Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[NH4+].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[NH:11]1[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:2][N:13]=[N:12]1
Reactant: N#Cc1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cncc(-c2nnn[nH]2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
To a solution of 3-cyanopyridine (1.1 g, 10.6 mmol) in DMF (15 mL) was added ammonium chloride (718 mg, 13.4 mmol) and sodium azide (824 mg, 12.7 mmol) and the resultant slurry was vigorously stirred at 90° C. for 15 h. The DMF was removed in vacuo, the residue was dissolved in aqueous potassium hydroxide (1 M, 20 mL), washed with EtOAc (2×25 mL), the aqueous layer was adjusted to pH ˜3 with aqueous HCl (6 N) and the solid was collected by filtration to afford the title compound 64 (904 mg, 46% yield) as a white solid: mp=239-241° C. dec.; 1H NMR (CDCl3) δ 9.21 (m, 1H), 8.76 (m, 1H), 8.39 (m, 1H), 7.64 (m, 1H); LRMS (ESI) m/z calcd for C6H6N5 [M+H]+ 148. found 148; HRMS (ESI) m/z calcd for C6H6N5 [M+H]+ 148.0623. found 148.0624; HPLC>99% (tR=4.88 min, 60 (A):40 (B): 0.009 (C); tR=3.74 min, 60 (A):40 (B): 0.02 (C)).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])C.C[O-].[Na+]>CO>[CH3:1][O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5]
Reactant: CCOC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 83.5 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.0 g) and sodium methoxide (28 % methanolic solution; 0.6 g) in methanol (30 ml) was refluxed for 10 hours. After removal of the solvent, the residue was extracted with chloroform (100 ml), washed with water and dried over anhydrous magnesium. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.8 g of 2-methoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound No. 3).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:24]=3[N:23]=[N:22]2)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.O>[CH2:6]([O:5][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:24]=3[N:23]=[N:22]2)[O:12]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C2OC(C)(C)OC12)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C(O)C1O)OCC
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Compound 6.4 (170 mg, 0.31 mmol) was dissolved in 90% TFA in H2O (10 mL). The mixture was stirred for 30 min and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to yield compound 6.5 (110 mg, 70% yield). 1HNMR (300 MHz, CD3OD) δ 1.24-1.28 (m, 6H), 3.96-4.06 (m, 4H), 4.63 (t, 1H, J=5.1), 4.73 (s, 1H), 4.97 (t, 1H, J=4.2), 5.92-6.04 (m, 1H), 6.5 (d, 1H, J=3.9), 6.81-6.96 (m, 1H), 7.55-8.12 (m, 5H), 8.77 (s, 1H). LRMS (ESI) MH+ C21H25N6O7P requires 505.2. Found 504.9.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1CC(=O)CC(c2ccccc2O)C1
Reaction time: 18 h

Procedure:
5-(2-Methoxyphenyl)-1,3-cyclohexanedione (15.0 g) was suspended in methylene chloride (150 ml). The mixture was cooled to -78° with stirring and a solution of boron tribromide (39.3 g) in methylene chloride (75 ml) was added dropwise over 1h. The mixture was stirred at -78° for 45 min after the addition was complete and at room temperature for a further 18h. Excess water was added and the mixture was stirred vigorously at room temperature for 4h. The solid which separated out was collected by filtration, washed with water and dried to afford the title dione (12.0 g). Recrystallisation from aqueous ethanol afforded white prisms m.p. 190°-192°.
Reaction SMILES: C1([O:7][S:8]([CH2:11][CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH2:22][C:23]3[C:24]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:25]=4[S:26][CH:27]=3)[C:14]2=[O:33])(=[O:10])=[O:9])C=CC=CC=1.[OH-].[Na+].Cl.O>C(O)C.C1COCC1.CO.C(Cl)Cl>[CH3:32][C:31]1[C:24]2[C:23]([CH2:22][N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:13]([CH2:12][CH2:11][S:8]([OH:10])(=[O:9])=[O:7])[C:14]3=[O:33])=[CH:27][S:26][C:25]=2[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCS(=O)(=O)Oc4ccccc4)c4ccccc43)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc2scc(Cn3c(=O)n(CCS(=O)(=O)O)c4ccccc43)c12
Temperature: 80 °C
Yield: 57.3 %

Procedure:
2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid phenyl ester (25 mg, 0.052 mmol) is dissolved in ethanol (1.0 mL) and THF (1.0 mL), 2.0N NaOH solution (1.0 mL) is added into it and the mixture is warmed up to 80° C. for 3 hr. Then 1.0 M HCl solution (5.0 mL) is added along with water (15 mL). The mixture is extracted with EtOAc (3×35 mL) and the organic layers are combined, dried (MgSO4) and concentrated to give crude product. The crude is then dissolved in 10% MeOH in CH2Cl2 and purified by column chromatography eluting with 10% MeOH in CH2Cl2 to give 12 mg (58%) of 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid. LCMS (ESMS): m/z 403.08 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[C:14]([C:19](OC)=[O:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:20][CH2:19][C:14]1[C:13]2[CH2:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[O:1])[NH:3][C:4]=3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2c(c3ccccc13)Cc1c(CO)cccc1-2
Temperature: 25 °C
Yield: 93 %

Procedure:
Fine powder of methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate (11.3 g, 28.8 mmol) was suspended in THF (150 mL) and stirred at room temperature. A 2M solution of Lithium aluminium hydride (LAH) in THF (39 mL) was added slowly to the stirred suspension. After the complete addition, the mixture was stirred at room temperature for 6 hours, then cooled to 0° C. The reaction mixture was quenched with dropwise addition of ethyl acetate (50 mL). During the quenching the reaction temperature was kept below 50° C. The reaction mixture was poured into 1N HCl solution (200 mL) and stirred for 1 hour. The resultant solid was collected by filtration, washed with 1N HCl solution (20 mL) and ethyl acetate, and dried in a vacuum oven overnight to provide 10-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline in 93% yield (9.5 g). 1H NMR spectrum (in DMSO-d6): δ 12.28 (s, 1H); 8.23 (d, J=8.1 Hz, 1H); 7.89 (m, 1H); 7.73 (m, 2H); 7.45 (m, 1H); 7.36 (m, 2H); 5.22 (d, J=5.1 Hz, 1H), 4.68 (d, 2H); 3.85 (s, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].C1(C)C=CC=CC=1>C1COCC1>[CH2:19]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a RT solution of 1-boc-4-hydroxypiperidine (1.20 g, 5.96 mmol) in THF (20 mL) was added sodium hydride dispersion in mineral oil (0.440 g, 11.00 mmol, 57%), in portions, as a solid. After 30 min propargyl bromide, 80% solution in toluene (1.80 mL, 16.16 mmol) was added dropwise via syringe and the reaction was allowed to stir for 2 h. The reaction was cooled to 0° C., quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with (EtOAc):hexanes (0:1→1:1) to give the titled compound as a colorless oil (861 mg, 60%). MS m/z=183.9 [M−tBu]+. Calculated for C9H12NO3: 182
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12]O)[CH2:4][CH2:3]1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: CN1CCC(=NO)c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(N)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
1-Methyl-2,3-dihydro-4(1H)-quinolinone oxime (360 mg) was dissolved in methanol (25 mL) and 20% Pd(OH)2 on carbon (100 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 1.5 hrs. The reaction mixture was filtered through a bed of Celite and washed with methanol. The filtrate was concentrated in vacuo to give the target compound as a colorless oil (330 mg)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].O>CC(C)=O>[C:26]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:28])[CH3:27]
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
6 g (22.7 mmol) of 2-hydroxy-5-octanoylbenzoic acid and 12 mL (0.145 mol) of pyridine are dissolved in 15 mL of acetone. The medium is cooled to 0° C., and 12 mL (0.166 mol) of acetyl chloride are then added dropwise. After stirring for 15 hours at room temperature, water is added and the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated. 7 g of 2-acetyloxy-5-octanoylbenzoic acid are obtained in the form of a white solid in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=5)OCC[O:19]4)[CH:16]=3)[N:11]([CH3:30])[C:10](=[O:31])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18](=[O:19])[C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH:16]=3)[N:11]([CH3:30])[C:10](=[O:31])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)cc(-c2cccc(Br)c2)c2cc(C3(c4ccc(Cl)cc4)OCCO3)cnc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(=O)cc(-c2cccc(Br)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Temperature: 70 °C
Yield: 87.1 %

Procedure:
To a solution compound H (0.4 g, 0.81 mmol) in dioxane (5 mL) was added 6 N HCl (0.5 mL) at 0° C. The mixture was heated at 70° C. for 1.5 h and cooled to RT. Dioxane was removed under reduced pressure; the reaction mixture was neutralized with saturated NaHCO3 solution and extracted with EtOAc (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 0.32 g (88%) of compound I as off-white solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1.[CH:21]1([CH:24]=[O:25])[CH2:23][CH2:22]1>C1COCC1.O>[CH:21]1([CH:24]([C:19]2[C:14]([Cl:13])=[N:15][CH:16]=[N:17][C:18]=2[Cl:20])[OH:25])[CH2:23][CH2:22]1
Reactant: O=CC1CC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: OC(c1c(Cl)ncnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Add slowly n-BuLi (2.37 g, 36.0 mmol) to a cooled solution of diisopropylamine (3.72 g, 36.0 mmol) in 50.0 mL THF at −78° C. under nitrogen atmosphere. Stir the reaction mixture for 30 min at the same temperature, then add 4,6-dichloropyrimidine (5.0 g, 33.0 mmol) dissolved in 15 mL of THF. Stir the resultant reaction mixture for an additional 30 min at −78° C., then add cyclopropane carbaldehyde (2.58 g, 36.8 mmol). Allow the reaction mixture to warm up to room temperature. Add 50.0 mL of water and extract the organic with ethyl acetate (3×50 mL), wash with saturated aqueous sodium chloride, then dry over anhydrous sodium sulfate. Concentrate under reduced pressure under vacuum to give Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanol (4.0 g, 54% yield). MS (APCI): m/z=220 [M+H]
Reaction SMILES: [CH3:1][C:2]([NH2:14])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1.[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][C:30]([C:33](=[O:36])[CH2:34]Br)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[C:30]([C:33]([CH2:34][NH:14][C:2]([CH3:1])([CH3:13])[CH2:3][C:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][O:12][C:6]=3[CH:5]=2)=[O:36])[CH:31]=[CH:32][C:23]=1[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:26]
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)CNC(C)(C)Cc2ccc3c(c2)OCO3)ccc1OCc1ccccc1
Reaction time: 5.5 h

Procedure:
A solution of 11.8 g (0.061 mole) of 1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethylamine in 151 ml of tetrahydrofuran was treated with 11.1 g (0.0306 mole) of methyl 2-benzyloxy-5-bromoacetylbenzoate. The resulting solution was stirred for 5.5 hours and allowed to stand for a further 48 hours after which it was cooled, the solid which had separated was filtered off and the filtrate was concentrated by evaporation. The filtered solid and the filtrate were then recombined and the mixture was covered with 100 ml of methanol, warmed to 35°, stirred at that temperature for 30 minutes and cooled. A solid which separated was filtered off, washed with methanol and air dried to give N-[1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethyl]aminomethyl 3-methoxycarbonyl-4-benzyloxyphenyl ketone as a white solid, m.p. 134°-141° C. (Yield 10.48 g, 72.0%).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)(=[O:5])=[O:4])[CH3:2].C1(=O)O[CH2:26][CH2:25][O:24]1>CN(C)C=O>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:26][CH2:25][OH:24])(=[O:5])=[O:4])[CH3:2]
Reactant: O=C1OCCO1
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCO)c2c1
Temperature: 120 °C

Procedure:
To a stirred solution of 5-(2-ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation 5; 350 mg, 1.1 mmol) in dry dimethylformamide (10 ml) at room temperature under nitrogen was added ethylene carbonate (160 mg, 1.8 mmol). The mixture was heated at 120° C. for 18 hours, allowed to cool, then partitioned between ethyl acetate and water. The organic phase was separated, washed with water (3×), dried (Na2SO4) and evaporated under reduced pressure to give a foam. Purification by column chromatography on silica gel, eluting initially with dichloromethane followed by a gradient of 0.880 aqueous ammonia:ethanol: dichloromethane (0:10:90 to 0.5:10:90), afforded the title compound as gum. Rf 0.35 (SS 4). Found: C,62.29; H,7.73; N,7.23. C19H28N2O3S; 0.05 CH2Cl2 requires C,62.04; H,7.68; N,7.60%. δ(CDCl3): 1.35(3H,t), 1.50-1.90(5H,m), 2.30(1H,m), 2.50(1H,m), 2.70(1H,m), 2.80-3.35(10H,m), 3.60-3.75(2H,m), 5.30(0.10H,s,CH2Cl2), 7.00(1H,d), 7.05(1H,s), 7.25(1H,d), 7.40(1H,s), 8.25(1H,br s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=O)[CH2:20][CH2:19]1>>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:21]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[O:18][CH2:19][C:20]2=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Product: c1ccc(COc2ccc3[nH]c4c(c3c2)COc2ccccc2-4)cc1

Procedure:
Following the procedure described in Example 4, using (4-benzyloxy-phenyl)-hydrazine hydrochloride salt and Chroman-4-one (2.93 g, 16.84 mmol) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.N[C@@H]1CCCC[C@H]1N>[N:10]1([CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:15]=[CH:16][C:2]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Ic1ccc(OCCCN2CCCC2)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: c1ccc2c(c1)ccn2-c1ccc(OCCCN2CCCC2)cc1
Yield: 35 %

Procedure:
1-[3-(4-Iodophenoxy)propyl]-pyrrolidine (66 mg, 0.2 mmol), indole (28 mg, 0.24 mmol), copper(I) iodide (0.4 mg, 0.002 mmol), trans-1,2-diaminocyclohexane (0.0024 mmol, 0.02 mmol), and potassium phosphate tribasic (89 mg, 0.42 mmol) were stirred at 90° C. in dioxane overnight. The reaction mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated, and the resulting residue was purified by semi-prep LC-MS to give 22.4 mg of the desired product (35% yield). LC-MS (C21H24N2O calc'd 320) m/z 321 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=6.9 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.40-7.35 (m, 2H), 7.27 (d, J=3 Hz, 1H), 7.22-7.10 (m, 2H), 7.04-6.99 (m, 2H), 6.64 (d, J=3 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 2.57-2.52 (m, 4H), 2.09-2.00 (m, 2H), 1.83-1.78 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.C(O)C.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: O
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 160 parts of ethanol, 12.5 parts of a 30% aqueous solution of ammonia and 1 part of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 8 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)OC1CCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: CCCC(=O)O[C@H]1CCN(Cc2ccccc2)C1
Yield: 49.5 %

Procedure:
First, 0.1 g of lipoprotein lipase (LPL Amano 3, derived from a Pseudomonas strain and available from Amano Seiyaku, Inc.) and 10 g of the racemate (RS)-N-benzyl-3-butyryloxypyrrolidine were added to 100 ml of 0.1 M phosphate buffer solution (pH 7.0). After adjustment of the mixture to pH 7.0 by the addition of HCl, this mixture was allowed to react at 40° C. with agitation for 28 hours. The reaction mixture was extracted three times with 100-ml portions of hexane, and the solvent was removed from the extract under reduced pressure to yield 4.95 g of (S)-N-benzyl-3-butyryloxypyrrolidine in oily form. The residue remaining after the above hexane extraction was adjusted to pH 13 by the addition of NaOH, and then extracted three times with 100-ml portions of hexane. The solvent was removed from the extract under reduced pressure to yield 3.42 g of (R)-N-benzyl-3-hydroxypyrrolidine in oil form. The (S)-N-benzyl-3-butyryloxypyrrolidine obtained as described above was treated by vacuum distillation at 132°-137 ° C./3 mm Hg to yield 4.5 g of a colorless, transparent, purified product. The specific rotation of this product was [a]D20 -19.2° (c=5, MeOH). The NMR and IR spectra of this product coincided with those of the reference sample, and the results obtained by elemental analysis agreed with the calculated values.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:3]=1[NH:4][C:5]1[C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:12])=[CH:9][N:8]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:7](=[O:26])[CH:6]=1.[OH-].[Na+].CCOC(C)=O.CO>CCO>[F:1][C:2]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:3]=1[NH:4][C:5]1[C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:12])=[CH:9][N:8]([CH2:18][C:19]([OH:21])=[O:20])[C:7](=[O:26])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: O=C(O)Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 86 %

Procedure:
tert-Butyl (4-(2-fluoro-4-iodoanilino)-5-{[(3-hydroxypropyl)amino]carbonyl}-2-oxo-1(2H)-pyridinyl)acetate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the t-butyl ester to give (4-(2-fluoro-4-iodoanilino)-5-{[(3-hydroxypropyl)amino]carbonyl}2-oxo-1(2H)-pyridinyl)acetic acid as a white solid (86%), m.p. (EtOAc/MeOH) 199-202° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.12 (s, 1H), 8.39 (t, J=5.3 Hz, 1H), 8.22 (s, 1H), 7.74 (dd, J=10.2, 1.9 Hz, 1H), 7.57 (br d, J=8.4 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.54 (s, 1H), 4.53-4.42 (m, 3H), 3.45 (t, J=6.3 Hz, 2 H—by D2O exchange), 3.24 (t, J=7.0 Hz, 2 H—by D2O exchange), 1.66 (pentet, J=6.6 Hz, 2H). HRMS (FAB+) calcd C17H18FIN3O5 (MH+) 490.0275, found 490.0279.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH2:13][Br:18])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nc(N)nc(-c2ccc(CBr)o2)c1C#N
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a stirred suspension of 500 mg (2.03 mmol) 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 20 ml carbon tetrachloride under argon were added 397 mg (2.23 mmol) N-bromosuccinimide and a small spatula end of benzoyl peroxide. Stirring was continued for 8 hours while the reaction mixture was irradiated with a 500 W halogen lamp. The reaction mixture was then concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 250 mg (38%) 2-amino-4-(5-bromomethyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. EI-MS m/e (%): 326 (M{81Br}+, 5), 325 ([M{81Br}-H]+, 6), 324 (M{79Br}+, 5), 324 ([M{79Br}-H]+, 6), 245 ([M—Br]+, 100).