Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1([CH2:25][CH3:26])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:12]=2)[C:7]1=[O:24])C.[OH-].[Na+].O>C(O)C>[CH2:25]([C:6]1([CH2:5][C:4]([OH:27])=[O:3])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:12]=2)[C:7]1=[O:24])[CH3:26]
Reactant: CCOC(=O)CC1(CC)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1(CC(=O)O)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of ethyl(3-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidin-3-yl)acetate (270 mg) obtained in Step E in ethanol (5 mL) was added dropwise 2M aqueous sodium hydroxide solution (1.4 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was washed with diethyl ether. The aqueous layer was neutralized with 2M hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])=[CH:20][N:19]=[C:18]2[N:28](CC3C=CC(OC)=CC=3)[N:29]=[CH:30][C:17]=12)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C.C(OCC)(=O)C>[CH2:8]([NH:15][C:16]1[C:21]([C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])=[CH:20][N:19]=[C:18]2[NH:28][N:29]=[CH:30][C:17]=12)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3c(NCc4ccccc4)c(C(=O)N(C)OC)cnc32)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CON(C)C(=O)c1cnc2[nH]ncc2c1NCc1ccccc1

Procedure:
Trifluoroacetic acid (5.35 ml, 69.6 mmol) was added to the solution of 4-(benzylamino)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (3 gm, 6.96 mmol) (example 6) in dichloroethane (20 ml) and the reaction mixture was refluxed for about 2 hours under inert atmosphere. It was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][CH:23]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1.CC(N(C)C)=O>CC(=O)CC>[O:31]([CH2:30][CH2:29][CH:23]([CH2:22][C:21]1[CH:38]=[CH:39][C:18]([O:17][CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:19][CH:20]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
2-(2-bromoethoxy)tetrahydropyran (1.24 g) and potassium carbonate (1.09 g) were added to a solution of ethyl 2-(4-hydroxybenzyl)-4-phenoxybutyrate (620 mg), which is the product of Reference example 3(d), in 2-butanone (8 ml). The mixture was stirred at 100° C. for 5 hours. To the reaction mixture dimethylacetamide (10 ml) was added and the mixture was stirred at 100° C. for 1.5 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (738 mg) as a syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1C)[CH:7]=[O:8])[CH3:2].C([O:15][C:16]1[CH:17]=[C:18](C=[CH:22][C:23]=1O)C=O)C.BrC(CC)CC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:15][CH:16]([CH2:17][CH3:18])[CH2:23][CH3:22])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(Br)CC
Product: CCOc1cc(C=O)ccc1OC(CC)CC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMF using K2CO3 as base. MS (ISP): 237.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(#N)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:30][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol), K2CO3 (3.8 g, 27.5 mmol) and ethyl bromopropionate (5 g, 27.6 mmol, 1.2 eq) in acetonitrile (200 ml) was heated at reflux for 16 hours. The mixture was cooled and filtered. The solvent was removed, and the residue was purified on a flash chromatography column (60 g, SiO2, eluted with DCM). The material thus purified weighed 7.27 g (83%). The fumarate salt was prepared by treatment of the free base (2.17 g) with fumaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from ethanol yielded 2.49 g of white crystals, m.p.=135°-136° C.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36](Br)[CH:37]=1)[C:33]#[N:34].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:29][C:30]1[CH:37]=[C:36]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:22]=2)[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1
Reactant: N#Cc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)[Si](OCc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCc1ccc(-c2cc(Br)cc(C#N)c2)cc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.49 g (3.83 mmoles) of boronic acid derivative from Example 4, 2.0 g (7.67 mmoles) of 3,5-dibromobenzonitrile, and 133 mg (0.1 mmoles) of tetrakistriphenylphosphine in 16 mL toluene and 3.4 mL 95% ethanol with 3.47 mL (6.97 mmoles) of 2 N sodium carbonate was stirred vigorously at 80° C. under nitrogen for 3.5 hours.
Reaction SMILES: [F:1][C:2]([S:5][C:6](Cl)=[N:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([F:4])[F:3].Cl[C:18](=[CH2:21])[C:19]#[N:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:21][C:18]=2[C:19]#[N:20])=[CH:10][CH:11]=1
Reactant: C=C(Cl)C#N
Reactant: FC(F)(F)SC(Cl)=NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Yield: 57.8 %

Procedure:
Under a nitrogen purge, a solution of trifluoromethyl-1-chloro-N-(p-chlorobenzyl)thioformimidate (1.1 g, 0.004 mol) and 2-chloroacrylonitrile (0.4 mL, 0.005 mol) is treated with a solution of triethylamine (1.3 mL, 0.009 mol) in toluene. After an induction period, solids begin to form as the reaction mixture exotherms slightly. When the exotherm subsides, the reaction mixture is heated at reflux temperature for 16 hours, cooled and filtered. The filter cake is washed with ehtyl acetate and the filtrate is concentrated in vacuo to obtain a semi-solid. The semi-solid is dissolved in ethyl acetate and the organic solution is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is twice recrystallized from 1,2-dichloroethane to give the title product as a beige solid (0.7 g, mp 203°-205° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH3:14].[H][H]>[Ni].CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[CH3:14]
Reactant: [H][H]
Reactant: Cc1c(NCCO)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1c(N)cccc1NCCO

Procedure:
10 g of the 2-(β-hydroxyethylamino)-6-nitro-toluene prepared under Example 3, stage 2 are transferred to a stainless steel autoclave together with 200 ml of methanol, about 2 g of Raney nickel are added, and catalytic reduction is carried out with hydrogen under a hydrogen pressure of 20 bar at 70° C. in the course of 6 hours. After the catalyst has been removed, the mother liquor is concentrated and the product is isolated and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)C(C1C=CC=CC=1)O>ClCCl>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)C(O)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A suspension of 10 g of 10-methoxyiminostilbene in 250 ml dichloromethane was treated with 17.5 g of sodium cyanate and 24 g of mandelic acid and was heated to reflux for about 6-8 hrs. The reaction mixture was cooled to room temperature and the reaction mixture was washed with distilled water and aqueous sodium bicarbonate and further the organic layer was distilled off completely. The resulting residue was treated with isopropanol; separated solid was filtered and dried to give 10-methoxy carbamazepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:9][CH:8]=1)[NH2:5].[CH2:19](N(CC)CC)C.[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:30](Cl)=[O:31]>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3](=[O:18])[C@:4]([CH3:19])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:9][CH:8]=1)[NH:5][C:30](=[O:31])[C:29]1[CH:28]=[C:27]([CH3:26])[CH:35]=[C:34]([CH3:36])[CH:33]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccsc2)cc1
Reactant: CCN(CC)CC
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@](C)(Cc1ccc(-c2ccsc2)cc1)NC(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 3-[4-(3-thienyl)phenyl]-alanine methyl ester (650 mg) and triethylamine (1.64 g, 11.8 mmol) in 1,4-dioxane (10 ml) is added 3,5-dimethylbenzoyl chloride (517 mg, 3.07 mmol) at room temperature. The mixture is stirred at room temperature overnight. The reaction mixture is diluted with ether and washed with 1N hydrochloric acid, sat. sodium bicarbonate and water. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica with ethyl acetate/hexane (1:2) to give N-(3,5-dimethylbenzoyl)-2-methyl-3-[4-(3-thienyl)phenyl]alanine methyl ester.
Reaction SMILES: [CH3:1]COCC.O=O.[C:8]1([O:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([O:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH4:1].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOCC
Agent: O=O
Solvent: COc1ccccc1
Product: C
Product: Oc1ccccc1

Procedure:
Another feedstock is an ether of general formula R--O--R'. At least one of R or R' must have non-aromatic carbon attached to the oxygen, and otherwise are defined as R above. If R is non-aromatic and R' is aromatic such as in anisole, only the non-aromatic side of the ether will be hydrogenolyzed. Thus anisole will yield methane and phenol. If both R and R' are non-aromatic both sides will be hydrogenolyzed. Thus bibenzyl ether will yield two moles of toluene.
Reaction SMILES: Cl[C:2]1[C@@H:3](N)[CH2:4][CH2:5][CH2:6][CH:7]=1.C1(=O)[N:13](N[C@H](C(O)=O)CC2C=CC=CC=2)[C:12](=[O:26])[C:11]2=CC=CC=[C:10]12>>[C:2]1([CH2:10][CH2:11][C:12]([NH2:13])=[O:26])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NN1C(=O)c2ccccc2C1=O
Reactant: N[C@H]1CCCC=C1Cl
Product: NC(=O)CCc1ccccc1

Procedure:
reacting (S)-2-chloro-cyclohex-2-enylamine with phthalimido-L-phenyalanine derivative to give (S)-N-(2-chloro-cyclohex-2-enyl)-2- 2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl.[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([O:33][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:3]3[C:4]([Cl:16])=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[Cl:1])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1
Reactant: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Yield: 63.7 %

Procedure:
A stirred solution of 1.0 gram (0.0028 mole) of 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene, 0.6 gram (0.0034 mole) of 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol (known compound), and 0.6 gram (0.0043 mole) of potassium carbonate in 25 mL of DMF was heated at 80° C. for about 18 hours. After this time, the reaction mixture was cooled and 50 mL of water was added. The mixture was then extracted with three 25 mL portions of diethyl ether. The combined extracts were washed with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using mixtures of 1:3 methylene chloride:hexane and 1:1 methylene chloride:hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.87 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O.[OH-].[K+]>C(O)C>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[N:9][CH:8]=1)[N:1]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:11]=[CH:4]2
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Nc1ncc(Br)cc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2ccc3cc(Br)cnc3n2)cc1
Yield: 65 %

Procedure:
A mixture of 2-amino-5-bromonicotinaldehyde [prepared by the method of Duggan et al., WO 9818461] (5.53 g, 27.5 mmol), 4-fluoroacetophenone (3.0 mL, 24.8 mmol) and 20% aqueous potassium hydroxide (3.5 mL) in ethanol (400 mL) was heated at reflux for 1 hour. The reaction mixture was allowed to stand at room temperature, the crystals formed collected under suction, washed with ethanol and dried in vacuo to afford 6-bromo-2-(4-fluorophenyl)-1,8-naphthyridine (4.86 g, 65%). 1H NMR (500 MHz, CDCl3) δ 9.12 (1H, d, J 2.5 Hz), 8.34 (1H, d, J 2.5 Hz), 8.32-8.28 (2H, m), 8.18 (1H, d, J 8.5 Hz), 7.99 (1H, d, J 8.5 Hz), 7.25-7.19 (2H, m).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OC[C:36]2[C:37]([C:42]3[CH:47]=CC=CC=3)=[N:38][O:39][C:40]=2C)C=1)=O.NC1CCOCC1>>[O:39]1[CH2:47][CH2:42][CH:37]([NH:38][C:3]([C:5]2[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:36][CH2:40]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(C3CCOCC3)noc2C)nn1C
Agent: NC1CCOCC1
Product: Cc1onc(C2CCOCC2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 76 %

Procedure:
As described for example 1b, 2-methyl-5-[5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (200 mg, 0.6 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (183 mg, 76%) which was obtained as a colorless gum. MS: m/e=403.1 [M−H]−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(#N)C>[N+:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:6](=[O:18])[CH2:7][CH2:8]2)([O-:17])=[O:16]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCCCC1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), piperidine (355 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension stirred in a heating block at a temperature of 65° C. for 18 hours. As starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a separatory funnel. The organic layer was collected, and the aqueous layer extracted twice more with dichloromethane (2×10 mL). The combined organic fractions were washed with brine (15 mL) and dried over sodium sulphate. The solution was decanted and concentrated to afford a yellow oil. The product was purified using flash chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5-5:95-97.5) to afford a yellow oil. Yield: 102 mg yellow oil (89%). 1H NMR (CDCl3) δ: 8.13 (dd, J=2.7, 9 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.39-2.35 (m, 6H), 1.88-1.79 (m, 2H), 1.64-1.45 (m, 6H). MS (EI): 317 (M+).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][C:4]([CH2:6]Cl)=[O:5].C(OCC)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl-:2].[Cl:2][CH2:3][C:4](=[O:5])[CH2:6][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: O=C(CCl)CCl
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CCl)C[n+]1ccccc1
Reaction time: 8 h

Procedure:
66.9 g of 1,3-dichloroacetone chloride are introduced into a three-necked flask containing 800 cm3 of diethyl ether. 28 cm3 of pyridine are added dropwise and the mixture is kept stirring overnight. The precipitate obtained is filtered, washed with twice 100 cm3 of diethyl ether and then dried at 40° C. under 90 Pa to give 29.2 g of 1-(3-chloro-2-oxopropyl)-pyridinium chloride in the form of a cream-coloured solid melting at 92° C. and which is used as it is.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH:4]=[N:5][C:6]([CH3:11])([CH3:10])[CH2:7][O:8][CH3:9].[BH4-].[Na+].C([O-])(O)=O.[Na+].O>CO>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]([CH3:11])([CH3:10])[CH2:7][O:8][CH3:9]
Reactant: COCC(C)(C)N=Cc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(C)(C)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution of the obtained N-(2,4-difluorobenzylidene)-N-[dimethyl(methoxymethyl)methyl]amine in methanol (7 ml) was cooled to 0° C. in ice-water bath. To the solution was added NaBH4 (117.1 mg, 3.09 mmol). The mixture was gradually warmed to room temperature and stirred for 14 hours. The mixture was added to sat. NaHCO3 aqueous solution and water was added to dissolve the precipitated white solid. The mixture was then extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ethyl acetate/triethylamine=50/25/1) to give N-(2,4-difluorophenylmethyl) -N-[dimethyl(methoxymethyl)methyl]amine (378.8 mg; 95% in 3 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:19]([CH3:20])[C:18]4[NH:21][CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:19]([CH3:20])[C:18]4[N:21]([CH3:31])[CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: CI
Reactant: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc(=O)c2cc[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ccc2c(=O)nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c21
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
Under argon gas, 2-[4-(4-chlorobenzoyl) benzyl]thio-1-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-one (103 mg) was dissolved in anhydrous DMSO (20 ml) with warming. Then, at room temperature, 60% sodium hydride-oil (11 mg) was added and the mixture was stirred for 20 minutes. Then, methyl iodide (42.6 mg) was added and the mixture was further stirred overnight. The reaction mixture was diluted with water (200 ml) and the resulting precipitate was collected by filtration, dried, and purified by flash column chromatography (silica gel; chloroform-ethanol: chloroform=1:49) to provide the title compound (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[CH3:27][C:28]1[CH:33]=[C:32]([NH2:34])[C:31]([NH2:35])=[C:30](C)[C:29]=1[CH3:37].[CH3:38][Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[N:35]([CH3:38])[C:31]4[CH:30]=[C:29]([CH3:37])[C:28]([CH3:27])=[CH:33][C:32]=4[N:34]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Cc1cc(N)c(N)c(C)c1C
Reactant: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc2cc(C)c(C)cc2n1C

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), trimethylbenzene-1,2-diamine (Intermediate-31, 0.048 g, 0.32 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 2.36 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.33 (s, 1H), 7.41 (s, 1H), 7.47-7.59 (m, 3H), 7.66-7.78 (m, 3H), 12.5 (br s, 1H); MS (m/z): 478.29 (M+H+).