Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]5O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.S(Cl)([Cl:41])(=O)=O>C(Cl)Cl>[Cl:41][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3Cl)sc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a stirred mixture of (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (282 mg, 0.7 mmol) from Example 162, DIEA (247 μL, 1.4 mmol), and CH2Cl2 (15 mL) at 0° C. under argon was added sulfuryl chloride (142 mg, 2.0 mmol). The mixture was warmed to rt and stirred for 15 h, and then stirred at 60° C. for 15 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase. The product was further purified by triturating in CH2Cl2 (5 mL) to afford N-((1R,2R)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine (29 mg, 10%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.24 (dd, J=1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63-1.75 (m, 3H), 1.29-1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[C:15]([Li])(C)(C)C.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:15][C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12
Reactant: [Li]C(C)(C)C
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At −78° C. a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (5 g, 23.8 mmol) in THF is treated with tert.-butyllithium (41 mL, 1.5 M in pentane). The mixture is stirred at −78° C. for 15 min before methyliodide (17.1 g, 120 mmol) is added dropwise. Stirring is continued at −78° C. for 30 min. The mixture is warmed to rt, diluted with water (400 mL), acidified with 10% aq. citric acid solution and extracted three times with EA. The combined organic extracts are dried over MgSO4 and evaporated. The remaining solid is suspended in heptane/diethyl ether, filtered and dried under HV to give 3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (4.01 g) as a beige powder; LC-MS: tR=0.97 min, [M+1]=225.13; 1H NMR (D6-DMSO): δ 12.49 (s br, 1H), 2.87 (t, J=6.7 Hz, 2H), 2.26 (s, 5H), 1.45 (t, J=6.7 Hz, 2H), 0.91 (s, 6H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[H-].[Na+].Br[C:11]1[S:12][C:13]([Br:16])=[CH:14][N:15]=1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[Br:16][C:13]1[S:12][C:11]2=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:1]=[CH:2][N:15]2[CH:14]=1
Reactant: Brc1cnc(Br)s1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ncn2cc(Br)sc12
Reaction time: 2 h
Yield: 85 %

Procedure:
Methyl isocyanoacetate (0.63 ml, 6.9 mmol) was gradually added dropwise to a suspension of sodium hydride (60% in mineral oil, 346 mg, 8.6 mmol) in N,N-dimethylformamide (5 ml) in an argon atmosphere under ice cooling, and the mixture was stirred at the same temperature for 2 hr. This solution was added dropwise to a solution of 2,5-dibromothiazole (1.0 g, 4.1 mmol) in tetrahydrofuran (10 ml) cooled to −20° C. (brine/ice water) through a cannula over a period of 15 min, and, while allowing the temperature to rise to about 0° C., the mixture was stirred for 2 hr. After the completion of the reaction, saturated brine was added thereto, and the mixture was extracted with dichloromethane (20 ml×5). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give methyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (910 mg, 85%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnc(N)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 17.3 %

Procedure:
To a 5-mL microwave vial was added DMSO (2 mL) and it was degassed with nitrogen for 5 min. Next added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine (49.7 mg, 0.225 mmol), sodium carbonate (59.5 mg, 0.562 mmol) and bis(triphenylphosphine)palladium(II) chloride (9.20 mg, 0.013 mmol). The mixture was degassed for additional 5 min, sealed, and irradiated (microwave) at 135° C. for 15 h. The mixture was filtered and the residue was washed with DMSO. The DMSO solution of the crude product was purified using reverse-phase HPLC. The TFA salt of the product was neutralized with saturated NaHCO3 solution, filtered, washed with water, and dried under high vacuum to give 14 mg (17%) of product. LCMS E-S (M+H)=433.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.40 (d, J=4.6 Hz, 2H) 5.22-5.41 (m, 1H), 5.90 (s, 1H), 7.18 (m, 2H), 8.08 (s, 1H), 8.34 (s, 1H), 8.86 (m, 1H), 9.11 (s, 2H), 11.58 (br. s., 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)(Cl)Cl>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=3[O-:22])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: c1ccc(C2CCC3(CC2)OCCO3)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccccc1C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
To an ice cold solution of 3 g (13.68 mmol) of 2-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine in chloroform (46 mL) was added 4.51 g (14.36 mmol) of meta-chloroperoxybenzoic acid (50-60%). The reaction mixture was stirred and allowed to come to room temperature over a four hour period. The volume of the reaction mixture was reduced by approximately 75% under reduced pressure and the residual material was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide solution. The organic phase was separated and washed with water and brine, then dried (sodium sulfate) and concentrated to yield 3 g of the product as an oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(Cl)Cl.C1COCC1>[C:9]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1oc(-c2ccccc2)nc2ccccc12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 2-phenyl-benzo[d][1,3]oxazin-4-one (5 mmol) in dry CH2Cl2 (20 mL) was added 1N solution of aryl magnesium bromide in THF (5 mL) at 0° C. The mixture was stirred at room temperature for 2 h and poured into water (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and was washed with water (3×50 mL), brine (1×50 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to afford N-(2-benzoyl-phenyl)-benzamide in 60-70% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]=[C:6]1[CH2:10][S:9][CH2:8][N:7]1[CH2:11][C:12]([OH:14])=O>ClCCl.O1CCCC1>[O:5]=[C:6]1[CH2:10][S:9][CH2:8][N:7]1[CH2:11][C:12]([Cl:3])=[O:14]
Reactant: O=C(O)CN1CSCC1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cl)CN1CSCC1=O
Reaction time: 5 h

Procedure:
Thionyl chloride (2.00 ml) was added dropwise to a solution of 4-oxo-3-thiazolidinylacetic acid (1.60 g) in a mixture of dichloromethane (20 ml) and tetrahydrofuran (5.0 ml) at room temperature. After the mixture was stirred for 5 hours at the same temperature, the solvent was evaporated in vacuo to give 4-oxo-3-thiazolidinylacetyl chloride (1.78 g) as brown semisolid.
Reaction SMILES: [C:1]1([C:15]([OH:17])=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>CN1CCCC1=O.O>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:15]([OH:17])=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc2c(Cl)c3ccccc3cc12
Yield: 59.2 %

Procedure:
Anthracene-1-carboxylic acid (15B, 24g, 0.108 mol) was treated with N-chlorosuccinimide (Aldrich, 24 g, 0.18 mol) in N-methylpyrrolidinone (Eastman, 600 mL) and heated under N2 at 90° for 1.5 h. The reaction mixture was diluted with H2O (3.5 L), filtered, dried, and the precipitate recrystallized from EtOAc to afford 16.41 g (59%) of 10-chloroanthracene-1-carboxylic acid mp 275°-277°, (C, H, Cl).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:17])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[OH:27]>>[C:1]([NH:4][C@@H:5]([CH3:17])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2[OH:27])=[O:14])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C)COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(C(=O)Nc2ccc(O)cc2O)cc1

Procedure:
Using 4-{[(2S)-2-(acetylamino)propyl]oxy}benzoic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20](O)=[O:21])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=[CH:26]1)=O.CN(C)C=O.CNC>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:20](=[O:21])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A suspension of 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole) and 1,1'-carbonyldiimidazole (1.6 g, 0.0101 mole) and dry dimethylformamide (10 ml) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (26.4 ml of a 2.29 M solution, 0.0606 mole) was added. The resulting solution was heated at 45° C. overnight under nitrogen. The solvents were evaporated under reduced pressure. The residue was triturated in water (300 ml), and the resulting solid was collected by filtration, rinsed with water, 5% potassium 5% potassium hydroxide solution and again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and allowed to cool to room temperature. A solid precipitated which was collected by filtration and dried under high vacuum to give 1.26 g (38%) of title compound, mp 204°-207° C.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][C:29]([C:31]1[N:35]=[C:34]([CH2:36]Cl)[O:33][CH:32]=1)=[O:30]>C(OCC)(=O)C>[CH3:27][O:28][C:29]([C:31]1[N:35]=[C:34]([CH2:36][N:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:13][CH2:14]2)[O:33][CH:32]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1coc(CCl)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1coc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 8 h

Procedure:
A dimethyl sulfoxide (10 mL) solution of tert-butyl-1-piperazine carboxylate (1.06 g, 5.70 mmol) and N,N-diisopropylethylamine (2.98 mL, 17.1 mmol) was treated at room temperature with methyl (2-chloromethyl)oxazole-4-carboxylate (1.0 g, 5.70 mmol; portion-wise addition) and stirred overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried on magnesium sulfate, filtered and concentrated to give the intermediate tert-butyl 4-((4-(methoxycarbonyl)oxazol-2-yl)methyl)piperazine-1-carboxylate (MS (ESI) m/z 325.7 [M+H]+. The intermediate was dissolved in dichloromethane (15 mL) at room temperature and treated with trifluoroacetic acid (5 mL) dropwise. The mixture was stirred for 4 hours and was then concentrated under vacuum to give the title compound (1.60 g). MS (ESI) m/z 226.1 [M+H]+.
Reaction SMILES: CO.[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=2[N+:20]([O-])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O=[Pt]=O.CC(O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=2[NH2:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(C)O
Product: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reaction time: 8 h

Procedure:
A mechanically stirred MeOH (3.8 L) suspension containing 1-[4-phenylmethoxy-3-nitrophenyl]ethanone (76.5 g, 282 mmol) was degassed with argon for 40 minutes at ~10° C. prior to addition of PtO2 (2.34 g, 10 mmol). Hydrogen was sparged into the reaction mixture at 8° C. to 10° C. via a subsurface gas inlet. After 8 hours, the completed reaction was degassed with Ar while being warmed to ~15° C., diluted with CHCl3 (250 mL) and filtered. The filtrate was stripped to give 70 g crude product which, after trituration for ten minutes with i-PrOH (450 mL) at 60° C., yielded 57.4 (84%) of the title compound.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([C:24]1[C:29]([NH2:30])=[CH:28][C:27]2[O:31][CH2:32][O:33][C:26]=2[CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[C:29]([NH:30][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])=[CH:28][C:27]2[O:31][CH2:32][O:33][C:26]=2[CH:25]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1cc2c(cc1NC(=O)c1cccc3ccccc13)OCO2
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Into solutions of 149 (5.0 mmol) in 200 mL of dry toluene were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (5 mmol). The mixtures were stirred at 20±2° C. for 24 h and then evaporated. The residues were washed with acetone and EtOH and then recrystallized from acetone or EtOH to form 150. Obtained as a grayish-white solid; mp 143-144° C.; ESI-MS (Positive mode): m/z 334 [M+H]+; 1H-NMR (400 MHz, DMSO-d6, δ): 2.59 (3H, s), 6.20 (2H, s), 7.60-7.68 (4H, m), 7.87 (1H, d, J=7.2 Hz), 8.05-8.07 (1H, m), 8.15 (1H, d, J=8.0 Hz), 8.33-8.38 (2H, m), 12.52 (1H, s); IR (KBr): 1647, 1672 (C═O) cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#[N:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Cc1cnc2c(c1)CCCC2C#N

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide was treated with P2S5 to give 3-methyl-8-cyano-5,6,7,8-tetrahydroquinoline which was treated with H2S as described in Example 8 giving the title compound as colourless needles from benzene m.p. 151° (50% yield) (Found: C, 63.71; H, 6.85; N, 13.38% C11H14N2S requires: C, 64.04; H, 6.84; N, 13.58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].Cl.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]Cl)([CH3:17])[CH3:16].[H-].[Na+]>CN(C)C=O>[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12])([CH3:17])[CH3:16]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a solution of 3.00 g of 5-methoxyisatin and 3.39 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry N,N-dimethylformamide was added 1.36 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 1 hour at room temperature and then heated at 80° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform) and recrystallized from hexane to obtain 3.33 g of 1-(2-diisopropylaminoethyl)-5-methoxyisatin having a melting point of 81°-82.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]#[N:37])=[CH:31][CH:30]=2)=[C:11]([CH3:38])[N:10]=1.[CH2:39]([NH2:44])[CH2:40][CH2:41][CH2:42][CH3:43].[OH-].[Na+]>C(OCCCC)(=O)C.C(#N)C>[NH2:8][C:9]1[N:10]=[C:11]([CH3:38])[C:12]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][C:36]#[N:37])=[CH:33][CH:34]=2)=[C:13]([NH:44][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[N:14]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Reactant: CCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (27.4 g) was slowly added to a suspension of the product from step (iii) (105.0 g) and n-pentylamine (62.9 g) in butyl acetate (877.8 g) and the mixture was heated at 120° C. for 2 hours. The mixture was cooled to 20° C. and 4% aq. NaOH (997.5 g) was added to the mixture. The organic layer was separated, washed with water (997.5 g) and 10% aq. NH4Cl (997.5 g) respectively and the solvent evaporated under reduced pressure to afford a solid. The solid was dissolved in acetonitrile (221.1 g) at 50° C. and the solution was cooled to 42° C., seeded and stirred at this temperature for 1 hour. After the mixture was cooled to 5° C. and stirred at 5° C. for 1 hour, the resulting precipitate was collected by filtration, washed with acetonitrile (2×31.5 g) and dried under reduced pressure to give the subtitle compound as a solid, 52.0 g; 1H NMR DMSO-d6: δ 7.23 (d, 2H), 7.11 (d, 2H), 6.17 (t, 1H), 5.68 (s, 2H), 3.96 (s, 2H), 3.73 (s, 2H), 3.27-3.22 (m, 2H), 2.00 (s, 3H), 1.47-1.40 (m, 2H), 1.28-1.19 (m, 2H), 1.17-1.09 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23](=[O:26])[CH2:24]Br.O>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23](=[O:26])[CH2:24][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: O=C(CBr)c1ccccc1F
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)n1c(=O)n(CC(=O)c2ccccc2F)c2ccccc21
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a stirred solution of 1-isopropenyl-1,3-dihydro-benzimidazol-2-one (1 g, 5.7 mmol) in DMF (50 ml) was added potassium carbonate (1.6 g, 11.5 mmol) followed by 2-fluorophenacyl bromide (1.5 g, 6.9 mmol). The resulting mixture was warmed to 80° C. for 2 h and cooled to ambient temperature. The reaction was poured into water and ethyl acetate and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×) and the combined organics were dried (MgSO4). Filtration and concentration gave the crude product which was purified via column chromatography (silica gel, 50% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 1.6 g (90%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (519 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionic acid (459 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 142–143° C.