Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2.[H-].[Na+].[CH2:22](OS([O-])(=O)=O)[CH3:23].O>C1COCC1>[CH2:22]([O:1][CH2:2][C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2)[CH3:23]
Reactant: CCOS(=O)(=O)[O-]
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 35 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
(1R, 2R, 3S)-2-hydroxymethyl-3(3,4-dichlorophenyl)tropane (26.9 g, 0.09 mol) in THF (200 ml) was added sodium hydride 60% in oil (4.6 g, 0.12 mol) and ethylsulphate (15.7 ml, 0.12 mol) and heated to 30-40° C. on an oil bath for ½ hour. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture is then heated to 30-40° C. on an oil bath for 1 hour and poured into water (500 ml). The mixture was extracted twice with tert.butylmethylether, the organic phases was washed with water and dried over MgSO4 and evaporated to yield the 32.82 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].F[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:19]([O:21][CH3:22])=[O:20].Cl>COCCOCCOC>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][C:24]1[CH:23]=[C:18]([CH:17]=[CH:16][C:25]=1[N+:26]([O-:28])=[O:27])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)aniline (2.15 g, 11.00 mmol) in diethylene glycol dimethyl ether (20 mL) was added sodium hydride (60% in oil, 440 mg, 11.00 mmol), and the resulting mixture was stirred at 80° C. for 30 min. To this reaction mixture was added methyl 3-fluoro-4-nitrobenzoate (1.99 g, 10.00 mmol), and the resulting mixture was stirred at 80° C. for 1 hr. After cooling, 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/1) and recrystallized from hexane/ethyl acetate to give crude methyl 3-[[2-chloro-5-(trifluoromethyl)phenyl]amino]-4-nitrobenzoate (1.92 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[Si:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Hydroxybenzaldehyde (70 g, 0.57 mol), tert-butyldimethylsilyl chloride (92 g, 0.61 mol), and imidazole (92 g, 1.35 mol) were combined in dimethylformamide (250 mL). The mixture was stirred at room temperature, under nitrogen, for 1 hour. The solution was poured into water (1.5 L) and extracted with 2×500 mL petroleum ether (35°-60° C. boiling range). The organic solution was washed with saturated sodium chloride solution (100 mL), dried over magnesium sulfate, treated with silica gel (20 g), filtered, and concentrated in vacuo. The residue was dried further under high vacuum to yield 126.6 g (94%) of the air and light-sensitive 3-((tert-butyldimethylsilyl)oxy)benzaldehyde as an amber oil. NMR (300 MHz, CDCl3): δ 0.22 (s, 6H); 0.99 (s, 9H); 7.10 (ddd, J1 =1.2 Hz, J2 =2.5 Hz, J3 =7.9 Hz, 1H); 7.32 (dd, J1 =1.5 Hz, J2 =2.4 Hz, 1H); 7.39 (t, J=7.8 Hz, 1H); 7.47 (ddd, J1 =1.3 Hz, J2 1.3 Hz, J3 =7.6 Hz, 1H); 9.95 (s, 1H). Mass spectrum (CI--CH4) m/e: 237 (M+1, 100%). Calculated for C13 H20O2Si: C, 66.05; H, 8.53. Found: C, 65.95; H, 8.56.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[OH:14].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>ClCCl>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[C:10]([CH3:13])=[N:11][N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([OH:14])[CH:4]=2)=[CH:19][CH:18]=1
Reactant: Cc1nnc(-c2ccc(C)c(O)c2)o1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2c(C)nnc2-c2ccc(C)c(O)c2)cc1
Temperature: 152.5 °C

Procedure:
A mixture of 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol (0.65 g; 3.42 mmol) (from Example 11 supra) and 4-methoxybenzylamine (3.10 g; 22.6 mmol) (Aldrich) in a sealed reaction vessel was heated in an oil bath at 150-155° C. for 42 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane and hexanes, forcing the product to precipitate out of solution. The crude solid was collected by filtration and then precipitated again from a dichloromethane-methanol solution as the solvent was evaporated off. The solid was collected and dried, to give 5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenol. (Yield 0.849 g, 76.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([NH2:19])[CH:9]=1.[H-].[Na+].[C:22]([C:26]1[C:27]([Cl:35])=[C:28]([C:32](O)=[O:33])[N:29]([CH3:31])[N:30]=1)([CH3:25])([CH3:24])[CH3:23].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([NH:19][C:32]([C:28]2[N:29]([CH3:31])[N:30]=[C:26]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:27]=2[Cl:35])=[O:33])[CH:9]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: COc1nc(-c2ccccc2Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-ylamine (8.10 g, 29.0 mmol, prepared as described in the previous step) in THF (200 mL) was treated with NaH (3.47 g, 86.8 mmol, 60% dispersion in oil) at 0° C. for 1 h. Simultaneously a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6.90 g, 31.8 mmol, prepared as described in Example B) in DCM (200 mL) was treated with oxalyl chloride (3.2 mL, 36 mmol) and DMF (50 μL) at 0° C. and stirred at room temperature for 1 h. The volatile components were removed in vacuo, and the resulting residue was dried in vacuo for 15 min taken up in THF (20 mL) and added to the above sodium anilide solution at 0° C. The resulting mixture was stirred at room temperature for 30 min, quenched with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (3×100 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The resulting solid was suspended in hexane (200 mL) and sonicated for 10 min and collected by suction filtration to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-yl]-amide as a tan-colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[NH:7][CH:6]=1)=[O:4].[CH3:13][O:14][CH2:15][CH2:16]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:16][CH2:15][O:14][CH3:13])=[N:7][CH:6]=1
Reactant: COCCO
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ncc(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
5-Bromo-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (15 g, 65 mmol, CA 381247-99-0) was suspended in THF (500 mL). To this suspension was added with stirring 2-methoxyethanol (7.1 mL, 97 mmol), diisopropylazodicarboxylate (21.5 mL, 97 mmol) and triphenylphosphine (25.4 g, 97 mmol). This mixture was stirred for 1 h at room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica (heptane/ethylacetate, 2:1) to give the title compound (8.65 g) as a yellow solid; MS (ISP) 290.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[CH:10]=1.[Cl-:16].[Al+3].[Cl-:18].[Cl-].Cl>O>[Cl:16][CH:2]([CH2:3][CH:4]([Cl:18])[CH3:5])[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CCCCC(=O)Cl
Reactant: Clc1cccc(Cl)c1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: O
Product: CC(Cl)CC(Cl)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To 48.0 g. (0.398 mole) of valeryl chloride in 100.0 g. (0.680 mole) of m-dichlorobenzene is added portionwise at less than 5°, 66.7 g. (0.5 mole) of aluminum chloride. When the addition is complete, the reaction mixture is allowed to stir and slowly warm up to ambient temperature for 2 hours. It is then heated at reflux for 3 hours, and stirred at room temperature for 16 hours. The reaction mixture is poured into iced water, and made acidic with hydrochloric acid. The oil which formed separates, and the aqueous phase is extracted twice with 200 ml. of ether. The oil and the extracts are combined, washed with water, dried and concentrated to give 122.2 g. of the crude product. A distillation (89°-93°/0.05 mm) gives 55.2 g. (60%) of the product.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=2)=[N:7][CH:6]=1
Reactant: CCCCOc1ccc(B(O)O)cn1
Reactant: Brc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 36.9 %

Procedure:
A reaction of 109 mmol of 2,5-dibromopyrimidine, 109 mmol of 2-butoxypyridine-5-boronic acid, 218 mmol of sodium carbonate and 1.1 mmol of tetrakis(triphenylphosphine)palladium(0) in 200 ml of toluene, 100 ml of ethanol and 100 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 12.4 g (37%) of a colorless solid, m.p. 134-138° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].C(OC(=O)N[C@H](C)C(N(OC)C)=O)(C)(C)C.COC1C=CC(Br)=CC=1>>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[C:9]([C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cccc(F)c1Br
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: COc1ccc(Br)cc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1c(F)cccc1F

Procedure:
With the exception that (S)-t-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate and 1-bromo-2,6-difluorobenzene were used instead of (R)-t-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate and 4-methoxybromobenzene, respectively, the same procedure as in Preparation Example 5-5 was repeated to afford the title compound. 0.26 g (17%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:25])([F:26])[F:16])[CH:19]=3)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(C(F)(F)F)c2)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 3-trifluoromethyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(3-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid as a white solid (774.7 mg, 93% for the final step); ES+-HRMS m/e calcd for C19H19N2O4F3 [M+H+] 397.1370, found 397.1368. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.21 (m, 2H), 1.35-1.77 (m, 7H), 1.97 (ddd, J=13.7, 9.1, 4.3 Hz, 1H), 2.15-2.26 (m, 1H), 5.33 (dd, J=10.9, 4.3 Hz, 1H), 5.87 (d, J=2.8 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.71-7.81 (m, 3H), 8.14 (d, J=2.8 Hz, 1H), 13.03 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12]1(C)[C:17]([SH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]1([CH3:20])[CH:13]=[CH:12][C:17]([S:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1ccccc1S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccccc2S(N)(=O)=O)cc1
Reaction time: 13 h
Yield: 32 %

Procedure:
3.0 g of 2-chlorobenzenesulfonamide, 2.0 g of thiocresol and 6.5 g of K2CO3 are stirred at 100° C. for 6 h in 30 ml of DMF and then at 120° C. for 13 h. The reaction mixture is poured onto 200 ml of water and extracted with 500 ml of EA. The organic phase is then washed with 100 ml of a saturated aqueous Na2CO3 solution. It is dried over MgSO4 and the solvent is removed in vacuo. Chromatography on silica gel using DIP yields 1.4 g of white crystals, m.p. 122-124° C.
Reaction SMILES: C(OC)(=O)/C=C/C=C/C(OC)=O.[CH:13]1([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14]1.[C:27]1([C:37]([O:39][CH3:40])=[O:38])[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH:28]=1>[Pd].COCCOCCOC>[C:19]([O:21][CH3:22])(=[O:20])[C:16]1[CH:17]=[CH:18][C:13]([C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:15]=1.[CH:30]1([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28][CH:27]([C:37]([O:39][CH3:40])=[O:38])[CH2:32][CH2:31]1
Reactant: COC(=O)C1C=CC(C(=O)OC)CC1
Reactant: COC(=O)C1=CCC(C(=O)OC)CC1
Agent: [Pd]
Agent: COC(=O)/C=C/C=C/C(=O)OC
Solvent: COCCOCCOC
Product: COC(=O)C1CCC(C(=O)OC)CC1
Product: COC(=O)c1ccc(C(=O)OC)cc1
Temperature: 165 °C

Procedure:
In a Parr reactor, a mixture of trans,trans dimethyl muconate (6.13 g, 36.0 mmol) and diglyme (120 ml, 0.30 M) is heated to 165° C. for 24 hours under ethylene pressure (pRT=259 psi (1.79 MPa)). After cooling to room temperature, the weakly yellow, clear solution is diluted using diglyme to 200 ml in a volumetric flask, transferred into a round-bottom flask equipped with a magnetic stirring bar, and catalytic palladium on carbon (Pd/C) is added (356 mg of Johnson-Matthey 5 percent Pd/C #6, 0.2 mole percent) at room temperature. The flask is equipped with a reflux condenser, fitted gas dispersion tube, and internal Temperature probe. Under N2 flow (190 ml/min) and stirring (190 rpm) the mixture is heated to reflux (Tmax, observed=169° C.) while samples were taken at appropriate intervals (t=0.0, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 h) to monitor the progress of the reactions occurring. Rapid (t≦1 h) disappearance of the dimethyl cyclohex-2-ene-1,4-dicarboxylate, □2, 2-ene is observed concurrent with some material undergoing tautomerization to its thermodynamically more stable isomer (dimethyl cyclohex-1-ene-1,4-dicarboxylate, □1, 1-ene), while also the desired oxidation/dehydrogenation/aromatization product dimethyl terephthalate (DMT) and some reduced material (dimethyl cyclohexane-1,4-dicarboxylate CHa) are formed. After 8 hours reaction time, 77 percent DMT, 17 percent cyclohexane, and 5 percent tautomer are present. The graph of FIG. 2 shows the concentration of materials at various time intervals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[Cl:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[Cl:40][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:18][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1)[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]1)=[O:28]
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(Cl)c2)CC1
Temperature: 160 °C
Yield: 19.7 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) 4-amino-3-chloro-N-(1-ethyl-4-piperidyl)benzamide (Intermediate 212; 118 mg, 0.42 mmol), and p-toluenesulphonic acid monohydrate (133 mg, 0.7 mmol) were combined in 4-methyl-2-pentanol (4 mL) and heated by microwave irradiation at 160° C. for 1 hour. The reaction mixture was loaded onto to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (38 mg, 20%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[OH2:10]>Cl>[F:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([OH:10])=[N:3][CH:4]=1
Reactant: O
Reactant: Cc1cc(F)cnc1Cl
Agent: Cl
Product: Cc1cc(F)cnc1O
Temperature: 150 °C

Procedure:
2-chloro-5-fluoro-3-methylpyridine (1 g, 6.870 mmol) is dissolved in hydrochloric acid (37%, 20 mL) and the reaction is heated under microwave irradiation at 150° C. for 15 h. The mixture is diluted with water and washed with DCM. The aqueous layer is basified with NaOH and re-extracted with DCM several times. The organic layer is separated, dried and evaporated to furnish 5-fluoro-3-methyl-pyridin-2-ol (140 mg, content 74%, 12%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:15](=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
m-Trifluoromethyl aniline (32.22 g) in benzene was dissolved in benzene and diketene added slowly with mixing. The reaction mixture was allowed to stand at 25° C. The resulting solid product was recrystallized from ethanol to yield 3'-trifluoromethyl acetoacetanilide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[BH4-].[Na+].C[O-].[Na+].COC(C)(C)C>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[F:12]
Reactant: O=C(CBr)c1ccc(Br)c(F)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: Fc1cc(C2CO2)ccc1Br
Temperature: 5 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
2-Bromo-1-(4-bromo-3-fluorophenyl)-ethanone [CAS 1003879-02-4] (32.3 g, 109 mmol) was dissolved in ethanol (250 ml). The reaction mixture was cooled to 5° C. to give a yellow suspension. Sodiumborohydride (4.13 g, 109 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 1 hour. Sodium methoxide (2.95 g, 54.6 mmol) was added. The reaction mixture was stirred at 50° C. for 6 h. The reaction mixture was poured into tert.butyl methyl ether and extracted with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to yield a yellow oil (25.1 g, 94%). GC-EI-MS: 216 ([M.+]).
Reaction SMILES: [NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([NH:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH3:15]
Reactant: CCC(N)(C(=O)OC)c1cccs1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCNC(CC)(C(=O)OC)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Methyl 2-amino-2-(2-thienyl)butyrate (11.94 g) is dissolved in hexamethylphosphoric triamide (200 ml), and ethyl iodide (28.7 g) and potassium carbonate (37.3 g) is added thereto. The mixture is stirred at room temperature for 4 hours and further stirred at 70° C. for one hour. Water is added to the reaction mixture and the mixture is extracted with ether. The extract is washed with water, dried and concentrated to remove solvent. The residue is purified by silica gel column chromatography, whereby methyl 2-ethylamino-2-(2-thienyl)butyrate (8.99 g) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:29][O:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Yield: 74.7 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (428 mg, 1.36 mmol), methyl (S)-4-(2-pyrrolidinylmethoxy)benzoate (330 mg, 1.40 mmol), EDC (312 mg, 1.63 mg), HOBt (220 mg, 1.63 mmol), and a catalytic amount of DMAP in DMF (15 mL) was stirred for 6 hr. The resulting mixture was diluted with EtOAc, washed with 0.5 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo to give an oily residue, which was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 540 mg (75%) methyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate as an oil. 1H-NMR (CDCl3) δ1.81-2.12 (m, 4 H) 2.88 (bs, 3 H), 3.48-3.61 (m, total 7 H), 3.88 (s, 3 H), 4.10-4.46 (m, 1 H), 6.75-8.08 (series of m, total 13 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(OCC)(=O)C.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc(COc2cccc3cc[nH]c23)cc1

Procedure:
Wet Raney nickel was added in portions to a stirred refluxing solution of 7-(benzyloxy)-3-(methylthio)indole (4.0 g, 14.9 mmol) in ethyl acetate (100 ml) and ethanol (60 ml) until all the starting material had been consumed (by RP HPLC). The mixture was filtered, the filtrate evaporated and the residue chromatographed on silica in ethyl acetate-hexane (1:8) to give a pale oil.