Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CNC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylamine (9.34 g) in methanol (300 ml) was added benzaldehyde (10.0 g) followed by activated 3 Å molecular sieves. After 1 h, sodium cyanoborohydride (7.13 g) was added followed by the dropwise addition of acetic acid (9.2 ml), and the reaction was stirred overnight. The reaction mixture was filtered through hiflo, the solvent removed in vacuo and the resulting white solid was heated under reflux in 5M potassium hydroxide solution for 30 mins. The product was extracted into dichloromethane (3×100 ml) and the combined organic layers were washed with brine (100 ml), dried over sodium sulphate and the solvent was removed in vacuo to give a clear oil. The product was purified by column chromatography (eluting with ethyl acetate) then distillation; bpt=137° C. at 1.0 mbarr. 1H NMR (360 MHz, D6 -DMSO) δ0.94-1.24 (5H, m), 1.48-1.88 (5H, m), 2.32 (1H, m), 2.32 (1H, m), 3.10 (2H, s(b)), 3.72 (2H, s), 7.14-7.40 (5H, m).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])[CH2:13][CH2:12]1)=[O:10])[CH3:7].[CH:25](=O)[CH3:26]>CO>[CH3:7][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][CH2:25][CH3:26])[CH2:13][CH2:12]1)=[O:10])[CH3:5]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Sodium cyanoborohydride (1.6 g) is added to a 0° solution of 1-[1,1-dimethylethoxycarbonyl]-4-(2-aminophenyl)piperazine (PREPARATION 13, 6.52 g) and acetaldehyde (1.48 ml) dissolved in methanol (65 ml). After 3 hr the reaction mixture is partially concentrated under reduced pressure. Then it is diluted with chloroform, washed with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, Rf =0.62 (ethyl acetate/hexane, 1/1), NMR (300 MHz, CDCl3) 7.04, 6.95, 6.66, 4.59, 3.70-3.50, 3.15, 2.82, 1.49 and 1.28 δ.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])(=[O:3])[CH3:2].[Se](=O)=[O:33].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])(=[O:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: COc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 120 °C
Yield: 97.3 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (20 mg, 0.047 mmol) in acetic acid (1 mL) was added selenium dioxide (16 mg, 1.44 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (20 mg, 97% yield).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH:17]([F:18])[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13]1>C(O)C.C(OCC)(=O)C.[Pd]>[F:18][C@H:17]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCC(F)C(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CNCC[C@@H]1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (+/−)-benzyl 3-(1,3-dioxoisoindolin-2-yl)-4-fluoropiperidine-1-carboxylate (1.0 equiv.) in ethanol and ethyl acetate (1:1, 0.2 M solution) was added Pd/C (20 wt %) under N2 atmosphere. The reaction mixture was flushed with H2 gas, equipped with H2 gas balloon, and stirred for 16 h at room temperature. The reaction mixture was filtered through Celite® Pad and the filtrate was dried in vacuo. The crude (+/−)-2-(4-fluoropiperidin-3-yl)isoindoline-1,3-dione was used for the next step without further purification (>99%). LCMS (m/z): 249.1 (MH+), Rt=0.49 min.
Reaction SMILES: O.O=[Al]O[Al]=O.O=[Si]=O.F[C:11]1[C:19](F)=[C:18](F)[C:17](F)=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2>CC1C=CC=CC=1C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Fc1c(F)c(F)c2[nH]ccc2c1F
Agent: O=[Al]O[Al]=O
Agent: O=[Si]=O
Solvent: O
Solvent: Cc1ccccc1C
Product: c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
In the drybox, to a 250 ml round bottom flask was added the TEAL-treated Benclay (10.390 g, as described in 1-2) and 100 mL of anhydrous o-xylene. To the stirred slurry was added an o-xylene solution of 4,5,6,7-tetrafluoroindole (1.891 g, 0.010 mole). After stirring for 15 minutes, the stirring was stopped and the reaction mixture was heated to 100° C. During this time, the reaction mixture was stirred periodically for 1-2 minutes every 15-20 minutes. After the first 30 minutes at 100° C., the color of the solution turns from colorless to golden yellow. The reaction mixture was allowed to cool to room temperature and collected by vacuum filtration to give a yellow (golden) solid and a pale yellow solution. The solid was washed with toluene (3×50 mL) and dried in vacuo for ˜15 hours. Indole-modified clay samples were recovered in >90% yield and stored in the drybox freezer (−35° C.) until they were to be used.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=O.C([O-])(O)=O.[Na+]>CCO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=4)[N:1]=[C:2]3[S:3][C:4]=2[CH:10]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COc1ccc2nc(N)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)sc1nc(-c3ccc(Br)cc3)cn12
Yield: 54 %

Procedure:
In the minimum volume of EtOH was dissolved the commercially available 2-amino-6-methoxybenzothiazole (2 mmol), then 2,4′-dibromoacetophenone (2 mmol) was added and the resulting mixture was refluxed for 5 h before addition of NaHCO3 (3 mmol). After 2 h more of reflux, the precipitate was filtered off, washed with a mixture 1/1 AcOEt/hexane and dried in vacuum and then used in the next step, optionally, without further purification. The result was a white solid as a 54% yield.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][OH:20])=[O:15]>N1C=CC=CC=1>[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:8]=[O:10])[OH:20])=[O:15]
Reactant: O=CO
Reactant: O=C(NCCNO)c1cc(Cl)cc(Cl)c1Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=CN(O)CCNC(=O)c1cc(Cl)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 28 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.5 mL) was added to a solution of 2,3,5-trichloro-N-(2-hydroxyamino-ethyl)-benzamide (0.27 g, 1.0 mmol) in pyridine (10 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 2 h at room temperature and the pyridine removed in vacuo. The residue was purified by preparative reverse-phase HPLC to provide the title compound (0.09 g, 28%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.70 (s, 1H); 7.42 (s, 1H); 3.78 (m, 1H); 3.73 (m, 1H); 3.60 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=311.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH2:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:40][C:36]3[S:35][CH:39]=[CH:38][N:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 42.4 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added 1,3-thiazol-2-amine (3.5 mg, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (7 mg, 40%). LC-MS m/z 551 (M+H)+; 1H-NMR (MeOD) δ 2.22 (s, 6H), 2.46 (m, 2H), 3.16 (m, 2H), 4.51 (s, 2H), 7.17 (m, 3H), 7.51 (m, 2H), 7.69 (m, 1H), 7.83 (d, 1H), 8.16 (d, 1H), 8.23 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][C:21]2[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH2:43])=[O:42])[CH2:37][CH2:36]3)=[C:23]3[CH:31]=[N:30][N:29]([CH2:32][CH3:33])[C:24]3=[N:25][C:26]=2[CH2:27][CH3:28])=[O:18])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[CH2:32]([N:29]1[C:24]2=[N:25][C:26]([CH2:27][CH3:28])=[C:21]([CH2:20][NH:19][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[CH:12][CH:13]=3)=[O:18])[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH2:43])=[O:42])[CH2:37][CH2:36]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CNC(=O)c1ccc(CCCCOCCCCBr)cc1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CNC(=O)c1ccc(CCCCOCCCCN2CCOCC2)cc1
Temperature: 65 °C
Yield: 27.1 %

Procedure:
A mixture of 4-{[5-({[(4-{4-[(4-bromobutyl)oxy]butyl}phenyl)carbonyl]amino}methyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxamide (1.1 g, 1.67 mmol, e.g. which can be as prepared in Intermediate 28) in N,N-dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (0.567 ml) and morpholine (0.300 ml, 3.3 mmol) and heated at 65° C. The solvent was removed under vacuum and the residue was applied directly to a 100 g silica SPE cartridge and eluted with a gradient of from 0% to 50% methanol in dichloromethane over 40 mins. Fractions containing product were pooled and evaporated to give a pale orange foam which appeared to be about 85% pure by analytical HPLC. The residue was further purified by mass directed preparative HPLC (Method C, using 0.1% trifluoroacetic acid) in 50 mg portions, and, following evaporation of the solvent from the appropriate fractions, the residual material was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution (NaHCO3). The organic fraction was collected by passing through a hydrophobic frit and evaporated to give the title compound (0.300 g) as a white foam. LCMS showed MH+=663; TRET=2.09 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:30])[CH2:17][N:18](CC1C=CC=CC=1)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=2[O:31]CC1C=CC=CC=1)=[O:6].CO.O1CCCC1>C(O)(=O)C>[C:5]([OH:6])(=[O:4])[CH3:7].[CH3:1][O:2][CH2:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH:16]([OH:30])[CH2:17][NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=2[OH:31])=[O:6]
Reactant: COCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COCOC(=O)c1cc2c(C(O)CNC(C)(C)C)ccc(O)c2[nH]1
Yield: 189.4 %

Procedure:
617 mg of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid methoxymethyl ester is combined with 10 ml of methanol, 40 ml of absolute tetrahydrofuran, and 0.3 ml of acetic acid and hydrogenated and worked up as described in Example 31(E), thus obtaining 450 mg of 7-hydroxy-4-(1-hydroxy-2-tert-butylaminoethyl)indole-2-carboxylic acid methoxymethyl ester acetate, decomposition point 165°-170° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>ClCCl>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCN1CCCC2CC=CC=C21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCCCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 233.4 g (1 mole) of N-hydroxyhexyltetrahydroquinoline and 153.1 g (1.5 moles) of acetic anhydride in dichloromethane are added 151.8 g (1.5 moles) of triethylamine and 8.5 g (1 mole %) of 4-N,N-dimethylaminopyridine, and the reaction is stirred at room temperature for 3 hours. The product solution is washed with cold 2N HCl followed by saturated sodium bicarbonate, and the organic layer is filtered through cotton and evaporated.
Reaction SMILES: [CH3:1][CH2:2][C:3]([O-:6])([CH3:5])[CH3:4].[Na+].CC[O:10][CH2:11][CH3:12]>C1C=CC=CC=1.O1CCCC1>[C:3]([O-:6])(=[O:10])[CH3:5].[CH3:1][CH2:2][CH2:3][CH2:4][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(=O)[O-]
Product: CCCCCC
Reaction time: 0.25 h
Yield: 95 %

Procedure:
0.38 ml of a 1.5M solution of sodium tert-amylate in benzene is added to 126 mg of the mesylate lactone obtained at stage A in 2 ml of anhydrous tetrahydrofuran, at 0° C. The temperature is allowed to rise to 20° C. over 15 minutes. After hydrolysis, extraction is done with ether, then the organic phase is washed with salt water. After chromatographing on a silica column (eluent acetate-hexane 40/60), 73 mg of the cis-cyclopropane lactone expected is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:12]([NH:14][C:15]([C:17]1[C:21](Br)=[C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:19][N:18]=1)=[O:16])[CH3:13].C(=O)([O-])O.[Na+].CN(C=O)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.O>[CH2:12]([NH:14][C:15]([C:17]1[C:21]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:19][N:18]=1)=[O:16])[CH3:13]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(OC)cc1
Temperature: 90 °C
Yield: 111.8 %

Procedure:
To a mixture of 4-methoxyphenylboronic acid (0.178 g, 1.17 mmol) and 5-(2,4-Bis-benzyloxy-5-chlorophenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide (0.507 g, 0.94 mmol) was added sodium hydrogen carbonate (237 mg, 2.82 mmol) followed by DMF (5 mL) and water (1.0 mL). The mixture was degassed by evacuation and flushing with nitrogen (three times), followed by bubbling nitrogen gas through mixture for five minutes. Dichlorobis(triphenylphosphine)palladium (II) (66 mg, 0.094 mmol) was added and reaction mixture was heated under a nitrogen atmosphere at 90° C. for two hours (reaction mixture becomes dark brown in colour). Another 10 mg of dichlorobis(triphenylphosphine)palladium (II) was added and reaction mixture was heated at 90° C. for 15 hours then allowed to cool to ambient temperature. The majority of solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). This mixture was filtered through a pad of celite to remove palladium residues and then the phases were separated and the organic phase was washed with water (2×30 mL), saturated aqueous sodium chloride solution (50 mL) then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a yellow oil (598 mg). The crude reaction product was purified by adsorption onto silica gel then flash chromatography on silica gel (20 g IST) eluting with a solvent gradient of 1 to 20% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-chlorophenyl)-4-(4-methoxy-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless solid (0.223 g, 40%). LCMS: [M+H]+ 571, 569 (37Cl; 35Cl). 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H), 3.44 (m, 2H), 3.79 (s, 3H), 4.73 (s, 2H), 6.45 (s, 1H), 6.65 (t, 1H), 6.80 (d, 2H), 7.14 to 7.44 (m, 8H), 6.95 (m 2H).
Reaction SMILES: [K].[Cl:2][C:3]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:13][OH:14]>>[Cl:2][C:3]1[N:11]=[C:10]([O:14][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CO
Agent: [K]
Product: COc1ccc(C(=O)O)c(Cl)n1
Yield: 52 %

Procedure:
Potassium botoxide (483 mg, 4.31 mmol) and MeOH (8 mL) were added to 2,6-dichloro-nicotinic acid (207 mg, 1.07 mmol), and the mixture was stirred using microwave at 60° C. for 1 hour. After the termination of the reaction, the reactant was filtered, and 1N HCl was added thereto at 0° C. to adjust the pH to 3. The solid was dried by N2 gas to obtain the title compound (106 mg, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].Cl[C:11]1[N:12]=[N:13][C:14]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[CH:15][CH:16]=1.O.C(=O)([O-])O.[Na+]>C(O)CCC.C(OC(=O)C)C>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[N:13]=[N:12][C:11]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:16][CH:15]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)cn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
tert-butyl carbazate, 8.98 g (67.3 mmol) and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (11.9 g, 61.1 mmol) were mixed in 1-butanol (245 mL). This mixture was heated till 90° C. and stirred at that temperature for 16 h. The reaction mixture was cooled and water (250 mL) and ethylacetate (250 mL) were added. The biphasic mixture was neutralised with sodium hydrogencarbonate till the pH is 7. Then the organic layer was separated and the water layer was extracted with ethylacetate (250 mL). The combined organic layers were washed once with water (250 mL) and evaporated. The residue was stirred in isopropylether, filtered off and dried under vacuum. Yield: 5.9 g (20.3 mmol; 33%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH3:21][N:22]([CH3:36])[C:23]1[CH:35]=[CH:34][C:26]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>>[CH3:20][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([N:27]([C:26]3[CH:25]=[CH:24][C:23]([N:22]([CH3:36])[CH3:21])=[CH:35][CH:34]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[O:8]2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: CN(C)c1ccc(Nc2ccccc2)cc1
Product: CN(C)c1ccc(N(c2ccccc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)cc1
Yield: 49.2 %

Procedure:
Following a procedure similar to that described in Example 1 but employing 2.6 g of 2-[4-(dimethylamino)benzoyl]benzoic acid and 2.1 g of 4-(dimethylamino)-N-phenylaniline there was obtained 2.2 g of 3-[4-(dimethylamino)phenyl]-3-{[4-(dimethylamino)phenyl]phenylamino}phthalide, m.p. 163°-166° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a brown-colored image.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.B(O)(O)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[N:20][CH:19]=1>>[F:24][C:21]1[N:20]=[CH:19][C:18]([C:2]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Product: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with methane sulfonic acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate.