Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([OH:19])=O)[CH:13]=2)[CH:7]=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.[NH2:68][CH2:69][CH2:70][CH2:71][N:72]1[CH2:76][CH2:75][CH2:74][CH2:73]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:68][CH2:69][CH2:70][CH2:71][N:72]3[CH2:76][CH2:75][CH2:74][CH2:73]3)=[O:19])[CH:13]=2)[CH:7]=1
Reactant: NCCCN1CCCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.43 mmol) in 10 ml of anhydrous DMF were added HATU (198 mg, 0.52 mmol) and N,N-diisopropylethylamine (166 mg, 1.3 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)pyrrolidine (110 mg, 0.86 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude which was purified by silica gel chromatography eluting with 10-20% of methanol in chloroform to give 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 160 mg, 65%.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:22]>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:2](=[S:22])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:14]=1)#[N:19]
Reactant: NC(N)=S
Reactant: N#Cc1ccc(-c2cc3ccccc3nc2Cl)cc1
Solvent: CCO
Product: N#Cc1ccc(-c2cc3ccccc3[nH]c2=S)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-3-(p-cyanophenyl)quinoline (6.25 g., see Example 30) and thiourea (1.8 g.) in ethanol (30 ml.) was heated under reflux for 2 hr. The solution was allowed to cool to ambient temperature, the solid which precipitated was filtered off, dispersed in 1 M-sodium hydroxide solution (100 ml.) and the dispersion heated on a steam bath for 20 min. The mixture was acidified with 2 M-hydrochloric acid solution. The resulting mixture was filtered, the solid residue was stirred with hot ethanol (75 ml.) for 5 min., and the mixture was then filtered. There was thus obtained as the solid residue 3-(p-cyanophenyl)quinolin-2-thione, m.p. 284°-9°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[CH:24]([O-])=[O:25].[Na+]>C(O)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[C:10](=[C:11]([OH:12])[C:2]([NH:1][CH:24]=[O:25])=[CH:3][CH:4]=3)[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: O=C[O-]
Reactant: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O=CO
Product: CC(C)c1oc2c(O)c(NC=O)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 7-amino-3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-chromen-4-one (1.1 g, 3.35 mmol) and sodium formate (0.23 g, 3.35 mmol) in formic acid (50 ml) is heated under reflux for 2 h. After cooling to room temperature, the reaction mixture is poured into ice/water (300 ml) with stirring. The resulting aqueous suspension is washed with ethyl acetate (2×100 ml). The combined organic layers are washed with water (3×100 ml) and brine (100 ml), dried (magnesium sulfate) and filtered. The solvent is removed by evaporation in vacuo to afford a dark brown oil. This is purified by flash chromatography (hexane/ethyl acetate=1:1, followed by 100% ethyl acetate) to afford the title compound.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:53]([CH3:54])=[N:52][N:51]=[N:50]2)=[C:45]([C:55]([F:58])([F:57])[F:56])[CH:44]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:53]([CH3:54])=[N:52][N:51]=[N:50]2)=[C:45]([C:55]([F:58])([F:57])[F:56])[CH:44]=1)=[CH:14]/[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nnnn1-c1ccc(Br)cc1C(F)(F)F
Reactant: COC(=O)/C(I)=C\CC1CCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)/C(=C/CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
A mixture of zinc dust (330 mg, 5 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (108 mg, 1 mmol) and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (590 mg, 2 mmol) in dry tetrahydrofuran (1 mL). After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (3 mL), and the stirring was stopped to allow the excess zinc dust to settle down (2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (38 mg, 0.07 mmol) and triphenylphosphine (73 mg, 0.28 mmol) in dry tetrahydrofuran (7 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (350 mg, 1.4 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 45-50° C. for 20 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (30 mL), and the organic compound was extracted into ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid methyl ester (360 mg, 65%) as an amorphous white solid: EI-HRMS m/e calcd for C19H21F3N4O2 (M+) 394.1617, found 394.1621.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20].[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][CH2:9][CH:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:18][C:19]=1[CH3:20]
Reactant: COc1ccc(C=CC=O)cc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1ccc(CCCC2OC(=O)NC2=O)cc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic reduction to yield 5-[3-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from chloroform-methanol to give colorless prisms, m.p.185-187° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18]>O1CCOCC1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CSc1ncc2ncnc(Cl)c2n1
Solvent: C1COCCO1
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1

Procedure:
3.0 g of 4-chloro-6-methylthiopyrimido[5,4-d]pyrimidine, 3.8 g of 3-chloro-4-fluoroaniline and 10 ml of dioxane are heated at 80° C. for 2 hours. After cooling, the reaction mixture is concentrated and portions are triturated first with water and then with diethyl ether, filtered off with suction and dried.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:17][CH3:18])[CH:10]=1)([O-:16])=[O:15]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-c1ccccc1

Procedure:
50 ml of a 2M aqueous solution of sodium carbonate is added to a solution containing 12 g of 2-bromo 5-nitro anisole, 8.2 g of phenylboronic acid and 1.2 g of tetra(triphenylphosphine) palladium. The whole is heated under reflux for 7 hours, under vigorous agitation. The reaction medium is left to return to 20° C., it is poured into water and extraction is carried out with ethyl acetate. The organic phases are collected, dried and evaporated under reduced pressure. The product obtained is chromatographed on silica, eluting with a heptane-isopropyl ether mixture (9-1) and in this way 11.4 g of sought product is obtained, melting at 71° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11]([C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:25])[N:24]=1)=[CH:21][C:20]([CH:26]=[O:27])=[CH:19][CH:18]=2)[CH2:12][CH2:13][CH3:14]>O1CCCC1>[CH2:11]([C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:25])[N:24]=1)=[CH:21][C:20]([CH:26]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:27])=[CH:19][CH:18]=2)[CH2:12][CH2:13][CH3:14]
Reactant: c1ccoc1
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)c3ccco3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7.88 ml of furan in 80 ml of dry tetrahydrofuran is cooled at 0° C. and 47.8 ml of n-butyl lithium (2.5 M in hexanes) is added dropwise. Stirring is continued for 1 hour at 0° C. and the mixture allowed to warm to room temperature. The reaction mixture is cooled to -78° C. and 5.0 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde added rapidly. The reaction mixture is stirred for 1.5 hours at -78° C., quenched with 100 ml of saturated ammonium chloride, allowed to warm to room temperature and the volatiles removed in vacuo. The reaction mixture is diluted with 500 ml of ethyl acetate and washed with water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried and evaporated to a residue which crystallizes from ethyl acetate to afford 3.75 g of the desired product, m.p. 183°-185° C. An additional 700 mg of the desired product is obtained from the filtrate as white crystals m.p. 183°-185° C. Fab Mass Spec 299 (M+H).
Reaction SMILES: C([O:8][N:9]1[C:38](=[O:39])[CH:37]=[C:12]2[N:13]([CH:34]3[CH2:36][CH2:35]3)[C:14]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[C:17]([F:33])=[CH:16][C:15]=3[N:11]2[C:10]1=[O:40])C1C=CC=CC=1>C(O)C.[Pd]>[CH:34]1([N:13]2[C:14]3[CH:19]=[C:18]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]4)[C:17]([F:33])=[CH:16][C:15]=3[N:11]3[C:10](=[O:40])[N:9]([OH:8])[C:38](=[O:39])[CH:37]=[C:12]23)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(O)c(=O)cc2n3C2CC2)CC1
Yield: 72 %

Procedure:
tert-Butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate (981 mg, 1.87 mmol) is dissolved in ethanol (250 ml) and hydrogenated with 5 percent palladium/carbon (200 mg) under hydrogen at normal pressure. The palladium/carbon is filtered off and washed with dimethylformamide (100 ml) at 100°. The combined filtrates are evaporated under reduced pressure. The residue is recrystallized from dimethylformamide. There are obtained 619 mg (72%) of tert-butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-2-hydroxy-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:17][O:18][C:19]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[P:20]([OH:23])([OH:22])=[O:21])[CH2:11]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:11][C@@H:10]([O:17][O:18][C:19]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[P:20]([OH:23])([OH:22])=[O:21])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:31]=[N-:32]
Reactant: CC(C)C(OO[C@H](COCc1ccccc1)COS(C)(=O)=O)(C(C)C)P(=O)(O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)C(OO[C@H](CN=[N+]=[N-])COCc1ccccc1)(C(C)C)P(=O)(O)O
Temperature: 105 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
(R)-3-O-Benzyl-2-O-(diisopropyl phosphonomethoxyl)-1-O-(methanesulfonyl)glycerol (15, 9 g, 20.53 mmol) (J. J. Bronson, etc. J. Med. Chem. 1989, 32, 1457) and sodium azide (4 g, 61.58 mmol) were mixed in 40 mL of anhydrous N',N'-dimethylformamide. The resulting mixture was stirred at 105° C. for 5 hours. After the solvent was removed under reduced presuure, the residue was added 100 mL of methylene chloride. The mixture was filtered, and the solid was washed with methylene chloride. The filtrate was evaporated, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=10:1 to 3:1) to give 6.15 g (78% yield) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:21]([CH:22]4[CH2:24][CH2:23]4)[CH:20]=[N:19][N:18]=3)[CH:12]=2)=[O:9])[CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:22]1([N:21]2[CH:20]=[N:19][N:18]=[C:17]2[C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(Br)ccn1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cccnc2)ccn1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
A suspension of 4-bromo-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide (120 mg, 0.31 mmol), 3-pyridine boronic acid (77 mg, 0.62 mmol), dppf(Pd)Cl2 (23 mg, 0.03 mmol), potassium carbonate (86 mg, 0.62 mmol) in degassed toluene (2 mL), degassed water (1 mL) and degassed ethanol (1 mL) was heated at 100° C. for 1 hour. The solvent was removed under reduced pressure and the residue purified by reverse-phase HPLC, to give N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide as a white powder (58 mg, 0.15 mmol, 48% yield). C22H18N6O. 383.1 (M+1). 1H NMR (DMSO) d 10.98 (s, 1H), 9.12 (d, J=1.6 Hz, 1H), 8.87 (d, J=4.8 Hz, 1H), 8.72 (dd, J=4.8, 1.2 Hz, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.34 (m, 1H), 8.11 (m, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.59 (m, 2H), 3.66 (m, 1H), 1.09 (m, 2H), 0.94 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:40])([CH3:39])[C:9]([N:11]1[CH2:15][CH2:14][C@@:13]([N:17]2[C:21]3[N:22]=[C:23]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:24]=[C:25]([C:26]4[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=4)[C:20]=3[CH2:19][CH2:18]2)([CH3:16])[CH2:12]1)=[O:10])(C)(C)C.Cl>C1(C)C=CC=CC=1>[NH2:7][C:8]([CH3:40])([CH3:39])[C:9]([N:11]1[CH2:15][CH2:14][C@@:13]([N:17]2[C:21]3[N:22]=[C:23]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:24]=[C:25]([C:26]4[CH:31]=[N:30][C:29]([NH2:32])=[N:28][CH:27]=4)[C:20]=3[CH2:19][CH2:18]2)([CH3:16])[CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC[C@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(N)C(=O)N1CC[C@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
In a foil covered flask, a solution of tert-butyl(1-{(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidin-1-yl}-2-methyl-1-oxopropan-2-yl)carbamate (369 mg, 0.65 mmol) in MeON (3 mL) was treated with HCl (3 mL, 4N in dioxane) and the mixture was stirred at room temperature for 18 h. The mixture was diluted with toluene and concentrated. The residue was dissolved in a minimum amount of MeOH, dropped into aqueous NaHCO3 and extracted with 15% i-PrOH in DCM (4×). The extracts were washed with brine, dried over MgSO4 and concentrated. The oily residue was suspended in a few mL of acetonitrile and sonicated briefly, inducing crystallization. The resulting solids were collected by filtration to give the title compound (206 mg, 68%) as an off-white solid. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 8.73 (s, 2 H), 6.68 (br s, 2 H), 4.40-4.00 (m, 2 H), 3.73-3.50 (m, 12 H), 3.12-3.07 (m, 2H, partially overlapped with water), 2.41-2.30 (m, 1 H), 2.06-1.97 (m, 1 H), 1.74 (br s, 2 H), 1.31 (s, 3 H), 1.27 (s, 6 H). m/z (APCI+) for C23H33CN9O2 468.3 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([C:4]1([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[C:18]=3Br)[CH:13]=2)[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)[CH3:3].[N+](C1C=CC=CC=1)([O-])=O.Br.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][CH:2]([C:4]1([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[CH:13]=2)[O:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9]1)[CH3:3]
Reactant: COc1ccc2cc(C3(C(C)Br)OCC(C)(C)CO3)ccc2c1Br
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Product: COc1ccc2cc(C3(C(C)Br)OCC(C)(C)CO3)ccc2c1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
2-(1-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-5,5-dimethyl-1,3-dioxane (9.16 g, 10 mmol) is dissolved in toluene (40 ml) and nitrobenzene (2 g) saturated with HBr at room temperature. Phenol (11.28 g, 120 mmol) is added as solid; the mixture is stirred for 2.5 hours, then is poured in 30 minutes under stirring into a 10% aqueous sodium carbonate solution (150 ml), the organic layer is separated and the aqueous phase is extracted with toluene. The combined organic extracts are washed with water, dried on sodium sulphate and the solvent is removed in vacuo. 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-5,5-dimethyl-1,3-dioxane is obtained (75% yield).
Reaction SMILES: N1C2C=CC=CC=2NC=1CN1C2C=CC=CC=2N=C1C[N:21]([CH3:43])[CH2:22][C:23]([C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34]C2C=CC=CC=2)=[O:32])=[CH:27][CH:26]=1)=[O:24]>CCOC(C)=O.CO>[CH3:43][NH:21][CH2:22][CH:23]([C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:41]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:42]=1)[OH:24]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)Cc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(O)c1ccc(OCC(=O)OC)c(OCC(=O)OC)c1
Yield: 90 %

Procedure:
Following the procedure of Example 82(e), except substituting dimethyl 4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate (2.1 g, 4.57 mmol) for benzyl 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]-phenoxyacetate and using EtOAc (50 mL) and MeOH (20 mL) as solvents, the title compound (1.34 g, 90%) was prepared: MS (ES) m/e 328.0 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19](OC)(OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:19]([O:18][CH3:17])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COC(OC)(OC)c1ccccc1
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Solvent: CC(=O)OC(C)=O
Product: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
30.0 g (0.137 mol) of 1-acetyl-5-nitro-2-indolinone are dissolved in 200 ml of acetic anhydride and after the addition of 50.0 g (0.274 mol) of trimethyl orthobenzoate stirred for 3 hours at 100° C. After cooling it is evaporated down to half the quantity, diluted with ether/petroleum ether, the precipitate is suction filtered and dried.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:23]([F:24])([F:25])[C:20]1[N:19]=[CH:18][C:17]([C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)nc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(C(F)(F)F)nc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)-piperidine-1-carboxylate (74.5 mg, 0.20 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 1.58 mL, 9.03 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)isoxazol-3(2H)-one (43 mg, 68%), 1H NMR (600 MHz, dmso) δ 1.36-1.53 (m, 2H), 1.89 (d, 1H), 2.04 (d, 1H), 2.70-2.78 (m, 1H), 2.90 (tt, 1H), 3.09-3.16 (m, 1H), 3.83 (d, 1H), 5.75 (s, 1H), 7.84 (d, 1H), 8.04 (dd, 1H), 8.75 (d, 1H). HRMS Calculated for [C14H14F3N3O2+H]+: 314.1116. Found: 314.1134
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=CC(OC(F)(F)F)=C[CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[N:40]1C=C(B(O)O)C=[N:42][CH:41]=1>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[N:40][CH:41]=[N:42][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cncnc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 85% yield using pyrimidin-5-ylboronic acid (0.0885 g, 0.000714 mol) as the reagent.