Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:17]([CH2:18][CH3:19])=[C:16]([CH3:20])[NH:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>>[CH2:21]([NH:23][C:24]([N:15]1[C:16]([CH3:20])=[C:17]([CH2:18][CH3:19])[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)=[N:14]1)=[O:25])[CH3:22]
Reactant: CCc1c(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]c1C
Reactant: CCN=C=O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)c(CC)c1C
Yield: 31.9 %

Procedure:
Reaction of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole with ethyl isocyanate was carried out in the same manner as in Example 158, to give a white solid of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole-1-carboxamide (0.36 g, yield: 31.9%). mp: 101-102° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.03 (t, J=7.6 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H), 2.25 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 3.38 (dq, J=5.9 and 7.3 Hz, 2H), 6.85-7.05 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-:22].[Na+].OO.Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH2:21])=[O:22])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [OH-]
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1OC
Yield: 84 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1H-indazole-5-carbonitrile (200 mg, 0.72 mmol) in ethanol (3.5 mL) was added 6 N NaOH (0.5 mL) followed by H2O2 (2.0 mL of a 30% solution). The solution was heated to 45° C. for 1 hour when water (80 mL) was added and the pH adjusted to <1 with 3 N HCl. The reaction was then filtered and the product dried to give the title compound (180 mg, 61 mmol, 84% yield). 1H NMR (DMSO-d6) δ 13.3 (s, 1H), 8.59 (s, 1H), 8.12 (br s, 1H), 7.92 (d, 1H), 7.6–7.5 (m, 2H), 7.52 (s, 1H), 7.3 (br s, 1H), 7.13 (d, 1H), 3.87 (s, 3H), 3.84 (s, 3H); ES-MS (m/z) 298 [M+1]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([C:15]4[C:19]([NH2:20])=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:21][CH:22]=2)[N:12]=[C:13]2[N:14]3[C:23](=[O:24])[NH:20][C:19]3[C:15]2=[N:16][NH:17][CH:18]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a mixture of 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (3.2 g, 10.7 mmol) in anhydrous THF (50 mL) stirring at ambient temperature was added 1,1′-carbonyldiimidazole (1.78 g, 11 mmol). The mixture was heated at reflux for 14 h and then cooled to ambient. The solid formed was collected by filtration, washed with THF (20 mL) and dried in vacuo to give 7-morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (2.34 g, 67% ) as a pink solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:13][CH2:12][N:11]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:10][CH2:9]1)C.[Li+].[OH-]>C(O)C>[C:18]([CH2:17][N:14]1[CH2:13][CH2:12][N:11]([CH2:25][C:26]([OH:28])=[O:27])[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])[CH2:16][CH2:15]1)([OH:20])=[O:19]
Reactant: CCOC(=O)CCCN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCN1CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
The ethanol liquid (0.5 mL) of the 4,7-bis(tert-butoxycarbonylmethyl)-1,4,7-triazonane-1-butyric acid ethyl ester (0.025 g, 0.0529 mmol) prepared at Step 1 was added with LiOH (0.0038 g, 0.159 mmol), followed by reaction at 50° C. for 24 hr. After confirming completion of the hydrolysis with ESI-mass, the reacted mixture was filtered through the Whatman syringe filter (0.45 μm) and dried under reduced pressure. The product was separated with RP-HPLC (10 mM HCl/EtOH; concentration increase from 0 to 40% for 20 min), and the filtrate underwent lyophilization to give final product.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Reaction time: 8 h

Procedure:
32.0 g of 1-acetylisonipecotoyl chloride, Example 1(b) are added portionwise to a stirred mixture of 45.3 g of aluminum chloride, 28.3 g of bromobenzene and 120 ml of ethylene dichloride. The solution is stirred overnight, poured onto ice, the organic phase is collected, and the aqueous layer is extracted with chloroform. The organic solutions are combined, dried, and the solvent is removed under reduced pressure to give a yellow oil which crystallizes to a soft solid. The solid is triturated with ether, collected and dried to give 1-acetyl-4-(4-bromobenzoyl)piperidine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>>[F:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:13][C:12]=1[F:17]
Reactant: Fc1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Temperature: -12 °C
Reaction time: 0.75 h

Procedure:
This material is prepared as described by R. W. Taft, G. B. Klingensmith, and S. Ehrenson, (J. Am. Chem. Soc., 87, 3620 (1965)). To a stirred mixture of 5.0 ml of concentrated nitric acid and 13.9 ml of concentrated sulfuric acid cooled to -12° C. is added 9.7 g (0.085 mole) of 1,2-difluorobenzene. A slight exotherm is observed and the mixture is cooled to -20° C. whereupon it solidifies. The mixture is stirred for 45 minutes at -5° to 0° and is then allowed to warm slowly to room temperature. After 1 hour the mixture is poured onto ice, and the mixture extracted with diethyl ether (3×75 ml). The combined ether extracts are washed with water, 10% aqueous Na2CO3, and water again. The ether solution is dried (MgSO4) and concentrated in vacuo without external heating to give the crude product (11.9 g), which is distilled (kugelrohr apparatus) to give 10.2 g of colorless liquid. The nmr spectrum of this material is consistent with the structure.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][SH:20].O>CN(C)C=O>[F:11][C:6]1[C:3]2[CH:4]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[S:20][C:2]=2[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(F)cc(F)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a suspension of 2,4,6-trifluorobenzaldehyde (5.00 g, 31.2 mmol) and potassium carbonate (5.61 g, 40.6 mmol) in N,N-dimethylformamide (63 mL) was added ethyl thioglycolate (3.40 g, 28.3 mmol) at 0° C. The mixture was stirred at room temperature overnight, and then heated to stir at 60° C. for 6 hours. The mixture was cooled to room temperature, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→93:7) to give ethyl 4,6-difluoro-1-benzothiophene-2-carboxylate (1.95 g, 29%) as a pale yellow solid.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[N:10][CH:9]=[CH:8]2.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>CO.CN(C=O)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:15]([OH:17])=[O:16])=[N:10][CH:9]=[CH:8]3)[CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(O)c1nccc2cc(O)ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 10 °C
Reaction time: 14 h

Procedure:
40 ml (20 mMol) of a 0.5 M solution of sodium methylate in MeOH are added to a suspension of 1.9 g (10 mMol) 6-hydroxy-isoquinoline-1-carboxylic acid (CAS 174299-07-1) in 50 ml MeOH and sonicated until a solution is obtained. The solvent is then evaporated off. The residue is dried in high vacuum for 4 h and 100 ml DMF are added. The suspension is cooled to 10° C. and a solution of 1.55 g (10 mMol) 4,6-dichloropyrimidine in 25 ml DMF is added. The reaction mixture is stirred at room temperature for 14 h. The solvent is evaporated off and the mixture is partitioned between H2O/EtOAc. After extraction, the aqueous phase is neutralized with a 1 N solution of HCl. The suspension is extracted with EtOAc, washed with H20 and brine, dried (MgSO4) and concentrated to give a beige powder: 1H-NMR (DMSO-d6): δ ppm 7.60 (s, 1H), 7.68 (dd, J=9.4, 2.3 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 8.59 (d, J=5.9 Hz, 1H), 8.66 (s, 1H), 8.68 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1)#[N:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][C:19]=1[OH:25].B(F)(F)F.CCOCC>>[Cl:17][C:18]1[C:19]([OH:25])=[CH:20][C:21]([OH:22])=[C:23]([C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])=[CH:12][CH:11]=2)[CH:24]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: N#CCCCOc1ccc(CC(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: N#CCCCOc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
This compounds was synthesised in the same manner as described above. [4-(3-Cyano-propoxy)-phenyl]-acetic acid (0.5 g, 2.28 mmol), 4-chlororesorcinol (0.33 g, 2.28 mmol), boron trifloride etherate (5 ml). After standing for two hours a precipitate formed which was filtered, washed (water), and dried to give 4-{4-[2-(5-Chloro-2,4-dihydroxy-phenyl)-2-oxo-ethyl]-phenoxy}butyronitrile as a white solid (0.62 g, 78.7%); Rf 0.6 hexane/ethyl acetate (20/80).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C([O-])(=O)C.[Na+].[BH4-].[Na+]>CO>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[OH:8]
Reactant: O=Cc1ccc[nH]1
Reactant: Cc1ccc(N)cc1O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(NCc2ccc[nH]2)cc1O
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
To a stirred solution of 5-amino-2-methylphenol (9.84 g, 80 mmole) in methanol (100 mL) at 4° C. was added pyrrole-2-carboxaldehyde (11.41 g, 120 mmole) and sodium acetate (13.13 g, 160 mmole). The reaction mixture was stirred for 15 minutes and sodium borohydride (3.78 g, 100 mmole) was added portionwise over 1 hour at 4° C. After the addition was complete, the reaction was allowed to stir for an additional 3 hours. The reaction mixture was poured onto crushed ice slurry (200 g) and the resulting precipitate was collected and washed with cold water three times and air-dried to afford 2-methyl-5-[(1H-pyrrol-2-yl-methyl)amino]phenol (6.62 g, 41% yield): mp 115.4-116.8° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H), 4.03 (d, 2H, J=5.6 Hz), 5.37 (t, 1H, J=5.6 Hz), 5.90 (m, 2H), 6.01 (dd, 1H, J=2.2, 8.0 Hz), 6.12 (d, 1H, J=2.1 Hz), 6.61 (m, 1H), 6.70 (d, 1H, J=8.1 Hz), 8.77 (s, 1H), 10.64 (s, 1H); MS m/z 202 (M+).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH:1]([CH3:3])[CH3:2])[CH2:25][CH2:24]3)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: CC(C)Br
Reactant: COc1ccc(C=Cc2nc(CC3CCNCC3)no2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2nc(CC3CCN(C(C)C)CC3)no2)cc1OC
Temperature: 25 °C

Procedure:
Isopropyl bromide (0.13 mL, 1.45 mmol) was added slowly into a mixture of 4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine (compound of Example 19; 0.4 g, 1.21 mmol) and anhydrous potassium carbonate (0.25 g, 1.82 mmol) in dry DMF (10 mL). The reaction mixture was heated at 55° C. to 60° C. for 4 h. The reaction mixture was cooled to room temperature and ice water (5 mL) was added into it. The solid obtained was filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 61.4 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (298 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)pyrrolidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (332 mg, 61%) as a yellow solid: ESI MS m/z 540 [C26H30BrN5O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:13]([NH:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(F)cc1N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1NCc1ccccc1

Procedure:
Methyl 2-amino-4-fluorobenzoate (0.90 g), benzaldehyde (0.54 mL), sodium triacetoxyborohydride (1.58 g) and acetic acid (0.3 mL) in CH2Cl2 (20 mL) were stirred for 3 hours. The reaction was quenched with methanol, concentrated, and chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: Cl.C([NH:5][C:6]1[C:11](=[O:12])[NH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1)(=O)C>C(O)C>[NH2:5][C:6]1[C:11](=[O:12])[NH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1
Reactant: CCOC(=O)c1cc(NC(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(=O)[nH]c1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride gas is bubbled into a solution of diethyl 5-acetamido-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (5.2 g, 0.018 mol) dissolved in absolute ethanol (400 mL) until the solution is saturated at 20° C. The reaction is stirred at room temperature overnight and is then concentrated in vacuo. The resulting residue is dissolved in water, neutralized with solid sodium bicarbonate, and extracted into methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give diethyl 5-amino-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as a yellow solid in quantitative yield.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:6]=1)[CH:2]=[CH2:3]
Reactant: COCCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCOC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.3 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 864 mg (11.50 mmol) of 2-methoxyethylamine was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 214 mg (yield: 74.7%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:10])=[O:9].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[C:8]([C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])[CH:13]=[CH:12][CH:11]=1)(=[O:9])[NH2:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NC(=O)c1cccc(CCCBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 14.0 g (0.057 mole) 3-(3-bromopropyl)benzamide (the product of step (d)), 11.5 g potassium phthalimide and 26.3 ml dimethylformamide was heated to reflux under argon gas for four hours. The heat source was removed and the mixture was stirred to cool to room temperature. Water (about 85 ml) was added. The resulting slurry was stirred for 20 minutes, then filtered and washed three times with about 50 ml cold water (each wash made a slurry solution in the funnel). The solids were then washed with about 20 ml cold 1:1 isopropyl alcohol: water and dried under vacuum overnight to give 17.04 g of the above-identified product.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[C:13]([O:19][CH3:20])=[N:14][C:15](F)=[CH:16][CH:17]=1>C1COCC1.O>[CH2:1]([O:8][C:15]1[N:14]=[C:13]([O:19][CH3:20])[C:12]([F:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COc1nc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(OCc2ccccc2)ccc1F
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
step 2—To a solution of benzyl alcohol (1.12 g, 10.3 mmol) in THF was added NaH (0.413 g, 10.3 mmol, 60% mineral oil dispersion) and stirred for 30 min. To this solution was added 140 (1.5 g, 10.3 mmol) and the resulting solution was irradiated in the microwave synthesizer at 100° C. for 1 h. The reaction was cooled, diluted with H2O, extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography to afford 1 g (41%) of 6-benzyloxy-3-fluoro-2-methoxy-pyridine (142).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH2:13][CH2:12]1)=[O:10].CI>CN(C)C=O>[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH3:1])[CH2:13][CH2:12]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](N(C)Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium tert-butylate (35 mg, 0.31 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid methyl ester (100 mg, 0.31 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by methyl iodide (10 μL, 0.16 mmol, 0.5 eq). After 15 hours stirring at room temperature methyl iodide (10 μL, 0.16 mmol, 0.5 eq) is added again. After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×5 mL) and water (5 mL). The combined organic layers are washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylic acid methyl ester as a brown oil (1.60 g, 98% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[CH:23]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:15][CH2:23][C:19]1[S:20][CH:21]=[CH:22][C:18]=1[Br:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccccc1
Reactant: O=Cc1sccc1Br
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)NCc1sccc1Br
Yield: 80 %

Procedure:
To a stirred solution of 2-Amino-3-phenyl-propionic acid tert-butyl ester (50.6 mg, 0.229 mmol) in ethanol (1 mL), were added 3-Bromo-thiophene-2-carbaldehyde (50 mg, 0.208 mmol.) and acetic acid (21 μL). The reaction mixture was stirred at room temperature under nitrogen for 2 hrs as the progress of imine formation was monitored by TLC. Then, sodium cyanoborohydride (20 mg, 0.312 mmol) was added. The mixture was acidified with sodium bicarbonate and then extracted with dichloromethane. After removal of the solvent, the crude product was purified by silica plate (hexane/ethylacetate 90%:10%) to give 2-[(3-Bromo-thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tert-butyl ester in 80% yield: 1H NMR (Varian 400 MHz, CDCl3) δ7.23 (m, 6H, ArH), 6.90 (d, 1H, J=5.3 Hz, thiophenH), 4.00 (d, 1H, J=14.6 Hz, NCH2), 3.85 (d, 1H, J=14.6 Hz, NCH2), 3.48 (m, 1H, CHCH2), 3.00 (m, 2H, CHCH2), 1.37 (s, 9H, tBu).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([N:25]([CH3:33])[CH3:24])=[CH:27][CH:28]=3)=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CN(C)c1ccc(NC(=S)NC2N=C(c3ccccc3)c3cc(Cl)ccc3N(C)C2=O)cc1

Procedure:
To a solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 7) (0.342 g, 1 mmol) in dichloromethane (20 ml) was added N,N-dimethyl-1,4-benzenediamine (0.136 g, 1 mmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.167 g, 35%). 1H-NMR (CDCl3): δ 7.70-7.22 (m, 10H), 6.75 (d, J=8.8 Hz, 2H), 6.05 (d, J=7.6 Hz, 1H), 3.42 (s, 3H) and 2.98 (s, 6H). MS (ESI) (M+H)+=478.