Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[F:21][C:22]([F:27])([F:26])[C:23](=O)[CH3:24].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:23]([CH3:24])[C:22]([F:27])([F:26])[F:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC(=O)C(F)(F)F
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1)C(F)(F)F

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1,1,1-trifluoro-propan-2-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=375.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].[CH:11](N)=O>O>[CH3:7][C:4]1[N:5]=[N:6][C:2]2[C:3]=1[C:8](=[O:9])[N:10]=[CH:11][N:1]=2
Reactant: NC=O
Reactant: Cc1n[nH]c(N)c1C(N)=O
Solvent: O
Product: CC1=C2C(=O)N=CN=C2N=N1
Temperature: 180 °C

Procedure:
A mixture of 5-amino-3-methyl-1H-pyrazole-4-carboxylic acid amide (11.06 g, 79.0 mmol, Example 1) and formamide (60 mL, Aldrich) was heated at 180° C. for 3.5 hours. After cooling to 80° C., icy water (100 g) was added and the mixture was vigorously stirred to give a white precipitate. The precipitate was filtered and washed with cold water and then dried in a vacuum desiccator to give 3-methyl-pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. (Yield 9.07 g). This material was used in the next step (described in Example 3) without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[CH:25][C:24]=3[O:42][CH3:43])[N:13]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]>[Pd].CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:42][CH3:43])[N:13]=1)(=[O:3])[NH2:2]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2cccc(C(N)=O)c2)n1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reaction time: 20 h

Procedure:
A mixture of tert-butyl 4-(4-((4-((3-carbamoylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I35) (0.073 g, 0.12 mmol) and 10% palladium on activated carbon (0.042 g) in DMF (3 mL) was stirred under a hydrogen atmosphere for 20 hours. The resulting mixture was filtered and filtrate evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (20-100% acetaneipetroleum benzine 40-60° C.) to give the title compound (I36) (0.070 g, 95%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:28]([NH:35][CH2:36][CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>ClCCl>[CH2:28]([NH:35][CH2:36][CH2:37][NH:38][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCNCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (50.0 mL, 359 mmol) and a solution of trityl chloride (93 g, 326 mmol) in dichloromethane (251 mL) were added dropwise over 1 hour to an ice bath cooled solution of N1-benzylethane-1,2-diamine (50 g, 326 mmol) in dichloromethane (251 mL) under argon. The mixture was then allowed to warm to room temperature and stirred for 48 hours. Water was added and the product was extracted with dichloromethane. The organic layer was washed with brine and water, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.44-7.36 (m, 5H), 7.32-7.24 (m, 10H), 7.21-7.15 (m, 5H), 3.56 (s, 2H), 2.62 (t, J=6.1 Hz, 20H), 2.10 (d, J=6.6 Hz, 2H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][CH2:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])=[CH:12][CH:11]=1)([O-:9])=[O:8]>>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH2:17][CH2:18][CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])=[O:2])=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(C)(C)CCCC(C)CCSc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Product: CCOC(C)(C)CCCC(C)CCS(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To 210 ml. of a 0.5M solution of sodium metaperiodate (aqueous methanol 1:1) at 0° is added 0.1 mol of 7-ethoxy-3,7-dimethyloctyl p-nitrophenyl sulfide. The mixture is stirred at 0° for 4 hours and then filtered to remove precipitated sodium iodate. The filtrate is diluted with water and then extracted with chloroform. The extract is dried over magnesium sulfate and solvent removed by evaporation to yield 7-ethoxy-3,7-dimethyloctyl p-nitrophenyl sulfoxide.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([N:11]([CH3:25])[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:16][CH:17]=1)[N:5]=2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:13]=1)[C:6]1[N:5]=[C:4]2[S:3][C:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])=[N:10][C:9]2=[CH:8][CH:7]=1
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)(methyl)amino]phenyl}-2,2,2-trifluoroacetamide (174 mg, 0.474 mmol) in pyridine (1.7 mL) was added cyclopropanecarbonyl chloride (55 μL, 0.610 mmol) at −20° C., and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (147 mg, 71%) as a pale-violet powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][CH:2]=1.[Li][CH3:14]>CCOCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([OH:12])[CH3:14])=[CH:3][CH:2]=1
Reactant: [Li]C
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCOCC
Product: CC(O)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To 4-quinolinecarbaldehyde (2 g, 12.73 mmol) in 20 ml anhydrous ether, MeLi (1.4M, 10 ml, 13.9 mmol) was added dropwise over a period of five minutes at 0° C. The reaction mixture was stirred at room temperature tor 3 hours. The solution was partitioned between ether (20 ml) and water (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give 1.43 g (59%) of the product which was then used as such for the subsequent step.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:22])=[CH2:21])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)CC1CCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC1CCN(Cc2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of LAH (17 mg, 0.44 mmol) in THF (2 mL) at reflux was added 1-3 (100 mg, 0.44 mmol) in THF (1 mL) dropwise over a 5 min period. The reaction mixture was then maintained at reflux for an additional 12 hrs and then quenched sequentially with H2O (17 μL), 15% NaOH (17 μL), and H2O (51 μL). After 10 min, MgSO4 was added followed by filtration and concentration of the filtrate to give 1-4 as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]O)[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2]
Reactant: CCOCc1nc2c(c3cc(O)ccc3n3nnnc23)n1CC(C)C
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2c(c3cc(OCc4cccnc4)ccc3n3nnnc23)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
5-(Ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-ol (260 mg, 0.76 mmol), was stirred in 10 mL of tetrahydrofuran (THF), 3-pyridylcarbinol (87 mg, 0.80 mmol), and triphenylphosphine (299 mg, 1.14 mmol). Diisopropyl azodicarboxylate (231 mg, 1.14 mmol) was added dropwise to the mixture. After 30 minutes, 2 additional drops of 3-pyridylcarbinol were added and the reaction was stirred overnight at ambient temperature. Analysis by thin layer chromatography indicated that a small amount of starting material still remained. Additional amounts of the reagents were added until all of the starting material was consumed. The reaction was filtered through an acidic ion exchange resin and the resin was washed with methanol, followed by 1M ammonia in methanol. The filtrate was concentrated under reduced pressure to provide 280 mg of 5-(ethoxymethyl)-6-(2-methylpropyl)-8-(pyridin-3-ylmethoxy)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinoline as an off white solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[O:40])[O:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[C:36]([CH:39]=[O:40])[O:37][CH:38]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: O=Cc1cc(Br)co1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 122.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 4-bromo-2-furancarbaldehyde (58 mg, 0.33 mmol), potassium carbonate (89.8 mg, 0.66 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was heated in the microwave for 20 min at 150° C. to give 58 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1H-indole-7-carboxamide.
Reaction SMILES: [F:1][C:2]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:31])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:31][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:14]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]2=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccccc1-n1c2ccccc2c2cccc(F)c21
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-n1c2ccc(Br)cc2c2cccc(F)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.7 g (22.2 mmol) of fluoro-9-(2-nitrophenyl)-9H-carbazole are initially duced in 150 ml of CH2Cl2. A solution of 3.9 g (22.3 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is stirred at room temperature for a further 4 h. For work-up, 150 ml of water are added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction.
Reaction SMILES: C1C(SSC2C=CC([N+]([O-])=[O:16])=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.CCCCCCCC[N:35]1[S:40][CH:39]=[CH:38][C:36]1=O.[P:41]([O-:45])([O-:44])([O-:43])=[O:42]>>[P:41]([O-:45])([O-:44])([O-:43])=[O:42].[S:40]1[CH2:35][C:36](=[O:16])[CH:38]=[N:39]1
Reactant: CCCCCCCCn1sccc1=O
Reactant: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=C1C=NSC1
Reaction time: 0.02 h

Procedure:
The spectrum of DTNB added to 10 ppm ITA was analyzed versus time at various pHs to evaluate the color change mechanism. 1.0 M Phosphate buffer was prepared and 30 mL aliquots were adjusted to the following pHs: 3, 7, 10, and 12. 22.2 uL of 1000 ppm KATHON® 886 MW was added to a semi micro cuvette followed by 2.065 mL of one of the above phosphate buffers. The solution was mixed and allowed to stand for one minute. These preparations resulted in a final isothiazolinone concentration 10 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])=[CH:7][C:2]=1[F:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1F
Reactant: CC(=O)C=C=O
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-fluoro-N1,N1-dihexylbenzene-1,4-diamine (2.94 g, 10.0 mmol) in toluene (50 mL) was added acetyl ketene (0.84 g, 10.0 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:4) to give the title compound as yellow oil (2.67 g, 70%).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])CCC.[NH2:17][CH:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:19]>O1CCCC1>[CH2:11]([O:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:17][CH:18]([CH3:19])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12][CH2:13][CH3:14]
Reactant: CC(N)C(C)(C)C
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCCCOc1c(NC(C)C(C)(C)C)c(=O)c1=O

Procedure:
Tetrahydrofuran (15 mL), 3,4-dibutoxy-3-cyclobutene-1,2-dione (2.26 g, 10 mmol) and 2-amino-3,3-dimethylbutane (1.01 g, 10 mmol) were stirred together for approximately 65 hours at room temperature. The waxy solid remaining after removal of solvent was dissolved in chloroform (15 mL) and chromatographed (flash, ethyl acetate/hexane) on silica. The appropriate fractions were freed of solvent to yield 2.41 g (95%) of cream-colored waxy solid: mp 90°-9° C.° (softens 85° C.).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[C@@H:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=4)=[O:20])[CH2:17][CH2:16][CH2:15][N:14]3[C:34](=[O:43])[C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCCl.ClCCl.O=[Mn]=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C@H:13]3[C@@H:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH:28]=[O:29])=[C:24]([C:30]([F:32])([F:33])[F:31])[CH:23]=4)=[O:20])[CH2:17][CH2:16][CH2:15][N:14]3[C:34](=[O:43])[C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of cis-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (130 mg, 0.22 mmol) in 1,2-dichloroethane (2 mL) was added MnO2 (380 mg, 4.4 mmol) at room temperature. The reaction mixture was stirred for 3 h and was then diluted with dichloromethane, filtered through a plug of SiO2, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to get the desired compound (as a mixture of cis enantiomers) in 31% yield (40 mg). 1H NMR (400 MHz, CDCl3) δ 10.2 (bs, 1H), 8.12-6.88 (m, 10H), 3.82-3.04 (m, 4H), 2.88-1.40 (m, 18H). MS: (ES) m/z 596 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][CH2:6][C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1cccc(F)c1
Product: O=C(Cl)CCc1cccc(F)c1

Procedure:
A solution of 3-fluorohydrocinnamic acid (28 g) in thionyl chloride (90 ml) was heated at reflux for 3 hours. 3-Fluorohydrocinnamoyl chloride (27 g) was isolated by distillation (150°-110° C. @ ca 20 mm.Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:19]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.NC1N=C(C2N(C3CCN(C(OC(C)(C)C)=O)C3)C=NC=2C2C=CC(F)=CC=2)C=CN=1.C(O)(=O)C.C(N)=N.FC1C=CC(C2N=CN(C3CCNC3)C=2C2C=CN=C(N)N=2)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)C1
Agent: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)C1
Agent: N=CN
Agent: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNC2)n1
Solvent: CC(=O)O
Product: Fc1ccc(-c2ncn(C3CCNC3)c2-c2ccncn2)cc1

Procedure:
tert-Butyl 3-[4-(4-fluorophenyl)-5-pyrimidin-4-yl-1H-imidazol-1-yl]pyrrolidine-1-carboxylate (C19, prepared according to the general procedure for the synthesis of tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]pyrrolidine-1-carboxylate (C17) in Example 7, except that formamidine acetate was used in place of guanidine hydrochloride) was converted to the product using conditions similar to those employed for transformation of tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]pyrrolidine-1-carboxylate (C17) to 4-[4-(4-fluorophenyl)-1-pyrrolidin-3-yl-1H-imidazol-5-yl]pyrimidin-2-amine (C18) in Example 7. The product was obtained as a solid. Yield: 1.58 g, 5.11 mmol, 70%. LCMS m/z 310.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.16 (m, 1H), 2.37 (m, 1H), 3.02 (m, 1H), 3.09 (dd, J=12.2, 4.6 Hz, 1H), 3.21 (m, 1H), 3.3 (m, 1H, assumed; obscured by solvent signal), 5.32 (m, 1H), 7.09 (dd, J=8.6, 8.6 Hz, 2H), 7.26 (d, J=5.2 Hz, 1H), 7.38 (dd, J=8.3, 5.5 Hz, 2H), 8.15 (s, 1H), 8.63 (d, J=5.5 Hz, 1H), 9.28 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[C:13](C(OC)=O)[C:12]2=[O:24])=[CH:2]1.[OH-].[K+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:24])[CH:13]=[C:14]([NH:16][CH:17]3[CH2:18][CH2:19]3)[O:15]2)=[CH:2]1
Reactant: COC(=O)C1=C(NC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(NC2CC2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 4.4 %

Procedure:
To a solution of the compound (0.25 g, 0.76 mmol) of Example 94 in ethanol (7.0 mL), 50% potassium hydroxide solution (4.0 mL, 0.071 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. The residue was diluted with water, 1M hydrochloric acid was added to adjust pH to acidic, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0090 g, y. 4%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15](Cl)[N:14]=[C:13]4[C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[O:25][C:12]=34)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36]1[O:44][C:43]2[CH:42]=[CH:41][C:40]([OH:45])=[CH:39][C:38]=2[O:37]1>CN(C=O)C.ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:45][C:40]4[CH:41]=[CH:42][C:43]5[O:44][CH2:36][O:37][C:38]=5[CH:39]=4)[N:14]=[C:13]4[C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[O:25][C:12]=34)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1c(Cl)nc2c(oc3ccccc32)c1-c1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(Oc2ccc3c(c2)OCO3)nc2c(oc3ccccc32)c1-c1ccc2c(c1)OCCO2
Reaction time: 8 h

Procedure:
A solution of 3.8 g of ethyl 4-(1,4-benzodioxan-6-yl)-2-chlorobenzofuro[3,2-b]pyridine-3-carboxylate and 3.1 g of caesium carbonate in 40 ml of DMF is treated with a solution of 1.7 g of 3,4-methylenedioxyphenol in 20 ml of dichloromethane and stirred overnight. The mixture is worked up in the customary manner and ethyl 4-(1,4-benzodioxan-6-yl)-2-(3,4-methylenedioxyphenoxy)benzofuro[3,2-b]pyridine-3-carboxylate is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](Cl)=[C:22]3[C:30]#[N:31])[C:16]([CH2:32][CH3:33])=[C:15]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23]([N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[C:22]3[C:30]#[N:31])[C:16]([CH2:32][CH3:33])=[C:15]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(c2)c(C#N)c(Cl)n3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(-c2ccc3c(c2)c(C#N)c(N2CCCC2)n3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-6-(2-chloro-3-cyano-1-methyl-1H-indol-5-yl)-5-ethylnicotinate (143 mg, 0.25 mmol) in DMF (2 mL) was added potassium carbonate (70 mg, 0.50 mmol, 2.0 eq) followed by pyrrolidine (0.05 mL, 0.61 mmol, 2.4 eq) at room temperature. The reaction was heated to 60° C. and the progress was monitored by LC-MS. Upon completion, the reaction was quenched with water then extracted with EtOAc (3×25 mL). The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (0-10% EtOAc in 1/1 CH2Cl2/hexanes) to afford the title compound (134 mg, 89%).