Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([CH2:11][O:12][C:13]1[CH:49]=[CH:48][C:16]([C:17]([N:19]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=5)[CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH2:23][CH2:22][C:20]2=[O:21])=[O:18])=[CH:15][CH:14]=1)=[O:10])C1C=CC=CC=1>CN(C=O)C.C(O)C.[Pd]>[C:9]([CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=5)[CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH2:23][CH2:22][C:20]2=[O:21])=[O:18])=[CH:48][CH:49]=1)([OH:10])=[O:8]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc(OCC(=O)OCc4ccccc4)cc3)CC2)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc(OCC(=O)O)cc3)CC2)cc1OC
Yield: 89.7 %

Procedure:
To a solution of 1-(4-benzyloxycarbonylmethoxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (4 g) in a mixture of DMF (30 ml) and ethanol (30 ml) was added 10% palladium on carbon (500 mg) and the mixture was hydrogenated at room temperature and atmospheric pressure. After completion of reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane. The solution was washed with water, dried and evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:2 to 1:1) to give 1-(4-carboxymethoxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (3.1 g).
Reaction SMILES: CC(C)(C)C(N[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[C:14]([N:16](C(C)C)C(C)C)=O)=O.Cl.C[OH:31]>>[C:10]1(=[O:31])[C:11]2[C:6](=[N:16][CH:14]=[C:13]3[C:12]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:7]=[N:8][CH2:9]1
Reactant: CO
Reactant: CC(C)N(C(=O)c1ccccc1-c1ccncc1NC(=O)C(C)(C)C)C(C)C
Agent: Cl
Product: O=C1CN=Cc2ncc3ccccc3c21
Reaction time: 24 h

Procedure:
All of 2-[3-(2,2-dimethyl-propionylamino)-pyridin-4-yl]-N,N-diisopropylbenzamide from the previous step was carried on and dissolved in methanol (20 mL). Concentrated HCl (1 mL) was added, followed by 24 h of refluxing. A white solid which precipitated out of solution was filtered and dissolved in H2O. After 15 minutes of stirring, the free base crashed out of solution. The solid was filtered and dried, providing 150 mg (33% for two steps) of the desired final product as a white solid. Mp=303–309° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (s, 1 H), 8.60 (d, 1 H), 8.41 (t, 2 H), 8.31 (d, 1 H), 7.95 (t, 1 H), 7.80 (t, 1 H); C12H8N2O.(0.3H2O).(0.2ClH). Anal: Calcd for: C, 68.99; H, 4.25; N, 13.41. Found: C, 68.83; H, 3.99; N, 13.26.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:8][C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13]>CO>[CH3:1][C:2]1[C:6]2[C:5](=[C:9]([CH3:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[CH2:4][CH:3]=1.[CH3:1][C:2]1[CH2:6][C:5]2[C:4]([CH:3]=1)=[C:12]([CH3:13])[CH:11]=[CH:10][C:9]=2[CH3:8]
Reactant: CC1=CC=CC1
Reactant: CC(=O)CCC(C)=O
Agent: [Na]
Solvent: CO
Product: CC1=CCc2c(C)ccc(C)c21
Product: CC1=Cc2c(C)ccc(C)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 2 %
Yield: 5 %

Procedure:
10.0 g (125 mmol) of methylcyclopentadiene were first added dropwise at 0° C. to a solution of 6.4 g (280 mmol) of sodium in 100 ml of methanol. This mixture was added dropwise at room temperature to a solution of 13.1 ml (112 mmol) of 2,5-hexanedione in 50 ml of methanol in the course of 1 hour. After the mixture had been stirred at room temperature for 4 hours, it was poured onto ice-water and acidified to pH 2. Hereafter, it was extracted with diethyl ether, dried over Na2SO4 and evaporated. The residue was chromatographed on 600 g of silica gel (long column) with hexane/methylene chloride (20:1). 0.90 g (5 %) of 3,4,7-trimethylindene (21) and 0.4 g (2%) of 2,4,7-trimethylidene (20) were obtained. For the NMR data, see Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N+:10]([O-])([O-:12])=[O:11].[K+].S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
3-Fluorobenzonitrile (25 g) was added dropwise to a stirred mixture of potassium nitrate (21.1 g) and concentrated sulphuric acid (150 ml) which had been cooled in a mixture of salt and ice. The mixture was stirred at ambient temperature for 45 minutes. The mixture was poured onto ice (800 ml) and the precipitate was isolated. The solid so obtained was dissolved in methylene chloride, dried (MgSO4) and the solution was evaporated to give 5-fluoro-2-nitrobenzonitrile (19 g).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.Cl.Cl.[NH2:29][CH:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1.C(N(CC)CC)C>>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[CH:30]([NH:29][CH2:2][C:3]1[NH:4][C:5]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=4)[N:8]=[C:7]([C:24]#[N:25])[C:6]=3[N:26]=1)[CH2:31]2
Reactant: NC1CN2CCC1CC2
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2cc3[nH]c(CNC4CN5CCC4CC5)nc3c(C#N)n2)cc1C(F)(F)F
Yield: 52.4 %

Procedure:
A solution of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.06 mmol), 3-aminoquinuclidine dihydrochloride (22.9 mg, 0.12 mmol) and triethylamine (18.2 mg, 0.18 mmol) in dimethylsulfoxide(500 μL) was heated in the Creator microwave at 120° C. for 5 minutes. The mixture was filtered and purified by preparative HPLC to afford 2-[(1-aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (14.8 mg) 1H NMR (MeOD) δ 8.34-8.27 (m, 3H) 7.29 (d, 2H) 4.95 (s, 2H) 4.29-4.21 (m, 3H) 4.00 (m, 1H) 3.86-3.69 (m 5H) 2.46 (m, 1H) 2.27-2.10 (m, 4H) 1.45 (t, 3H). MS m/z 471.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:29](C1NC=CN=1)(C1NC=CN=1)=[O:30].[F:41][C:42]([F:46])([F:45])[CH2:43][NH2:44]>C1COCC1.CN(C)C1C=CN=CC=1>[F:41][C:42]([F:46])([F:45])[CH2:43][NH:44][C:29](=[O:30])[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(CO)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(COC(=O)NCC(F)(F)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 8.1 %

Procedure:
3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropan-1-ol (prepared from LiAlH4 reduction of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate in Example 1(g)) (37 mg) in THF (1 ml) was treated with carbonyl diimidazole (29 mg, 0.176 mmol) at room temperature overnight. To the reaction solution was added 2,2,2-trifluoroethanamine (26 mg, 0.264 mmol). The reaction was heated at 50° C. for 14 hours. Additional 2,2,2-trifluoroethanamine 26 mg, 0.264 mmol) was added followed by addition of N,N-dimethylpyridin-4-amine (10 mg, 0.080 mmol), after which stirring was continued for 14 hours. The reaction was concentrated. The crude material was purified via chromatography on silica gel eluting with 10% ethyl acetate in hexane to afford the compound of Example 14 (4 mg, 10% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, s) 7.97 (1 H, s) 7.71 (2 H, dd, J=9.16, 4.58 Hz) 7.63 (2 H, s) 7.54 (2 H, d, J=7.12 Hz) 7.26-7.34 (4 H, m) 7.19 (1 H, t, J=7.38 Hz) 4.26 (1 H, s) 3.73-3.82 (4 H, m) 1.11 (6 H, d, J=3.05 Hz). LC/MS (m/z) 500.29 [(M+H)+]; HPLC Rt: 3.871 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](C)=NN=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(N(CC)CC)C.CN(C=[O:38])C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[C:3]([CH3:14])[CH:4]=1)=[O:38]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CN(C)C=O
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 100 °C
Yield: 39 %

Procedure:
A stirred solution of methyl 4-bromo-3-methylbenzoate (EP 0533268 A1) (1.0 g, 0.0044 mole) in dry DMF (10 ml) under argon was treated with 4-boronobenzoic acid (0.73 g, 0.0044 mole) and tetrakis (triphenylphosphine) palladium(0) (80 mg), followed by triethylamine (1.8 ml, 0.016 mole), the mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (0.46 g, 39%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[H-].[Na+].Br[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18]>C1(C)C=CC=CC=1>[C:2]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C@H:16]([C:17]([OH:19])=[O:18])[CH3:22])(=[O:3])[CH3:1]
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(C)=O)[C@@H](C)C(=O)O)cc1
Yield: 70 %

Procedure:
A mechanically stirred solution of dry 4-methoxyacetanilide (0.25 mol) in anhydrous toluene (500 mL) was treated with NaH (57% oil dispersion, 11.57 g, 0.28 mol) and heated under reflux for 2 h (hours). Ethyl 2-bromopropionate (37.5 mL, 0.29 mol) was added and the mixture was refluxed for 2 h. The cooled mixture was centrifuged to facilitate separation of the NaBr and filtered, and the toluene solution was evaporated to dryness in vacuo. The syrupy residue was dissolved in ethanol (300 mL), a solution of NaOH (20 g) in water (30 mL) was added, and the mixture was heated under reflux for 1 h. The cooled solution was concentrated in vacuo, water (700 mL) was added, and the mixture was extracted with CH2Cl2 (2×200 mL). The mixture was acidified to pH 1 with concentrated HCl, the precipitate which formed was collected and crystallized from ethanol-water to give N-acetyl-N-(4-methoxyphenyl)alanine in 70% yield: mp (melting point) 197°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>O=S(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([NH:18][N:19]2[CH2:25][C:23](=[O:24])[NH:22][C:20]2=[O:21])=[O:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: NN1CC(=O)NC1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=Cc1ccc(Cl)c(C(F)(F)F)c1)NN1CC(=O)NC1=O

Procedure:
A stirred mixture of 4-chloro-3-trifluoromethylcinnamic acid (50 g, 0.2 mole) in 200 ml of SOCl2 was heated at reflux for 2 hours. The excess SOCl2 was removed in vacuo and the residue flushed with dry benzene. The residue was treated with a mixture of 1-aminohydantoin hydrochloride (30 g, 0.2 mole) in 400 ml of pyridine. The reaction mixture was heated at reflux for 3 hours; then poured into ice/HCl. The crude residue (74 g, 100%) was recrystallized from CH3NO2 (Darco) to give an analytical sample melting at 270°-273°.
Reaction SMILES: [CH3:1][I:2].[CH3:3][C:4]([CH3:19])=[CH:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1>CC(C)=O>[I-:2].[CH3:3][C:4]([CH3:19])=[CH:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1
Reactant: CC(C)=CCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC(C)=CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(3-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (3 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.92 g (79%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:6]2=[N:19]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)[C:6]2=[NH:19])=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
HCl (4M in 1,4-dioxane, 3.38 mL, 13.51 mmol) was added to a solution of N-(5′-bromo-4,4-difluorospiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 27 Step 1, 565 mg, 1.35 mmol) in anhydrous 1,4-dioxane (4 mL). The resulting mixture was stirred under a nitrogen atmosphere at r.t. for 90 min. Et2O (2 mL) was added and the precipitate was filtered off and washed with Et2O. The solid was partitioned between DCM (8 mL) and sat. aq. NaHCO3 (8 mL). The phases were separated and the organic layer was dried over MgSO4 and concentrated to give 6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (418 mg, 99% yield), that was used directly in the next step. MS (ES+) m/z 314 [M+H]
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH:71]=[CH:70][N:69]=[CH:68]1>C(O)C.CN(C=O)C>[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([C:77]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:75][CH:74]=2)[CH:71]=[CH:70][N:69]=[CH:68]1
Reactant: O=Cc1ccc(Cn2ccnc2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(Cn4ccnc4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 22.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-imidazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (6 mg, 22%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 5.28 (s, 2H, PhCH2), 6.93 (s, br, 1H, imidazole H-2), 7.21 (s, br, 1H, imidazole H-4 or H-5), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.40 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 7.78 (td, J=7.7, 1.5 Hz, 1H, pyridine H-4), 7.79 (s, br, 1H, imidazole H-4 or H-5), 8.15 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.56 (d, J=1.5 Hz, 1H, pyridine H-2), 13.51 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27]C(Cl)=O)=[CH:24][CH:23]=1.[CH2:33]([N:35]1[C:47]2[CH:46]=[CH:45][C:44]([NH2:48])=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH3:34]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH2:27][O:26][C:25]2[CH:31]=[CH:32][C:22]([Cl:21])=[CH:23][CH:24]=2)[C@H:8]([C:18]([NH:48][C:44]2[CH:45]=[CH:46][C:47]3[N:35]([CH2:33][CH3:34])[C:36]4[C:41]([C:42]=3[CH:43]=2)=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)COc2ccc(Cl)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z=545.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([Br:21])(C)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Br
Reactant: OCc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1

Procedure:
A solution of 3-benzyloxybenzyl alcohol (2.04 g) in methylene chloride (20 mL) with TMS Bromide (2.5 eq. 3.14 mL) was heated at reflux for 6 hr. After cooling, the reaction was concentrated and then reconcentrated 2× from methylene chloride. The residue was chromatographed on silica gel with 5% methylene chloride in hexane to afford 3-benzyloxybenzyl bromide (1.26 g) as an oil.
Reaction SMILES: [C:1]([NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C@@H:3]([CH3:4])[CH2:2][C:1]([NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])=[O:5])=[CH:16][CH:15]=1
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NC(=O)C[C@H](C)Nc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
1-Methylethyl (2E)-2-butenoylcarbamate (for a preparation see Intermediate 11) (9.38 g, 54.8 mmol) was stirred in toluene (281 mL) under nitrogen and (R-BINAP)ditriflatebis(acetonitrile)palladium(II) (Intermediate 24, 3.35 g, 3.01 mmol) added. The catalyst formed a gummy ball, the solution turned to an opaque yellow mixture and was stirred for 20 min. 4-Bromoaniline (14.14 g, 82 mmol) was added, the solution turned to a clear light brown and the gummy catalyst dissolved further. The mixture was stirred for 16 h. Similarly a second batch of 1-methylethyl (2E)-2-butenoylcarbamate (Intermediate 11, 8.51 g, 49.7 mmol) was stirred in toluene (255 mL) under nitrogen and (R-BINAP)ditriflatebis(acetonitrile)palladium(II) (3.04 g, 2.73 mmol) added. The catalyst formed a gummy ball, the solution turned to an opaque yellow mixture and was stirred for 20 min. 4-Bromoaniline (12.83 g, 74.6 mmol) was added, the solution turned to a clear light brown and the gummy catalyst dissolved further. The mixture was stirred for 16 h. The two reaction mixtures were combined and loaded on to a 1.5 kg Isco silica Redisep column. The column was eluted with DCM/MeOH (0%->0.5%, 19 CV). The clean, product containing fractions were evaporated to a pale brown oil. The mixture was dried in a vacuum oven overnight at 40° C. to give a white solid (24.2 g, 67% overall). LCMS (Method C): Rt=0.91, MH+=343. ee=92%.
Reaction SMILES: [C]=O.C=O.[C:5]([OH:11])(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].C([O:18][CH2:19][C:20]([OH:22])=[O:21])(=O)CCCC>O>[C:20]([OH:22])(=[O:21])[CH2:19][OH:18].[C:5]([OH:11])(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)OCC(=O)O
Agent: C=O
Agent: [C]=O
Solvent: O
Solvent: CCCCC(=O)O
Product: O=C(O)CO

Procedure:
Use of a hydrophobic solvent for extraction of the carboxylic acid from the hydrolyzed mixture is necessary if the carboxylic acid and aqueous glycolic acid does not phase separate and may be helpful to improve the separation even if not required to form two phases. In a second embodiment of the invention as set forth in FIG. 2, Carbon Monoxide Stream 1, Aqueous Formaldehyde Stream 2, and Valeric Acid Stream 3 are fed to Hydrocarboxylation Reactor 50 which comprises a fixed bed, solid catalyst (not shown). The Effluent Stream 4 comprises the esters of glycolic and valeric acid including 2-valeryloxyacetic acid. Effluent Stream 4 and Water Stream 8 are fed to Hydrolyzer 55. Hydrolyzer 55 is operated at sufficient temperature, pressure, and residence time to produce Hydrolyzed Mixture Stream 9 comprising glycolic acid, valeric acid, and water. Hydrolyzed Mixture Stream 9 is separated into two phases in Decanter 65. The organic phase is recycled to Hydrocarboxylation Reactor 50 as Valeric Acid Stream 3. Aqueous Glycolic Acid Stream 12 exits Decanter 65 and is fed, along with First Ethylene Glycol Stream 13 to Esterification Unit 80. Water Stream 14 and Glycolate Ester Oligomer Stream 15 exit Esterification Unit 80. Glycolate Ester Oligomer Stream 15 is hydrogenated using Hydrogen Stream 16 in Hydrogenation Unit 90. Hydrogenation Unit 90 produces Second Ethylene Glycol Stream 17 which can be split into Ethylene Glycol Product Stream 18 and First Ethylene Glycol Stream 13 which is recycled to Esterification Unit 80.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.S(=O)(=O)(O)O.Cl.S([O:23][CH3:24])(OC)(=O)=O.[CH:25]1C=CC=CC=1>CO>[C:4]([O:23][CH3:24])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([O:6][CH3:25])=[O:11]
Reactant: c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)OC

Procedure:
Accordingly the present invention provides a method of producing dimethyl phthalate, which comprises treating phthalic anhydride with methanol, adding a catalyst, such as sulphuric acid, hydrochloric acid or mixture thereof and a promoter, such as, dimethyl sulphate; refluxing the resultant mixture at a temperature in the range of 60 to 100 degree Celsius, for a time period in the range of 6 to 12 hours, in the presence of benzene; separating the distillate into two layers; removing the aqueous layer and recycling the benzene layer, recovering unreacted methanol by distillation; neutralizing the residue with caustic soda followed by extraction with benzene; distilling the extract under vacuum to obtain benzene; continuing the distillation process at a temperature in the range of 145 to 146 degree Celsius under 10 mm of mercury to obtain dimethyl phthalate.