Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH3:20])=[CH2:3].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:5]1[CH3:20])([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)n1c(C)c(-c2ccc(F)cc2)c2cccnc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)c2cccnc2n1C(C)C
Reaction time: 16 h

Procedure:
Into a parr vessel are placed 330 mg of the olefinic product of Step 4, above, 20 ml of 100% ethanol and 100 mg of 5% palladium on carbon. Hydrogen gas is added at 40 to 50 psi and held at R.T. for about 16 hrs. Ethyl acetate is then added, the mixture filtered through Celite® and then evaporated to dryness to give the title product of this step as a slightly yellowish gum, which solidified on standing to a light cream solid (mp 57°-68°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:17]>COCCOC>[Br:17][CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Solvent: COCCOC
Product: Cc1noc(-c2ccc(Br)cc2)c1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (2.88 g, 10.74 mmol) in DME (23 mL) was treated with phosphorus tribromide (1.5 mL, 16.11 mmol) and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:46][C:47](=[N:49]O)[CH3:48].CN(C)C=O>O>[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([O:27][N:49]=[C:47]([CH3:48])[CH3:46])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Reactant: CC(C)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 47.9 %

Procedure:
First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic acid (compound a-2), 49 mg of acetone oxime, and 2 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 2 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of acetone O-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetyloxime (compound a-98).
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11](O)=[O:12])=[CH:8][CH:7]=1.S(Cl)([Cl:32])=O>>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][CH2:4][O:5][C:6]1[O:10][C:9]([C:11]([Cl:32])=[O:12])=[CH:8][CH:7]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Reactant: O=S(Cl)Cl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)Cl)o1

Procedure:
A mixture of 57.2 g (0.14 mole) of 5-(3,7,11,15-tetramethylhexadecyloxy)-2furoic acid in 300 ml of thionyl chloride is heated to reflux for 1 hour, and the excess thionyl chloride is removed by distillation to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furancarboxylic acid chloride with is combined with 2.8 g of 2% palladium-BaSO4 catalyst, 0.6 g of quinoline-sulfur in 800 ml of xylene. A slow stream of hydrogen gas is passed through the mixture until hydrogen chloride is no longer evolved (about 8 hours). After cooling, the catalyst is removed by centrifuging, and the solvent is removed under reduced pressure. The residue is distilled to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furancarboxaldehyde.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23](O)=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[S:37]([NH2:41])([NH2:40])(=[O:39])=[O:38]>>[F:35][C:2]([F:36])([F:1])[C:3]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23]([NH:40][S:37](=[O:39])(=[O:38])[NH2:41])=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O
Product: NS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-sulfamoylacetamide was prepared from {5-[1-(2,4-bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}acetic acid (Example 59) and sulfamide following General Procedure L.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1C=O.[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:24]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:25])[CH:45]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)c1nc(-c2ccccn2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: O=Cc1ccccn1
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(-c3ccccn3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carboxylic acid (prepared according to the procedure of Example 70, steps a and b, with the modification that pyridine-2-carboxaldehyde was used instead of 2-dimethylamino-benzaldehyde in step a) was reacted with 3-amino-benzoic acid benzyl ester according to the procedure of Example 177, step a to afford 3-{[5-(2-adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 13.18 (1H, br s), 9.84 (1H, br s), 8.63 (1H, d), 8.48 (1H, s), 8.23 (1H, d), 8.00 (1H, d), 7.93 (1H, td), 7.63 (1H, d), 7.42 (2H, m), 2.99 (2H, m), 1.95 (3H, br s), 1.65 (6H, m), 1.54 (6H, s), 1.42 (2H, m). The product was converted to the L-tartaric acid salt and lyophilised from water/dioxan. Found: C, 58.35; H, 6.11; N, 8.80%. C32H36N4O9.2.0 mols H2O requires: C, 58.23; H, 6.14; N, 8.53%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: NCc1ccc(F)c(N)c1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Reaction time: 8 h

Procedure:
TEA (1.92 mL, 13.8 mmol) was added to a mixture of 3-amino-2,4-difluoro-benzylamine (0.58 g, 2.5 mmol) in THF (40 ml) followed by pivaloyl chloride (0.31 mL, 2.5 mmol) and it was stirred overnight. The mixture was diluted with EtOAc, washed successively with satd. NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered and concentrated.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Nc1ccccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1N

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodopyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (example 98, intermediate a) and 2-amino-phenylboronic acid after a reaction time of 4 hours. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Further purification by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (19%). MS (ESI): m/z=440.119 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][N:11]=[C:9]3[S:10][C:6]=2[CH:5]=1)([O-])=O.N.[H][H]>[Pt].CO>[N:11]1[CH2:12][CH2:13][CH2:14][N:8]2[C:7]3[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][C:6]=3[S:10][C:9]=12
Reactant: O=[N+]([O-])c1ccc2c(c1)SC1=NCCCN12
Reactant: [H][H]
Agent: [Pt]
Agent: N
Solvent: CO
Product: Nc1ccc2c(c1)SC1=NCCCN12

Procedure:
A mixture of 14 parts of 3,4-dihydro-8-nitro-2H-pyrimido[2,1-b]benzothiazole and 400 parts of methanol, saturated with ammonia is hydrogenated at normal pressure and at room temperature with 5 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 9.3 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-8-amine; mp. 186.5° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:11](=[O:17])OC(Cl)(Cl)Cl)Cl.[NH2:19][C:20]1[CH:21]=[C:22]([N:26]2[C:31](=[O:32])[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:29][C:28]3[CH:40]=[CH:41][CH:42]=[N:43][C:27]2=3)[CH:23]=[CH:24][CH:25]=1.C(=O)(O)[O-].[Na+]>ClCCCl.O1CCOCC1.C(N(CC)CC)C>[CH2:33]([C:30]1[C:31](=[O:32])[N:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:11]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:17])[CH:21]=2)[C:27]2[N:43]=[CH:42][CH:41]=[CH:40][C:28]=2[N:29]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCC1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)OC1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of cyclopentanol (0.08 ml) and triphosgene (87 mg) in 1,2-dichloroethane (2 ml) was stirred at room temperature for 20 hours. Then the mixture was added to a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (193 mg) and triethylamine (0.25 ml) in 1,4-dioxane (3 ml). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (chloroform-methanol, 40:1) to give 2-benzyl-4-(3-cyclopentyloxycarbonylaminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (41 mg).
Reaction SMILES: I[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:7]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[F:18][C:19]1[CH:20]=[C:21]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:7]=2)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: FC(F)(F)c1cccc(-c2csc(CI)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, to a mixed solvent of the compound (270 mg, 0.72 mmol) obtained in Example 190c, 3-fluoro-4-methoxycarbonylphenylboronic acid (170 mg, 0.86 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in tetrahydrofuran-water (v/v=5/1, 6 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (120 mg, 0.14 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound as colorless crystals.
Reaction SMILES: FC(F)(F)C(O[C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+]>COCCOC.CO.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>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OC(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of Example 6A (4.0 g, 12 mmol) and 4-fluorophenylboronic acid (1.68 g, 12 mmol) in 1,2-dimethoxyethane (100 mL) and methanol (50 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.416 g, 0.36 mmol) and CsF (3.64 g, 24 mmol), heated to reflux, and stirred overnight. The reaction was concentrated and the concentrate was dissolved in ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:6 ethyl acetate/hexanes to provide the desired product (2.6 g, 78%). MS (CI) m/e 278 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[CH:10]=[C:9]1[CH2:27]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[CH:10]=[C:9]1[CH2:27][N:33]1[C:29](=[O:39])[C:30]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:31]2[C:32]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(CO)cc2c(C(=O)OCc3ccccc3)cccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(CN2C(=O)c3ccccc3C2=O)cc2c(C(=O)OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonyl-2-hydroxymethylindole-4-carboxylate (465 mg), phthalimide (179 mg) and triphenylphosphine (640 mg) in tetrahydrofuran (15.0 ml) was added diethyl azodicarboxylate (425 mg) and the mixture was stirred at ambient temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was chromatographed on silica gel with n-hexane:ethyl acetate (6:1). The solid was triturated with methanol to give benzyl 1-tert-butoxycarbonyl-2-phthalimidomethylindole-4-carboxylate (440 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:20][CH:21]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: ClCc1ccncc1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3ccncc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=333.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-(chloromethyl)pyridine hydrochloride.
Reaction SMILES: [I:1][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[C:24]#[N:25].[OH-].[Na+].OO.[O-:30]S([O-])(=S)=O.[Na+].[Na+]>CO>[I:1][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:3]=1[C:24]([NH2:25])=[O:30]
Reactant: O=S([O-])([O-])=S
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3C#N)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3C(N)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carbonitrile (example 221A) (220 mg, 0.5 mmole) in MeOH (3 mL) cooled at 0° C. is added dropwise a solution of 1N NaOH (1 mL) and 30% H2O2 (0.1 mL). The reaction mixture is stirred at 0° C. for 1 hour, then aqueous 1N Na2S2O3 is added. The aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) from (100:0:0) to (90:10:1) to give 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid amide melting at 85° C.
Reaction SMILES: C(OC([O:11][C:12]1([CH2:50][CH3:51])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:49])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:44])([CH3:43])[CH2:33][CH2:34][CH2:35][O:36][C:37]([CH:39]2[CH2:42][CH2:41][CH2:40]2)=[O:38])=[C:23]2[CH:45]=[CH:46][CH:47]=[CH:48][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:50]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:49])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:44])([CH3:43])[CH2:33][CH2:34][CH2:35][O:36][C:37]([CH:39]2[CH2:42][CH2:41][CH2:40]2)=[O:38])=[C:23]2[CH:45]=[CH:46][CH:47]=[CH:48][C:22]2=[N:21][C:20]3=1)[CH3:51]
Reactant: [H][H]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1CCC1
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1CCC1

Procedure:
A mixture of Compound 61 (70 mg, 0.1 mmol), 10% palladium on carbon (20 mg, 20%) in 20 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:14]([NH:16][C@H:17]([C:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH3:18])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4]>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:14]([NH:16][C@H:17]([C:19]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])[CH3:18])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](N)C(C)C
Reaction time: 2 h

Procedure:
30.7 g (60.8 mMol) BOC-Val-MeLeu-Ala-Bzl dissolved in 100 ml trifluoroacetic acid are stirred for 2 hrs. at room temperature. The obtained solution is concentrated under vacuum and the residue diluted with 500 ml methylene chloride. The solution is washed 3× with 200 ml saturated potassium carbonate solution, ice being added, the aqueous phases extracted with 200 ml methylene chloride and the combined organic phases dried over potassium carbonate. The title compound is obtained as a pale-yellow oil after further filtration and concentration: rotation, [α]D25 =-87.1° (c=1.0 in chloroform).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.Br>C1COCC1.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(c2ccc(O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.8 %

Procedure:
To a stirred 0° C. solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (1.0 g, 2.61 mmol) in THF (10 mL), aqueous HBr (908 mg, 5.2 mmol) was added under a nitrogen atmosphere. The reaction mixture was then stirred for 12 h at RT, diluted with water and extracted with hexane (2×50 mL). The organic layers were concentrated in vacuo to afford 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (100 mg) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 10.25 (s, 1 H), 8.48 (d, J=7.8 Hz, 1 H), 8.16-8.00 (m, 2 H), 7.95 (t, J=7.8 Hz, 1 H), 7.72 (t, J=7.8 Hz, 1 H), 7.63 (t, J=7.2 Hz, 1 H), 7.56 (d, J=7.2 Hz, 2 H); 7.18 (d, J=7.2 Hz, 2 H), 7.12 (d, J=7.2 Hz, 2 H), 6.89 (d, J=7.6 Hz, 2 H), 5.32 (s, 2 H), 1.37 (s, 6 H). MS: M+H: m/z=438.2; and LC MS: 88%, (Condition-H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.92 min, m/z=459.1-460.1 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.61 (m, 1H) 1.78-1.88 (m, 1H) 2.17-2.25 (m, 1H) 2.96 (dd, J=11.00, 6.60 Hz, 1H) 3.10-3.37 (m, 5H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.48 (dd, 1H) 7.81 (dt, J=7.82, 1.83 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H) 8.57 (dd, J=4.65, 1.47 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.76 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).