Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]=[CH2:10])[CH:2]=[CH2:3].[Cl:11][SiH:12]([Cl:14])[Cl:13]>O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[Cl:11][Si:12]([Cl:14])([Cl:13])[CH2:3][CH2:2][CH2:1][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][Si:12]([Cl:14])([Cl:13])[Cl:11]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOCCOCC=C
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: Cl[Si](Cl)(Cl)CCCOCCOCCC[Si](Cl)(Cl)Cl
Temperature: 80 °C
Yield: 70 %

Procedure:
3-(2-Allyloxy-ethoxy)-propene (20 g, 0.141 mol) and 40 mg of hydrogen hexachloroplatinate (IV) hydrate were added to a 250-mL air-free flask with a condenser. Trichlorosilane (40 mL, 0.396 mol) was added dropwise to the stirred solution which was subsequently heated in an oil bath of 80° C. The reaction mixture was heated at reflux for 4 hours and then distilled in vacuum. The fraction containing di(3-trichlorosilyl)propyl ethylene ether (39 g, 0.0944 mol) at 90° C. and 20 mtorr was collected with a yield of 70% based on 3-(2-allyloxy-ethoxy)-propene. 1H NMR (400 Mz, CDCl3): δ 1.5 (t, 2H), 1.8 (m, 2H), 3.4 (t, 2H), 3.6 (t, 2H). 29Si NMR (79.6 Mz, CDCl3): 13.4 (s).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([C:23]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)=[O:30])[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Reactant: O=C(O)c1cccnc1
Product: O=C(c1cccnc1)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 35, the title compound was prepared from the compound obtained in step (e) of Example 1 and nicotinic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=1.[ClH:34].[NH:35](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:36]([C:43]([OH:45])=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:35][C@H:36]([C:43]([OH:45])=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH2:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:7]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=1.[ClH:34]
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCC1c2ccccc2-c2ccccc21
Agent: C=Cc1ccc(C=C)cc1
Agent: Cc1ccc(C(N)c2ccccc2)cc1
Agent: Cl
Solvent: C=Cc1ccccc1
Product: N[C@H](C(=O)O)c1ccccc1

Procedure:
The commercially available MBHA resin (2.6 g, 1.12 mmol/g, 2.91 mmol) was transferred to a 250 mL fritted solid phase reaction vessel equipped with a nitrogen inlet. It was then washed thoroughly with 30 ml portions of dichloromethane, methanol, dimethylformamide and dichloromethane and coupled over 18 hours to the commercially available Fmoc-Phg-OH (2.17 g, 5.82 mmol) according Procedure A with 99.82% efficiency. The resin was then subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a is small aliquot gave dark blue resin and solution, indicating a successful reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:45])[F:46])[CH:36]=3)(=[O:43])=[O:42])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (42 mg, 0.094mmol) in anhydrous CH2Cl2 (5 ml) was added 3-(Trifluoromethyl)benzene sulfonyl chloride (22.5 μl, 0.14 mmol) and diisopropylethylamine (32.7 μl, 0.19 mmol). The reaction stirred at room temperature overnight, was diluted with EtOAc and washed with sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (48.5 mg, 79%). Calcd for C33H35F6NO4S (M+H) 655.69, Found 656.2.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=C3/C=C(C4C=CC(C=O)=CC=4)C(C)(C)O/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.N1(CCOCCO)CCNCC1.C([BH3-])#N.[Na+].C1COCC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CO.O.CC(O)=O>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[CH2:6][C:7]1=[O:11]
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: OCCOCCN1CCNCC1
Agent: [BH3-]C#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (55 mg, 0.16 mmol), 2-(2-(piperazin-1-yl)ethoxy)ethanol (56 mg, 0.32 mmol) and 4 Å molecular sieves (100 mg) in anhydrous DMF (3 mL) was stirred at room temp for 16 hours. To this stirred mixture was added AcOH (10 mg), 1M sodium cyanoborohydride in THF solution (0.32 mL, 0.32 mmol) and 3 mL of anhydrous methanol. The reaction mixture was stirred at room temp for 5 hours and poured into 100 mL of water. Saturated NaHCO3 solution was then added until pH=9. The precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3 to give (3E)-6-fluoro-3-{4-[4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 45 mg, 56%.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]1=2.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][CH2:4][C:3]([OH:19])=[O:2])[O:10]1
Reactant: COC(=O)CCC1OB(O)c2cc(OC)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1)B(O)OC2CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of 3-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-propionic acid methyl ester (0.160 g, 0.60 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (0.116 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated to approximately half its volume and the precipitated solid was filtered, washed with water and dried to give 3-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-propionic acid (0.140 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.02 (d, J=2 Hz, 1H), 6.81 (s, 1H), 5.12 (m, 1H), 3.72 (s, 3H), 2.30-2.20 (m, 5H), 2.10 (m, 1H), 1.50 (m, 1H). MS (ES) m/z: 249 (M−1)−. HPLC purity: 97.16% (220 nm), 96.94% (Maxplot).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:24](=[O:27])([O-])[O-:25].[Na+].[Na+]>ClCCl.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>[CH2:2]([O:25][C:24]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1)=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(CN)c2)CC1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(CNC(=O)OCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 4-(3-Aminomethyl-phenyl)-1-tert-butoxycarbonyl-piperidine-4-carbonitrile in 15 ml of dichloromethane was added a few drops of triethylamine followed by a few drops of benzyl chloroformate. The mixture was stirred for 1 hour at room temperature and was poured into aqueous sodium carbonate and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and was filtered. The filtrate was evaporated and the residue was used directly in the next step without further purification: 1H-NMR (300 MHz, CDCl3)δ (TMS) 1.39-1.52 (m, 9H), 1.80-2.16(m, 4H), 3.08-3.42(m, 4H), 4.19-4.50(m, 2H), 5.08-5.13(d, 2H), 7.28-7.79(m, 9H), MS (ESI) m/e 450 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[C:20]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:22]=2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:28]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:23]2[N:24]=[C:25]([CH3:27])[N:26]=[C:21]([C:20]3[C:11]([NH:1][C:2]4[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:22]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc4ccccc4nc3Cl)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc4ccccc4nc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 5-amino-2-methoxypyridine (0.08 mL, 0.61 mmol, Aldrich, St. Louis, Mo.) and 4-(2-chloroquinolin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (210 mg, 0.410 mmol) in THF (3 mL) was cooled to 0° C. and LiHMDS (1 M in THF, 1.23 mL, 1.23 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h, diluted with an aqueous satd solution of NH4Cl (5 mL) and extracted with EtOAc (20 mL). The organic extract was washed with water and dried over Na2SO4. The solution was filtered and concentrated in vacuo, and the residue was adsorbed onto a plug of silica gel. Purification by chromatography through a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 2% to 3% 2 M NH3.MeOH in CH2Cl2 gave the title compound as an orange solid (65% pure) that was used without further purification. m/z (ESI, +ve ion) 599.8 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:13](I)[CH3:14]>CN(C=O)C>[Cl:3][C:4]1[N:8]([CH2:13][CH3:14])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a cooled (0° C.) stirred suspension of NaH (60% dispersion in mineral oil; 7.08 g, 0.118 mol) in DMF (100 mL) was added 2-chlorobenzimidazole (15.00 g, 0.098 mol). The mixture was warmed to room temperature and stirred for 1 hour. Ethyl iodide (18.40 g, 0.118 mol) was added and stirring was continued for 3 hours. The mixture was poured onto the ice water and the resulting off-white solid was collected by filtration to give 10.0 g (61%) of product m.p. 48°-50° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:17]=3[C:18]([NH2:20])=[O:19])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.C(Cl)Cl>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][N:28]([C:45](=[O:46])[CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:27][CH2:26]4)[CH:22]=[CH:21][C:17]=3[C:18]([NH2:20])=[O:19])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(N2CCNCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCN(C(=O)Cc3ccccc3)CC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
To a suspension of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperazin-1-yl)nicotinamide (28 mg, 0.068 mmol) and Et3N (0.019 mL, 0.136 mmol) in THF (2 mL) and CH2Cl2 (2.000 mL) was added 2-phenylacetyl chloride (10.55 mg, 0.068 mmol). The reaction mixture was stirred at rt for 10 min, diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, extracted with CH2Cl2, separated, and concentrated to give 14 mg of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(4-(2-phenylacetyl)piperazin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=529.40. 1H NMR (400 MHz, CDCl3) δ ppm 11.17 (1H, s), 7.63 (2H, d, J=8.56 Hz), 7.55 (1H, d, J=8.81 Hz), 7.35-7.40 (2H, m), 7.31-7.35 (2H, m), 7.23-7.31 (3H, m), 5.99 (1H, d, J=8.81 Hz), 5.59 (2H, s), 3.50-3.81 (18H, m).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2N1CCC2C(=CC(OC)=CC=2)C1.CC1(C)C(C)(C)OB(C2C=C3C=CN([Si](C(C)C)(C(C)C)C(C)C)C3=NC=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)CN(c1ncnc3ccc(I)cc13)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2ncncc2c1
Yield: 64 %

Procedure:
0.20 g of 6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)quinazoline, 0.28 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 0.11 g of sodium hydrogencarbonate and 0.03 g of Pd(PPh3)2Cl2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 5 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 5-30% in 13 min), giving 0.20 g of 4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-[(2-trimethylsilanylethoxymethyl)-3H-imidazo]4,5-b]pyridin-6-yl]quinazoline as white powder (yield 64%, content 79%); MS-FAB (M+H+)=553.3; Rf (polar method): 2.14 min.
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][O:13][CH:12]([C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH2:11]1)C1C=CC=CC=1.[ClH:34].C(O)C>[Pd].C(O)(C)C>[ClH:34].[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([CH2:17][C:16]([CH:12]2[O:13][CH2:14][CH2:15][NH:10][CH2:11]2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[OH:27])[CH:23]=1
Reactant: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CNCCO1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Alternatively, the following method may be used. A glass hydrogenation flask was loaded with methanol (1.55 L), Pd/C (10%, 31 g, 20% loading), 1-(4-benzyl-morpholin-2-yl)-2-(5-fluoro-2-methoxy-phenyl)-1-phenyl-ethanol (155 g, 0.368 mole) and a solution of HCl in ethanol (2.5N, 233 ml, 0.582 mole, 1.6 eq.). The reactor was mounted on a Parr instrument and pressurized with H2 (49 Psi). The reaction mixture was shaken overnight between 20° C. and 15° C. The catalyst was filtered off and washed with methanol (0.5 L). The filtrates were concentrated under vacuum. The yield of crude title compound was 109.5 g (81%). The catalyst was washed again with methanol (2×500 ml). The filtrates were combined and concentrated under vacuum. The yield of the second crop of crude title compound was 21.7 g (16%). A reactor was loaded with crude title compound (131 g, 0.356 mole) and isopropanol (1.3 L) under N2. The suspension was heated under reflux for 4 hours. The mixture was cooled to 20° C. and the solid was filtered, washed with isopropanol (130 ml), and dried at 50° C. under vacuum. The yield of pure title compound was 115.9 g (88.5% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[C:4]([CH:1]([NH:38][OH:39])[CH3:2])[CH:5]=[CH:6][C:7]=2[NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[CH2:27][CH2:28]2)=[O:22])=[N:13][CH:14]=1
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NO)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a stirring solution of 5-acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.25 g, 0.56 mmol) in methanol (2 mL) was added sodium acetate (0.1 g, 1.2 mmol) followed by hydroxylamine hydrochloride (46 mg, 0.67 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The resulting residue was partitioned between I dichloromethane and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 3% 2 M ammonia/methanol solution in dichloromethane to give 0.22 g (85%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:19][CH:18]=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:33][CH:34]=1)=[O:15]
Reactant: Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reaction time: 12 h
Yield: 90.3 %

Procedure:
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2Cl2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH2Cl2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1N HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure to afford N-(2-methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 1H NMR (DMSO-d6) δ3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M+H)+, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(N(CC)CC)C.C(OCC)(=O)C.Cl>CS(C)=O>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH:2]=[O:1])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
8-(4-Hydroxymethylbicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Example 86a, 1 wt) and dimethyl sulphoxide-(4 vol)are mixed and stirred under nitrogen; the mixture is stirred for 5 to 15 mins and triethylamine (2.42 vol) is added. A mixture of sulphur trioxide pyridine complex (1.275 wt) in dimethyl sulphoxide (6 vol) is added, maintaining the internal temperature below 30°. The temperature is adjusted to 14 to 20°and the reaction mixture is then stirred at 14 to 20° for 16 to 20 hours until complete by NMR. If there is any starting alcohol remaining sulphur trioxide pyridine complex (0.15 wt) is added and the reaction stirred for a further 2 to 3 hours at 14 to 20°. Ethyl acetate (20 vol) and hydrochloric acid (1 M, 10 vol) are added to the reaction mixture and stirred vigorously for 5 to 15 mins. The phases are separated and the organic phase is washed with hydrochloric acid (1 M, 10 vol). The phases are separated and the organic phase is again washed with hydrochloric acid (1 M, 10 vol). The phases are separated and the organic phase is washed with saline (5 vol); dried over magnesium sulphate (0.5 wt) for 5 to 10 mins and filtered. The filter cake is washed with ethyl acetate (1 vol). The solvent is removed under reduced pressure at 40 to 45° to give the title compound.
Reaction SMILES: [C:1]([C@:3]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:5][C@@H:4]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[N:2].CC(C)([O-])C.[K+].[CH2:25]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>CN(C=O)C>[C:1]([C@:3]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:35][CH:36]=4)=[CH:47][CH:46]=3)=[CH:16][CH:17]=2)[CH2:5][C@@H:4]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[N:2]
Reactant: CCCCCCCCOc1ccc(-c2ccc(CBr)cc2)cc1
Reactant: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ccc(COc3ccc([C@@]4(C#N)C[C@@H]4CCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 95.1 %

Procedure:
In 10 ml of DMF was dissolved 49 mg of (1R,2S)-1-cyano-2-hexyl-1-(4-hydroxyphenyl)cyclopropane as obtained in Example 11. Thereto was added 34 mg of potassium t-butoxide, and the resulting mixture was stirred at room temperature for 70 minutes. Thereto was added dropwise a solution of 98 mg of 4-(4-octyloxyphenyl)benzyl bromide in 3 ml of DMF, and this mixture was stirred for 6 hours. Thereafter, 20 ml of 5% hydrochloric acid was added to the reaction mixture, and the resulting mixture was subjected to extraction with 50 ml of ether. The resulting organic layer was washed with water and then with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=10/1), thereby obtaining 103 mg of the desired compound in the form of white crystals.