Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C2=CCCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2CCCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 94 %

Procedure:
(2-Cyclopent-1-enyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Example 74) is hydrogenated in MeOH in presence of 10% Pd/C under a hydrogen pressure of 50 bar at 50° C. for 18h. Filtration, evaporation of the solvent and purification of the residue by preparative HPLC on a C-18 column with a H2O/MeCN gradient provided (2-Cyclopentyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone in 94% yield as colourless foam (M+H+: 481.5.).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=O.C([O:28]OC(C)(C)C)(C)(C)C>ClC1C=CC=CC=1>[C:10]([CH:7]1[CH:8]=[CH:9][C:4]2[C:5](=[C:14]3[C:19](=[CH:1][N:3]=2)[CH:18]=[CH:17][C:16]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:15]3)[C:6]1=[O:28])([CH3:12])([CH3:11])[CH3:13]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CC(C)(C)c1cccc(-c2cc(C(C)(C)C)ccc2NC=O)c1
Solvent: Clc1ccccc1
Product: CC(C)(C)c1ccc2cnc3c(c2c1)C(=O)C(C(C)(C)C)C=C3
Temperature: 110 °C

Procedure:
The above compound, N-formyl-2-amino-3′,5-di-t-butyl biphenyl (6.5 g, 21 mmol) was dissolved into 50 mL of chlorobenzene to which 5 equivalents of di-t-butyl peroxide was added. The reaction mixture was heated to 110° C. for 72 hours. The reaction mixture was concentrated in half and cooled to 0° C. The precipitate that formed was collected by vacuum filtration. The off-white solid was washed with hexanes to give 2,9-di-tert-butylphenanthridinone as determined by GCMS and not purified any further.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1ncnc(Cl)c1-c1ccncc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ncnc(Cl)c2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 77.2 %

Procedure:
To a mixture of 4,6-dichloro-5-(pyridin-4-yl)pyrimidine (1.07 g, 4.8 mmol), 4-chlorophenylboronic acid (740 mg, 4.8 mmol) and tetrakis(triphenylphosphine)palladium (550 mg, 0.48 mmol) in toluene (10 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 5 mL, 10 mmol). The resulting mixture was stirred at 100° C. under argon for 15 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, water (25 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (1.12 g, HPLC purity about 92%) as a white solid. 1H NMR (CDCl3): δ7.18 (d, 2H), 7.2-7.3 (m, 4H), 8.66 (d, 2H), 9.07 (s, 1H).
Reaction SMILES: NC1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.IC.[CH3:12][N:13]([CH:15]=O)[CH3:14]>[H-].[Na+].CCOC(C)=O>[Br:8][C:6]1[CH:7]=[C:15]([N:13]([CH3:14])[CH3:12])[C:3]([F:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-5-bromo-2-fluoropyridine (Matrix Scientific, Columbia, S.C., USA, 1.571 mmol) in DMF (3 ml) and 55% NaH in oil (1.571 mmol) was stirred for 15 min at rt. Was added iodomethane (Aldrich, Buchs, Switzerland, 1.571 mmol) and the RM was stirred for 13 h at rt. The RM was diluted with EtOAc, washed with brine (4×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fraction containing the first eluting product were evaporated to give (5-bromo-2-fluoro-pyridin-3-yl)-dimethyl-amine as an orange oil (HPLC: tR 3.15 min (Method A); M+H=219, 221 MS-ES) and the fraction containing the second eluting product were evaporated to give the title compound as a red solid (HPLC: tR 2.90 min (Method A); M+H=205, 207 MS-ES).
Reaction SMILES: [CH3:1][Si:2]([N-:5][Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[Li+].Cl[C@@H:12]([B:17]1[O:21][C@@H:20]2[CH2:22][C@@H:23]3[CH2:26][C@H:25]([C@:19]2([CH3:29])[O:18]1)[C:24]3([CH3:28])[CH3:27])[CH2:13][CH:14]([CH3:16])[CH3:15]>O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[N:5]([C@H:12]([B:17]1[O:21][C@@H:20]2[CH2:22][C@@H:23]3[CH2:26][C@H:25]([C@:19]2([CH3:29])[O:18]1)[C:24]3([CH3:27])[CH3:28])[CH2:13][CH:14]([CH3:16])[CH3:15])[Si:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)C[C@@H](Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1)N([Si](C)(C)C)[Si](C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (189 ml, 0.189 mol) was added, over 30 minutes, to a solution of crude 2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole of Step 2 (59.0 g, 91% purity, 0.189 mol) in tetrahydrofuran (580 ml) while cooling at −78° C. The reaction mixture was allowed to slowly warm to room temperature overnight. The solvent was removed by rotary evaporation and the residue taken up with dry hexane (800 ml). The resulting suspension was stirred at room temperature for 2 hours, then the solid was removed by filtration on a celite cake, which was washed with dry hexane (3×100 ml). The filtrate was concentrated giving a satisfactorily pure product as a brown oil (79 g) in practically quantitative yield. The product was used for the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].CCOC(C)=O.O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c(N2CCOCC2)cncc1[N+](=O)[O-]

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XLVI) (1 eq.), in neat morpholine in a sealed tube was heated at 120-140° C. overnight. The solution was poured into a mixture of EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4 and concentrated to get a residue. The crude product was purified on a silica gel column eluting with chloroform:MeOH gradient. The fractions containing product were mixed and concentrated under vacuum. The residue was triturated with hexane to give 3-morpholino-5-nitropyridin-4-amine (LIII).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[O:3][SiH:4]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[C:17]([O:20]CC=C)(=[O:19])[CH3:18].C>[Ru]>[CH3:8][Si:6]([CH3:7])([CH3:9])[O:5][Si:4]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([O:3][Si:2]([CH3:16])([CH3:15])[CH3:1])[O:20][C:17](=[O:19])[CH3:18]
Reactant: C[Si](C)(C)O[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C=CCOC(C)=O
Agent: [Ru]
Product: CC(=O)O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 105 °C

Procedure:
A mixture containing 296 g of tris-(trimethylsiloxy)silane, 110 g of allyl acetate and 2.4 g of ruthenium supported on activated charcoal (5 percent by weight of ruthenium and 95 percent by weight of activated charcoal), in which the 2.4 g refers to the total wieght of the charcoal and the ruthenium, are heated to boiling under reflux (approx. 105° C.) for 4 hours. The tris-(trimethylsiloxy)-acetoxysilane yield is quantitative.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:27]=[C:28]([OH:30])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:28]2[CH:27]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:25]=[C:24]([F:23])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COC(=O)CCc1cc(O)cc(F)c1
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCc1cc(F)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 76.9 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (350 mg) in acetonitrile (25 mL) were added methyl 3-(3-fluoro-5-hydroxyphenyl)propanoate (208 mg) and cesium carbonate (1.41 g), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (390 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:19])[CH2:24][CH:23]=[CH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: COCOc1cccc(NC(=O)OC(C)(C)C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cccc(OCOC)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14 (141 mg, 0.37 mmol) in 12 mL anhydrous DMF was cooled to −10° C., and treated with NaH (22.3 mg, 0.55 mmol) in small portions. The resulting suspension was stirred for 15 min and treated with neat allyl bromide (0.16 mL, 1.56 mmol) in a slow dropwise manner. The reaction mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with the addition of 5% aqueous NaHCO3 (20 mL), and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with H2O (5×10 mL), dried (Na2SO4), and condensed under reduced pressure to yield 15 as a 2:1 mixture of amide rotamers as a yellow oil. Flash chromatography (SiO2, 2.5×10 cm, 10% EtOAc/hexane) yielded 15 (149 mg, 96%) as a colorless oil: 1H NMR (CDCl3, 250 MHz) δ 7.17 (m, 1H), 6.95-6.78 (m, 2H), 5.98-5.84 (m, 1H), 5.21 (s, 2H), 5.09-5.03 (m, 2H), 4.46 (m, 1H), 3.50 (s, 3H), 1.50 and 1.31 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 157.5 and 157.0, 153.7, 146.1 and 145.7, 133.8 and 133.6, 129.5 and 129.0, 123.6 and 123.5, 117.6 and 117.1, 113.5 and 113.2, 95.0 and 94.1, 80.5 and 80.1, 56.4, 53.1, 51.9, 28.3 and 28.1; IR (film) νmax 2975, 1688, 1582, 1463, 1381, 1253, 1154, 1065, 990 cm−1; FABHRMS (NBA/NaI) m/z 420.0663 (C16H22INO4+H+ requires 420.0672).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(N)c(F)c1
Yield: 49.7 %

Procedure:
A solution of (3-fluoro-4-nitro-phenoxy)-acetic acid tert-butyl ester (2.14 g, 8 mmol) in ethanol (3 ml) was hydrogenated 5 h at room temperature and atmospheric pressure over 10% palladium on charcoal. The catalyst was removed by filtration, the solvent evaporated under reduced pressure and the residue purified by column chromatography on silica gel (1:0 to 1:1 heptane/ethyl acetate eluant) to afford the product as a brown oil (960 mg, 50%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[F:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1F
Yield: 67 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and methyl 2-fluoro-4-aminobenzoate (125 mg, 0.739 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-fluoro-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (95 mg, 67%) as colorless prisms.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].OO.[C:9]([C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:19]1[CH2:18][CH2:17][CH:16]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:15][C:14]2=1)#[N:10]>CS(C)=O.O>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:20]1[C:21]2[CH:22]=[CH:23][C:11]([C:9]([NH2:10])=[O:2])=[CH:12][C:13]=2[C:14]2[CH2:15][CH:16]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH2:17][CH2:18][C:19]1=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(N)=O)ccc3n2Cc2cccc(F)c2)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Add K2CO3 (0.26 g, 1.93 mmol) and 30% H2O2 (2.0 mL) portionwise to N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 51) (1.50 g, 3.85 mmol) in DMSO while cooling in an ice bath. Stir for 18 h and add more H2O2 with warming to 50° C. if needed to facilitate complete reaction. Dilute with water and collect the precipitate by filtration (1.45 g, 92%). Recrystallize from EtOAc to yield a white solid. MS (ES): m/z 408 (M+1); m.p.=192-194° C.
Reaction SMILES: Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:5]2.[Li]CCCC.[C:36]([O:43][CH2:44][CH3:45])(=[O:42])[C:37]([O:39]CC)=O>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=3)[CH:10]=[C:11]([CH3:12])[C:2]=2[C:37](=[O:39])[C:36]([O:43][CH2:44][CH3:45])=[O:42])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c(-c2ccc(Cl)cc2)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C)cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
To a solution of (6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-yloxy)triisopropylsilane (2.5 g, 4.9 mmol) in THF (50 mL) cooled to −78° C. was added n-BuLi (1.6 M in hexanes, 4.6 mL, 7.4 mmol) dropwise. The resulting solution was allowed to stir at −78° C. for 30 min before addition of diethyl oxalate (1.7 mL, 12.4 mmol). After 45 min at −78° C., the cold bath was removed and the reaction allowed to warm to room temperature over 1 h. 5% citric acid (50 mL) solution was added and the layers separated. Following extraction with EtOAc, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-10% EtOAc/Hex) to afford 2.10 g (81%) of the title compound as a colorless syrup. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H38ClO4Si: 526.16; found: 526.89.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:51])[N:25]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1)[C:26]#[C:27][Si](C(C)C)(C(C)C)C(C)C)([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24](=[O:51])[N:25]([C:26]#[CH:27])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)=[CH:41][CH:40]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
TBAF (2.18 g, 6.9 mmol) was added to a solution of (4-morpholin-4-yl-benzyl)-[(triisopropylsilanyl)-ethynyl]-carbamic acid t-butyl ester (1.42 g, 3 mmol) in THF (23 ml) at 0° C. The mixture was stirred for 1 hour at this temperature and was then warmed to RT. H2O (15 ml) was added and the organic phase was extracted with Et2O (3×15 ml) and dried over Na2SO4. The solvent was removed under reduced pressure and the desired compound was obtained after purification by column chromatography (PE/AcOEt:80/20 to 75/25). The title compound was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.Cl>O1CCCC1.CCCCCC>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])([OH:18])[CH2:14][CH2:13]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2[N+](=O)[O-])CC1
Temperature: -100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 19.3 g of 2-bromonitrobenzene in 480 ml of anhydrous tetrahydrofuran cooled to -100° C., 79 ml of 1,6M solution of n-Buli in hexane are dropped under N2. After two hours 10.9 g of 1-methyl-4-piperidone are added and the resulting mixture is stirred eight hours at -100° C. Then 1N hydrochloric acid is added at 0° C. to acidify to pH 2 and the solution is extracted with hexane. The aqueous phase is brought to pH 10 and extracted with ethyl ether. Evaporation of the extracts gives 8.95 g of 1-methyl-4(2-nitrophenyl)-4-hydroxypiperidine, m.p. 166°-167°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[CH3:32][C:33]([C:36]1[NH:47][C:39]2=[N:40][CH:41]=[CH:42][C:43](B(O)O)=[C:38]2[CH:37]=1)([CH3:35])[CH3:34]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CO.O>[CH3:35][C:33]([C:36]1[NH:47][C:39]2=[N:40][CH:41]=[CH:42][C:43]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([NH:11][C:12]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)=[O:13])[CH:3]=3)=[C:38]2[CH:37]=1)([CH3:32])[CH3:34]
Reactant: CC(C)(C)c1cc2c(B(O)O)ccnc2[nH]1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(C(=O)Nc2cc(-c3ccnc4[nH]c(C(C)(C)C)cc34)cc3[nH]ncc23)cs1
Temperature: 150 °C

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (50 mg), Pd(dppf)Cl2-DCM adduct (12 mg), 2 M sodium carbonate (aq) (0.22 ml), 1,4-dioxane (0.5 ml) and water (0.278 ml) were added to [2-(1,1-dimethylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (39 mg). The reaction was heated under microwave irradiation at 150° C. for a total of 25 min. The reaction was passed through a silica cartridge, preconditioned with MeOH, washing with MeOH. The solvent was evaporated and the residue purified using the following system:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:14]1[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]2=[C:16]([Cl:24])[CH:15]=1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:24][C:16]1[CH:15]=[C:14]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]=12
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Reactant: OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: [O-][n+]1c(OC2CCCC2)cc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a solution of cyclopentanol (0.050 g, 0.59 mmol) in NMP (3 mL) at rt was added potassium tert-butoxide (0.060 g, 0.54 mmol). The mixture was stirred at rt for 1 h. 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.100 g, 0.49 mmol) in NMP (1 mL) was added and the mixture was heated to 80° C. for 1 h. The mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford crude product (0.140 g) as a brown oil. MW=253.72. 1H NMR (CDCl3, 300 MHz) δ 6.69 (s, 1H), 5.04 (s, 1H), 3.23 (t, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.20 (quin, J=7.6 Hz, 2H), 2.00-1.56 (m, 8H); APCI MS m/z 254 [M+H]+.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH:16]S(O)(=O)=O>>[C:1]([N:5]=[N:6][C:7]([C:14](=[O:16])[NH2:15])([CH3:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)O
Reactant: O=S(=O)(O)O
Product: CC(C)(C)N=NC(C)(CCC(=O)O)C(N)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To 20 ml of 95% H2SO4 cooled to -10°C in a 50 ml round bottom flask immersed in an ice-salt bath, was added 6.0 grams (0.0284 moles) of 4-t-butylazo-4-cyanovaleric acid (from Example X) in small portions over one-half hour holding the temperature at -10°C. After the addition was complete, the mixture was stirred for an additional 4 hours at -5° to -10°C. After 3 hours, the reaction mixture was poured into 75 ml of ice water and the product extracted with 50 ml of methylene chloride. The methylene chloride layer was washed with 100 ml of cold water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure to leave 4.3 grams (66% yield) of a white-yellow solid. The solid was slurried in 50 ml of pentane, filtered and the filter cake air dried. The purified material had a melting point of 97° -102°C (dec.) and its infrared spectrum was in agreement with the structure of 4-t-butylazo-4-carbamylvaleric acid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:15])[CH2:6][N:7]1[C:11]([Br:12])=[C:10]([Br:13])[N:9]=[C:8]1[Br:14]>CO>[Br:14][C:8]1[N:7]([CH2:6][C:5]([OH:15])=[O:4])[C:11]([Br:12])=[C:10]([Br:13])[N:9]=1
Reactant: COC(=O)Cn1c(Br)nc(Br)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(Br)nc(Br)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
18 mL 4 mol/L aqueous sodiumhydroxide solution was added to 18.1 g (2,4,5-tribromo-imidazol-1-yl)-acetic acid methyl ester in 200 mL MeOH. The reaction was stirred 1 h at RT and evaporated. Water was added to the residue and the resulting mixture acidified with 1 mol/L aqueous HCL solution. The precipitate was filtered and dried to give 17.2 g desired product.