Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:10]=O)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:10]=[N:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(C=O)CCCC1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCCC1
Yield: 43.7 %

Procedure:
A mixture of 1-formyl-cyclopentanecarboxylic acid methyl ester (3.1 g, 19.8 mmol), sodium acetate (2.74 g, 39.72 mmol) and O-benzylhydroxylamine hydrochloride (6.34 g, 39.7 mmol) were stirred in methanol (120 mL) for 18 h. The methanol was removed in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5 to 90:10) provided the title compound as a clear colorless oil (2.26 g, 44%). MH+262.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:16]1[O:27][C:26]2[C:18](=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=O)[O:17]1.[NH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[NH:31][N:30]=1>C1COCC1.O>[Cl:45][C:41]1[CH:40]=[C:39]([NH:38][C:36]2[N:35]=[CH:34][N:33]=[C:32]3[NH:31][N:30]=[C:29]([NH:28][C:20](=[O:22])[C:19]4[CH:23]=[CH:24][CH:25]=[C:26]5[O:27][CH2:16][O:17][C:18]=45)[C:37]=23)[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)c1cccc2c1OCO2
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12)c1cccc2c1OCO2
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, 320 μl (2.9 mmol) of NMM and 210 1 (1.6 mmol) of isobutyl chloroformate are added at −20° C. to 250 mg (1.5 mmol) of 2,3-methylenedioxybenzoic acid [for preparation see: Chem. Ber. 104 (1971) 2347] in 3.2 ml of THF and then stirred for 45 min. 378 mg (1.45 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine (see Step 1.6) are then added and the reaction mixture is allowed to rise to RT and is stirred for 1 hour to complete the reaction. The reaction mixture is poured into 100 ml of water and stirred for 1 hour, and the crude product is filtered off and washed with water and ethanol. Dissolution in 3 ml of DMSO at =110° C., cooling, filtering and washing with ethanol yield 4-(3chloro-phenylamino)-3-(2,3-methylenedioxy-benzoylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=16.5; FAB-MS: (M+H)+=409.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].NC(N)=N.C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(F)ccc1N
Agent: N=C(N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc(F)c([N+](=O)[O-])cc1N
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a suspension of 4-fluoro-2-methoxyaniline (0.71 g) in concentrated sulfuric acid (7.5 mL) was added guanidine nitrate (0.61 g) under ice-cooling over 15 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution cooled in ice, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.78 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]([CH3:31])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23](OS(C)(=O)=O)[CH3:24])[C:17](=[O:18])[C:12]=2[C:11](=[O:32])[CH:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CS(C)=O>[N:34]([C@H:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17](=[O:18])[C:12]2[C:11](=[O:32])[CH:10]=[C:9]([CH3:33])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@H](C)OS(C)(=O)=O)c(=O)n(C)c2n1Cc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n(C)c2n1Cc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of the crude (S)-8-benzyl-1,7-dimethyl-3-(5-methanesulfonyloxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione, dimethylsulfoxide (6 ml) and sodium azide (116 mg, 1.79 mmol) was heated at 600 C for 18 hours. After cooling to room temperature, the mixture was partitioned between water (50 ml) and ethyl acetate (50 ml) and the aqueous layer was extracted with ethyl acetate (50 ml). The combined extracts were rinsed with water and with saturated aqueous sodium chloride solution. Concentrating under reduced pressure afforded (R)-3-(5-azidohexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (380 mg, 99% yield for 2 steps) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.22 (d, 3H), 1.36-1.60)m, 4H), 1.62-1.78 (m, 2H), 2.48 (s, 3H), 3.43 (m, 1H), 3.64 (s, 3H), 4.03 (t, 2H), 5.29 (s, 2H), 6.55 (s, 1H), 7.29
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C.Cl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Br)cc1NC1CCCCC1

Procedure:
A mixture of 4-bromo-2-fluorobenzoic acid (1.0 g) and cyclohexylamine (10 ml) was stirred under reflux for 5 hours. The mixture was poured into ethyl acetate (50 ml) and water (50 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-bromo-2-(cyclohexylamino)benzoic acid (1.32 g).
Reaction SMILES: [N+:1](=[C:3]([C:19](=[O:21])[CH3:20])[C:4]([O:6][CH2:7][C@@H:8]([C:16]([OH:18])=[O:17])[NH:9]C(=O)C(F)(F)F)=[O:5])=[N-:2]>O>[N+:1](=[C:3]([C:19](=[O:21])[CH3:20])[C:4]([O:6][CH2:7][C@@H:8]([C:16]([OH:18])=[O:17])[NH2:9])=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Solvent: O
Product: CC(=O)C(=[N+]=[N-])C(=O)OC[C@H](N)C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
A solution of O-(2-diazo-1,3-dioxobutyl)-N-trifluoroacetyl-L-serine (193 mg) and Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (60 mg) in water (6 ml) was neutrized to pH 7.0-7.3 with 2M tris buffer solution and the mixture was stirred for 4 hours at 40° C. The reaction mixture was chromatographed on carbon (20 ml) eluting successively with water, a 1:1 mixture of acetone and water and acetone to give a crude solid (100 mg). The above solid (50 mg) was chromatographed on silica gel (2.5 g) eluting successively with a 9:1 mixture of chloroform and methanol and a 65:25:4 mixture of chloroform, methanol and water to give O-(2-diazo-1,3-dioxobutyl)-L-serine (22 mg).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].C(N(C(C)C)CC)(C)C>C(#N)C>[C:7]1([C:6]2[C:2]([O:1][S:13](=[O:16])(=[O:15])[NH2:14])=[N:3][S:4][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1nsnc1-c1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)Oc1nsnc1-c1ccccc1

Procedure:
A slurry of 3-hydroxy-4-phenyl-1,2,5-thiadiazole (15.0 g, 0.084 mole) in acetonitrile (100 ml) was treated by the simultaneous dropwise addition of a sulfamoyl chloride solution in acetonitrile (0.20 mole, 66 ml of 3M) and a diisopropylethylamine solution (0.22 mole in enough 1:1 acetonitrile/methylene chloride to make 66 ml). High Pressure Liquid Chromatography analysis indicated a maximum of 85% conversion of starting material to product. The reaction was worked up by concentration of the reaction mixture and partitioning the residue between ethyl ether and water. Concentration of the ether fraction gave a white paste from which desired product was separated by dissolving in a small amount of acetonitrile. The product was crystallized from the acetonitrile to give 2.8 g (13%) of the title compound as a white powder, mp 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=2[O:25][CH3:26])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C(C)=CC=CC=1C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O.O>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:1][C:2]2[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[O:25][CH3:26])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3ncccc3c2N)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2ncccc2c1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 24.4 (36 mg, 0.1 mmol) and 2,6-lutidine (0.024 mL, 0.2 mmol) in THF (0.5 mL) was added 4-chlorobenzenesulfonyl chloride (26 mg, 0.12 mmol). The mixture was stirred at 70° C. overnight. After cooling, water (1 mL) and 10N NaOH (0.5 mL) were added. The mixture was stirred at room temperature for 5 h. 3N HCl (1.7 mL) and EtOAc were added to the mixture, and the organic layer was separated, dried with MgSO4 and concentrated. Flash column chromatography of the residue afforded 24. MS ESI (pos.) m/z: 499.1 (M+H). 1H NMR (DMSO-d6) δ 10.2 (bs, 1H), 8.82 (d, 1H); 8.50 (d, 1H); 7.92 (d, 1H); 7.71 (d, 2H); 7.61 (dd, 1H); 7.55 (d, 2H); 7.03 (d, 1H); 6.95 (d, 1H); 6.79 (dd, 1H); 6.38 (d, 1H); 3.73 (s, 3H); 3.58 (s, 2H).
Reaction SMILES: C(OC(=O)[C@H](O[C:8]1C=C(Cl)N=C(SCC2C=CC=C(F)C=2F)[N:9]=1)C)C.C([O:28][C:29](=O)[C@H:30]([O:32][C:33]1[CH:38]=[C:37]([NH:39][S:40]([N:43]2[CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])[N:36]=[C:35]([S:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=2[F:56])[N:34]=1)[CH3:31])C.CN>C(O)C>[N:43]1([S:40]([NH:39][C:37]2[N:36]=[C:35]([S:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=3[F:56])[N:34]=[C:33]([O:32][C@H:30]([CH3:31])[C:29]([NH:9][CH3:8])=[O:28])[CH:38]=2)(=[O:41])=[O:42])[CH2:44][CH2:45][CH2:46]1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: CN
Solvent: CCO
Product: CNC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 23) (100 mg) in ethanol (1.5 mL) was added 8M methylamine in ethanol. The resulting mixture was stirred in a sealed tube at ambient temperature for 16 h. The solvent was evaporated under reduced pressure. Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) to give the title compound as a white solid. Yield: 60 mg
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[C:20](=[O:21])[N:11]3[C:12]4[C:17]([C:18]([CH3:19])=[C:10]3[CH2:9][CH2:8]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=[CH:2]1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]2[C:20](=[O:21])[CH:7]([CH2:6][C:4]3[N:3]=[CH:2][N:1]([CH3:24])[CH:5]=3)[CH2:8][CH2:9][C:10]=12
Reactant: CI
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1c[nH]cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1cn(C)cn1)CC2
Temperature: 5 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a solution of 8,9-dihydro-7-[(1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.4 g) in N,N-dimethylformamide (14 ml) at 5° C. was added sodium hydride (60% in mineral oil) (220 mg). After stirring for 1 hour at 5° C., methyl iodide (852 mg) in dimethylformamide (5 ml) was added dropwise at 5° C. for 10 minutes. The mixture was stirred at 5° C. for 1 hour and at 20° C. for 2 hours. After evaporation of the solvent, the residue was diluted with 5% methanol-chloroform. The organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The obtained residue contained two products which showed close Rf values (0.5 and 0.4 respectively) by TLC (20% methanol-chloroform). Separation with silica gel column chromatography (5% methanol-chloroform) gave two fractions. The first eluted fraction, containing a mixture of two products, was concentrated. The crystalline residue was recrystallized from ethyl acetate to give 8,9-dihydro-10-methyl-7-[(1-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)=[C:5]([F:26])[CH:4]=1)#[N:2].[Cl-].[Li+].[OH-].[Li+].Cl>CN1CCCC1=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])=[C:5]([F:26])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3F)c2OC)nc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)c(F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Combined the product of the preparation above, methyl 6-(4-(4-cyano-2-fluorophenyl)-5-methoxy-1H-pyrazol-1-yl)nicotinate (300 mg, 0.638 mmol) and lithium chloride (135 mg, 3.19 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) and heated at 60° C. for 16 h. Then 1.0 M aqueous lithium hydroxide (3 mL, 3.00 mmol) was added and stirred at 20° C. for 4 h. The reaction mixture was then acidified with 1 N aqueous HCl (5 mL) to form a yellow precipitate. The precipitate was collected by filtration, rinsed with water and dried under high vacuum (ca. 10 Pa) to give the title compound containing 0.9 equiv. N-methyl-2-pyrrolidinone (230 mg, quantitative yield) as a brown solid. MS m/z 325 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (dd, J=8.2, 1.6 Hz, 1H) 7.80 (dd, J=11.7, 1.6 Hz, 1H) 8.24 (br. s., 1H) 8.38-8.44 (m, 1H) 8.52 (br. s., 2H) 8.87-8.94 (m, 1H) 13.40 (br. s., 1H).
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:10]2[C:5]([NH:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]2[CH3:22])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][O:36][CH3:37])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][O:36][CH3:37])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH3:22])[C:8](=[O:23])[C:7]([CH3:25])([CH3:24])[NH:6]2
Reactant: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Reactant: COCOc1ccc(B(O)O)c(OC)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-1, 2.32 g, 5.70 mmol), 2-methoxy-4-methoxymethoxyphenylboronic acid (Reference Compound No. 7, 2.43 g, 11.5 mmol), cesium carbonate (9.46 g, 29.0 mmol), and bis(triphenylphosphine)palladium (II) dichloride (415 mg, 0.591 mmol) was suspended in anhydrous N,N-dimethylformamide (25 ml) and the mixture was stirred at 80° C. for 5 hours. After cooling down, ethyl acetate (150 mL) and water (150 mL) were added and partitioned. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (2.73 g) as a colorless solid. (Yield 97%)
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]C1C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:43]=[C:44]([CH2:50][NH:51][CH2:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=[CH:46][C:47]=1[CH:48]=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([O:41][C:42]1[CH:43]=[C:44]([CH2:50][NH:51][CH2:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=[CH:46][C:47]=1[CH:48]=[CH:7][C:3]1[S:2][CH:6]=[CH:5][CH:4]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)OCCNCc1ccc(C=O)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCCNCc1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Thiophene-2-ylmethyl triphenylphosphonium chloride (9.0 g, 22.7 mmol) was added to THF (80 ml), and PhLi (12.0 g of 19% solution in hexane, 27.2 mmol) was added dropwise thereto in an ice bath. After 20 minutes, 2,2-dimethylpropionic acid 2-[(3-benzyloxy-4-formylphenyl)methylamino]ethyl ester (7.0 g, 18.9 mmol) dissolved in THF (20 ml) was added dropwise. The mixture was reacted for 2 hours. After the reaction mixture was added to 300 ml of ice water, the oily matter was subjected to 3 times of extraction with dichloromethane (50 ml). Washing with a saturated saline solution, drying over Na2SO4, and concentration were performed. The residue was purified by silica gel chromatography to give a yellow oily matter (yield: 7.15 g (84.5%)).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2.[OH-].[Na+]>O.CC(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Clc1cc(Oc2ccc3ncccc3c2)ncn1
Reaction time: 3 h

Procedure:
A solution of 7.45 g (50 mMol) of 4,6-dichlor-pyrimidine, 7.64 g (50 mMol) of 6-hydroxy-chinolin and 2.0 g (50 mMol) NaOH dissolved in 200 ml of H2O/acetone 1:1 is stirred for 3 h. The resulting solid is filtered off, washed with H2O/acetone ans dried: m.p.: 136-137° C.; MS: [M+1]+=258.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([Cl:11])=[CH:9][N:8]([CH:12]([F:14])[F:13])[N:7]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])(O)(=O)=O.[K+].CCOCC>O1CCCC1>[Cl:11][C:10]1[C:6]([CH:4]=[O:5])=[N:7][N:8]([CH:12]([F:13])[F:14])[CH:9]=1
Reactant: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1nn(C(F)F)cc1Cl
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (930 mg, 3.9 mmol) in tetrahydrofuran (30 ml) was cooled to 0° C. and treated dropwise with a solution of lithium aluminium hydride in tetrahydrofuran (1M, 2 ml). Stirring was continued at 0° C. for 45 minutes. In order to complete the reaction, another 2 ml of the solution of lithium aluminium hydride in tetrahydrofuran (1M) was added. After 45 minutes the reaction mixtures was cooled to −15° C. and a saturated solution of potassium hydrogensulphate (25 ml) was added dropwise. Stirring was continued at −15° C. for 10 minutes, then ether (30 ml) was added and again stirred for 30 minutes. Thereafter, the reaction mixture was left to warm to room temperature, the organic layer separated, washed with water, finally dried over sodium sulphate and evaporated. The crude material was purified by chromatography on silica gel using a 4:1-mixture of cyclohexane and ethyl acetate as the eluent. The 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde was obtained as a colourless oil (582 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[C:19]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:32]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[CH:19]=[O:32]
Reactant: CO
Reactant: Cc1cn(-c2cc(C#N)c(N)c(C(F)(F)F)c2)c(C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(C=O)c(N)c(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C

Procedure:
To an ice-cooled stirred solution of 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4-dimethylimidazole (0.7 g) in tetrahydrofuran (10 cm3) was added 3.5 cm3 of a 1.5M solution of diisobutyl aluminium hydride in toluene. The mixture was heated at 40° for 2 hours, cooled in ice, treated with methanol (2 cm3), and evaporated in vacuo. The residue was treated with water (25 cm3) and 2M hydrochloric acid (5 cm3), and heated on a steam bath for five minutes. The solution was then cooled, basified to pH 8 with aqueous sodium carbonate solution, and extracted with chloroform:methanol, 20:1 (3×30 cm3). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 50:1, to afford 1-(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazole, m.p. 200°-202°, (0.391 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30]([NH:17][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCN1CCCC1
Yield: 0.1 %

Procedure:
Following preparation as described in PCT application WO 2002/101146, 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (59 mg, 0.25 mol) was stirred overnight in DMF (2 mL) containing with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (65 mg, 0.25 mol), EDC (96 mg, 0.50 mol), HOBT (77 mg, 0.50 mol) and NaHCO3 (116 mg, 1.37 mol). After dilution of the reaction with 40 mL of EtOAc, the organic layer was washed with H2O (10 mL×2) and brine. The organic layer was dried over Na2SO4, and cone, in vacuum to a brown oil. The oil was purified by flash column chromatography (silica gel, CH3OH in CH2Cl2, 0-10% gradient) to yield 109 mg (99%) of the title compound as a colorless oil. MS (ESI) 440 (M+H)+.