Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:24]3[N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=4)[N:27]=[C:26](C4C=CC(C(C)(C)C)=CC=4)[N:25]=3)[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)O1.Cl[C:52]1[CH:65]=[CH:64][C:63]2[C:54](=[C:55]3[C:60](=[CH:61][CH:62]=2)[CH:59]=[CH:58][CH:57]=[N:56]3)[N:53]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>[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(O)C.C1(C)C=CC=CC=1>[N:53]1[C:54]2[C:63](=[CH:62][CH:61]=[C:60]3[C:55]=2[N:56]=[CH:57][CH:58]=[CH:59]3)[CH:64]=[CH:65][C:52]=1[C:9]1[CH:14]=[C:13]([C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:32][CH:31]=3)[N:29]=[C:24]([C:11]3[CH:10]=[CH:9][C:14]([C:30]([CH3:35])([CH3:31])[CH3:28])=[CH:13][CH:12]=3)[N:25]=2)[CH:12]=[C:11]([C:57]2[CH:58]=[CH:59][C:60]3[C:55](=[C:54]4[C:63](=[CH:62][CH:61]=3)[CH:64]=[CH:65][CH:52]=[N:53]4)[N:56]=2)[CH:10]=1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3cc(B4OC(C)(C)C(C)(C)O4)cc(B4OC(C)(C)C(C)(C)O4)c3)n2)cc1
Reactant: Clc1ccc2ccc3cccnc3c2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3cc(-c4ccc5ccc6cccnc6c5n4)cc(-c4ccc5ccc6cccnc6c5n4)c3)n2)cc1
Temperature: 100 °C
Reaction time: 88 h

Procedure:
In a stream of argon, 168 mg of 2-[3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine, 129 mg of 2-chloro-1,10-phenanthroline, 32 mg of lithium chloride and 23 mg of tetrakis(triphenylphosphine) palladium were suspended in a toluene (6.0 mL)/ethanol (1.5 mL) mixed solvent. 1.0 mL of a 2.0 M aqueous sodium carbonate solution was added in the obtained suspension, and the mixture was stirred at 100° C. for 88 hours. Then the reaction mixture was left to be cooled to room temperature, and distilled under a reduced pressure to remove low-boiling point ingredients. Water was added to the residue to give a crude product. The crude product was collected by filtration, and evaporated to dryness under a reduced pressure. The dried crude product was recrystallized from a dichloromethane/hexane mixed solvent to give 179 mg of target 2-[3,5-bis(1,10-phenanthrolin-2-yl)phenyl]-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine as a yellow solid (yield, 92%).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:56])[C:36]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([CH3:48])[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:38]([CH2:37][C:36]([CH3:48])([O:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:35]([OH:56])=[O:34])=[CH:39][CH:40]=3)[N:11]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)c2ccccc12
Temperature: 55 °C
Yield: 24 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 2, Part F) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (see Ex. 12, Part B) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce a white solid (24%). MS [EI+] 584 (M+H)+, [EI−] 582 (M−H)+
Reaction SMILES: [C:1]([N:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:10]1=[CH:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:29][C@H:17]1[CH2:16][CH2:15][C@H:14]2[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:28])[C:10]([N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26](=[O:27])[CH2:25][CH2:24]1)=[CH:11][CH2:12]3)[CH3:37]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the alcohol product from Step B, above and ethyl diazoacetate (0.5 ml) in methylene chloride (6.5 ml) was added rhodium diacetate dimer (15 mg) intermittently during 2 hours. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was purified via preparative TLC using two silica gel plates (2000μ) developed with 40% EtOAc in hexanes to afford the title compound (Rf=0.33).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:26][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[CH:21][CH:22]=2)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 20 h

Procedure:
A solution of 18.8 g of trans-4-propylcyclohexanecarbonyl chloride in 20 ml of toluene was added dropwise to a solution of 18.8 of 4'-fluoro-4-hydroxybiphenyl and 8 g of pyridine in 25 ml of toluene and the mixture was heated, with stirring, at 80° for 20 hours. After cooling down water was added, the phases were separated, the organic phase was washed, evaporated and 4'-fluorobiphenyl-4-yl trans-4-propylcyclohexanecarboxylate was obtained, m.p. 96°, c.p. 174°.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:17])[N:12]([CH2:14][CH2:15][OH:16])[CH3:13])[N:10]=2)[CH2:3]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:16][CH2:15][CH2:14][N:12]([CH3:13])[C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:17])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CN(CCO)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 58.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[N-(2-hydroxyethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (576 mg, 2.24 mmol) (obtained as described in Reference Example 40(3)) in dimethylformamide (29 ml) were added t-butyldimethylsilyl chloride (354 mg, 2.35 mmol) and imidazole (160 mg, 2.35 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1)→ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (489 mg, yield 60%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][CH:5]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:22]>C(O)(=O)C.O.[OH-].[Na+]>[CH3:8][C:7]([C:6]1[N:22]=[C:1]([CH3:2])[O:4][C:5]=1[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:10])[CH3:9]
Reactant: [NH4+]
Reactant: CC(=O)OC(C(=O)C(C)(C)C)C(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Yield: 92.5 %

Procedure:
A solution of 4-(acetyloxy)-2,2,6,6-tetramethyl 3,5-heptanedione (22 g, 0.09 mol) in acetic acid (100 mL) is treated with ammonium acetate (44 g). The reaction mixture is heated at reflux overnight. The reaction mixture is diluted with water and neutralized (to pH 5) by the addition of aqueous sodium hydroxide. The product is extracted into ethyl acetate (3×150 mL) and the combined organic layers are washed with 0.1N NaOH, water, and then brine. The organic layer is dried and evaporated. The residue is taken up in hexane (50 mL) and applied to a pad of silica gel (500 g). The silica pad is eluted with hexane (100 mL). Then the product is eluted from the silica with hexane/ethyl acetate (4:1) to give 18.6 g (91%) of 1-[4-(1,1-dimethylethyl)-2-methyl-5-oxazolyl]-2,2-dimethyl-1-propanone as an oil.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[N:11]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.C(OC(=O)[C@H](C(C)C)N(C(OCCC)=O)CC1C=CC(C2C=CC=CC=2C#N)=CC=1)C1C=CC=CC=1.C([Sn](N=[N+]=[N-])(CCCC)CCCC)CCC>>[C:9]([C@@H:10]([N:11]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:26][N:27]=[N:28][N:29]=2)=[CH:15][CH:14]=1)[CH:36]([CH3:37])[CH3:38])([OH:39])=[O:8]
Reactant: CCCOC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: CCCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Product: CCCOC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
N-Carbopropoxy-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester starting from 1.04 g of N-carbopropoxy-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 1.1 g of tributyltin azide and subsequent flash chromatography using the system N6. Amorphous product, TLC (system N6) Rf : 0.21.
Reaction SMILES: C([O:9][CH:10]1[O:42][C@@H:41]([CH3:43])[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]1[O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1>CO.C1COCC1>[C:13]([O:12][C@@H:11]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:41]([CH3:43])[O:42][CH:10]1[OH:9])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1OC(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1OC(O)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The compound (V) (22.4 g, 38.6 mmol) is dissolved in MeOH:THF (3:7, 400 ml), and then NH3 gas is bubbled for 15 minutes at 0° C. and stirred at 0° C. for 1 hour. The reaction process is identified by thin layer chromatography while repeating the above process. The solvent is vacuum concentrated, and then the compound (VI) (16 g, 87%, α:β=14:1) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]1=[O:25].[B-](F)(F)(F)[CH:27]=[CH2:28].[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:25]=[C:9]1[C:10]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][CH2:12][N:8]1[C:3]1[CH2:4][O:5][C:6](=[O:7])[C:2]=1[CH:27]=[CH2:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Br)C(=O)OC1)C2=O
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C=CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 70 °C

Procedure:
tert-butyl 2-(4-bromo-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.2 g, 5.30 mmol), potassium trifluoro(vinyl)borate (1.06 g, 7.95 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.345 g, 0.530 mmol) and potassium phosphate tribasic (10.60 mL, 10.60 mmol) were taken up in THF (44.1 mL) in a sealed tube, de-gassed and the resulting mixture was heated overnight at 70° C. The reaction mixture was cooled to room temperature and then was diluted with EtOAc and water. After separation of layers, the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous MgSO4, filtered, concentrated and purified by silica gel column chromatography using (30-100) % EtOAc/hexanes as mobile phase to provide the title compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[S:9][CH:10]=[CH:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:27])=[CH:21][CH:20]=1
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.72 (s, 2H) 7.41 (s, 4H) 7.56 (dd, J=4.42, 2.59 Hz, 4H) 7.63-7.80 (m, 2H) 8.36 (d, J=5.19 Hz, 1H) 11.81 (s, 1H); MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[C:31]1([N+:30]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: Nc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccc3)[n+](-c3ccccc3)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
A 500 mL round-bottomed flask equipped with a condenser was charged with 2,4,6-triphenyl-pyrylium tetrafluoroborate (22.4 g, 0.056 mole), aniline (5.8 g, 0.060 mole) and ethanol (200 mL). The resulting solution was magnetically stirred and refluxed under a nitrogen atmosphere for 6 hours. The solution was cooled to room temperature, and the product 27 precipitated as greenish-yellow, crystalline solid. The product was collected by filtration and dried in a vacuum oven at 100° C. (23 g, 87% yield). Mp=253° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=1>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([CH3:38])[CH:30]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1C
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1C
Temperature: 120 °C
Yield: 3982.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.5 g 21.6 mmol), K2CO3(3.5 g), 1-[4-(3bromopropoxy)-2-methylphenyl]-ethanone (4.83 g, 17.8 mmol) in dimethylformamide (25 ml) and acetonitrile (75 ml) was heated at 120° C. for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml) and the solution was washed with water and brine. The organic solution was dried and evaporated to a crude oil. The purification was done by flash chromatography over a silica gel column (80 g, eluted with dichloromethane, 1 l; 1% methanol: dichloromethane, 1.2 l; 2% methanol dichloromethane, 1.2 l). The purest fractions were combined and afforded 291 g of solid. Recrystallization from dichloromethane and ethanol gave 1-[4-[3-4-(6fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-2-methylphenyl]ethanone as off-white crystals: 2.42 g, m.p.=113-114° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)CCC>C1(C)C=CC=CC=1.[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>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Cc1ccc(C)n1-c1cccc(Cl)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cccc(-c2ccccc2)n1
Yield: 88.3 %

Procedure:
2-Chloro-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (0.097 g, 0.47 mmol) prepared as described in Example 8a was reacted for 24 h with tributyl-phenyl-stannane (0.185 mL, 0.564 mmol) under nitrogen in toluene at 75° C. in the presence of 2 mole % tetrakis(triphenylphosphine) palladium(0). The volatiles were subsequently removed under reduced pressure to yield the crude product, which was purified by flash chromatography on silica gel to give the title compound (0.103 g, 88%).
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4](=[C:20]([CH3:23])[O:21][N:22]=2)[N:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:3]2[C:4](=[C:20]([CH3:23])[O:21][N:22]=2)[N:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:24])=[CH:11][C:10]=1[F:15]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylisoxazolo[4,3-b]pyridine-5-carboxylate (1.35 g, 4.25 mmol) in DMF (40 ml) is added N-iodosuccinimide (1.43 g, 6.37 mmol) and TFA (2.5 ml). After stirring at room temperature for 4 h, the reaction is quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution is washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]>CN(C=O)C.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccnc1
Reaction time: 64 h
Yield: 102.1 %

Procedure:
3-Hydroxypyridine(2.83 g, 29.83 mmol) was dissolved in DMF (70 mL), the solution was cooled in an ice bath, NaH (1.3 g, 32.81 mmol) and N-(3-bromopropyl)phthalimide (8 g, 29.83 mmol, Aldrich) were added, the ice bath was removed, and the reaction mixture was stirred for 64 hours. The reaction was diluted with CH2Cl2 and filtered through celite to give a 1:1 mixture of N- and O-alkylated products. Recrystallization from EtOH afforded a 4:1 mixture of N- and O-alkylated products. The mother liquor was taken up in water and extracted with CH2Cl2, then the organic layer washed with water (5x) to afford the desired N-(3-(3-pyridyloxy)propyl)phthalimide (8.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cncc(Br)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A mixture of (5-bromo-pyridin-3-yl)-acetic acid (2.0 g, 9.3 mmol), benzyl alcohol (1.0 g, 9.2 mmol), DCC (1.9 g, mmol), and DMAP (1.0 g, mmol) in DCM (30 mL) is stirred at room temperature for 16 h. The mixture is filtered and the filtrate is concentrated to give the crude product. Purification by flash column chromatography affords 1.2 g of (5-bromo-pyridin-3-yl)-acetic acid benzyl ester.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][CH2:37][CH:38]([OH:40])[CH3:39]>C(O)C.CCCCCC>[OH:40][CH:38]([CH3:39])[CH2:37][NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4]
Reactant: CC(O)CN
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: Cc1c(NC(=O)NCC(C)O)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 1-amino-2-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 58%. Melting point: 171-182° C. (ethanol-hexane).