Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][N+:21]([O-])=O)[CH3:17].[Si]([N:29]=[N+:30]=[N-])(C)(C)C.[F-]>C1COCC1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]1[N:29]=[N:30][NH:21][C:20]=1[C:19]([O:18][CH2:16][CH3:17])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=Cc1ccccc1Oc1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nnc1-c1ccccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-phenoxybenzaldehyde (8) (1.0 equiv), ethyl-2-nitroacetate (2.0 equiv) and TMS-azide (3.0 equiv) in dry THF (0.4 M) under inert atmosphere and at 0° C. was treated with fluoride-bound resin (Aldrich #387789, 1:1 w/w with respect to aldehyde). The resulting mixture was heated to reflux for 24 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (hexane/ethyl acetate) to provide ethyl 4-(2-phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylate (9) as a yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:32]([O:31][CH3:30])[CH:33]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml of triethylamine and 241 mg of 3,4-dimethoxybenzoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for approximately 5 hours. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. In this way 230 mg of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([C:30]2[CH:35]=[CH:34][C:33](=[O:36])[NH:32][CH:31]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:38](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.IC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:10][N:9]2[C:28]([C:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([CH3:38])[CH:31]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CN(C(=O)c2ccc(=O)[nH]c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)N2CC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)ccc1=O
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile (15.1 mg, 0.0277 mmol, example 40), cesium carbonate (27 mg, 0.0829 mmol, Aldrich) in DMF (3 mL) and iodomethane was stirred at room temp. for 3 hrs before it was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(1-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile (15.0 mg, 96%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]([CH2:31][C:32]([O:34]C(C)(C)C)=O)[CH2:28][CH2:29][OH:30])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:31][CH2:32][O:34][C:29](=[O:30])[CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N(CCO)CC(=O)OC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOC(=O)C2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(1-benzyl-3-(4-chlorophenyl)-N-(2-hydroxyethyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamido)acetate (171 mg, 0.310 mmol) was dissolved in DCM (18 mL). TFA (2 mL) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue co-evaporated with DCM (2×). The product was purified by flash chromategraphy (silica, gradient heptane/EtOAc, 1:0→2:1), to give 97 mg (66%) of SC-50.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:11]=[C:10]3[C:22]([OH:24])=O)[CH:2]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:22]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:11]=2)=[O:24])[CH:27]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXXIII) (0.39 g, 1.21 mmol) and 3-aminopyridine (CXXVII) (0.11 g, 1.21 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (0.42 mL, 1.21 mmol). The solution was cooled to 0° C. before adding HATU (0.46 g, 1.21 mmol). The ice bath was removed, and the reaction warmed to room temperature and stirred for 2 h. The DMF was removed under reduced pressure, and the residue was partitioned between chloroform and water. The organic phase was separated and washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography using a 25 g Thomson normal phase silica gel cartridge (100% CHCl3→2:98 MeOH:CHCl3) to afford N,5-di(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXXIV) (0.36 g, 0.90 mmol, 75% yield) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 10.56 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.34-8.33 (m, 1H), 8.31-8.29 (m, 1H), 8.16-8.14 (m, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.8, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.43-7.41 (m, 1H), 7.43-7.41 (m, 1H), 6.08-6.06 (m, 1H), 4.01-3.99 (m, 1H), 3.87-3.82 (m, 1H), 2.64-2.57 (m, 1H), 2.11-2.06 (m, 2H), 1.84-1.80 (m, 1H), 1.69-1.65 (m, 2H); ESIMS found for C23H21N5O2 m/z 400 (M+H).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].C1CCN2C(=NCCC2)CC1.[C:43]([CH2:45][C:46](OC)=[O:47])#[N:44].C([O-])(O)=O.[Na+]>>[C:43]([CH2:45][C:46]([N:19]1[CH2:20][CH2:21][C:16]([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)([CH2:22][C:23]#[N:24])[CH2:17][CH2:18]1)=[O:47])#[N:44]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Reactant: COC(=O)CC#N
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1

Procedure:
To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl) piperidinium trifluoroacetate (60 mg, 0.14 mmol) in Me-THF (2.0 mL) was added DBU (0.065 mL, 0.43 mmol), followed by methyl cyanoacetate (28 mg, 0.29 mmol). The resulting mixture was allowed to stir for 1 hour before saturated aqueous NaHCO3 solution was added and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100%, EtOAc/hexanes followed by elution with 10% MeOH/EtOAc) to afford the title compound, Example #36-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14](=[O:22])[CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[F:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[F:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccsc1F)C1=CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: O=C(Cc1ccsc1F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
After dissolving 292 mg of 1-benzyl-4-[2-(2-fluoro-3-thienyl)acetyl]-1,2,3,6-tetrahydropyridine in 10 ml of ethanol, 0.1 g of 20% palladium-hydroxide-carbon (hydrous) was added and the mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (239 mg, 81% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A mixture of 26.4 g. of ethyl N-[4-(8-cyclohexyloctylamino)benzoyl]glycinate, 110 ml. of 1 N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone to yield the product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH:11]([C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[CH:22]=[O:23])=[CH:18][CH:19]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(/C=C/CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(/C=C/C=O)cc1

Procedure:
Following General Procedure H, oxalyl chloride (9.5 ml, 19.0 mmol, 2M in CH2Cl2), DMSO (1.8 ml, 25.3 mmol), (E)-3-(4-isopropylphenyl)prop-2-en-1-ol (Compound 109, 2.2 g, 12.6 mmol) and triethylamine (7.1 ml, 50.7 mmol) in CH2Cl2 (100 ml) were reacted to obtain the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C)=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(OC1C=NC(C2C=CC(CCCCCCCCCC)=CC=2)=NC=1)CCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCC)=CC=2)=NC=1)CCCCCC>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCc1ccc(-c2ncc(OCCCCCCC)cn2)cc1
Agent: CCCCCCCCCc1ccc(-c2ncc(OCCCCCCC)cn2)cc1
Product: CCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-heptyloxy-2-(4-hexylphenyl)pyrimidine ##STR7## 5-heptyloxy-2-(4-heptylphenyl)pyrimidine ##STR8## 5-heptyloxy-2-(4-octylphenyl)pyrimidine ##STR9## 5-heptyloxy-2-(4-nonylphenyl)pyrimidine 5-heptyloxy-2-(4-decylphenyl)pyrimidine
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), a solution of 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.87 mmol, 1.10 equiv) in Dioxane (9 mL), tetrakis(triphenylphosphane)palladium (40 mg, 0.03 mmol, 0.05 equiv), and a solution of sodium carbonate (179 mg, 1.67 mmol, 2.50 equiv) in water (3 mL). The resulting solution was stirred for 12 h at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum, and the solution was diluted with 20 mL of ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 250 mg (71%) of tert-butyl (2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole (140 mg, 0.38 mmol) and 1,2,4-benzenetricarboxylic anhydride (72 mg, 0.38 mmol) the title compound was obtained (100 mg, 22%). 1H NMR (DMSO) δ 13.79(s, 1H), 8.44(dd, 1H), 8.34(s, 1H), 8.22(m, 2H), 8.11(d, 1H), 8.01(d, 1H), 7.97(s, 1H), 7.92(d, 1H), 7.87(m, 2H), 7.73(dd, 1H), 7.48(d, 1H), 7.40(m, 2H), 4.04(s, 3H). MS 547.0 m/z (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[NH:21][CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:30]([O:37]CCC=O)[C:31]1C=CC=C[CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[N:21]([CH2:32][CH2:31][CH2:30][OH:37])[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CCCOCc1ccccc1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1CCCO
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane (3.4 mL) was added 3-(benzyloxy)propanal (160 mg, 0.98 mmol) at room temperature. After 10 min of stirring, NaBH(OAc)3(140 mg, 0.65 mmol) was added in one portion and the reaction mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was taken-up in a mixture of 50/50 CH3CN—H2O containing 0.05% TFA, The mixture was concentrated to dryness and the residue was dissolved in CDCl3(5 mL) and briefly exposed to daylight. The purple solution was stirred open to the atmosphere at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was treated with Pd—C (10 mg) in MeOH (2 mL) under 1 atm of H2 2 h. The catalyst was filtered through Celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC 30% ethyl acetate/hexanes to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-(3-hydroxypropyl)-1H-indol-5-yl)cyclopropanecarbox amide (18 mg, 8% from 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropane-carboxamide). 1 H NMR (400 MHz, CDCl3) δ 8.11(d, J=7.8 Hz, 1H), 7.31(d, J=2.2 Hz, 1H), 6.94(dd, J=7.9, 1.7 Hz, 1H), 6.91(d, J=1.6 Hz, 1H), 6.85(d, J=11.7 Hz, 1H), 6.79(d, J=7.9 Hz, 1H), 6.10(s, 1H), 5.94(s, 2H), 4.25-4.21(m, 2H), 3.70(dd, J=5.7, 5.7 Hz, 2H), 1.93-1.86(m, 2H), 1.61(dd, J=6.8, 3.7 Hz, 2H), 1.35(s, 9H), 1.04(dd, J=6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 453.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13](Br)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:19][NH2:20])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(OCc2ccccc2)ccnc1Br
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(OCc2ccccc2)ccnc1NN
Temperature: 150 °C
Yield: 95.3 %

Procedure:
To a solution of compound D2 (1.2 g, 4.15 mmol) in THF (12 ml) was added hydrazine monohydrate (0.416 g, 8.301 mmol). The reaction mixture was heated at 150° C. under microwave irradiation for 1 min. After cooling, additional hydrazine monohydrate (1 eq) was added to the reaction mixture, which was then heated at 150° C. under microwave irradiation for 0.5 min. After cooling, the reaction mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield intermediate compound D3 (0.95 g, 95%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]([C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:15])[N:14]=1)[NH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:8][NH:7][C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:13]([CH3:15])[N:14]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Yield: 64.8 %

Procedure:
A solution of ethyl chloroformate (1.98 g) in methylene chloride (5 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.68 g) in methylene chloride (40 ml) under ice cooling in 15 minutes, and the reaction mixture was treated with a solution of triethylamine (1.8 g) in methylene chloride (10 ml) under ice cooling. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of water. The extract was washed with 5% hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was pulverized with diisopropyl ether. The resulting precipitates were collected by filtration, washed with water and dried to give 3-(2-ethoxycarbonylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.23 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH2:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][C:35](=O)[CH3:36])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][CH:35]([CH3:36])[CH2:34][CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Reactant: CC(=O)CCc1cccc(Cl)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(Cl)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using [4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-acetic acid ethyl ester and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:17])[CH2:14][C:13](=O)[O:12][C:11]1=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:12])[CH2:14][C:10]([CH3:17])([CH3:9])[C:11]2=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Nc1cccc(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC1(C)CC(=O)N(c2cccc(Br)c2)C1=O
Temperature: 50 °C

Procedure:
3-Bromo-phenylamine (10.0 g, 58.1 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione (8.2 g, 63.9 mmol) were suspended in 387 ml of methylene chloride and heated at 50° C. for 3 hours. Carbonyldiimidazole (11.3 g, 69.7 mmol) was added in portions and the reaction was heated at 50° C. overnight. Most of the solvent was removed on a rotary evaporator. The solid residue was triturated with 20% ethyl acetate in hexanes, filtered and dried to give 15 g (92%) of somewhat impure 1-(3-bromo-phenyl)-3,3-dimethyl-pyrrolidine-2,5-dione which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:15])/[C:5](/O)=[CH:6]/[C:7](=[O:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.Cl.[NH2:17]O.[OH-].[Na+].Cl>CCO>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]1[O:13][N:17]=[C:5]([C:4]([OH:3])=[O:15])[CH:6]=1
Reactant: CCOC(=O)/C(O)=C/C(=O)CC(C)(C)C
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)Cc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (Z)-2-hydroxy-6,6-dimethyl-4-oxo-hept-2-enoic acid ethyl ester (298.5 g, 1.39 mol) in EtOH (1600 ml) is added hydroxylamine hydrochloride (106.5 g, 1.53 mol) and the resulting solution is stirred at room temperature for 24 h. 2N aq sodium hydroxide (1740 ml, 3.48 mol) is added to the reaction and the resulting solution is stirred at rt for 2 h. The reaction mixture is acidified with 6N aq hydrochloric acid, concentrated to about 3 L, and extracted with EtOAc (2000 ml). The combined organic layers are washed with brine, dried over magnesium sulfate and concentrated. The resulting solid is washed with ether and dried to afford the product.