Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:14]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:14][C:10]1[C:11]([CH3:12])=[C:2]([F:1])[C:3]([OH:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)c(F)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(C)c(F)c1O
Reaction time: 2 h

Procedure:
To a solution of methyl 3-fluoro-2-hydroxy-4-methylbenzoate (6.40 g) in acetic acid (120 mL) was added bromine (1.87 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added 10% aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a mixture (7.99 g) of the title compound and the raw material (about 2:1). The obtained product was used in the next step without an additional purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH2:16]([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH3:17]>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:25])[C:20](=[O:21])[CH2:12][C:11](=[O:13])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:14])([F:15])[F:3])=[CH:10][CH:9]=1)[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Yield: 79.7 %

Procedure:
Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of 1-(4-trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic acid diethyl ester (8.7 mL, 63.7 mmol) in 75 mL dry DMF at 0° C. The reaction was allowed to come to room temperature and then heated to 45° C. for 45 minutes. The reaction was then cooled, concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed with 2 M HCl (1×100 mL), dried (Na2SO4) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate 2,4-dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g, 80%) which was then taken up in EtOH and refluxed in the presence of hydroxylamine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reaction was then cooled, diluted with EtOAc, washed with dilute NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from EtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][O:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:8]1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([N:16]2[CH:15]=[CH:14][S:13][CH:12]2[O:11][CH2:10][CH:9]([OH:7])[CH3:8])[CH2:2][CH2:3]1
Reactant: c1csc(OCC2CO2)n1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(O)COC1SC=CN1N1CCOCC1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I of the invention. In this example 1 g. of morpholine is added to a solution of 0.3 g. of 1,2-epoxy-3-(thiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of 1,2-epoxy-3-(thiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-(N-morpholino-3-(thiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][C:21]3=O)[CH:7]=1>>[Cl:3][C:21]1[C:20]2[C:25](=[C:16]([C:8]3[CH:7]=[N:6][C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:17]=[CH:18][CH:19]=2)[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[N:22]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(C(F)(F)F)[nH]c2c(-c3cnc4ccccc4c3)cccc12
Product: FC(F)(F)c1nc(Cl)c2cccc(-c3cnc4ccccc4c3)c2n1

Procedure:
A suspension of compound (114a) (0.57 g), 3-quinolineboronic acid (0.45 g), Pd2dba3 (0.031 g), X-Phos (0.064 g), and potassium phosphate (1.4 g) in butanol was stirred at 100° C. for 15 hours in a nitrogen atmosphere. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g) as a white solid. Phosphorus oxychloride (5 ml) was added to the obtained 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g), and the mixture was heated to reflux for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The reaction solution was neutralized with an aqueous sodium bicarbonate solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline (0.43 g) as a white solid. Compound (114) was obtained as a yellow solid (yield based on 4 steps: 25%) according to Example 1(5) using the obtained 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline instead of compound (1d) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[N:19]=[C:18]([NH:20][C:21]4[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=4)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[O:29][CH2:28][CH2:27][O:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nc(C3(c4ccc(F)cc4)OCCO3)nc3ccccc23)n[nH]1
Yield: 1 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (0.20 g, 0.58 mmol) in toluene (20 mL) were added ethylene glycol (0.2 mL) and p-toluenesulfonic acid monohydrate (catalytic quantity). The mixture was heated under reflux overnight while collecting water in a Dean-Stark trap. Additional ethylene glycol (1.5 mL) and p-toluenesulfonic acid monohydrate (50 mg) were added and mixture was heated at reflux overnight with collection of water. After cooling, the mixture was evaporated to dryness, and then dissolved in DMSO (8 mL). A 5 mL aliquot of this solution was purified by preparative reverse-phase HPLC (Varian diphenyl reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) followed by additional purification by preparative reverse-phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2 mg, 1%). 1H NMR (300 MHz, DMSO-d6) δ 2.20 (s, 3H) 4.05-4.22 (m, 4H) 6.2 (s, 1H) 7.19 (t, 2H) 7.5-7.65 (m, 3H) 7.81 (m, 2H) 8.59 (d, 1H) 10.38 (s, 1H) 12.08 (s, 1H); LC-MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([C:6](=[O:15])[CH:7]([CH3:14])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[CH3:17]I>O1CCCC1>[CH3:10][C:9]([CH3:12])([C:8](=[O:13])[C:7]([CH3:17])([CH3:14])[C:6](=[O:15])[C:4]([CH3:3])([CH3:16])[CH3:5])[CH3:11]
Reactant: CI
Reactant: CC(C(=O)C(C)(C)C)C(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(C)(C)C(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of 1.6 g of NaH at 80% by weight in 42 ml of anhydrous tetrahydrofurane are added dropwise 8 g of 2,2,4,6,6-pentamethyl-3,5-heptanedione (0.04 moles). The content is stirred at ambient temperature until a homogeneous solution is obtained. 7.7 ml of methyl iodide are then added and a white precipitate forms almost immediately. The content is allowed to agitate at ambient temperature for 12 hours and then the solvent is evaporated. Some water is added (10 ml) and the content is extracted with ether and then anhydrated on Na2SO4. The ether is evaporated to the rotavapor, isolating a white needle-shaped solid, which is then purified by way of sublimation.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:13][C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][C@H:6]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CC[C@H]1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(=O)CC[C@H]1C

Procedure:
reacting said ethyl (1R,2R,5R)-5-hydroxy-2-methylcyclohexane-1-carboxylate (10) with pyridinium chlorochromate in methylene chloride to produce ethyl(1R,2R)-2-methylcyclohexane-5-one-1-carboxylate (11),
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:15][CH:16]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[C:23]=2[N:22]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]>>[Cl:15][CH:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:21]([NH:22][C:23]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[O:27])[CH:8]([C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:26]
Reactant: CC(C)(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CCOC(=O)CC(=O)Nc1nccs1
Product: CCOC(=O)C(C(=O)Nc1nccs1)C(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)C(C)(C)C
Yield: 88.5 %

Procedure:
Using the procedure of Step A of Example 4, 7.7 g of ethyl 3-(2-thiazolylamino)-3-oxo-propanoate and 10.55 g of 2-(1-chloro-2,2-dimethylpropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared according to the process described in the European Pat. No. 0040573] were reacted to obtain 15.6 g of ethyl 2-[(2-chloro-1-oxo-3,3-dimethylbutyl)-amino]-β-oxo-α-[(2-thiazolylamino)-carbonyl]-3-(trifluoromethyl)-benzene-propanoate melting at 180° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH2:6][CH:5]1[CH3:28])(=[O:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2]
Reactant: CCOC(=O)NC1CC(C)N(C(C)=O)c2ccc(-c3ccc(CCl)cc3)cc21
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N[C@@H]1C[C@H](C)N(C(C)=O)c2ccc(-c3ccc(CN4CCCCC4)cc3)cc21
Temperature: 85 °C

Procedure:
(cis)-1-Acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 2) (50 mg, 0.132 mmol) was dissolved in dichloromethane (DCM) (2 mL), mixed with ethyl chloridocarbonate (0.015 mL, 0.159 mmol), and DIPEA (0.046 mL, 0.265 mmol) and stirred under nitrogen for 2.5 days. Another sample of ethyl chloridocarbonate (0.015 mL, 0.159 mmol) was added to the reaction, along with a sample of DIPEA (0.046 mL, 0.265 mmol). LCMS analysis after 73 hours reaction time indicated that the reaction had produced a side-product. The reaction was allowed to stir overnight. The reaction mixture was loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Fractions were evaporated to dryness to give a solid which was further purified on a 12+M Biotage silica columns, eluting with cyclohexane:EtOAc (1:0 to 1:1). Product-containing fractions were evaporated to dryness to give a white solid (38 mg) that was characterised as ethyl {1-acetyl-6-[4-(chloromethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate. Some of this material (24 mg, 0.060 mmol) was added to a solution of piperidine (0.036 mL, 0.363 mmol) mixed with acetonitrile (4 mL), along with six equivalents of potassium carbonate (60.2 mg, 0.435 mmol) and the solution was refluxed under nitrogen at 85° C. for 15 hours then cooled and loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Product-containing fractions were evaporated to dryness to give a clear, colourless solid (35 mg). This was purified on a 12+M Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 49:1). Product-containing fractions were evaporated to dryness to give a clear, colourless solid (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:31])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][Br:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([O:29]C)[CH:12]=3)=[CH:4][CH:3]=1.Br.CC(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:31])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][Br:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:29])[CH:12]=3)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-(2-bromoethoxy)benzyl)-7-methoxychromen-2-one (16.5 grams, 33 mmol) and 150 mL of 30% HBr/HOAc in a sealed tube was warmed at 100° C. for 8 h. The reaction mixture was cooled to room temperature and poured into 300 mL of water. The resulting solid was collected by filtration and purified using flash chromatography to provide the desired product (12.5 g, 78%). 1H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 7.47 (d, 2H, J=8.5 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.33 (d, 2H, J=8.5 Hz), 7.05 (d, 2H, J=8.5 Hz), 6.83 (d, 2H, J=8.5 Hz), 6.75 (d, 1H, J=2.2 Hz), 6.70 (dd, 1H, J=8.8, 2.2 Hz), 4.24 (t, 2H, J=5.7 Hz), 3.94 (s, 2H), 3.76 (t, 2H, J=5.7 Hz). MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22](Cl)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]([C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH2:32])([CH3:29])[CH3:28].C(N(CC)CC)C>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22]([NH:32][C:31]2[C:33]([CH:37]([CH3:38])[CH3:39])=[CH:34][CH:35]=[CH:36][C:30]=2[CH:27]([CH3:29])[CH3:28])(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [1,1':3', 1"-terphenyl]-2'-yl(chlorosulfonyl)carbamate (5.0 g, 12.9 mmol) in 75 mL tetrahydrofuran was added dropwise to a solution of 2,6-diisopropyl aniline (2.29 g, 12.9 mmol) and triethylamine (1.3 g, 12.9 mmol) in 100 mL tetrahydrofuran at -15° C. under an atmosphere of nitrogen. The resulting mixture was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and partitioned the residue between water and ethyl acetate. Dried the organic layer over MgSO4 and evaporated to give an off-white solid. Chromatography on silica gel gave the title compound, mp 166°-168° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([CH3:28])[C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[C:12]([CH3:28])=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(O[C@H]2CCC[C@@H]2c2ccnn2C)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 100.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.18 g, 0.31 mmol) prepared in Example 65c, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (2.0 mL), to yield the title compound (134 mg, 99%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:22])([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:50][C@H:51]([CH2:72][O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:52]([N:54]1[CH2:71][CH2:70][CH2:69][C:56]2([C:60](=[O:61])[N:59]([CH3:62])[CH2:58][CH:57]2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:55]1)=[O:53]>CN(C=O)C.Cl>[CH3:22][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([CH2:13][O:14][Si:15]([CH3:17])([CH3:16])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:10](=[O:12])[NH:50][C@@H:51]([C:52]([N:54]1[CH2:71][CH2:70][CH2:69][C:56]2([C:60](=[O:61])[N:59]([CH3:62])[CH2:58][CH:57]2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:55]1)=[O:53])[CH2:72][O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: CC(C)(C)OC(=O)NC(C)(CO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccccc3)C2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 0.25 h

Procedure:
A mixture comprising 2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)-2-methylpropanoic acid (intermediate from step 1) (311 mg, 0.934 mmol) and DIPEA (0.652 ml, 3.73 mmol) in DMF (5 mL) was treated with a solution of ®T3P (50% in EtOAc) (1.090 ml, 1.867 mmol) dropwise at room temperature. The resulting solution was stirred for 15 minutes, then 7-((R)-2-amino-3-(benzyloxy)propanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (intermediate from step 3) (500 mg, 0.934 mmol) in DMF (1 mL) was added dropwise at room temperature. The reaction mixture was stirred for 20 hours. The reaction mixture was diluted with 0.1M HCl (10 mL) and extracted with DCM (3×10 mL). The combined organic portions were washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), water (10 mL) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-70% EtOAc/iso-hexane afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(F)(F)F)c1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: Cc1onc(C(F)(F)F)c1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 0.45 g (2.5 mmoles) of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol dissolved in 10 ml of diethyl ether was cooed to 0° C. Thereto was added 0.2 g (8.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 74.0%) of 4-bromomethyl-5-methyl-3-trifluoromethylisoxazole.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CO>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CCNCC
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Solvent: CO
Product: CCN(CC)CCCCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1
Temperature: 50 °C

Procedure:
A 25 mL pressure tube is charged with 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (75 mg, 0.173 mmol), diethylamine (2 mL) and the reaction mixture is heated at 50° C. for 3 h. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The organic layer is washed with saturated aqueous NaHCO3 solution, brine, and dried over anhydrous Na2SO4. The organic layer is collected by filtration and concentrated to give a yellow solid. The solid is broken up in MeOH and collected by filtration to give the named compound as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]1[N:36]([CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][O:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:39][CH2:38][CH2:37][N:36]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCN4CCOCC4)c3)C(C)(C)C2=O)cc1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 37 μl of 1-(2-aminoethyl)morpholine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol/aqueous ammonia (6/1 by volume) to give 77 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-(2-morpholin-4-ylethyl)urea, the characteristics of which are as follows: