Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2S(C(F)(F)F)(=O)=O)[O:7][CH2:6]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN(C)[CH:63]=[O:64].[CH3:66][OH:67]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:66]([O:64][CH3:63])=[O:67])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCN(CCC)C1COc2cccc(S(=O)(=O)C(F)(F)F)c2C1
Reactant: CN(C)C=O
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
3-Dipropylamino-5-trifluoromethanesulfonylchroman (Example 1; 4.43 g, 11.6 mmol) was dissolved in 80 mL dimethylformamide/methanol 6:2 and the solution was degassed (10 mm Hg, 20° C., 15 min). PdOAc2 (76 mg, 0.34 mmol), 1,3-bis-diphenylphosphinopropane (141 mg, 0.34 mmol) and triethylamine (3.5 mL, 25 mmol) were then added. The mixture was heated to 70° C. under CO atmosphere and stirred for 5 hours. The solution was cooled, diluted with toluene (200 mL), washed with aqueous NaHCO3, dried with Na2SO4 and evaporated to dryness. The oil was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:43][N:44]([CH3:75])[C:45](=[O:74])[O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([C:56]2([CH2:72][NH2:73])[CH2:61][CH2:60][N:59]([C:62]3[C:63]4[C:70]([CH3:71])=[CH:69][NH:68][C:64]=4[N:65]=[CH:66][N:67]=3)[CH2:58][CH2:57]2)=[O:55])[CH:48]=1>C(Cl)Cl.O>[CH3:75][N:44]([CH3:43])[C:45](=[O:74])[O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([C:56]2([CH2:72][NH:73][C:7](=[O:9])[CH2:6][C:5]3[NH:1][CH:2]=[N:3][CH:4]=3)[CH2:57][CH2:58][N:59]([C:62]3[C:63]4[C:70]([CH3:71])=[CH:69][NH:68][C:64]=4[N:65]=[CH:66][N:67]=3)[CH2:60][CH2:61]2)=[O:55])[CH:48]=1
Reactant: O=C(O)Cc1cnc[nH]1
Reactant: Cc1c[nH]c2ncnc(N3CCC(CN)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c2ncnc(N3CCC(CNC(=O)Cc4cnc[nH]4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
To a suspension of 2-(1H-imidazol-5-yl)acetic acid (0.238 g, 1.47 mmol) and HATU (0.372 g, 0.978 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (0.51 mL, 2.93 mmol). The resulting solution was allowed to stir for 20 min. at room temperature. To this solution was added the acetate salt of 3-(4-(aminomethyl)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)phenyl dimethylcarbamate (from example 20, 0.500 g, 0.978 mmol) and N,N-diisopropylethylamine (0.17 mL) in CH2Cl2 (5 mL). The reaction was allowed to stir at room temperature for 6 h, and then diluted with H2O (10 mL) and CH2Cl2 (20 mL). The mixture was extracted with CH2Cl2 (2×10 mL), and the combined organics were washed with NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (3-10% MeOH:CH2Cl2) to afford the title compound (0.393 g, 72% yield) as a white solid. This solid was suspended in water, and acetic acid was added until the solution became clear. This solution was frozen and lyophilized to the di-acetate salt of the title compound (0.477 g).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>O>[CH3:33][O:32][C:30]([O:20][CH2:19][N:15]1[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]2[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:30]([O:32][CH3:33])=[O:31])[C:4](=[O:22])[CH2:5]2)[CH2:17][C:16]1=[O:18])=[O:31]
Reactant: COC(=O)Cl
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)OC)C(=O)C2)CC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (2.20 g, 7.0 m mol) and pyridine (20 ml), methyl chloroformate (1.41 g, 14.9 m mol) was added gradually at 0° C., and the mixture was stirred for 1.5 hours at 0° C., then successively for 3 hours at room temperature. The reaction mixture was added to water and was extracted with chloroform. The extract solution was washed with 10% sulfuric acid solution and successively with water, and was dried over magnesium sulfate. The crystals obtained by concentrating the extract solution under reduced pressure were washed with ethyl acetate and dried under reduced pressure to give the titled compound (1.76 g; yield 58.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl.CCCCCC>[F:11][C:12]([F:20])([F:19])[C:13]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([OH:14])[C:15]([F:18])([F:17])[F:16]
Reactant: Nc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 64 %

Procedure:
Aniline (10.35 ml, 0.1 mol) and 250 mg of p-toluenesulfonic acid catalyst are placed in a two-necked flask surmounted by a condenser. Hexafluoroacetone trihydrate is added dropwise (15.8 ml, 1.1 eq.) and the bath (graphite) is brought to 180° C. for 14 h. The product AHFHP (4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)aniline) is obtained by recrystallization from a dichloromethane/hexane mixture, in the form of a white powder (yield 52%). 1 g of nitrosonium tetrafluoroborate (NOBF4) (8.56 mmol, 1.1 eq.) is then placed in a round-bottomed flask dried under argon and is dissolved with 10 ml of anhydrous acetonitrile ACN. The whole mixture is brought to −30° C. by means of an acetone-liquid nitrogen bath and then 7.78 mmol of the arylamine precursor, solubilized in the minimum amount of ACN (5 to 30 ml), are added dropwise. The mixture is allowed to return to ambient temperature, and the product is precipitated from 100 ml of cold ether, filtered off on a frit and washed with cold ether. The white powder obtained is recrystallized with an ACN/Et2O mixture and obtained with a yield of 64%.
Reaction SMILES: N[CH2:2][C:3]1([OH:31])[C:12]2[C:7](=[C:8]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+].C(Cl)Cl>CC(O)=O.O>[Si:14]([O:13][C:8]1[C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:31])[CH2:2][C:12]=2[CH:11]=[CH:10][CH:9]=1)([C:27]([CH3:30])([CH3:28])[CH3:29])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2(O)CN)(c1ccccc1)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC(=O)C2)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 37.8 %

Procedure:
To a solution of 1-aminomethyl-5-(tert-butyldiphenyl-silyloxy)-1,2,3,4-tetrahydronaphthalen-1-ol (34.5 g) in 20% AcOH (700 ml) was added NaNO2 (7.18 g) in water (60 ml) at 5° C. The mixture was stirred at the same temperature for 2.5 hours. After addition of CH2Cl2 (70 ml), the mixture was stirred for 30 minutes. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and then brine. It was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc 10:1) to give 1-(tert-butyldiphenylsilyloxy)-6,7,8, 9-tetrahydro-5H-benzocyclohepten-6-one (12.52 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[C:3](=[N:6]\[OH:7])/[S:4][CH3:5].[CH3:10][N:11]=[C:12]=[O:13]>C(N(CC)CC)C>[F:1][C:2]([F:9])([F:8])/[C:3](=[N:6]\[O:7][C:12](=[O:13])[NH:11][CH3:10])/[S:4][CH3:5]
Reactant: CS/C(=N/O)C(F)(F)F
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)O/N=C(/SC)C(F)(F)F
Yield: 73.9 %

Procedure:
One drop of triethylamine was added to a mixture of 6.37 g (0.04 mol) of S-methyl (E)-2,2,2-trifluoro-N-hydroxythioacetimidate and 2.28 g (0.04 mol) of methyl isocyanate. An exothermic reaction ensued, and the reaction mixture was cooled in an ice-bath. The reaction mixture solidified on cooling. Recrystallization from ether gave 6.39 g (74% yield) of S-methyl (E)-2,2,2,-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as colorless crystals, mp. 83°-85°. Analysis of the isomer prepared in a similar procedure follows:
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=O)[C:14]([CH3:17])([CH3:16])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:16][C:14]1([CH3:17])[CH2:13][C:12]2[CH:19]=[CH:20][C:9]([OH:8])=[CH:10][C:11]=2[O:15]1
Reactant: CC1(C)Oc2cc(OCc3ccccc3)ccc2C1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2ccc(O)cc2O1
Yield: 87.5 %

Procedure:
To a solution of 6-(benzyloxy)-2,2-dimethylbenzofuran-3(2H)-one (0.85 g, 3.20 mmol) in methanol (100 mL) was added palladium hydroxide (0.22 g, 20 wt. % loading, 0.32 mmol). The resulting mixture was hydrogenated for 16 hours under 60 psi of hydrogen. The reaction mixture was filtered through celite, washed with methanol. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.46 g, 88%): 1H NMR (300 MHz, CDCl3) δ 6.92 (d, 1H), 6.30-6.21 (m, 2H), 4.77 (s, 1H), 2.90 (s, 2H), 1.44 (s, 6H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)(C)[CH3:7])=O.[Cl:17][C:18]1[C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:43])=[CH:32][C:33]=3[O:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[N:28]=[CH:27][N:26]=2)=[C:22]2[O:44][CH2:45][O:46][C:21]2=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.N>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:17][C:18]1[C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:43][CH2:6][CH3:7])=[CH:32][C:33]=3[O:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[N:28]=[CH:27][N:26]=2)=[C:22]2[O:44][CH2:45][O:46][C:21]2=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (0.26 g) in methylene chloride (1 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.12 g), ethanol (0.019 g), triphenylphosphine (0.15 g) and methylene chloride (2 ml) and the resultant mixture was stirred at ambient temperature for 1 hour. A 2M solution of hydrogen chloride in diethyl ether (3 ml) was added and the mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (1 ml) was added and the precipitate was isolated and dried under vacuum. The solid so obtained was dissolved in a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated. The residue was triturated under pentane and the resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (0.092 g); NMR Spectrum: (CDCl3) 1.5 (t, 3H), 1.95–2.1 (m, 2H), 2.15–2.5 (m, 2H), 2.3 (s, 3H), 2.3–2.4 (m, 2H), 2.7 (br s, 2H), 4.15 (m, 2H), 4.6 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: M+H+ 457 and 459.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[C:2]([CH3:4])=[O:3].[CH:23]([NH2:26])([CH3:25])[CH3:24].[ClH:27].C([BH3-])#N.[Na+]>CO>[OH2:3].[ClH:27].[CH:23]([NH:26][CH:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH3:25])[CH3:24]
Reactant: COc1ccc(C2=C(CC(C)=O)C(=O)NCCC2)cc1OC
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1OC
Product: O

Procedure:
The solution of 15.1 g of 3-acetonyl-4-(3,4-dimethoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 25.5 ml of isopropylamine 10 ml of 5.8 N methanolic hydrogen chloride and 3.4 g of sodium cyanoborohydride in 260 ml of methanol is refluxed for 3 days. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid, evaporated and the residue diluted with water. It is washed with ether, basified with 3 N aqueous sodium hydroxide to pH=11 and extracted with diethyl ether. The extract is dried, evaporated and the residue dissolved in 75 ml of acetone. The solution is treated with 4.4 N ethanolic hydrogen chloride, and the precipitate collected, to yield the 3-(2-isopropylaminopropyl)-4-(3,4-dimethoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone hydrochloride monohydrate melting at 135°-138°.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:16]([CH3:18])([CH3:17])[CH:15]2[C:19]([OH:21])=[O:20])[CH:7]=1.[O:22]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CCOCC>[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:16]([CH3:17])([CH3:18])[CH:15]2[C:19]([O:21][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:30]=2)=[O:20])[CH:7]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)O)C12C=C(Cl)c1ccccc12
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1(C)C(C(=O)OCc2cccc(Oc3ccccc3)c2)C12C=C(Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
Pyridine (1.68 g) and thionyl chloride (2.5 g) are added to a mixture of 3'-chloro-3,3-dimethyl-spiro[cyclopropane-1,1'-indene]-2-carboxylic acid (5.0 g; 0.02 mole) and ether (50 ml). After two hours at room temperature, pyridine (1.68 g) and m-phenoxybenzyl alcohol (4.0 g) are added and the reaction mixture stirred at room temperature overnight. The reaction mixture is then washed with water, the ether fraction dried over magnesium sulfate and evaporated to dryness. The residue is purified on a dry column (silica gel; 20% methylene chloride:hexane) to afford 3.0 g of title compound, a yellow-orange liquid. The sample is 90-95% pure by NMR, and shows an ester carbonyl stretch at 1730 cm-1 in IR.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:3]=1[NH2:4].C(OCC)(=O)C.CN(C)C=O>C(O)C.[Pt]>[NH2:4][C:3]1[C:2]([Br:1])=[CH:8][C:7]([NH2:9])=[CH:6][C:5]=1[Br:12]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Br)c(N)c(Br)c1

Procedure:
3.0 g of 2,6-dibromo-4-nitro-aniline are dissolved in 150 ml of ethanol, 150 ml of ethyl acetate and 30 ml of dimethylformamide and, after addition of 0.5 g of platinum-on-charcoal (5%), are hydrogenated in a Parr apparatus at room temperature under a hydrogen pressure of 1.5 bar for 1 hour. After cooling, the mixture is filtered, the solvent is distilled off in a rotary evaporator and the residue is purified by column chromatography.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1CCCC1.[CH3:28][N:29]1[CH2:34][CH2:33]O[CH2:31][CH2:30]1.[NH2:35][C:36]1[N:45]=[C:44]([C:46]([N:48]2[CH2:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:49]2)=[O:47])[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:57]3[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=3[C:59]([OH:61])=O)[CH:42]=2)[N:37]=1>CN(C)C=O>[NH2:35][C:36]1[N:45]=[C:44]([C:46]([N:48]2[CH2:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:49]2)=[O:47])[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:57]3[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=3[C:59]([N:6]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)=[O:61])[CH:42]=2)[N:37]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C(=O)O)ccc2n1
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CN1CCN(C(=O)c2ccccc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
175.9 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 33.8 μl of pyrrolidine and 200.9 μl of 4-methylmorpholine are added to a solution of 150 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzoic acid in 1 ml of dimethylformamide. The mixture is subsequently stirred at 25° C. for 12 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cl
Product: O=C(CCCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1)c1ccccc1

Procedure:
A mixture of 6 g (0.018 mol) of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazine, 6.6 g (0.036 mol) of 4-chloro-1-phenyl-1-butanone and 5 g of powdered potassium carbonate in 100 ml of methyl isobutyl ketone was refluxed for 6 hours with stirring. The reaction mixture was concentrated by evaporation of the solvent and water and diethyl ether were added to the residue, after which the ethereal layer was separated off, washed with water, dried on sodium sulfate and the solvent was evaporated. The residue obtained was purified by columnchromatography (silicagel, eluent: chloroform/methanol 9:1). The proper fractions were concentrated and the residue was taken up in anhydrous diethyl ether, after which the solution was carefully acidified with a solution of hydrogen chloride in diethyl ether to pH=2. The precipitate obtained of 4-[4-[2-[bis(4-fluorophenyl)methoxy]-ethyl]-1-piperazinyl]-1-phenyl-1-butanone dihydrochloride was filtered off and crystallized once from 2-propanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:43])([F:42])[C:38]([NH:40][NH2:41])=O>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:38]([C:37]([F:43])([F:42])[F:36])=[N:40][N:41]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NNC(=O)C(F)(F)F
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)(F)F)CO4)cc2)CCC1
Yield: 21.8 %

Procedure:
A solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (70 mg, 0.144 mmol) and 2,2,2-trifluoroacetohydrazide (7.3 mg, 0.057 mmol) in p-xylene (1 ml) was heated to 150° C. for 30 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (7 mg, 20%). LCMS (Method D): RT=1.633 min, M+1=564. 1H NMR (500 MHz, CDCl3): 7.96 (1H, s), 7.36-7.27 (7H, m), 7.21-7.17 (2H, m), 5.63 (2H, s), 2.55-2.40 (4H, m), 2.14-1.98 (1H, m), 1.88-1.78 (1H, m), 1.37-1.20 (9H, bs).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[N:4][C:5]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:7]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[C:23]1(C)[CH:28]=CC=C[CH:24]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C:2]1[C:3]([O:21][CH3:22])=[N:4][C:5]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:7]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:23]=[CH2:24]
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1Br
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1c(CO[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)nc1OC
Yield: 100 %

Procedure:
A mixture of 3-bromo-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridine (2.51 g, 6.27 mmol), allytributyltin (2.92 mL, 9.41 mmol), tetrakis(triphenylphosphine)palladium(0) (750 mg, 0.627 mmol) and toluene (15 mL) was flushed with nitrogen several times. The reaction mixture was stirred at reflux overnight. The reaction was filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100% hexane to 5% EtOAc/hexane) to yield 3-allyl-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridine (2.62 g, 100%). 1H-NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 5.85 (m, 1H), 4.93-5.11 (m, 2H), 4.74 (s, 2H), 4.04 (s, 3H), 3.37 (d, J=5Hz, 2H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:9]1([S+:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35]12([C:45](Cl)=[O:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2.Cl>C(Cl)Cl>[C:35]12([C:45]([O:1][CH2:2][CH2:3][CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:46])[CH2:42][CH:41]3[CH2:40][CH:39]([CH2:38][CH:37]([CH2:43]3)[CH2:36]1)[CH2:44]2.[C:22]1([S+:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)([O-])CCCO
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCS(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a mixture of 2.1 g (5 mmol) of the triphenylsulfonium 3-hydroxypropanesulfonate prepared in Synthesis Example 1-14, 0.6 g (6 mmol) of triethylamine and 10 g of methylene chloride, 2.9 g (6 mmol) of 1-adamantanecarbonyl chloride was added dropwise, followed by stirring for 3 hours at room temperature. Then 5.5 g of 5% aqueous hydrochloric acid was added to quench the reaction. The organic layer was separated from the reaction solution, washed with water, and concentrated in vacuum. Methyl isobutyl ketone was added to the concentrate, which was concentrated in vacuum again while azeotroping off the residual water. Diisopropyl ether was added to the residue, followed by decantation and drying. There was obtained the target compound, triphenylsulfonium 3-(adamantane-1-carbonyloxy)propanesulfonate. Colorless oily matter, 2.3 g, yield 79%. The compound, designated PAG-5, has the following structure.