Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:32]1([C:31]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[O:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (90 mg, 0.276 mmol) (Example 11b) in chloroform (2 mL) was added triethylamine (0.115 mL, 0.827 mmol) followed by benzoyl chloride (0.053 mL, 0.414 mmol). The reaction mixture was stirred at room temperature for 1 hr. A saturated solution of NH4Cl was added, and layers were separated. The organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Phenyl(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methanone (45 mg, 0.128 mmol, 46.3% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.44-7.50 (m, 3H), 7.36-7.43 (m, 2H), 7.20-7.28 (m, 2H), 7.10-7.17 (m, 1H), 7.03-7.09 (m, 2H), 4.66 (d, J=12.88 Hz, 1H), 3.74 (d, J=12.63 Hz, 1H), 3.03-3.22 (m, 1H), 2.87 (t, J=12.51 Hz, 1H), 2.66 (dd, J=3.03, 6.32 Hz, 2H), 2.22-2.37 (m, 1H), 1.80-2.05 (m, 3H), 1.74 (d, J=13.14 Hz, 1H), 1.12-1.40 (m, 2H), 1.09 (dt, J=4.86, 9.47 Hz, 1H), 0.98-1.05 (m, 1H); LC-MS Rt=0.81 min; MS (ESI): 335.3 [M++H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:13][S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:19][CH2:18][CH2:17][S:14]2(=[O:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=S(=O)(CCCCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of N-[3,5-bis(trifluoromethyl)phenyl]-3-chloropropanesulfonamide (7.10) obtained in Reference Example 37 in N,N-dimethylformamide (100 mL) was added sodium hydride (60% in oil, 0.84 g), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated ammonium chloride and the solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-40:60) to give the title compound (2.44 g, yield 38%) as a pale-brown solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6](=[O:14])[C:5]2[CH:15]=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:17]=[CH:18][C:4]1=2)[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([N:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6](=[O:14])[C:5]2[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1Cc2ccccc2C(=O)c2cc(CC(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1Cc2ccccc2C(=O)c2cc(CC(=O)O)ccc21
Yield: 81.5 %

Procedure:
A mixed liquid of methyl 5,6-dihydro-5-ethyl-11-oxodibenz[b,e]azepine-2-acetate (0.9 g), sodium hydroxide (2 g), methanol (50 ml) and water (20 ml) was heated under refluxing for 2 hours. After the reaction, methanol was distilled off, and the remaining aqueous layer was washed with ether. The aqueous layer was treated with activated carbon powder, and a 5% sulfuric acid aqueous solution was added while cooling the layer with ice. The precipitated crystals were collected by filtration, washed in water, and vacuum-dried over P2O5 to obtain 5,6-dihydro-5-ethyl-11-oxodibenz[b,e]azepine-2-acetic acid (0.7 g), the desired compound, as yellow powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][N:13]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][CH:10]=2)=[CH:5][C:4]=1[N+:18]([O-])=O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][N:13]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][CH:10]=2)=[CH:5][C:4]=1[NH2:18]
Reactant: CCCN1CCC=C(c2ccc(OC)c([N+](=O)[O-])c2)C1
Agent: Cl
Solvent: CCO
Product: CCCN1CCC=C(c2ccc(OC)c(N)c2)C1
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To 5-[4-(methyloxy)-3-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (0.25 g, 0.91 mmol) in absolute ethanol (50 mL) was added Sn2CL2×2H2O (1.22 g, 5.41 mmol, Aldrich) and a catalytic HCl (1 mL, 1M solution in dioxanes). After stirring overnight, the reaction was quenched with saturated sodium bicarbonate solution (50 mL), stirred at RT for 1 hr, solids removed by vacuum filtration through a celite pad and rinsed with methanol. The solvent was removed under reduced pressure, aqueous layer extracted with dichloromethane (2×50 mL), combined organic extracts adsorbed to silica gel and purified by silica gel chromatography (dichloromethane to 5% methanol/dichloromethane+0.1% NH4OH) to afford 2-(methyloxy)-5-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)aniline (0.145 g, 65%). 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (t, J=7.52 Hz, 3 H) 1.56-1.66 (m, 2 H) 2.28-2.36 (m, 2 H) 2.43-2.48 (m, 2 H) 2.58 (t, J=5.87 Hz, 2 H) 3.23-3.29 (m, 2 H) 3.84 (s, 3 H) 5.94-6.01 (m, 1 H) 6.68-6.76 (m, 3 H). ESIMS (M+H)+=247.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C(F)(F)F)c1
Yield: 95.9 %

Procedure:
A solution of 4-nitro-3-trifluoromethylanisole (26 g, 120 mmol) in ethyl acetate (250 mL) was hydrogenated over 10% palladium on carbon (5.3 g) at 50 psi for 1.5 h. At this time, the solution was filtered through Celite and washed with ethyl acetate (250 mL). The filtrate was concentrated in vacuo to give the title compound (22 g, 97%) as an amber oil which was pure enough for further use.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[OH:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:66](=[O:65])[CH2:67][OH:68])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro-phenyl)-1,3-oxazinan-2-one stirred in anhydrous CH2Cl2 (5 ml) was added HOBT (36 mg, 0.264 mmol), EDCl (52 mg, 0.264 mmol), DIEA (0.5 ml) and hydroxy-acetic acid (50.1 mg, 0.66 mmol) at 0° C. under N2 atmosphere. The solution was stirred at rt overnight. Then the solvent was removed under reduced pressure to give the residue, which was purified by preparative HPLC to afford N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-2-hydroxyacetamide (19.2 mg, 28.6%). 1H NMR (CDCl3): 1.49-1.50 (d, 3H), 2.01-2.13 (m, 1H), 2.14-2.15 (m, 3H), 2.17 (m, 1H), 2.97-2.98 (m, 2H), 3.46-3.52 (m, 4H), 4.01-4.02 (m, 2H), 5.60-5.61 (m, 1H), 6.82-6.88 (m, 2H), 6.98-7.04 (m, 3H), 7.17 (s, 1H), 7.19-7.22 (m, 3H), 7.25-7.27 (m, 3H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([CH2:24][C:25]([O:27]CC)=[O:26])[CH:18]=[CH:17][C:16]=3[CH2:15]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([CH2:24][C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]=3[CH2:15]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
28 ml of ethanol and 10 ml of a 2N aqueous sodium hydroxide solution are added to 2.81 g of ethyl 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate, and the mixture is stirred at room temperature overnight. After ethanol is removed from the mixture, water is added thereto, and the mixture is washed with methylene chloride. 10% hydrochloric acid is added to the water layer, and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent, and the residue is recrystallized from a mixture of ethyl acetate and n-hexane to give 2.16 g of 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetic acid as pale brown prism.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:15]([OH:23])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:24][CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[CH:34]=2)[NH:29][C:28]([CH3:45])([CH3:44])[CH:27]=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(Cl)Cl>[CH3:43][O:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:45])([CH3:44])[CH:27]=[C:26]2[CH2:25][NH:24][C:15](=[O:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CN)=CC(C)(C)N2
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccccc1-c1ccc2c(c1)C(CNC(=O)c1ccccc1)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
A round bottom flask equipped with a stir bar was charged with EDC (0.224 mmol, 1.1 equiv), HOBT (0.224 mmol, 1.1 equiv), benzoic acid (0.224 mmol, 1.1 equiv), 4-aminomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline (0.204 mmol, 1 equiv) and 3.3 mL of methylene chloride. Diisopropyl ethyl amine (0.224 mmol, 1.1 equiv) was added last, the reaction was placed under argon, and stirred at room temperature overnight. The crude reaction mixture was transferred to a separatory funnel, diluted with EtOAc, and washed with 1 N HCl, aqueous saturated sodium bicarbonate (NaHCO3) solution, and brine. The organics were concentrated in vacuo to afford a brown oil. The product was purified by column chromatography using silica gel eluting with a gradient of 10-50% EtOAc/hexanes. The product fractions were pooled and concentrated in vacuo to afford 18 mg of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:29]=[CH2:30])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.[OH2:39].CC(C)=O.[OH2:44]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:29]([OH:44])[CH2:30][OH:39])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: C=Cc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(C(O)CO)ccn12
Temperature: 25 °C

Procedure:
To a solution of N-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide (27 mg; 0.069 mmol) in acetone/water (3:2; 1 mL) were added osmium tetroxide (0.1 equivalents as a 2% solution in t-butanol) and N-methylmorpholine N-oxide (1.2 equivalents as a 50% solution on water). The mixture was stirred at ambient temperature for several days. Further aliquots of osmium tetroxide and N-methyl morpholine N-oxide were added at intervals until the reaction was complete by LC. The mixture added to water and extracted into ethyl acetate. Some insoluble material was isolated by filtration. The extracts were combined, concentrated under vacuum and combined with the solids isolated by filtration. The combined material was purified by preparative thin layer chromatography on silica, eluting with dichloromethane/ethanol/ammonium hydroxide (100:20:0.5) to give the desired product (2.6 mg). MS (APCI), m/z=428.2 (M+H).
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.[CH2:15](O)[CH3:16]>>[CH2:15]([O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1)[CH3:16]
Reactant: CCO
Reactant: Cc1ccc2c(O)cc(=O)oc2c1
Agent: Cl
Product: CCOc1cc(=O)oc2cc(C)ccc12
Yield: 72 %

Procedure:
Dry hydrogen chloride was passed through a solution of 4-hydroxy-7-methylcoumarin (14 g; 0.08 mole) in ethanol (300 ml) for 15 mins and the resulting solution was refluxed for 30 minutes. After cooling, the solvent was removed in vacuo and the residue recrystallized from ethanol to give 11.74 g (72%) of product of m.p. 142°-143° C.; (Found; C, 70.24; H, 5.95; C12H12O3 requires; C, 70.60; H, 5.88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][NH2:23])[C:7]=1[CH2:13][CH3:14]
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: NCCCl
Agent: Cl
Product: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 53.5 %

Procedure:
The pyrazole of Example 11 (5.47 g, 19.3 mmol) was mixed with 2-chloroethylamine hydrochloride (2.46 g, 21.3 mmol) and heated neat at 150° C. for 20 hours. After cooling, the solid was partitioned between dichloromethane and 10% aqueous potassium carbonate solution. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (3.37 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([Cl:11])=[CH:7][CH:8]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)#[N:19]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:10]([CH2:23][C:22]2[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=2)[C:18]#[N:19])[C:9]2[C:4](=[N:5][C:6]([Cl:11])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Clc1ccc2[nH]c(Br)cc2n1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1

Procedure:
2-Bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (2.0 g, 8.6 mmol, prepared as in Example 103, Step 1) in DMF (20. mL) was treated with K2CO3 (1.8 g, 13 mmol) and m-cyanobenzyl bromide (1.9 g, 9.5 mmol, Aldrich) overnight. The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The solid obtained was triturated with hexanes/diethyl ether and isolated by filtration. Yield: (2.3 g, 77%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:22](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15]#[N:22])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)o1
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)o1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1c) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-2-furaldehyde (9.1 g, 38 mmol) [reference literature: Tetrahedron, vol. 50 (23), 6767 (1994)], hydroxylamine hydrochloride (2.9 g, 42 mmol), triethylamine (11 ml, 76 mmol) and N,N′-dicyclohexylcarbodiimide (8.6 g, 42 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (7.5 g) in a yield of 84% as a colourless oily product.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(O)C>O.[OH-].[Na+]>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[C:3]2[O:4][CH:5]=[CH:6][C:7](=[O:8])[C:2]=2[OH:1])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=c1ccocc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1ccoc(C(O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[4-Fluorophenyl)-hydroxy-methyl]-3-hydroxy-pyran-4-one: With stirring at room temperature, 5.6 g of pyromeconic acid (3-hydroxy-pyran-4-one) [CAS No.: 496-63-9] are dissolved in 10 ml of water and 24.5 ml of 2N NaOH. 6.33 g of 4-fluorobenzaldehyde and 25 ml of ethanol are added and the reaction mixture is stirred at room temperature for 18 hours. For working-up, the ethanol is removed using a rotary evaporator and the aqueous solution that remains is neutralised with 24.5 ml of 2N HCl. The product that has crystallised out is filtered off, washed with water and dried, yielding 2-[(4-fluorophenyl)-hydroxy-methyl]-3-hydroxy-pyran-4-one in the form of colourless crystals. M.p.: 154°-156° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]=[C:2]1[N:8]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc2c1NC(=O)CCC2
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1N(COCC[Si](C)(C)C)C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.500 g of methyl 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-9-carboxylate are dissolved under argon in 30 ml of N,N-dimethylformamide and the solution is cooled to 0° C. in an ice bath. 0.600 g of sodium hydride dispersion (60%) is added in portions and the reaction mixture is subsequently stirred at 0° C. over a further 1 hour. 0.502 ml of 2-(trimethylsilyl)ethoxymethyl chloride is added and the reaction mixture is subsequently stirred at room temperature over 11 hours. The reaction mixture is poured onto 150 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2×150 ml of tert-butyl methyl ether. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a reddish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (1:1 EtOAc-heptane); Rt=5.02.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH:27]1[CH2:29][C:28]1([F:31])[F:30]>C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:11])[N:10]([CH2:26][CH:27]3[CH2:29][C:28]3([F:31])[F:30])[C:5]2=[CH:4][CH:3]=1
Reactant: FC1(F)CC1CBr
Reactant: O=c1[nH]c2ccc(Cl)nc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1sc2nc(Cl)ccc2n1CC1CC1(F)F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 5-chloro[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-4) (3.5 g, 19 mmol), anhydrous NMP (30 mL), anhydrous 1,4-dioxane (60 mL), cesium carbonate (12 g, 37 mmol), followed by 2-(bromomethyl)-1,1-difluorocyclopropane (3.4 g, 20 mmol). The reaction mixture was then heated to 95° C. while stirring in a hot oil bath for 18 hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-40% EtOAc/Hex) to give 5-chloro-1-[(2,2-difluorocyclopropyl)methyl][1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-5) as a tan solid. HRMS (M+H)+: observed=277.0008, calculated=277.0008.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2([CH2:21][CH2:22][CH3:23])[O:18][CH2:17][CH2:16][N:15]([CH3:19])[C:14]2=[O:20])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([C:13]2([CH2:21][CH2:22][CH3:23])[O:18][CH2:17][CH2:16][N:15]([CH3:19])[C:14]2=[O:20])[CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1(c2cccc(OC)c2)OCCN(C)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCC1(c2cccc(O)c2)OCCN(C)C1=O
Reaction time: 16 h

Procedure:
BBr3 (1M in CH2Cl2) (0.341 mL, 0.341 mmol) was added dropwise to a solution of 2-(-3-methoxy-phenyl)-4-methyl-2-propyl-morpholine-3-one, as described above in Step D, (0.06 g, 0.227 mmol) in CH2Cl2 (3 mL) at 0° C. with stirring. The ice bath was removed and stirring was continued for 16 h. The reaction mixture was quenched with H2O, concentrated to dryness, then dissolved in MeOH and purified by RP preparative HPLC on a PrepPak (95/5 to 5/95 H2O/CH3CN w/0.1% TFA, flow=65 mL/min) to give the title compound. FAB MS (M+1) 250.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[Br:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Br
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1Br

Procedure:
Using 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (55 mg, 0.20 mmol) and methyl 2-bromo-4-hydrazinocarbonylbenzoate (60 mg, 0.22 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a yellow solid (92 mg, yield 87%).