Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([Cl:32])=[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH:28]([CH3:30])[CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:12]=3)[CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[Cl:32][C:5]1[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH:28]([CH3:29])[CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:42]([NH:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[O:43])=[C:3]([F:33])[CH:4]=1
Reactant: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(NC(=O)Nc4cccc(F)c4)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-((4-methoxybenzyl)amino)-1,6-naphthyridin-2(1H)-one (0.11 g, 0.236 mmol) in THF (5 mL) was treated with TEA (0.1 mL) and 3-fluorophenyl isocyanate (0.032 mL, 0.259 mmol) and stirred at RT for 5 h. The mixture was concentrated to dryness, treated with DCM and the solid collected via filtration and dried to afford 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (94 mg, 66% yield). MS (ESI) m/z: 604.1 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl>C(O)C>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccccc1CCl
Reactant: Sc1ncc[nH]1
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1CSc1ncc[nH]1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 1.5 g (15 mmol) of 2-mercaptoimidazole in 15 ml of ethanol was added at room temperature 2.66 g (15 mmol) of 2-aminobenzyl chloride hydrochloride. The mixture was then stirred for one hr. at room temperature. The obtained homogeneous solution was placed under reduced pressure at a temperature below 40° C. to distill off the solvent. To the residue were successively added water and saturated aqueous sodium hydrogencarbonate to precipitate a crystalline product. The product was collected by filtration, washed twice with water, and dried to give 2.5 g of the desired compound as a pale gray crystalline product, yield 80.9%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH:14]12[CH2:19][CH:18]1[CH2:17][NH:16][CH:15]2[C:20](O)=[O:21].C[Al](C)C.O>C(Cl)Cl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH:6][C:20]([CH:15]2[NH:16][CH2:17][CH:18]3[CH:14]2[CH2:19]3)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C(O)C1NCC2CC21
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Product: C#CCOc1cc(NC(=O)C2NCC3CC32)c(F)cc1Cl
Temperature: 5 °C
Yield: 35.7 %

Procedure:
To a mixture of 2.36 g (11.79 mmol) of 4-chloro-2-fluoro-5-(2-propynyl)oxyaniline and 1.5 g (11.79 mmol) of (±)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid in methylene chloride (150 mL) stirred under nitrogen and cooled to 5° C. was added trimethylaluminum dropwise (2.0M, 11.8 mL, 23.58 mmol). The resultant mixture was stirred at room temperature for 48 h. Water (100 mL) was added dropwise at ice-bath temperature. The solid inorganic material which formed was filtered, and the filtrate was dried (MgSO4) and evaporated under reduced pressure to dryness. Flash chromatography on silica gel yielded 1.3 g of the product of Step F as a tan solid; m.p. 113°-115° C. IR (mineral oil, cm-1): 1687.1 (C=O); 2123.5 (C≡C).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.Cl>CN(C=O)C.CCOCC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: Fc1ccccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Oc1ccc2cc(OCc3ccccc3F)ccc2c1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A stirred solution of 15.0 g (94.0 mM) of 2,6-dihydroxynaphthalene in 60 mL of DMF was treated with 3.21 g (80.0 mM) of NaH under nitrogen. The resulting dark solution was treated dropwise with a solution of 5.94 g (31.0 mM) of 2-fluorobenzyl bromide in 20 mL of Et2O over 0.75 h. The mixture was stirred an additional 2 h then treated cautiously with 200 mL 1N HCl. The mixture was stirred 8 to 16 hours then filtered. The solid was washed thoroughly with water and dried. Flash chromatography produced a solid which was recrystallized from i-PrOH to afford 4.51 g (56%) of product as gray crystals mp 143-144° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 13.7 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 3-methoxyphenylboronic acid 49 mg, sodium carbonate 57 mg and polymer-carried bis(acetato)triphenylphosphine palladium (II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. To the obtained residue were added 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL and ethanol 6.0 mL, and it was stirred at room temperature for 1 hour. 0.5 mol/L Hydrochloric acid was added to the reaction mixture, solid matter was filtrated to give 2-(4-fluoroanilino)-4-(3-methoxyphenyl)benzoic acid 10 mg of pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].CCN(C(C)C)C(C)C.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([N:20]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCNCCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a 0° solution of oxalyl chloride (479 mL, 5.49 mmol) in THF (10 mL) under nitrogen was added DIPEA (2.28 mL, 13.07 mmol) and dibutylamine (925 mL, 5.49 mmol). The resulting mixture was stirred at 0° for 5 min, whereby (dibutylamino)oxoacetyl chloride is formed, then transferred via syringe to a solution of 4-(4-aminophenyl)-2-aminothiazole (corresponding to the deprotected title compound of either Example 1(a) or 1(b)). The resulting mixture was stirred under nitrogen for 4 h, after which time another batch of freshly prepared (N,N-dibutylamino)oxalylchloride (prepared in the same manner and with the same amounts as above) was added to the reaction mixture. The stirring was continued for 1 h. The mixture was then diluted with EtOAc and extracted with 10% aqueous HCl. This aqueous extract was washed with EtOAc:Hex (1:1), then filtered. The collected solid, containing the desired product as its hydrochloride salt, was treated with 2N aqueous NaOH and extracted with EtOAc. This latter extract was washed with H2O, dried (MgSO4) and concentrated under reduced pressure to give a solid (398 mg) which was further purified by crystallization from EtOAc/MeOH to give the title compound (240 mg, 12% yield) as a beige solid: M.p. 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ10.68 (s, 1H), 7.75 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=9.0 Hz), 7.02 (s, 2H), 6.92 (s, 1H), 3.33 (m, 4H), 1.50-1.60 (m, 4H), 1.33 (sixt., 4H, J=7.5 Hz), 1.25 (sixt., 4H, J=7.5 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.82 (t, 3H, J=7.5 Hz); MS (FAB) m/z 375 (MH)+. Anal. Calcd for C19H26N4O2S: C, 60.94; H, 7.00; N, 14.96. Found: C, 60.82; H, 6.85; N, 14.95.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1>CS(C)=O>[N:1]([CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
8.13 g of sodium azide are added over 5 minutes to a solution of 5.73 g of methyl 4-(bromomethyl)benzoate in 30 ml of DMSO and the mixture is stirred for 3 hours 30 minutes at RT. The reaction mixture is extracted with ether, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 4.72 g of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:44]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(=[O:46])[CH3:45]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2Br)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C(C)=O)cc1
Reaction time: 6 h
Yield: 46.6 %

Procedure:
A mixture of ethyl 4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (122.0 mg, 0.20 mmol) prepared in Example 153, tributyl(1-ethoxyvinyl)tin (94.0 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (14.0 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was heated to reflux under argon atmosphere for 16 hours. After cooling, the reaction solution was diluted with ethyl acetate, and poured into aqueous potassium fluoride solution. The mixture was stirred for 6 hours. The insoluble was filtered off, and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water. Then, thereto was added 2 mol/L hydrochloric acid, and the mixture was stirred for 3 days. Then, the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2) to give ethyl 4-({(4-acetylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (53.4 mg, 47%) as a white powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: COc1ccc(OC)c(C=O)c1
Product: C=CCOc1ccc(C(=O)C=Cc2cc(OC)ccc2OC)cc1
Reaction time: 2.5 h
Yield: 77.1 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 2,5-dimethoxy-benzaldehyde were under an inert atmosphere (argon) dissolved in 10 ml of dry freshly distilled ethanol, and 100 mg of sodium hydroxide was added to the solution. The mixture was left under stirring for 2.5 h and filtered. The precipitate was recrystallized from methanol to give 2.50 g (83%) of 2,5-dimethoxy-4′-prop-2-enyloxychalcone, m.p. 86-87° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:17]([NH:11][CH2:10][CH2:9][CH2:8][N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])=[O:18])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Cc1cn(CCCN)c(C)n1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1cn(CCCNC(=O)c2ccc(Cl)nc2)c(C)n1

Procedure:
When 2,4-dimethyl-1H-imidazole-1-propanamine is treated with a mixture of 6-chloronicotinic acid and 1,1'-carbonyldiimidazole by the procedure of Example 30 the compound of the Example is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[OH:23].[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=O)[CH:28]=[N:29][C:30]=1[CH2:31][OH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:4][C@H:3]2[OH:23])[CH:28]=[N:29][C:30]=1[CH2:31][OH:32]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@H](N)[C@H](O)C3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](NCc4cnc(CO)c(Cl)c4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 33 as a free base: 200 mg, 0.628 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (108 mg, 0.628 mmol) in DCE (10 ml) and Methanol (0.5 ml) was stirred at room temperature overnight. Sodium triacetoxyborohydride (399 mg, 1.885 mmol) was added. The mixture was stirred under N2 at rt for 6 h. LCMS showed imine and desired compound. An excess of sodium triacetoxyborohydride (399 mg, 1.885 mmol) was added. The mixture was stirred overnight. Full conversion to the amine was observed by LCMS. It was quenched with saturated NaHCO3, extracted with DCM/MeOH 9/1, dried (MgSO4), filtered, and concentrated affording 242 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (179.8 mg, 0.360 mmol, 57% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N:11]3[C:10](=[O:19])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]3[CH3:1])=[CH:13][CH:14]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-methyl-3-(4-hydroxyphenyl)-4 (3H)quinazolinone synthesized according to Example 1-(1) and -(2) (1.0 g, 3.96 mmol), N-(t-butoxycarbonyl)-4-piperidinol (956 mg, 4.75 mmol) and triphenylphosphine (1.56 g, 5.94 mmol) were dissolved in dry tetrahydrofuran (2 mL) in a current of nitrogen, and cooled on an ice bath. Diethylazodicarboxylate (1.17 mL, 5.94 mmol) was dripped in at 0° C., and stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, ether was added, the solid precipitate was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3), and the target substance (1.1 g, 64%) was obtained as a light brown solid.
Reaction SMILES: CC([Si](C)(C)[O:6]C1CC(CCC2C3C(=CC(C)CC3O)C=CC2C)OC(=O)C1)(C)C.[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1>[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38]([OH:6])=[O:39])=[CH:34][CH:33]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CC1C=C2C=CC(C)C(CCC3CC(O[Si](C)(C)C(C)(C)C)CC(=O)O3)C2C(O)C1
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of [1S-[1α(4R*,6R*),2α,6β,8β,8aα]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one in an amount of 1.00 g (2.29 mmol), 18.6 ml of dry pyridine, 1.40 g (1.15 mmol) 4-N,N-dimethylaminopyridine and 5.34 g (22.9 mmol) of 2-(4-chlorophenoxy)-2-methylpropionyl chloride was heated at 50° C. for 63/4hour, then stirred overnight at room temperature. Ice chips were then added, and after 30 min the mixture was poured into ice water and extracted four times with diethylether. The combined ether layers were washed with water, then washed with 0.1M H2SO4 and then dried over a conventional drying agent, preferably anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure (i.e. below atmospheric pressure, preferably around 30 mm). The residue was dissolved in diethylether, washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure to leave 1.6 of 2-(4-chlorophenoxy)-2-methylpropionic acid-[1S-[1α,3α,7β,8β(2R*,4R*),8aβ]]-8-[2[tetrahydro-4-[ [(1,1-dimethylethyl)dimethylsilyl]oxy]6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester as a brown oil which was used directly without further purification.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.COC[C@H]1CCC[NH:32]1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:32]
Reactant: COC[C@H]1CCCN1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 252.2 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. (R)-2-(Methoxymethyl)-pyrrolidine (0.207 g, 1.800 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.300 g (82%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 407 (M+1); Anal. Calcd for C25H30N2O3.1 HCl.1H2O: C, 65.14; H, 7.22; N, 6.08; Found: C, 65.07; H, 7.08; N, 6.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[N:6]=[CH:5]2.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>O1CCCC1.CCCCCC>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([B:18]([OH:23])[OH:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)[CH3:12]
Reactant: CCn1ncc2cc(Br)ccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCn1ncc2cc(B(O)O)ccc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 5-bromo-1-ethyl-1H-indazole (598 mg, 2.67 mmol) in dry tetrahydrofuran (30 mL) was cooled below −60° C. Then a solution of butyllithium in hexane (2.5 ml, 2.5M) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (1.5 g, 7.98 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (3N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 ml). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuum to give 1-ethyl-1H-indazol-5-ylboronic acid (450 mg, 89%) which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][CH2:13]O)[N:8]([C:15](=[O:26])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:7]=2[CH:27]=1.S(Cl)([Cl:30])=O>ClCCl>[Cl:30][CH2:13][CH2:12][CH:9]1[N:8]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:7]2[CH:27]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10]1
Reactant: COc1ccc2c(c1)N(C(=O)c1cccc(C(F)(F)F)c1)C(CCO)CO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)N(C(=O)c1cccc(C(F)(F)F)c1)C(CCCl)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 14.74 g (0.039 mol) of (±)-6-methoxy-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 165 ml of dichloromethane are added 14 ml (0.19 mol) of thionyl chloride and the mixture is stirred at room temperature for 5 h.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:4]=1.[NH4+].[OH-].Cl.O.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:37](=[O:39])[CH3:38])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:4]=1
Reactant: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridin-2-ylamine (example 55) (2.00 g, 4.47 mmol) in acetic anhydride (15 mL) was stirred at 120° C. for 1 h. Cooled to 60° C., concentrated in vacuum to dryness (water bath temperature 60° C.) and dried in HV to give an orange solid (2.465 g, 113%, mixture of mono- and diacetylated compound). Suspended in THF (30 mL) at 23° C., added NH4OH (25%, 13.3M, 1.0 mL, 13.4 mmol) and stirred at 23° C. for 1.5 h resulting in a clear red solution, adjusted pH with 1N HCl until pH 1, added H2O (total volume 200 mL), filtered the precipitate off, washed with H2O and dried in HV, followed by trituration with ether and drying in HV to give the title compound as an orange solid (2.130 g, 97%). MS [ISN] 488.1 [(M−H)−]; mp 266° C.