Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(O[C:7]1([C:27]#[N:28])[CH2:20][C:19]([CH3:21])=[CH:18][CH2:17][CH2:16][C:15]([CH3:22])=[CH:14][CH2:13][CH2:12][C:11]([CH3:23])=[CH:10][CH:9]=[C:8]1[CH:24]([CH3:26])[CH3:25])C)C.[Cl-].[Na+]>CO>[CH3:26][CH:24]([C:8]1[CH:7]([C:27]#[N:28])[CH2:20][C:19]([CH3:21])=[CH:18][CH2:17][CH2:16][C:15]([CH3:22])=[CH:14][CH2:13][CH2:12][C:11]([CH3:23])=[CH:10][CH:9]=1)[CH3:25]
Reactant: CCOC(C)OC1(C#N)CC(C)=CCCC(C)=CCCC(C)=CC=C1C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC=C(C(C)C)C(C#N)CC(C)=CCCC(C)=CCC1
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 1-(1-ethoxyethoxy)-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraene -1-carbonitrile (31.8 mg, 0.08 mmol) prepared in Example 1 in methanol (3 ml) is stirred on an ice-water bath and thereto is added a very small amount of paratoluenesulfonic acid. After stirring the mixture at this temperature for 1 hour, a saturated aqueous sodium chloride solution (3 ml) is added and the mixture is extracted with ether (10 ml ×2). The solvent is removed by distillation under reduced pressure and the resulting residue is purified by silica gel column chromatography (n-hexane/ethyl acetate=7:1) to give 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraene-1-carbonitrile (13.7 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15]#[N:16])[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S:19]P([O-])(OCC)=S)C.C(OCC)(=O)C>O1CCCC1.O>[CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15](=[S:19])[NH2:16])[CH2:11][CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CCC1(COCc2ccccc2)CCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)CC1(COCc2ccccc2)CCC1
Yield: 71.3 %

Procedure:
To a solution of 9.7 g (45 mmol) of {1-[(benzyloxy)methyl]cyclobutyl}acetonitrile in 100 mL of tetrahydrofuran and 10 mL of water was added 15.13 mL (90.2 mmol) of diethyldithiophosphate and the contents heated at reflux for 16 h. Ethyl acetate and water were added, and the layers separated. The organic phase was dried using magnesium sulfate and concentrated under vacuum to afford the crude product, which was purified by silica gel chromatography using ethyl acetate:hexane (2:8) as the eluent to afford 8.0 g (71%) of 2-{1-[(benzyloxy)methyl]cyclobutyl}ethanethioamide as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.00 (br s, 2H), 7.39-7.30 (m, 5H), 4.59 (s, 2H), 3.58 (s, 2H), 3.09 (s, 2H), 2.14-1.87 (m, 6H).
Reaction SMILES: [N:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>NC1C=CC=CC=1>[CH:12]1[CH:13]=[CH:14][C:9]([NH:1][C:12]2[CH:11]=[CH:10][C:9]([N:1]=[N:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: c1ccc(N=Nc2ccccc2)cc1
Solvent: Nc1ccccc1
Product: c1ccc(N=Nc2ccc(Nc3ccccc3)cc2)cc1
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 25% aqueous tetramethylammonium hydroxide (8 mL) was concentrated under vacuum at 75° C. until solid material formed. Azobenzene (1.8 g) and aniline (10 mL) were added and the solution was stirred under the same conditions for 4 hours and then in the presence of air for 12 hours. Analysis of the reaction by HPLC revealed 90% yield of 4(phenylazo)diphenylamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH:14]=3)[O:9]2)[CH2:4][CH2:3]1.[NH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21]([NH:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[O:22])[CH:14]=3)[O:9]2)[CH2:4][CH2:3]1
Reactant: NOC1CCCCO1
Reactant: CN1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Product: CN1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid (330 mg, 0.94 mmol) was treated with NH2OTHP according to the procedure described in Example 23, Step C, giving (±)-(E)-3-[1′-methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (220 mg).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:10]1([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>C1COCC1>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([N:15]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N(C(=O)Nc2ccccc2)n2ccnc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Phenyl isocyanate (3.6 ml, 32.6 mmol) was added to a solution of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (5 g, 27.17 mmol) in THF (50 ml). The mixture was stirred at 50° C. overnight and after evaporation was crystallised in acetone/EtOH to give white crystals (2.5 g, 30.3%, 178° C.).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[C:16]([OH:25])[CH:17]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:26]1(O)C=CC=CC=1.IC>C1COCC1>[CH3:26][O:25][C:16]1[CH:15]=[C:14]([C:5]2[N:4]=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[C:18]([O:20][C:21]([F:24])([F:22])[F:23])[CH:17]=1
Reactant: Nc1nnc(-c2cc(O)cc(OC(F)(F)F)c2)c(-c2ccccc2)n1
Reactant: Oc1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(OC(F)(F)F)cc(-c2nnc(N)nc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol (100 mg, 0.287 mmol). The phenol was dissolved in THF (2 mL) and treated with iodomethane (17.87 μL, 0.287 mmol) at 0° C. After ˜15 minutes, the mixture was then allowed to warm to r.t. slowly.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2
Reactant: CC(=O)Oc1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
To a mixture of acetic acid quinolin-6-yl ester (120 g, 0.642 mol) and pyridine (114 mL, 1.41 mol) in 6 L of CCl4 was added Br2 (66 mL, 1.28 mol) dropwise. The mixture was heated to reflux for 2 hours before being cooled to room temperature. The liquid in the flask was decanted and washed with saturated aqueous NaHCO3 and water. The dark solid on the bottom of the flask was partitioned between aqueous NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness in vacuo. The crude product was purified through flash column chromatography eluting with Petroleum Ether/ethyl acetate (10/1˜1/1) to provide 108 g of acetic acid 3-bromo-quinolin-6-yl ester as a yellow solid (63% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:35])[C:33]=1[F:34]>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:30]2[CH:29]=[C:28]([F:27])[C:33]([F:34])=[C:32]([F:35])[CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)c(F)c(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3,4,5-trifluorophenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:33][C:34]#[N:35])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenol (0.300 g, 0.916 mmol) was reacted with K2CO3 (0.152 g, 1.099 mmol) and bromoacetonitrile (0.132 g, 1.099 mmol) in acetone (10 ml) to give the product (0.207 g, 0.565 mmol, 62%) as a pale-blue solid, mp 167-169° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 2.28 (s, 3H), 5.19 (s, 2H), 5.39 (s, 2H), 6.98 (d, J=7.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.26-7.30 (m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.65-7.67 (m, 3H); [ESI(+)], m/z 367 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]([OH:17])[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:17][C@@H:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=2)[CH2:10][CH2:11]1)[CH3:16])(=[O:28])=[O:27]
Reactant: CC(C)c1noc(N2CCC([C@@H](C)O)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (1.68 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. was treated with Et3N (1.98 mL, 14.0 mmol) followed by methanesulfonyl chloride (0.66 mL, 8.4 mmol). The mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with 1M NaH2PO4 (75 mL×2) and brine, and dried over Na2SO4 and concentrated to give (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 100% yield) as a brown oil, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([S:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)(=[O:27])=[O:26])[CH2:12][CH2:13][NH:14]C(=O)OCC3C=CC=CC=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C1COCC1.[H][H]>CO.[Pd]>[NH2:14][CH2:13][CH2:12][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)[S:25]([C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1)(=[O:27])=[O:26]
Reactant: COc1cc(S(=O)(=O)N(CCNC(=O)OCc2ccccc2)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(S(=O)(=O)N(CCN)c2ccc3c(ccn3C)c2)cc(OC)c1OC

Procedure:
A solution of Example 51A in methanol:THF (1 mL:1 mL) was treated with 10% palladium on carbon (30 mg), stirred under with hydrogen (1 atm) for 2 hours, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.O.CCOCC>C1COCC1>[Br:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1c(Br)cnc2[nH]ccc12
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
3H2O (80.8 mL, 80.8 mmol; 1.0M solution in THF) was added to 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (30.0 g, 80.8 mmol) in THF (200 mL) at room temperature. The reaction was stirred for 20 minutes, and then water (200 mL) and ether (500 mL) were added. The aqueous phase was extracted with ether. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The solid was crystallized from EtOAc to provide 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (12.5 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 11.06 (br s, 1H), 8.39 (d, 1H), 7.35 (dd, 1H), 6.60 (dd, 1H); LCMS (APCI+) m/z 214.9, 216.9 (M+H)+, Retention time=2.75 minutes (Method 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][NH:10][CH3:11].O>C1COCC1>[F:1][C:2]1[N:3]=[C:4]([N:10]([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Fc1cccc(F)n1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cccc(F)n1
Temperature: 150 °C

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at −60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
Reaction SMILES: [NH4+]=[S:2].C(O)C.[CH2:6]([N:10]1[C:14]([C:15]#[N:16])=[C:13]([CH2:17][OH:18])[N:12]=[C:11]1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[C:7]#[C:8][CH3:9]>C(OCC)(=O)C>[CH2:6]([N:10]1[C:14]([C:15](=[S:2])[NH2:16])=[C:13]([CH2:17][OH:18])[N:12]=[C:11]1[N:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(N)=S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10 ml of a 50% aqueous solution of ammonium sulfide was added to a 50 ml ethanol solution of 3.596 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 400 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 3.221 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (4:1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]([CH3:25])[N+:17]=3[O-:26])[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]([CH3:25])[N+:17]=3[O-:26])[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c4c(n(C)[n+]3[O-])CCCC4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3c4c(n(C)[n+]3[O-])CCCC4)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82112.1 %

Procedure:
To a pale yellow solution of 3-(7-(isopropylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 92.8 μmol) in dichloromethane (2.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmo140), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. Pure white solid product was sonicated with hexanes. The solid was separated by decantation and dried under high vacuum to give 3-(7-(isopropylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (27 mg, 76.2 mmol, 82.1%) as a white solid. MS (M+H)+=377 (100% purity); 1H NMR (DMSO-d6) δ: 12.93 (br. s., 1H), 8.93 (s, 1H), 8.45 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 4.13-4.33 (m, 1H), 3.35 (s, 3H), 2.37-2.46 (m, 2H), 1.83-2.18 (m, 6H), 1.22 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[NH:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)[NH:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)N(C3CCCC3)C3CCC(C)CC3)s2)n1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and ethyl-2-mercapto-1H-imidazole-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7](C3C=C(C(F)(F)F)C=CC=3C([O-])=O)[CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br.[OH2:43]>>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([OH:43])[CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH:3]=1
Reactant: O
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)cc(-c4cc(C(F)(F)F)ccc4C(=O)[O-])c3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c2c(O)cc(O)cc2c(Br)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzoate (0.47 g, 0.86 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and sealed with a septa. Anhydrous methylene chloride (20 mL) was added via a syringe at room temperature. BBr3 (8.60 mL of 1.0 M CH2Cl2 solution, 8.60 mmol) was added drop wise with stirring at room temperature. The resulting solution was heated to reflux for 20 hours and then stirred at room temperature for 3 days. 20 mL of water was added to quench the reaction. CH2Cl2 layer was separated and the aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.05 g, 16.7% yield. MS: m/e 347.8 [M−H]−. 1H NMR (DMSO-d6, 300 MHz): δ 13.12 (s, 1H), 10.78 (s, 1H), 9.81 (s, 1H), 7.75 (s, 1H), 7.28 (d, 2H, J=8.7 Hz), 6.85 (d, 2H, J=8.7 Hz), 6.61 (d, 1H, J=2.1 Hz), 6.37 (d, 1H, J=2.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]([CH2:25][C:26](O)=[O:27])[CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[CH3:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[C:26](=[O:27])[CH2:25][N:23]([C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:24])[CH3:30]
Reactant: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Reactant: COc1cc(CC(=O)N(C)CC(=O)O)ccc1NC(=O)Nc1ccccc1C
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: CCOC(=O)CCN(Cc1ccc(OC)c(OC)c1)C(=O)CN(C)C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetic acid [18.4 g, Reference Example 1] and 3-(3,4-dimethoxy-benzylamino)-propionic acid ethyl ester [13.4 g, Reference Example 2(a)] in dimethylformamide (400 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate] (19.1 g) and diisopropylethylamine (10.5 ml). After stirring at ambient temperature for 20 hours the reaction mixture was evaporated to dryness. The residue was treated with water (800 ml) followed by hydrochloric acid (175 ml 1 M) and the mixture was extracted twice with ethyl acetate (500 ml). The combined organic extracts were washed with hydrochloric acid (500 ml, 1M), then with water (400 ml), then with saturated aqueous sodium bicarbonate solution (500 ml), then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give the title compound as a fawn coloured foam (26.4 g), m.p. 97-105° C. [Elemental analysis:- C,63.4; H,6.7; N,8.7% Calculated for C34H42N4O8.0.5H2O:- C,63.3; H,6.8; N,8.8%].
Reaction SMILES: [O-]O.[CH2:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]O.[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]>[Ti]>[CH2:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:3][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH2:13][CH3:14]
Reactant: C=CCCCCCC
Agent: [Ti]
Agent: [O-]O
Solvent: CCc1ccccc1
Product: CCCCCCCCC
Yield: 10.9 %

Procedure:
This example demonstrates the utility of titanium-containing catalysts prepared in accordance with the present invention in an olefin epoxidation reaction using an organic hydroperoxide. In each run, catalyst (0.5 g) was added to a 4-neck round bottom flask equipped with a condenser, thermocouple, stir bar and a sampling port. A mixture containing 17.9 g 1-octene, 10 g of an ethylbenzene hydroperoxide solution obtained by air oxidation of ethyl benzene, and 1 g nonane (internal standard) was added to the flask under an inert atmosphere. A sample was taken after the reaction mixture was stirred thoroughly. The mixture was then heated to 90° C. and maintained at that temperature for 1 hour. The observed performance of each catalyst is summarized in the following table.