Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]3[CH2:23][O:22]C4(CCCCC4)[O:20]3)[N:15]=2)=[N:11][CH:12]=1.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[ClH:37].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]([OH:20])[CH2:23][OH:22])[N:15]=2)=[N:11][CH:12]=1
Reactant: COCCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2cccnc2C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
(S)—N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (85 mg, 0.16 mmol) was dissolved in ethanol (5 ml) and 1M HCl (0.5 ml) was added. The mixture was heated to 70° C. and agitated 3 hours. Upon cooling, the reaction was diluted with ethyl acetate, basified with sodium carbonate solution and washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was dissolved in small amount of dichloromethane and treated with 1M HCl in ether. After evaporation, (S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (65 mg, 90% yield) was obtained as white solid. Mass Spectrum (apci) m/z=450.1 (M+H−HCl).
Reaction SMILES: [C:1]1(=[O:6])O[CH:2]1[CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:4][CH:3]=[C:2]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:1]2=[O:6]
Reactant: Clc1ccccc1
Reactant: CCC1OC1=O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCCc2c(Cl)cccc21

Procedure:
Reaction of alpha-butyrolactone with chlorobenzene in the presence of aluminum chloride, as described in U.S. Pat. No. 3,657,400, produced 5-chloro-3,4-dihydro-1(2H)-naphthalenone. The latter was formylated with a combination of phosphorous oxychloride and dimethylformamide, yielding 1,5-dichloro-3,4-dihydronaphthalen-2-carboxaldehyde; mp 83.5°-84°, which was then reacted with ethyl thioglycolate and triethylamine in pyridine, as described in J.C.S. Perkin I, 2956 (1973), to produce ethyl 6-chloro-4,5-dihydronaphtho[1,2-b]thiophen-1-carboxylate; mp 81°-82°.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=O)=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([CH2:64][NH2:65])[OH:63]>CN(C=O)C>[OH:63][CH2:62][CH2:64][NH:65][C:26]([C:10]1[C:11](=[O:25])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:13]([CH3:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=2)[CH:9]=1)=[O:28]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCCO)cn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-(4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1, 70 mg, 0.102 mmol), TBTU (37 mg, 0.115 mmol), DIPEA (40 μL, 0.234 mmol) in DMF (0.5 mL) is stirred for 15 min at room temperature. Ethanolamine (7 μL, 0.116 mmol) is added and the reaction mixture is stirred for 1.5 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 16 mg (34% of theory); ESI mass spectrum: [M+H]+=456; Retention time HPLC: 1.34 min (Z002—005).
Reaction SMILES: [ClH:1].[CH:2]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[N:11][C:12]=3[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[ClH:1].[ClH:1].[CH:2]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([NH:24][CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[N:11][C:12]=3[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O[C@H]1CC[C@H](Nc2nc(NCc3ccccc3)c3ncn(C4CCCC4)c3n2)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C1CCC(Nc2nc(NCc3ccccc3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
The operation is carried out starting from the product of Example 4 by oxidation in DMF in the presence of (PDC) pyridinium dichromate and in this way the expected product is obtained after filtration on silica eluting with CH2Cl2/methanol: 80/20.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1I>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=[CH:25][C:20]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(Cl)c(I)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(S(C)(=O)=O)ccc1Cl

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-chloro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 74), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.ClC[C@@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:18][C:15]1([CH3:19])[O:16][C@H:17]([CH2:1][O:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)[CH2:13][O:14]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@@H](COc2ccc(C=O)cc2)O1

Procedure:
2 g (16.38 mmol) of p-methoxybenzaldehyde together with 3.7 g (24.57 mmol) of (4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane and 15.8 g (114.64 mmol) of potassium carbonate are stirred in 10 ml of DMF at 130° C. overnight. The mixture is then added to water and extracted with methylene chloride. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 2.42 g (61% of theory) of the target compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]1COCC1>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH2:28])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccccc3)cn2)CC1
Reactant: C1CCOC1
Product: C=C(c1ccccc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The above solution was added to a solution of tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.7 mmol) in dry THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for 2 h. The reaction was quenched by water (20 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 10:1 to give tert-butyl 4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate (890 mg, 89%) as a white solid. MS (ES+) C21H26N4O2 requires: 366, found: 367 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]([Mg]Br)=[CH2:44].Cl>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][N:27]=[C:19]2[N:18]1[C@H:28]1[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH:43]=[CH2:44])[CH2:32][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)CO[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.50 g) was dissolved in tetrahydrofuran (5 mL), vinylmagnesium bromide (2.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13]([O:15]C)=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](C3CNCC3)[CH:26]=2)[C:21]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:20]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:15])[NH:36][C:34](=[O:35])[C:33]=3[C:21]3[C:22]4[C:27](=[CH:26][C:25]([N:8]5[CH2:9][CH2:5][CH2:6][CH2:7]5)=[CH:24][CH:23]=4)[N:19]([CH3:18])[CH:20]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(CC(N)=O)c2ccc(C3CCNC3)cc21
Reactant: COC(=O)C(=O)c1cn(C)c2cc(Br)ccc12
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)NC2=O)c2ccc(Br)cc21
Yield: 84.6 %

Procedure:
3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (49 mg, 46%) was prepared from methyl (6-bromo-1-methyl-1H-indol-3-yl)-glyoxylate (68 mg, 0.23 mmol) and (1-methyl-6-pyrrolidin-4-yl-1H-indol-3-yl)acetamide (54 mg, 0.21 mmol).
Reaction SMILES: O[CH:2]([C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C:16]([CH3:23])([CH3:22])[CH2:15][CH2:14][C:13]([CH3:25])([CH3:24])[C:12]=2[CH:11]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[O:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][O:20][C:19]1[C:10]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[O:9])[O:6][CH:7]=2)=[CH:11][C:12]2[C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][C:16]([CH3:22])([CH3:23])[C:17]=2[CH:18]=1
Reactant: COc1cc2c(cc1C(O)c1coc(C=O)c1)C(C)(C)CCC2(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1Cc1coc(C=O)c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution containing 4-[hydroxy(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furaldehyde (2.9 g, 8.5 mmol), triethylsilane (2.9 g, 25.4 mmol) and anhydrous methylene chloride (40 mL) was cooled to 0° C. To this mixture was added trifluoroacetic acid (˜1.0 mL, 8.5 mmol) and the reaction was allowed to stir at RT for 16 hours. The reaction was quenched with saturated NaHCO3 and the organics were separated and dried over MgSO4. The resulting oil (2.5 g) was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=N[CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11].[CH:31](Cl)(Cl)Cl>[O-2].[O-2].[Mn+4]>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:31][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: ClC(Cl)Cl
Reactant: OC(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1

Procedure:
To a round bottomed flask was added (1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol (0.992 g, 2.459 mmol) and manganese dioxide (1.069 g, 12.29 mmol) to stir in chloroform (8.20 mL) for 1 hr. Reaction was filtered through celite. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 mM, 0.1% TFA in ACN/H2O, gradient 40% to 80% over 18 min to provide (1H-Imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 401.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:6][C:5]=1[CH3:16])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[CH3:16])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C(C)C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)O)ccc1C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 2-(4-isopropyl-3-methylphenoxy)acetate (13.0 g, 58.5 mmol) in abs. ethanol (240 mL) was treated with aq. sodium hydroxide solution (13 mL, 5 M). The resulting solution was stirred for 4 h at ambient temperature, then poured into aq. HCl (800 mL, 1 N). This was extracted with ether (2×200 mL), and the extracts were washed with brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the solid product, 2-(4-isopropyl-3-methylphenoxy)acetic acid, which was dried under vacuum (12.0 g, 58.5 mmol, 100%). 1H NMR (d6-DMSO, 300 MHz): δ 12.91 (1H, s), 7.12 (1H, d, J=8 Hz), 6.70-6.65 (2H, m), 4.58 (2H, s), 3.02 (1H, m, J=6.7 Hz), 2.24 (3H, s), 1.12 (6H, d, J=6.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[C:12]=2[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:34][CH3:35])[CH2:18][CH3:19])=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc3ccccc3o2)cc1
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
When 2-(p-chlorophenyl)benzofuran is acylated with 4-(3-diethylaminopropoxy)benzoyl chloride hydrochloride by the procedure described in Example 6, the title compound is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][CH:38]=3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OCC1CC1
Temperature: 70 °C
Yield: 16.4 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (15 mL), was added potassium carbonate (102 mg, 0.740 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (122 mg, 0.490 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-45% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 16.5%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.Cl.[F:10][C:11]1[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=1>C(#N)C>[Br:8][C:15]1[CH:16]=[C:11]([F:10])[C:12]([NH2:17])=[N:13][CH:14]=1
Reactant: Nc1ncccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Reaction time: 1 h
Yield: 157.1 %

Procedure:
Solid NBS (750 mg, 4.2 mmol) was added to a solution of 3-fluoropyridin-2-amine HCl salt (1.66 g, 7.18 mmol) in ACN (30 mL) at RT with stirring. The reaction was shielded from light and stirred under nitrogen. After 1 h, an additional amount of NBS (250 mg, 1.4 mmol) was added to the reaction. After 1 h, the solvent was removed under reduced pressure and the residue purified by silica gel flash chromatography eluting with 70% EtOAc/hexane followed by 100% EtOAc to afford 5-bromo-3-fluoropyridin-2-amine as a yellow-brown solid (1.26 g, 92% yield). LC/MS (m/z): 191.0/193.0 (MH+), Rt 1.18 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:27][Si:28](N=C=O)([CH3:30])[CH3:29]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1cc(F)cc2cc([Si](C)(C)C)oc12)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 0.20 gm (0.68 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in 10 mL tetrahydrofuran was cooled to −78° C. under a nitrogen atmosphere. To this solution were then added 0.96 mL (1.53 mMoL) n-butyllithium (1.6 M in hexane) dropwise, resulting in an orange solution. After 50 minutes 0.14 mL (1.02 mMol) trimethylsilylisocyanate were added dropwise. After 15 minutes the reaction mixture was quenched by addition of 2 mL saturated aqueous ammonium chloride and was then allowed to warm to room temperature. The reaction mixture was partitioned between 150 mL ethyl acetate and 150 mL water. The phases were separated and the organic phase was washed sequentially with 150 mL water and 150 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](=O)([O:27]C(C)(C)C)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (354.6 g) in acetonitrile (12 L) was added triethylamine (366.9 g) at 20° C. in a water-bath, and the mixture was stirred for 15 minutes. To the reaction solution was added dropwise a solution of di-t-butyl carbonate (474.5 g) in acetonitrile (700 ml) at 15˜19° C. in a water-bath, and further thereto was added N,N-dimethylamino-pyridine (11.06 g). The mixture was stirred at room temperature for 12 hours, and the solvent was removed by evaporation under reduced pressure. The obtained residue was diluted with methylene chloride (10 L), and washed with 1M hydrochloric acid (×3) and 5% saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium hydrogen sulfate, and the solvent was evaporated under reduced pressure to give a crude product (470.6 g). The obtained crude product was purified by silica gel column chromatography (methylene chloride/methanol=1/0→50/1) to give the title compound (456.8 g).
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[C:30]1([CH2:36][CH2:37]C=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:37][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: O=CCCc1ccccc1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCc1ccccc1

Procedure:
The product of Example 100 is treated with 3-phenylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:8]2.Cl.[BrH:18]>>[BrH:18].[CH2:14]([NH:13][C@H:7]1[CH2:6][CH2:5][C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:15][CH3:16]
Reactant: CCCN[C@H]1CCc2c(cccc2OC)C1
Agent: Br
Agent: Cl
Product: CCCN[C@H]1CCc2c(O)cccc2C1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthalenamine (10.0 g, 0.0391 mol) as the HCl salt, or its corresponding free base, was heated at reflux in 48% hydrobromic acid (150 mL) for a period of two to three hours. The solution was cooled to room temperature and the resulting solid was collected by filtration. Drying under high vacuum at 60° C. gave 10.7 g of the product (96% yield).
Reaction SMILES: COC1C=CC(C[N:8]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([O:28][CH2:29][CH3:30])[N:19]=2)CC2C=CC(OC)=CC=2)=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:8][C:18]1[N:19]=[C:20]([O:28][CH2:29][CH3:30])[C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1
Reactant: CCOc1nc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)ccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(N)ccc1C(F)(F)F
Temperature: 25 °C

Procedure:
Stir a mixture of N,N-Bis-(4-methoxybenzyl)-(6-ethoxy-5-trifluoromethylpyridine-2-yl)amine (630 mg, 1.41 mmol) and TFA (5 mL) at 60° C. for 18 hours. At this time, TLC (80% Hexanes/EtOAc) reveals no remaining starting material. Cool the reaction mixture to room temperature, and remove excess TFA under vacuum to give a greenish-brown oil. Add EtOAc (20 mL) and sat. aqueous NaHCO3 (20 mL), and stir the mixture until the entire solid dissolves. Separate the layers, and extract the aqueous layer with another 10 mL EtOAc. Dry the combined EtOAc extracts (Na2SO4), filter, and evaporate to give a brown oil. Purification by column chromatography affords the title product as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 1H, J=8.4 Hz), 6.0 (d, 1H, J=8.4 Hz), 4.56 (bs, 2H), 4.37 (q, 2H, J=6.8 and 7.2 Hz), 1.36 (t, 3H, J=7.2 and 6.8 Hz). Mass spec. (207.13, M+H).