Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:27][C:28]([CH2:30]Br)=[CH2:29]>C1COCC1>[Br:27][C:28](=[CH2:29])[CH2:30][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=C(Br)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Lithium diisopropylamide (29.1 mL, 58.3 mmol) was added dropwise at −78° C. To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (9.56 mL, 38.9 mmol) in THF (200 mL), and stirred at this temperature for 50 min. 2,3-Dibromoprop-1-ene (5.47 mL, 56.0 mmol) in THF (10 mL) was added to the reaction mixture slowly and the resulting mixture was stirred for 1.5 hr at −78° C. The reaction mixture was quenched with NH4Cl solution (15 mL) and was allowed to warm to room temperature and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organics were washed with brine (30 mL), dried over MgSO4 and concentrated to get the crude product which was purified by silica gel column chromatography (RediSep 220 g Gold column) using (0-30) % EtOAc/Hexanes as mobile phase to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:5]([C:11]([O:13]CC)=O)[CH:4]=[N:3]1.O.[NH2:17][NH2:18]>>[CH3:1][N:2]1[C:6]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:5]([C:11]([NH:17][NH2:18])=[O:13])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1S(N)(=O)=O
Reactant: NN
Solvent: O
Product: Cn1ncc(C(=O)NN)c1S(N)(=O)=O
Yield: 90 %

Procedure:
Ethyl 1-methyl-5sulfamoylpyrazole-4-carboxylate (1.0 g), prepared according to Bellemin and Festal, J. Heterocycl. Chem. 1984, 21, 1017, was stirred with 1 ml of hydrazine monohydrate at room temperature for 3 h and then evaporated to dryness. The residue was taken up in 5 ml of water and extracted with 25 ml of dichloromethane. The aqueous phase was evaporated to give 0.85 g (90%) of the title compound as a slowly crystallizing oil. Trituration with 5 ml of a 2:1 mixture of methanol and ethyl acetate gave a pure product: m.p. 172°-173° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[CH3:28][N:14]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1[N+](=O)[O-])OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A mixture of tert-butyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-ylcarbamate (2.3 g, 7.8 mmol) in DMF (25 mL) was stirred at 0° C. Sodium hydride (373 mg, 9.3 mmol) was added slowly. Dimethyl sulfate (1.017 g, 9.3 mmol) was added dropwise and the mixture was stirred at 0° C. for 0.5 h. To the reaction mixture was slowly added water (40 mL). The mixture was extracted with toluene (40 mL), the organic phase was washed with water (40 mL) and dried, and the solvent removed. The product was purified by silica gel column (5% v/v EtOAc in PE) to give tert-butyl methyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate (2.2 g, 92% yield). ESI MS: m/z 311 [M+H]+,
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].C(Cl)(Cl)Cl.S(=O)(=O)(O)O.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Cl)c(F)c(NC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL three-neck round-bottomed flask was charged the methyl 4-amino-3,6-dichloro-5-fluoropicolinate (12.1 mmol), toluene (50 mL), and CHCl3 (15 mL). To this suspension was added dropwise a premixed solution of sulfuric acid (0.05 mmol) and acetic anhydride (24.2 mmol), in toluene (5 mL). The reaction mixture was then heated, under a N2 stream, to 55-60° C. and the reaction was monitored by TLC. Once the reaction was deemed complete the heating mantle was removed and the reaction solution was cooled to ambient temperature. The mixture was then added dropwise to a mixture of saturated aqueous NaHCO3/toluene/CHCl3 (180 mL, 3/10/5), stirred for 20 min, and the layers separated using a reparatory funnel. To the organic layer was added silica gel (14.8 g) and the solvent was removed using a rotary evaporator. The crude product on silica was then purified using a Combi-Flash silica gel purification system using ethyl acetate and hexane as eluents. The purity of the product was analyzed by HPLC: mp=183-186° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H, NH), 3.93 (s, 3H), 2.17 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 167.9, 162.8, 151.7, 149.0, 142.8 (d, JF-C=24 Hz), 136.2 (d, JF-C=80 Hz), 134.7 (d, JF-C=56 Hz), 126.6, 53.2, 22.5; 19F NMR (376.5 MHz, DMSO-d6) δ −114.5; MS Calcd. for C9H7Cl2FN2O3: 280.0. Found: 281 (MH+), 245, 180.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(N)c(N)c1
Yield: 98.2 %

Procedure:
5 g 2-Amino-3,5-dinitropyridine in a mixture of 66 ml methanol and 33 ml THF were hydrogenated over 800 mg 10% palladium on charcoal at room temperature and atmospheric pressure. After the calculated amount of hydrogen was consumed, the catalyst was filtered off and the filtrate was concentrated under vacuum yielding 3.31 g of the crude product which was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]([O:22]C)=[O:21])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cnc(C(=O)CCCCCCc2ccccc2)o1
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 88.5 %

Procedure:
The title compound was prepared from methyl 2-(7-phenylheptanoyl)oxazole-5-carboxylate (71 mg, 0.225 mmol) following General Procedure E. Flash chromatography (EtOAc-2% AcOH/EtOAc) yielded the title compound as a white solid (60 mg, 88%): 1H NMR (CD3OD, 600 MHz) δ 7.62 (s, 1H), 7.22-7.19 (m, 2H), 7.14-7.09 (m, 3H), 3.04 (t, 2H, J=7.5 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.71-1.68 (m, 2H), 1.62-1.59 (m, 2H), 1.41-1.32 (m, 4H); 13C NMR (CD3OD, 150 MHz) δ 189.0, 159.4, 159.4, 143.3, 143.3, 134.6, 128.9, 128.7, 126.1, 39.6, 36.3, 32.0, 29.5, 29.4, 23.9; MALDI-FTMS m/z 302.1382 (M+H+, C17H20NO4, requires 302.1387).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30](OC)(OC)([O:33]C)[O:31][CH3:32].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][O:15][C:30]([O:31][CH3:32])=[O:33])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reactant: COC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)OCC(CO)CCn1cnc2cnc(N)nc21
Reaction time: 1.67 h

Procedure:
To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (237 mg, 1.0 mmol) in dry tetrahydrofuran (3 ml) were added p-toluene-sulphonic acid monohydrate (0.21 g, 1.1 mmol) and tetramethyl orthocarbonate (0.53 ml, 4.0 mmol) and the mixture was stirred for 100 minutes. Water (0.8 ml) was added and after a further 15 minutes the solution was neutralised by addition of aqueous sodium bicarbonate. The solvent was removed and the residue was extracted with chloroform-methanol (3:1). The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (10:1) to afford 2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine which was obtained as a white crystalline solid after trituration with ethyl acetate (65 mg, 22%), m.p. 129°-132°; νmax (KBr) 3440, 3220, 1745, 1650, 1615, and 1580 cm-1 ; &H [(CD3)2SO] 1.73 (1 H, m, 3'-H), 1.81 (2H, m, 2'-H), 3.41 (2H, t, J 5.1Hz, D2O exchange gives d, CH2OH) 3.68 (3H, s, CH3), 4.0-4.2 (4H, m, CH2OCO and 1'-H), 4.65 (1H, t, J 5.2Hz, D2O exchangeable, OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 8.06 (1H, s, 8-H), and 8.55 (1H, s, 6-H); (Observed M+, 295.1286, C12H17N5O4 requires 295.1280).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1
Reactant: C1COCCN1
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Product: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3

Procedure:
A 22.40 gm (0.100 mole) quantity of 3-amino-6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine was added to 225 ml of morpholine and the mixture was refluxed for 7 hours. The mixture was then evaporated. A 250 ml volume of water was added to the residue and the mixture was stirred. The resulting solid was filtered and dried, yielding 27.2 gm of 3-amino-6-(4-morpholinyl)-7,8,9,10-tetrahydro-1,2,4triazolo [3,4-a]phthalazine; mp 260-262° C.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:5]=2[N:4]=1.C(N(CC)CC)C.Cl[CH2:42][CH2:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([N:27]4[CH2:42][CH2:43][CH2:44][C:45]4=[O:46])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOCC4)nc(N[C@H]4CC[C@H](N)CC4)n3)c2c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOCC4)nc(N[C@H]4CC[C@H](N5CCCC5=O)CC4)n3)c2c1
Reaction time: 1 h

Procedure:
To a solution of trans-N-{4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}cyclohexane-1,4-diamine (50 mg) in methylene chloride (1 mL) were added triethylamine (46 μL) and 4-chlorobutyryl chloride (16 mg), followed by stirring for 1 hour in a water bath. The reaction solution was concentrated under reduced pressure and to the residue were added tetrahydrofuran (5 mL) and 60% sodium hydride (13 mg), followed by stirring at 0° C. for 30 minutes and at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate, and the extracts were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100 and chloroform:methanol=100:0-90:10) to obtain 1-[trans-4-({4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]pyrrolidin-2-one (40 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[N:6]=1.[F:11][CH:12]([F:27])[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21](O)=[C:20]([CH3:26])[CH:19]=2)[N:14]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][C:21]2[C:20]([CH3:26])=[CH:19][C:18]([C:15]3[N:14]=[C:13]([CH:12]([F:11])[F:27])[O:17][N:16]=3)=[CH:23][C:22]=2[CH3:24])[S:9][N:8]=1
Reactant: Cc1nsc(CCCO)n1
Reactant: Cc1cc(-c2noc(C(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nsc(CCCOc2c(C)cc(-c3noc(C(F)F)n3)cc2C)n1
Temperature: 20 °C
Yield: 81 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (242 mg, 1.53 mmol), 4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol described in allowed U.S. patent application Ser. No. 07/869,287, incorporated herein by reference (400 mg, 1.67 mmol) , and DEAD (290 mg, 1.67 mmol) was dissolved in 16 mL of THF. To the above solution was added triphenylphosphine (438 mg, 1.67 mmol) at 0° C. and the mixture was allowed to warm to 20° C. overnight. The solvent was removed in vacuo, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride (7×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (10 cm column, ethyl acetate/hexane, from 1/6 to 1/4) followed by recrystallization from ethyl acetate/hexane to afford 471 mg (81%) of 3-methyl-5-[3-[4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole, as a white crystalline solid, m.p. 62°-64° C. 3-Methyl-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole (I, Thi=3-methyl-1,2,4-thiadiazol-5-yl, Y=1,3-propylene, R1 =R2 =methyl, R3 =5-methyl-1,2,4-oxadiazol-3-yl)
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH:7]2[CH3:13].N([O-])=[O:15].[Na+].[Na+].[Cl-]>OS(O)(=O)=O>[OH:15][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH:7]2[CH3:13]
Reactant: O=N[O-]
Reactant: CC1c2cccc(N)c2C(=O)N1C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CC1c2cccc(O)c2C(=O)N1C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
7-amino-2,3-dimethyl-2,3-dihydro-isoindol-1-one (11.45 g) is suspended in a mixture of ice (27 g) and H2SO4 conc. (9.70 mL) and cooled to −10° C. Aqueous sodium nitrite solution (2.5 molar, 31.18 mL) is added dropwise, so that the temperature does not rise above 0° C. and the solution is stirred for 15 min at this temperature. Then H20 (135 mL) is added and the solution is heated to 80° C. for 15 min. For working up it is combined with 10% NaCl solution (100 mL) and extracted twice with 100 mL of CH2Cl2. The organic phase is extracted with NaOH solution (0.2 molar) and then the aqueous phase is acidified (HCl aq. conc.) and re-extracted with CH2Cl2. The organic phase is dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15]>>[Cl:8][C:7]1[C:2]2[NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[N:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CC(C)N=C=S
Reactant: Nc1c(Cl)cc(Cl)cc1S(N)(=O)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)cc(Cl)c2N1
Yield: 15.7 %

Procedure:
Starting from 2-amino-3,5-dichlorobenzenesulfonamide (0.5 g; 2.07 mmol) and isopropyl isothiocyanate (251 mg; 2.48 mmol) with the use of the procedure described in example 4, 100 mg (17.4%) of the title compound was isolated; m.p. >230° C.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[NH:8][CH:7]=[N:6][C:5](=O)[CH:4]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[CH:4]=[C:3]([CH:2]([F:10])[F:1])[N:8]=[CH:7][N:6]=1
Reactant: O=c1cc(C(F)F)[nH]cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)c1cc(Cl)ncn1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
6-(Difluoromethyl)-4(1H)-pyrimidinone (0.50 g, 3.42 mmol) was treated with triethylamine (0.477 mL, 3.42 mmol) and phosphorus oxychloride (1.595 mL, 17.11 mmol) and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure and the residue was poured into 2M aqueous hydrochloric acid solution (5 mL). This solution was extracted with DCM (×2). The DCM layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (117 mg);
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][CH3:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][C:6]([F:16])=[CH:7][C:8]=2[F:15])[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23]>>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:16])=[CH:7][C:8]=2[F:15])[N:3]=[C:2]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[C:11]=1[CH2:12][CH3:13]
Reactant: O=C1CCCCN1
Reactant: CCc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure I using 2,4-dichloro-5,7-difluoro-3-ethylquinoline (400 mg, 1.50 mmol) and piperidin-2-one to give 1-(4-chloro-3-ethyl-5,7-difluoroquinolin-2-yl)piperidin-2-one. Mass Spectrum (ESI) m/e=325.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].CO>O1CCCC1>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COc1c(F)cc(F)cc1C=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(F)cc(F)cc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
To an ice-cold solution of 1.7 g (9.03 mmol) of 3,5-difluoro-2-methoxy-benzaldehyde in 10 ml of dry tetrahydrofuran was added under an argon atmosphere 1 ml of borane dimethylsulfide complex. The reaction mixture was warmed up and stirred for 24 hours at room temperature. Thereupon, the mixture was again cooled to 0° C. and 5 ml of methanol were added dropwise within 30 minutes. Subsequently, the solvent was distilled and the crude product was purified by chromatography on silica gel with a 1:1 mixture of diethylether and dichloromethane as the eluent. There were obtained 0.89 g (56% of theory) of (3,5-difluoro-2-methoxy-phenyl)-methanol as a colorless liquid; MS: 174 (M)+.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]([OH:55])[CH3:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(C)=O.O.Cl>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]([OH:55])[CH3:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(C)O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCCc1nc2ccc(C(C)O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 68.8 %

Procedure:
To a suspension of 2.00 g of 2-butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 70 ml of 3:1 acetone-water is added one drop of 5% aqueous hydrochloric acid solution. The mixture is then heated at reflux for 16 hours. After cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel by elution with 9:1 chloroform-methanol to afford 0.915 g of the desired product as a white solid, m.p. 146°-147° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]([C:7]([N+:13]([O-:15])=[O:14])=[CH:8][C:9]=1[CH2:10][CH:11]=[CH2:12])[CH2:5][OH:6]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc([N+](=O)[O-])c(CO)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1cc([N+](=O)[O-])c(CO)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
4.68 g of 3-hydroxy-6-nitro-4-(2-propenyl)benzylalcohol was dissolved in 90 ml of N,N-dimethylformamide. Thereafter, 3.71 g of potassium carbonate and 3.81 g of iodomethane were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 3.93 g of the subject compound.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]\[CH2:7][N:8]([CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: CNCC=CC#CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Yield: 14.8 %

Procedure:
The procedure described in Example 1 was repeated, except that N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (trans:cis=about 3:1) (17.7 g; 116.8 mmol), sodium carbonate (17.7 g; 166.8 mmol), and 3′-bromomethylacetophenone (23.7 g; 111.2 mmol) were used, to thereby yield 4.67 g of the target compound (yield: 14.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6](=[O:8])[C:5]([C:9](=O)[CH2:10][CH3:11])=[C:4]([OH:13])[CH2:3]1.[Cl:15][C:16]1[S:20][C:19]([CH2:21][O:22][NH2:23])=[CH:18][CH:17]=1>C(O)C.C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([CH2:21][O:22][N:23]=[C:9]([C:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=2[OH:13])[CH2:10][CH3:11])=[CH:18][CH:17]=1
Reactant: NOCc1ccc(Cl)s1
Reactant: CCC(=O)C1=C(O)CC(C)(C)CC1=O
Solvent: CCO
Solvent: ClCCl
Product: CCC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
In this example, a mixture containing 4.0 gms (0.02 mol) of 5,5-dimethyl-3-hydroxy-2-propionylcyclohex-2-en-1-one and 3.6 gms (0.022 mol) of O-[(5-chlorothien-2-yl)methyl]hydroxylamine in 75 mls of ethanol was stirred at room temperature for about 12 hours. The mixture was then evaporated to remove the ethanol, affording a thick syrup. The syrup was then dissolved in methylene chloride and extracted twice with aqueous 5% wt. sodium hydroxide. The aqueous layer was separated and acidified with concentrated hydrochloric acid and then extracted twice with methylene chloride. The methylene chloride layer was separated, dried with magnesium sulfate, and filtered. The filtrate was evaporated under vacuum, affording a viscous liquid which was then purified via column chromatography eluting with tetrahydrofuran-hexane (1:2 vol. ratio) affording 4.8 gms of 2-{1-[(5-chlorothien-2-ylmethoxy)imino]propyl}-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11].[CH3:12][Sn](C)(C)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:12][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1ccc2nc[nH]c2c1Br
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(N)ccc2nc[nH]c12
Temperature: 145 °C
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A solution of 4-bromo-5-aminobenzimidazole (180 mg, 0.84 mmol), tetramethyltin (330 mg, 2.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (20 mg) in 5 ml of anhydrous DMF was placed in sealed tube and stirred for 12 h at 145° C. The reaction mixture was concentrated in vacuo, yielding an oily residue which was subjected to column chromatographic separation (NH3 sat'd 10% MeOH/EtOAc) to yield 140 mg (0.83 mmol, >95%) of 4-methyl-5-aminobenzimidazole.