Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: COC(=O)CCc1cccc(N)c1
Product: COC(=O)CCc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
5-Phenyl-furan-2-carboxylic acid (56) (40 mg, 0.21 mmol) was coupled to 3-(3-amino-phenyl)-propionic acid methyl ester (41 mg, 0.23 mmol) using Method D to give the title compound.
Reaction SMILES: C[Mg]I.[CH:4](/[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[CH:5]\[CH2:6][CH2:7][CH3:8].C1(C)C=CC=CC=1.C([O:32][CH2:33][CH3:34])C>>[CH:4](/[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:33](=[O:32])[CH3:34])=[CH:21][CH:22]=2)[CH2:13][CH2:14]1)=[CH:5]\[CH2:6][CH2:7][CH3:8]
Reactant: CCOCC
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: C[Mg]I
Solvent: Cc1ccccc1
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1

Procedure:
A solution of methylmagnesium iodide in diethyl ether (prepared from 384 mg of magnesium shavings and 0.984 ml of methyl iodide in 30 ml of diethyl ether) was treated dropwise at room temperature with a solution of 2.0 g of p-[trans-4-(trans-1-pentenyl)cyclohexyl]benzonitrile. The mixture was heated to reflux for 15 minutes. 30 ml of toluene were subsequently added to the mixture, the diethyl ether was distilled off and the resulting mixture was heated to reflux for a further 1.5 hours. The mixture was then treated cautiously at 0° C. with saturated ammonium chloride solution and partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the yellow, crystalline residue (2.6 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 1.85 g (87%) of p-[trans-4-(trans-1-pentenyl)cyclohexyl]acetophenone as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O-:18])=O)[CH2:8][CH2:7]1.[Li+].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Br:48][C:49]1[C:50]([C:55](=[N:57]O)[NH2:56])=[N:51][N:52]([CH3:54])[CH:53]=1>ClCCl.N1C=CC=CC=1.C(N(CC)CC)C.CN(C)C=O>[Br:48][C:49]1[C:50]([C:55]2[N:57]=[C:16]([CH2:15][CH2:14][C:13]([NH:12][CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]4[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=4)[CH2:11][CH2:10]3)=[O:19])[O:18][N:56]=2)=[N:51][N:52]([CH3:54])[CH:53]=1
Reactant: O=C([O-])CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cn1cc(Br)c(C(N)=NO)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cn1cc(Br)c(-c2noc(CCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)n1
Yield: 37.9 %

Procedure:
To lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (0.292 g) in dichloromethane (6 ml) was added dimethylformamide (1.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.183 g), 1-hydroxybenzotriazole hydrate (0.130 g), 4-bromo-N′-hydroxy-1methyl-1H-pyrazole-3-carboximidamide (0.175 g) and triethylamine (0.161 g). Reaction was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5 ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure, followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by reverse phase hplc (RPHPLC; 75%-5% 0.1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the title compound (0.164 g).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].C1COCC1.[CH3:12][C:13]1[C:14]([NH:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]2[CH2:17][CH2:18][CH2:19][C:20](=O)[C:21]=2[CH:22]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][C:13]1[C:14]([NH:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]2[CH2:17][CH2:18][CH2:19][C:20](=[CH2:1])[C:21]=2[CH:22]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Nc1cc2c(cc1C)C(=O)CCC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCCc2cc(NC(C)=O)c(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
In a mechanically stirred 50 L vessel, Et2O (12.5 L) was added to methyltriphenylphosphonium bromide (1.81 kg, 5.06 mol). KOtBu (566 g, 5.06 mol) was added. The mixture was heated to reflux for about 1 h. THF (5 L) was added followed by addition of N-(3-methyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (75) (475 g, 2.19 mol). The mixture was warmed to reflux overnight. The reaction was diluted with Et2O (5 L). The resulting mixture was cooled to rt and then poured into water (30 L). After stirring for about 1 h at rt, the layers were left standing to separate. The aqueous layer was removed and the organic mixture was filtered rinsing with Et2O. The solids were dried in vacuo to afford N-(3-methyl-5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (76) (284 g, 60% yield). 1H NMR (300 MHz, DMSO): δ 9.24 (s, 1H), 7.49 (s, 1H), 7.24 (s, 1H), 5.48 (m, 1H), 4.86 (m, 1H), 2.65 (m, 2H), 2.49 (m, 2H), 2.35 (s, 3H), 2.06 (s, 3H), 1.75 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([O:22]CC)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([OH:22])=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CCOCC2)c2nc(C3CC3)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an EtOH solution (30 mL) of ethyl 6-cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (300 mg, 0.911 mmol) was added sodium hydroxide (1.82 mL, 1.82 mmol) and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in 20 mL of water. The contents were acidified with acetic acid, and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the final product as 265 mg (97%). LCMS E-S (M+H)=302.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.09 (m, 4H), 1.81 (dd, J=12.38, 2.27 Hz, 2H), 2.15 (qd, J=12.25, 4.42 Hz, 2H), 2.28-2.37 (m, 1H), 2.54 (s, 3H), 3.46-3.60 (m, 2H), 3.89-4.02 (m, 2H), 4.91 (m, J=11.56, 11.56, 4.17, 4.04 Hz, 1H), 7.42 (s, 1H), 13.73 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17])([O-:12])=[O:11]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: COc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 91.1 %

Procedure:
Using m-anisidine (2.03 g, 16.5 mmol) and 3-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.72 g (91.3%) of the title compound in the form of colorless powder.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9](O)[CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:11]([CH:10]1[O:15][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:9]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(O)CO
Reactant: O=Cc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCCCC1COC(c2ccccc2)O1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of benzaldehyde (5.1 mL, 50.0 mmol), 1,2-hexanediol (6.5 g, 55.0 mmol), and camphorsulfonic acid (0.58 g, 2.5 mmol) in 50 mL of toluene was heated to reflux (Dean-Stark) with azeotropic removal of water. When the theoretical amount of water was distilled (4.5 hours), the mixture was cooled to room temperature and diluted with 80 mL of ether. The solution was extracted with 2M aqueous sodium carbonate, water and brine, dried (Na2SO4), filtered, and concentrated to provide 10.54 g (102%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:9][O:8]2)[CH:2]=1.[NH2:10][C@H:11]([CH3:31])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([O:22][CH2:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1>O.C(O)C>[CH2:29]([N:26]([CH2:27][CH3:28])[C:24](=[O:25])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:12][C@H:11]([NH:10][CH2:9][C@H:7]([OH:8])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:31])[CH3:30]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Yield: 20.6 %

Procedure:
A solution of (R)-(pyridin-3-yl)oxirane (97 mg, 0.80 mmol) and (R)-2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-N,N-diethylacetamide (243 mg, 0.80 mmol) in water (0.8 mL) and ethanol (8 mL) is refluxed for 5 hours. After concentrated, the resulting residue is purified by preparative TLC (SiO2, 20×20 cm, 0.5 mm, iPrOH/saturated ammonia solution in chloroform=1/10) to give the desired N,N-diethyl-2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}-acetamide (70 mg, yield: 21%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[CH3:29][S:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])[CH:13]=[CH:12][CH:11]=1)[C:23]([CH3:25])([CH3:24])[CH2:22]2)(=[O:28])=[O:27]
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
A mixture of 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (100 mg, 0.23 mmol) in tetrahydrofuran (20 mL), 2M lithium hydroxide in water (10 mL) was stirred at 25° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (19 mg, 7%) as a white solid: LC/MS m/e calcd for C22H28N2O4S (M+H)+: 417.54, observed: 417.0.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: COC(=O)CCCBr
Product: COC(=O)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 63 %

Procedure:
Obtained in 63% yield by an analogous method to Example 19, preparation of starting materials, starting from 4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol and methyl 4-bromobutanoate.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[F-].[Cs+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OB(O)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccccc3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.3 %

Procedure:
4-Chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (100 mg, 0.159 mmol) was dissolved in dimethoxyethane (5.0 mL), and the solution was added with phenylboronic acid (58.2 mg, 0.478 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (10.4 mg, 0.0130 mmol) and cesium fluoride (145 mg, 0.954 mmol), followed by stirring at 90° C. for 6.0 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to obtain 4-chloro-5-phenyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (44.5 mg, yield 50%).
Reaction SMILES: N1C=CC=CC=1C(O)=O.[Cl:10][C:11]1[CH:12]=[C:13](I)[CH:14]=[C:15]([Cl:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:32][CH3:33])(=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CO.[Cu]I.O.O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:26]([C:25]([O:32][CH3:33])=[O:31])[C:27]([O:29][CH3:30])=[O:28])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: COC(=O)CC(=O)OC
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Yield: 85.8 %

Procedure:
To a 3-neck 1 L reactor equipped with temperature probe, overhead stirrer, reflux condenser, and nitrogen bubbler, was added copper (1) iodide (4.0 g, 0.021 mol), 2-picolinic acid (5.2 g, 0.042 mol), 3,5-dichloroiodobenzene (99 g, 0.36 mol), and cesium carbonate (233 g, 0.72 mol) under nitrogen. Dioxane (600 mL) and dimethyl malonate (91 g, 0.69 mol, 1.9 eq.) were then added to the solid mixture with stirring under nitrogen. The resulting mixture was then heated to 90° C. for 7 h, forming a pale yellow-green slurry. Water (300 mL) and hexanes (200 mL) were added to the cooled reaction mixture at room temperature, stirred for 5 min, and transferred to a separatory funnel, and extracted twice with 75 mL dioxane-hexanes (2:1). The combined organic phases were washed with saturated aqueous ammonium chloride (200 mL) and concentrated to dryness to remove all dioxane. The residue was mixed with MeOH (100 mL) and water (200 mL). After stirring for 30 min, the mixture was cooled to 0° C. with an external ice-water bath and slowly stirred for 2 h. Filtration gave 98.6 g of crude material which was dissolved in MeOH (160 mL) at 50° C., with stirring, cooled to 0° C. over 6 h then maintained at 0° C. for 2 h. Filtration gave 85.6 g of the title compound as a fine white crystalline solid. The filtrate was concentrated to remove all MeOH, and the residue was filtered to give an additional 4.12 g of the title compound for a combined 89% yield.
Reaction SMILES: FC(F)(F)OC1C=CC([N+:10]([O-])=O)=CC=1O.N([O-])=O.[Na+].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[NH2:25].Cl.[F:36][B-:37]([F:40])([F:39])[F:38].[Na+]>O>[F:36][B-:37]([F:40])([F:39])[F:38].[F:20][C:21]([F:33])([F:34])[O:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[N+:25]#[N:10]
Reactant: Nc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c(O)c1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Solvent: O
Product: N#[N+]c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Reaction time: 0.5 h

Procedure:
2-Trifluoromethoxy-5-nitrophenol can be prepared according to the following method: an aqueous sodium nitrite (0.82 g) solution (2 ml) is added dropwise to a suspension of 2.35 g of 2-trifluoromethoxy-5-nitroaniline in 17 ml of distilled water cooled to 5° C. and in the presence of 5 ml of concentrated hydrochloric acid. After stirring for 30 minutes at the same temperature, an aqueous sodium tetrafluoroborate (1.66 g) solution (5 ml) is added dropwise to the reaction mixture, which has become clear. After reacting for 30 minutes, still at the same temperature, the precipitate formed is filtered off, washed with water and dried. 1.85 g of 2-trifluoromethoxy-5-nitrophenyldiazonium tetrafluoroborate are thus obtained in the form of a white powder used without additional purification in the subsequent syntheses. This diazonium salt is then divided into 4 portions of approximately 0.5 g. Each portion is added to a solution of 150 g of copper nitrate (trihydrate) in 100 ml of distilled water. 0.15 g of copper oxide are then added and the reaction is continued for 30 minutes at a temperature in the region of 20° C. After filtering off the insoluble material on a Celite bed and washing with dichloromethane, the organic phase is extracted from the filtrate with dichloromethane and the 4 organic phases are combined and concentrated to dryness under reduced pressure. The crude product (1 g of brown oil) is purified by flash chromatography on a silica column, an ethyl acetate/cyclohexane (10/90 by volume) mixture being used as eluent. 0.4 g of the expected phenol is thus obtained in the form of a pale yellow powder [1H N.M.R. spectrum (200 MHz, d6-(CD3)2SO, δ in ppm): 7.61 (broad d, J=9 Hz, 1H, aromatic H meta to the OH), 7.78 (dd, J=9 and 2.5 Hz, 1H, aromatic H para to the OH), 7.86 (d, J=2.5 Hz, 1H, aromatic H ortho to the OH), 11.38 (broad unresolved peak, 1H, OH)].
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:9][CH2:12][CH2:11][Br:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
To a solution of benzoic acid (2.44 g, 20 mmol) and 2-bromoethan-1-ol (1.42 mL, 20 mmol) in 40 mL of anhydrous dichloromethane, a solution of 1,3-dicyclohexylcarbodiimide (4.12 g, 20 mmol) in dichloromethane was slowly added followed by addition of a catalytic amount of 4-(dimethylamino)pyridine. The resulting mixture was stirred at room temperature for 16 hrs. After filtration, the filtrate was washed with 5% NaHCO3, brine, and dried over Na2SO4. After removing the solvent, chromatography (silica gel, 10% ethyl acetate in hexane) of the residue gave 3.7 g (82%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 3.62 (t, J=6 Hz, 2H), 4.60 (t, J=6 Hz, 2H), 7.42 (m, 2H), 7.54 (m, 2H), 8.04 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[CH3:25][N:26]([CH:28]=[O:29])[CH3:27]>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:3][CH2:4][C:5]4[C:28](=[O:29])[N:26]5[CH2:27][CH2:15][CH2:16][CH2:2][C:25]5=[N:7][C:6]=4[CH3:9])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 5.3 parts of 3-(2-chloromethyl)-6,7,8,9-tetrahydro-2-methyl-4 H-pyrido(1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 part of potassium iodide, and 90 parts of DMF is stirred overnight at 80°-90° C. After cooling, the reaction mixture is poured into water. The product is filtered off and crystallized from a mixture of DMF and 2-propanol. The product is filtered off and dried, yielding 3.8 parts (46%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:24][C:23]([CH2:25][N:26]3[CH2:35][C:30]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][CH2:28][CH2:27]3)=[N:22][N:21]=2)[CH:3]=1.[CH3:36][O:37][C:38]1[C:43]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:36][O:37][C:38]1[C:43]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:42][C:41]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[C:4]([C:20]3[O:24][C:23]([CH2:25][N:26]4[CH2:35][C:30]5([CH2:31][CH2:32][CH2:33][CH2:34]5)[O:29][CH2:28][CH2:27]4)=[N:22][N:21]=3)[CH:3]=2)=[CH:40][N:39]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCOC5(CCCC5)C4)o3)cc(Br)cc21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4CCOC5(CCCC5)C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 100 °C
Yield: 99.6 %

Procedure:
To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane (74 mg, 0.133 mmol) in 1,4 dioxane (2.5 ml) and water (1 ml) was added N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (47.8 mg, 0.146 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (19.39 mg, 0.027 mmol) and potassium phosphate tribasic (84 mg, 0.398 mmol). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the crude residue was dissolved in DMSO (1 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a white solid (71.5 mg).