Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccccc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and benzyl bromide
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.F[B-](F)(F)F.[H+].[N:25]([O-])=O.[Na+].CC([O-])=O.[K+].C1OCCOCCOCCOCCOCCOC1>O.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:10](=[CH:12][C:13]=2[F:14])[NH:11][N:25]=[CH:15]3)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1cc(Oc2ccc(Br)cc2F)c(F)cc1N
Reactant: O=N[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cc(Br)ccc1Oc1cc2cn[nH]c2cc1F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 4-(4-bromo-2-fluorophenoxy)-5-fluoro-2-methylaniline (5.2 g, 16.6 mmol) in water (100 mL) is added fluoroboric acid (6.06 g, 33.1 mmol) at RT. The solution is cooled to 0° C. and NaNO2 (1.71 g, 24.8 mmol) in water (2 mL) is added. The reaction is stirred at 0° C. for 40 min. CHCl3 (200 mL) is added. The organic phase is separated, dried over Na2SO4, and filtered. To the filtrate is added KOAc (7.31 g, 74.5 mmol) and 18-crown-6-ether (0.218 g, 0.82 mmol). The reaction is stirred at RT for 1 hour. The reaction mixture is washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered and evaporated. The residue is washed with DCM and filtered to offer the desired product as a light yellow solid. The filtrate is purified by chromatography eluting with DCM then EtOAc:hexane (1:1) to give additional desired product. Both portions of the solid are combined to offer the desired product (3.2 g, 59% yield). MS (m/z): 324.8 (M+H).
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1>>[CH:13]1([CH:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccccc12
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccccc12

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran (429 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (408 mg) synthesized in Example 2(2) and in the same manner as in Example A7(3), the title object compound (247 mg, 34%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].F.F.F.C(N(CC)CC)C>CN(C=O)C.CCCCCC.CCOC(C)=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:14][CH2:15][OH:16])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCOc1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
4-trifluoromethoxyphenol (8.9 g, 50.2 mmol) was dissolved in DMF and treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (16.81 g, 70.3 mmol) followed by Cs2CO3 (17.99 g, 55.2 mmol). The reaction mixture was heated to 60° C. for 3 hrs. The reaction was quenched with water and hexane was added. The two layers were separated, and the aqueous phase was further extracted twice with hexane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was used without further purification. The residue was dissolved in acetonitrile (100 mL) and treated with triethylamine trihydrofluoride (20.23 g, 125 mmol) the mixture was left to stir at RT for 3 hrs. TLC (10% EtOAc in hexane) showed the reaction was complete. Quenched with water (150 mL) and added ether (1000 mL). The organic layer was washed with brine, dried (Na2SO4) filtered and concentrated in vacuo. The residue was purified by silica gel chromatography. The eluting solvent was 0-20% EtOAc in hexanes. 9.7 g of the title product was isolated.
Reaction SMILES: C[C:2]([OH:15])([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].O.O.[OH-].[Li+]>CO.O1CCCC1>[OH:15][CH:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(O)(C(=O)O)C(C)(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(c1ccccc1)C(O)C(=O)O
Temperature: 62.5 °C
Reaction time: 16 h

Procedure:
According to general procedure, methyl 2-hydroxy-3-methyl-3-phenylbutanoic acid (0.27 g, 1.3 mmol, from Reference Example 37) is dissolved in methanol (6 mL) and tetrahydrofuran (6 mL). To this solution is added water (3 mL) and lithium hydroxide monohydrate (0.12 g, 2.9 mmol), and the resulting mixture is stirred at 60-65° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a light pink oil, which solidified under vacuum (0.25 g, 100%). TOF MS (ES−): (M−H)=193.0
Reaction SMILES: Cl[C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[CH3:18][CH:19]([OH:21])[CH3:20].N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>O>[CH:19]([O:21][C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3])([CH3:20])[CH3:18]
Reactant: CC(C)O
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Solvent: O
Product: CC(C)OC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-chlorocarbonylphenoxy phenyl methane (12.3g.; 0.05 mole), propan-2-ol (3.6g.; 0.6 mole), pyridine (5g) and xylene (50ml) were boiled under reflux for 18hr. The cooled mixture was poured into water and extracted with dichloromethane. The organic extract was washed well with water and dried (anhyd. MgSO4), filtration and evaporation yielded 4-isopropoxycarbonylphenoxy phenyl methane, m.p. 62°-3° C.
Reaction SMILES: [CH2:1]([C@:4]1([CH2:47][CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:46])[CH:2]=[CH2:3].C([C@@]1(CCOCC2C=CC(OC)=CC=2)C[C@H](C2C=CC=C(Cl)C=2)[C@@H](C2C=CC(Cl)=CC=2)N([C@@H](CC)CO[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)C1=O)C=C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C@:4]1([CH2:47][CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][OH:26])[C:5]1=[O:46])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(CCOCc2ccc(OC)cc2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: C=CC[C@@]1(CCOCc2ccc(OC)cc2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@]1(CCOCc2ccc(OC)cc2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O

Procedure:
To a solution of a mixture of (3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-one and (3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-one (19.23 g, 23.03 mmol; Example 408, Step A) in THF (92 ml) at rt was slowly added a solution of TBAF (1.0M in THF, 34.5 ml, 34.5 mmol). The reaction was monitored by LCMS, and when judged complete was concentrated under reduced pressure (no heat), then diluted in 400 mL of EtOAc. HCl (1N, 150 ml) was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed several times with water, dried over MgSO4, filtered, and the filtrate was concentrated. Purification by chromatography on silica gel (eluent: 10 to 20% EtOAc/hexane, gradient elution over 30 min) provided the title compound along with its C3 epimer as a clear, colorless foam. Individual steroisomers were separated by chiral HPLC (flowrate: 120 ml/min, 1 g per injection, on a Chiralcel® OD-H 5 cm I.D.×50 cm, 20 μm column; Daicel Chemical Industries LTD, using 6% isopropyl alcohol/hexane as the eluent) to give the title compound as the first eluting isomer (tR=11-23 min) as a clear, viscous oil.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1>CN1C(=O)CCC1>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)#[N:3]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(C#N)cc1
Temperature: 200 °C

Procedure:
5.1 g (56.7 mmol) of copper(I) cyanide were added to a solution of 10 g (43.7 mmol) of methyl 4-bromophenylacetate in 44 ml of NMP, and, in a microwave oven, the mixture was then heated to 200° C. for 60 min. The reaction mixture was then purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). This gave 4.65 g (61% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[O:11][N:10]=1.O.O.[Sn](Cl)Cl.[Sn](Cl)Cl>C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[O:11][N:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(-c3c(Cl)cccc3Cl)no2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2nc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The nitro oxadiazole prepared in Step 1 (200 mg) was dissolved in ethyl acetate (20 mL) and tin (II) chloride dihydrate (162 mg, 1.2 molar equivalent) was added. The mixture was stirred at room temperature for 1 h. An additional 1.2 molar equivalents of tin (II) chloride was added. After a further 4 h at room temperature, the reaction mixture was diluted with ethyl acetate and washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired 3-(2,6-dichlorophenyl)-5-(3-aminophenyl)-1,2,4-oxadiazole as a white solid in quantitative yield. NMR (300 MHz, DMSO-d6): 7.70 (m, 3H), 7.36 (s, 1H), 7.24 (d, 2H), 6.91 (m, 1H), 5.57 ppm (broad s, 2H). LC-MS tr=33.1 min (Method W) MH+=307
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>O.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[C:22]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1)#[N:23]
Reactant: O=C(N(Cc1ccc(Cl)nc1)C1CCCCC1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(CN(C(=O)C(F)(F)F)C2CCCCC2)cn1
Temperature: 95 °C
Yield: 93 %

Procedure:
Under a nitrogen atmosphere add 6-chloro-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine (3.7 g, 11.5 mmol), zinc cyanide (2.02 g, 17.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.48 g, 0.57 mmol) and DPPF (0.63 g, 1.15 mmol) to DMF (40 mL). Heat the mixture at 95° C. for 2 h. Cool the mixture to room temperature and dilute with water and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (400 g) eluting with hexane/EtOAc (1:0 to 3:2 gradient) to obtain the desired intermediate (3.33 g, 93%). MS (APCI+) m/z: 312 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C:29]1([C:32](=[O:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:21]([O:25][C:26]([NH:28][C:29]1([C:32]([CH:33]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:15])=[N:10]3)=[O:4])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:39])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At RT, a mixture of 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (1.01 g, 3.00 mmol) and ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (0.978 g, 3.60 mmol) in 5 mL of THF and 5 mL of DMF was treated with K2CO3 (1.04 g, 7.51 mmol). After the reaction mixture was stirred at RT for 18 h, it was diluted with 100 mL of EtOAc and filtered. The filtrate was washed with sat. NH4Cl (2×15 mL) followed by brine (10 mL), and concentrated. The crude material was purified by silica gel chromatography (25-50% EtOAc in hexanes) to afford ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-4-oxobutanoate as a yellow amorphous solid (324a). m/z (ESI, +ve) 527.3 (M+H)+. In a glass tube, a solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-4-oxobutanoate as a yellow amorphous solid (324a) in 5 mL of EtOH and 2.5 mL of AcOH was treated with NH4OAc (1.39 g, 18.02 mmol). The glass tube was sealed, and heated in an oil bath at 55° C. for 8 h. The reaction mixture was concentrated to half of its volume. The residue was diluted with 150 mL of EtOAc and washed sequentially with 15 mL of water, 10 mL of 0.5 N NaOH and 10 mL of brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (25-50% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (1.4 g, 2.76 mmol, 92% yield) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (1H, br.), 7.87 (1H, d, J=7.2 Hz), 7.61 (1H, dd, J=8.0, 1.4 Hz), 7.40 (1H, d, J=2.7 Hz), 7.35 (1H, t, J=7.8 Hz), 6.92 (1H, br.), 5.90 (1H, s), 4.25 (2H, q, J=7.1 Hz), 2.56 (3H, s), 1.58 (9H, s), 1.26-1.39 (14H, m), 1.13 (2H, m). m/z (ESI, +ve) 508.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[Na+]>CO>[O:9]([C:7]1[CH:8]=[C:3]([OH:2])[CH:4]=[N:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cncc(Oc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cncc(Oc2ccccc2)c1
Temperature: 150 °C
Yield: 54 %

Procedure:
A mixture of 0.6 g (3.37 mM) of 3-methoxy-5-phenoxypyridine and 1.15 g (10 mM) of pyridinium hydrochloride is prepared. It is heated by microwaves for 40 minutes at 150° C. and then cooled, taken up with methanol and brought to pH 7 with 1 N sodium hydroxide solution. After concentration under reduced pressure, the residue obtained is purified by chromatography on silica gel using a toluene/isopropanol mixture (95/5; v/v) as the eluent to give the desired product in the form of an off-white solid with a yield of 54%.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][C:23]([CH3:33])([CH3:32])[N:22]2[N:34]=[CH:35][C:36]([C:37](=[O:47])[CH:38]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH3:39])=[C:21]12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.IC>C1COCC1>[CH2:13]([N:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][C:23]([CH3:33])([CH3:32])[N:22]2[N:34]=[CH:35][C:36]([C:37](=[O:47])[C:38]([CH3:1])([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH3:39])=[C:21]12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
To 0.110 mL (0.785 mmol) of diisopropyl amine dissolved in 5 mL of THF at −78° C. was added 0.314 mL (0.785 mmol) of a 2.5 M solution of n-butyllithium in hexanes. After stirring for 30 min, 0.28 g (0.604 mmol) of 5 was added as a solution in 1 mL of THF. The reaction was stirred at room temperature for 1 h before 0.049 mL (0.79 mmol) of iodomethane was added as a solution in 1 mL of THF. After 1 h the reaction was quenched by addition of approximately 0.5 mL of saturated aqueous ammonium chloride, diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product. Purification by flash chromatography eluting with 90% hexanes/AcOEt gave 0.067 g (23%) of the title compound as an off white solid. MS Calcd.: 477. Found: 478 (M+H).
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH2:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[N:8]2.Cl>C1COCC1>[NH2:22][C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:7]2[C:6]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:5][C:4]3[C:3](=[O:2])[NH:12][CH:11]=[CH:10][C:9]=3[N:8]=2)=[CH:18][CH:17]=1)([CH3:21])[CH3:20]
Reactant: COc1nccc2nc(-c3ccc(C(C)(C)N)cc3)c(-c3cccs3)cc12
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)c1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-{4-[5-methoxy-3-(2-thienyl)-1,6-naphthyridin-2-yl]phenyl}propan-2-amine (2-6, 66 mg, 0.176 mmol) in THF (10 mL) was added concentrated HCl (1 mL) and stirred for 5 h at rt. The volatiles were evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound as an off-white solid. LRMS m/z (M+1) Calcd: 362.1,. Found 362.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([N:40]=[C:41]=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1>ClCCl>[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([NH:40][C:41]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:16][CH2:17]2)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: c1ccc(N2CCNCC2)c(COc2ccncc2)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2COc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
The impure 1-[2-(Pyridin-4-yloxymethyl)phenyl]piperazine (˜50 mg) was dissolved in 5 mL of dichloromethane along with triethylamine (50 μL, 0.36 mmol). 3,5-Bis(trifluoromethyl)phenyl isocyanate (50 μL, 0.29 mmol) was added and the reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in 2 mL methanol. The reaction mixture was purified by reverse phase HPLC to give 10 mg of product as a white solid. 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.28 (d, 2H), 8.17 (s, 2H), 7.73 (s, 1H), 7.49 (d, 1H), 7.38 (t, 1H), 7.18-7.25 (m, 4H), 5.39 (s, 2H), 3.80-3.85 (m, 4H) 3.00-3.04 (m, 4H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)C2CCCC2)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.2 %

Procedure:
To a mixture of cyclopentyl(3-methyl-1-benzothiophen-2-yl)methanone (1.54 g) synthesized above, methyl 4-aminobenzoate (1.05 g), triethylamine (7.02 mL) and methylene chloride (30 mL) was added titanium (IV) chloride (829 μL), and the mixture was stirred under argon atmosphere at room temperature for 3 days. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran were added acetic acid (721 μL) and sodium cyanoborohydride (792 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (1.56 g, 65%) as an orange solid.