[CH:37]=[CH:36][C:35]([C:33]([NH:32][CH2:31][CH2:30][N:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[O:34])=[CH:40][CH:39]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was placed into a 10 ml round bottom flask with 0.250 g (0.9198 mmol) of procainamide hydrochloride. 2 ml of dimethylsulfoxide was added and the solution was heated to 40° C. for four days. The solution was then poured into 40 ml acetone and was stirred vigorously for 20 minutes. The solid was collected by vacuum filtration and washed with acetone. The solid was placed into a 25 ml round bottom flask with 5 ml ethanol and was stirred for 15 minutes. The solid was collected by vacuum filtration and washed with ethanol and then with ether. This yielded 133 mg of 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-N-[2-(diethylamino)ethyl]-benzamide monohydrochloride (AIT-0095) as a slightly yellow non-hygroscopic solid. m.p. 210°-213° C. (no decomposition).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4]1)[CH3:2].C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[Br:23][C:5]1[C:6]2[CH:7]=[N:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:11]=2[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCn1ccc2cnc(C(=O)OC)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCn1cc(Br)c2cnc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To an ice-cooled solution of methyl 1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (IF, 700 mg, 3.43 mmol) in DCM (5 ml) was added NBS (610 mg, 3.43 mmol). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, EtOAc) to give methyl 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (3A, 950 mg, 3.36 mmol, 98% yield) as a white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (t, J=7.33 Hz, 3 H) 4.04 (s, 3 H) 4.25 (q, J=7.33 Hz, 2 H) 7.33 (s, 1 H) 8.22 (d, J=0.76 Hz, 1 H) 8.92 (d, J=1.01 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([Br:34])[CH:3]=1.[N:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)=[CH:37][CH:36]=1>O1CCOCC1>[Br:34][C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:31])([F:32])[F:30])=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:42]([NH:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[O:43])[CH:3]=1
Reactant: Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 80 °C
Yield: 5.4 %

Procedure:
(4-Amino-2-bromo-5-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.358 mmol, 200 mg) and phenyl pyridin-4-ylcarbamate (0.537 mmol, 115 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (13 mg). MS (ESI) m/z 679.3 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][CH:19]=1>>[N:8]1([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:14][C:15]3[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][CH:19]=3)=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Reactant: Oc1ccc(-n2ccnc2)cc1
Product: C(=C/c1nc(COc2ccc(-n3ccnc3)cc2)co1)\c1ccccc1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 37, 1-(4-hydroxyphenyl)imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give 4-[4-(1-imidazolyl)phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 160-162° C.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=1)=[O:28]>CN1CCCC1=O>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[CH:31][N:30]=1)=[O:28]
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 5-chloro-pyrazine-2-carboxylic acid methyl ester following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.44 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:4]2[N:5]([CH:15]=[N:16][N:17]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.Cl>C(O)(=O)C>[OH:2][C:3]1[C:4]2[N:5]([CH:15]=[N:16][N:17]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc2c(c1)nc(OC)c1nncn12
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)nc(O)c1nncn12

Procedure:
A mixture consisting of 1.6 g. (0.0069 mole) of 4,7-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 16 ml. of 1N hydrochloric acid and 48 ml. of glacial acetic acid was refluxed for a period of three hours. Upon completion of this step, the reaction mixture was poured over ice and filtered. The recovered product was then collected on the filter funnel and washed with diethyl ether to ultimately afford 1.19 g. (80%) of pure 4-hydroxy-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([N+:19]([O-])=O)=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[NH2:19][C:8]1[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate (750 mg, 2.54 mmol), 10% Pd/C (50% H2O, 500 mg, 0.23 mmol Pd), and methanol (10 mL) was stirred vigorously at rt under an atmosphere of H2. After 21 h, the mixture was filtered through Celite and concentrated to give methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 266.5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[O:13]1.Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:20]3[O:21][CH2:22][CH2:12][O:13][C:14]=3[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3,4-ethylenedioxyaniline (34 g, 225 mmol), MeOH (100 mL), H2O (300 mL) and 2,4-dichloro-5-fluoropyrimidine (25 g, 150 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with H2O (1.5 liter), acidified with 2N HCl (200 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to obtain 33 g (78%) of the desired product, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (R926087). 1H NMR (CDCl3): δ 8.02 (1H, d, J=3 Hz), 7.25 (d, 1H, J=1.2 Hz), 6.98 (dd, 1H, J=2.4 and 8.1 Hz), 6.85 (d, 1H, J=5.7 Hz), 4.27 (m, 4H); 19F NMR (CDCl3): −44570; LCMS: ret. time: 26.70 min.; purity 100%; MS (m/e): 283 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(/C=C/C(=O)O)c1
Yield: 28.6 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.7 g of ethyl (E)-3-{3-[2-((2RS,5SR)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}cinnamate in solution in 60 cm3 of methanol and 0.4 g of potassium hydroxide dissolved in 20 cm3 of water and after treatment, 1 g of (E)-3-{3-[2-((2RS,5SR)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}cinnamic-acid is obtained [proton NMR (250 MHz, DMSO D6, δ in ppm, J in Hz), 2 rotamers at room temperature, preponderant rotamer description, general description valid for the other products of the series: 1.5 (bs, 9H, (CH3)3 ; 1.9 and 2.2 (2m, 4H, H in position 3 and 4 on pyrrolidine); 3.2 and 3.9 (ABX, 2H, CH2N); 4.35 (dd, 1H, H in position 2 on pyrrolidine); 5.20 (dd, 1H, H in position 5 on pyrrolidine); 6.30 (dd, 1H, NH); 6.4 (bd, 1H, J=15, CH= trans); 7.1 to 7.7 (m, 10H, aromatic and CH= trans); (s, 1H, NH). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 3075, 3030, 3700 to 2250 with a maximum at 2475, 2980, 2935, 2875, 1735, 1705, 1695, 1640, 1610, 1590, 1560, 1495, 1450, 1430, 1395, 1370, 1315, 1250, 1225, 1155, 985, 910, 890, 860, 840, 790, 760, 705, 685].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:22][CH2:23][CH2:24][OH:25])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:27].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[C:24]([CH2:23][CH2:22][N:17]([C:3]1[C:2]([Cl:1])=[C:11]([CH3:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2)[S:18]([CH3:21])(=[O:20])=[O:19])([OH:27])=[O:25]
Reactant: COc1nc2cc(C)c(Cl)c(N(CCCO)S(C)(=O)=O)c2nc1OC
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2cc(C)c(Cl)c(N(CCC(=O)O)S(C)(=O)=O)c2nc1OC

Procedure:
N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-hydroxypropyl)methanesulphonamide (0.94 g, 2.41 mmol) and pyridinium dichromate (2.42 g, 9.63 mmol) in DMF (24 ml) were stirred at room temperature for 18 hours. The reaction mixture was poured into water (25 ml) and extracted twice with dichloromethane. The combined dichloromethane extracts were extracted twice with 10% potassium carbonate solution. The potassium carbonate extracts were acidified to pH1 with 2M HCl and extracted twice with dichloromethane. These combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure to give N-(2-carboxyethyl)-N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide an off-white solid (0.49 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1
Solvent: CCCCO
Product: O=C(Nc1ccccc1)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 95.7 %

Procedure:
The procedure is carried out as in Example 1, starting with 195 mg of 2,6-dichloropurine, 5 ml of butanol and 272 mg of 4-amino-N-phenylbenzamide. 360 mg of the expected product are thus obtained.