Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCc2cc(C)ccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)c(COc2ccc(C(=O)CCC(=O)O)cc2)c1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(4-(2,5-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step B, 2.62 g, 7.7 mmol) in abs ethanol (30 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred for 3 hours and then acidified with 1M HCl. The occuring white precipitate was filtered, washed with water and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].Cl>C1COCC1.CO>[F:3][C:4]1[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: COCCOc1ncc(C(=O)OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ncc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A 5M sodium hydroxide aqueous solution (2 ml) was added to a THF/MeOH (2 ml/2 ml) solution containing methyl 5-fluoro-6-(2-methoxyethoxy)nicotinate (264 mg) obtained in the 2nd step, followed by stirring at room temperature for 1 hour. Next, 6M hydrochloric acid (2 ml) was added to the reaction solution at 5° C. or less so as to acidify the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a white solid of 5-fluoro-6-(2-methoxyethoxy)nicotinic acid (197 mg) was thus obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)(=O)C>CN(C)C=O>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Ethyl hydroxyacetate (600 mg, 5.76 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium hydride (55%; 277 mg, 0.447 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 30 minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (1.46 mL, 6.34 mmol) was added, and the mixture was stirred at room temperature for 6.5 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water (×3) and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1, v/v) to give the title compound (842 mg; yield, 53%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[N:13]=[C:6]2[C:5]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[CH2:2][CH3:3].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[S:14]([C:12]1[N:13]=[C:6]2[N:7]([C:8]([CH3:10])=[N:9][C:4]([CH2:1][CH2:2][CH3:3])=[C:5]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[N:11]=1)(=[O:15])=[O:16]
Reactant: CCCc1nc(C)n2nc(S(=O)(=O)Cl)nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CNC
Product: CCCc1nc(C)n2nc(S(=O)(=O)N(C)C)nc2c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
Formula (XII): R1 =n-propyl, R2 =methyl, X=N, Y=C--SO2N(CH3)2X Y=double bond, ##STR122## 8 g of {7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2-yl}sulphonyl chloride, prepared in Example 45, are stirred with 40 ml of a 40% aqueous solution of dimethylamine for one hour at 50° C. The mixture is then extracted with chloroform, and the organic phase is dried over magnesium sulphate and then concentrated under vacuum to give 5.5 g of N,N-dimethyl-{7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2-yl}sulphonamide in the form of crystals of melting point 158° C. The following examples were prepared according to the same procedure:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[C:9]2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[O-:21][Mn](=O)(=O)=O.[K+].OO>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:21])=[O:15])=[C:9]2[CH3:16])=[C:4]([C:17]([F:20])([F:18])[F:19])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C=O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Yield: 62 %

Procedure:
To a solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (1.5 g, 5.3 mmol) in acetone (150 mL) was added a 0.3 M solution of KMnO4 (150 mL). The reaction mixture was stirred 3h at room temperature and then was charged with 10% H2O2 (5 mL). After 15 minutes the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove acetone. The remaining aqueous suspension was acidified with acetic acid. The precipitates were recovered by filtration and dried under high vacuum to afford 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.99 g, 62%) as a faintly yellow powder; 1H NMR (CDCl3): δ 7.56 (dd, J=8, 3 Hz, 1H), 7.41 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.42 (s, 1H), 2.21 (s, 3H), 1.90 (s, 3H); MS (ESI) m/z 302 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10])[CH3:2].[Br:12]Br>>[Br:12][CH2:10][C:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:11]
Reactant: BrBr
Reactant: CCc1ccncc1C(C)=O
Product: CCc1ccncc1C(=O)CBr
Yield: 85.4 %

Procedure:
By the reaction in the same manner as in Example 53-ii) using 1-(4-ethylpyridin-3-yl)ethanone (1.68 g) and bromine (1.60 g), the title compound (1.95 g) was obtained as a pale-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:22]3[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(N2CCC(N3CCNC(=O)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 72.5 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (Example 57, step B) (1.00 g, 4.00 mmol) and 2-piperazinone (0.801 g, 8.00 mmol) were dissolved in 50 mL of toluene and 25 mL of acetonitrile with stirring. TEA (1.40 mL, 9.97 mmol) and HOAc (0.34 mL, 5.9 mmol) were added via syringe. Sodium triacetoxyborohydride (2.12 g, 10.0 mmol) was added in four equal portions over 1 h. The reaction was allowed to stir overnight and quenched by the addition of approximately 50 mL of 1N NaOH solution and 50 mL of MeOH. The mixture was stirred for 10 min and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.970 g (73%) of the title compound of step A. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=9.5 Hz, 1H), 7.68 (br. s., 1H), 6.55 (dd, J=9.5, 2.4 Hz, 1H), 6.46 (d, J=2.56 Hz, 1H), 4.07-3.94 (m, 2H), 3.86 (s, 3H), 3.07 (br. s., 2H), 3.00 (s, 2H), 2.97-2.86 (m, 2H), 2.66-2.37 (m, 3H), 1.87-1.75 (m, 2H), 1.48-1.32 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1)(=[O:3])C.FCCN1CC(NC2C=CC(NC3N=[C:59](NC4C=C(NC(=O)C=C)C=CC=4)[C:58]([C:73](F)(F)F)=[CH:57]N=3)=C(OC)C=2)C1.FC(F)(F)C(O)=[O:82]>O1CCOCC1>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([C:34]([F:35])([F:37])[F:36])=[CH:18][N:17]=[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][CH:6]4[CH2:7][N:4]([C:1]([O:3][C:58]([CH3:73])([CH3:59])[CH3:57])=[O:82])[CH2:5]4)=[CH:10][C:11]=3[O:38][CH3:39])[N:21]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(C(C)=O)C4)cc3OC)ncc2C(F)(F)F)c1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(CCF)C4)cc3OC)ncc2C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3OC)ncc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 2, a mixture of intermediate 1 of Scheme 2 (16 mg) and intermediate 1 of Scheme 1 (tert-butyl 3-(4-amino-3-methoxyphenylamino)azetidine-1-carboxylate, 20 mg) in dioxane (1.0 mL) with catalytic trifluoroacetic acid was stirred overnight at 50° C. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier) to give the title compound (10 mg) as a TFA salt. 1H-NMR (DMSO-d6, 400 MHz) δ 10.1 (s, 1H), 8.4 (br, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.62 (br, 1H), 7.43 (br, 1H), 7.23-7.26 (m, 2H), 6.25 (dd, J=4, 10 Hz, 1H), 6.10-6.14 (m, 1H), 5.72 (d, J=10 Hz, 1H), 5.72 (d, J=10 Hz, 1H), 3.67-4.03 (m, 5H), 3.52-3.55 (m, 2H), 1.35 (s, 9H); calculated mass for C29H32F3N7O4: 599.3. found: 600.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH2:20][NH2:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:21][CH2:20][CH2:19][NH2:22])[N:6]=1)[CH:2]=[CH2:3]
Reactant: NCCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCN)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 230 mg (0.87 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 899 mg (14.96 mmol) of ethylenediamine was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 200 mg (yield: 79.9%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1O
Product: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In one embodiment, the compounds can be prepared as shown in Scheme II. A dihydroxy benzoic acid methyl ester is reacted with benzyl chloride, to produce a Bis-benzyloxy benzoic acid methyl ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl to produce a phenyl-benzamide (3). The phenyl-benzamide (3) is then reacted with hydrazine to give a triazol (4). The hydroxy groups can then be unprotecxted in the presence of palladium on charcoal to give the final product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]([CH2:17][C:18]([F:23])([F:22])[C:19]([NH2:21])=[O:20])(O)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:24][CH3:25])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:17][C:18]([F:23])([F:22])[C:19](=[O:20])[NH:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:24][CH3:25])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(O)(CC(F)(F)C(N)=O)c1cc(Br)cnc1O2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: COc1ccc2c(c1)C1(CC(F)(F)C(=O)N1)c1cc(Br)cnc1O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-(3-bromo-5-hydroxy-7-methoxy-5H-chromeno[2,3-b]pyridin-5-yl)-2,2-difluoropropanamide (0.120 g, 0.289 mmol) was added to a saturated solution of ammonium acetate (2.228 g, 28.9 mmol) in 2-propanol (20 mL) and the mixture was heated to reflux. After 2.5 hours the reaction was allowed to cool to rt and the 2-propanol was removed in vacuo. The derived residue was partitioned between CH2Cl2 (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×25 mL) and EtOAc (3×25 mL). The combined organic layers were washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, and concentrated. The product was precipitated from 1:1 chloroform and diethyl ether to afford 3-bromo-4′,4′-difluoro-7-methoxyspiro[chromeno[2,3-b]pyridine-5,2′-pyrrolidin]-5′-one as a gold solid. MS m/z=397.1 [M+H].
Reaction SMILES: [C:1]1([C:7]2([CH2:13][C:14]3[CH:18]=[CH:17][O:16][CH:15]=3)SCCCS2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:20].O>Cl[Hg]Cl>[O:16]1[CH:17]=[CH:18][C:14]([CH2:13][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])=[CH:15]1
Reactant: CO
Reactant: c1ccc(C2(Cc3ccoc3)SCCCS2)cc1
Agent: Cl[Hg]Cl
Solvent: O
Product: O=C(Cc1ccoc1)c1ccccc1

Procedure:
3-(2-Phenyl-[1,3]dithian-2-ylmethyl)-furan (11.5 g, 41 mmol) was suspended in 9:1 methanol/water (v/v) (150 mL) with slight heating. A solution of HgCl2 (22.3 g, 82 mmol) in methanol/water (50 mL) and solid HgO (8.0 g, 36.9 mmol) was added, and the mixture was heated at reflux under a nitrogen atmosphere for 6-7 h. The reaction mixture was filtered through celite to remove solids, and then concentrated. The resulting aqueous mixture was extracted with ethyl acetate, the combined organic extracts were washed with water, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography using 2% ethyl acetate in hexane as eluent. Yield: 5.7 g, 75%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.[BH4-].[Na+]>CCO>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:18][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CN2CCC1CC2
Reactant: COc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(NC2CN3CCC2CC3)c1
Yield: 44.8 %

Procedure:
(Method 2A) A solution of 1-azabicyclo[2.2.2]octan-3-one (8.1 g, 50 mmol), m-anisidine (6.2 g, 50.0 mmol) and 4Å molecular sieves in 50 mL of EtOH was stirred at room temperature overnight. NaBH4 pellets were added until the reaction was judged complete by TLC, at which point most of the EtOH was evaporated in vacuo and the residue was partitioned between 3N NaOH and EtOAc. The aqueous layer was extracted with a second portion of EtOAc. The organic layers were combined and washed with water and then brine and then dried over NaSO4. The solution was filtered and the solvent was evaporated in vacuo. The residue was dissolved in 2-PrOH and treated with 1.5 g of fumaric acid. The product was collected and recrystallized from 2-PrOH to give N-(3-methoxyphenyl)-1-azabicyclo[2.2.2]octan-3-amine (5.2 g, 30%) as an intermediate, an off-white solid. MH+=233.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([O-:7])=[O:6].[CH2:12](N(CC)CC)C.[CH:19]1(Br)[CH2:22]C[CH2:20]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[CH:1]1([S:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([O:7][CH3:12])=[O:6])[CH2:22][CH2:19][CH2:20]1
Reactant: BrC1CCC1
Reactant: CSc1ccccc1C(=O)[O-]
Reactant: CCN(CC)CC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.6 %

Procedure:
To methylthiosalicylate (3.92 mL, 28.5 mmol) in DMF at 0° C. was added triethylamine (3.97 mL, 28.5 mmol) then cyclobutyl bromide (5.00 g, 37.0 mmol). The ice bath was removed and the reaction was stirred at rt for 1 h then heated to 50° C. overnight. After cooling to rt, diethyl ether was added and the mixture was filtered. The filtrate was diluted with ethyl acetate, then washed with water (6×) and brine (1×). The organic layer was dried (MgSO4), filtered and concentrated to provide a yellow oil. The yellow oil was dissolved in CH2Cl2 (143 mL) and MCPBA (˜75%, 19.7 g, ca. 85.5 mmol) was added. The reaction was stirred for 2.5 h, then was cooled to 0° C. 1 N NaOH was added, and the reaction was stirred for 5 min. The layers were separated, and the organic layer was washed with 1 N NaOH (2×). The aqueous layer was back-extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to provide 2A as a clear oil (7.20 g). LC-MS: 255.01 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:26]2[CH2:27][CH2:28][CH2:29][CH:25]2[CH3:24])=[O:21])=[CH:22][CH:23]=1
Reactant: CC1CCCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCC2C)cn1
Yield: 99 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using 2-methyl-pyrrolidine instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 99%) which was obtained as a colourless. MS: m/e=378.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1ccc2ccc(OCCCCBr)cc2[nH]1
Yield: 41.4 %

Procedure:
A mixture of intermediate 14 (193 mg, 1.2 mmol), 1,4-dibromobutane (0.43 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers was washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(4-bromobutoxy)quinolin-2(1H)-one (intermediate 15) (147 mg, 41%) as a yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].[OH-].[NH4+:34]>O>[CH2:29]([O:28][C:26]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([NH2:34])[N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)Cl
Reactant: [NH4+]
Reactant: CN1Cc2c(N)cccc2C(c2ccccc2)C1
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCOC(=O)c1cccc2c1C(N)N(C)CC2c1ccccc1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
A solution of 2.4 g (0.01 mole) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline and 100 ml of anhydrous benzene is admixed with a solution of 1.4 g (0.012 mole) of butyl chloroformate and 10 ml of anhydrous benzene and the reaction mixture is heated to boiling for 2 hours. After cooling the mixture is diluted with 50 ml of icecold water, the pH is adjusted to 9 by adding a concentrated ammonium hydroxide solution, the benzene phase is separated and extracted twice with 20 ml of benzene each, dried over anhydrous sodium sulfate and evaporated in vacuo. Thus 3.6 g of an orange oil are obtained. The product is recrystallized twice from ethanol to give 1.8 g of the title compound, yield 52.9%. Mp: 106° C. (white powder)
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCCc2ccccc21
Product: CC(=O)NC1CCCc2ccccc21

Procedure:
1,2,3,4-Tetrahydro-1-naphthylamine is stirred with acetic anhydride to afford N-(1,2,3,4-tetrahydro-1-naphthyl)-acetamide, which is oxidized to N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide by the method of Example 1.
Reaction SMILES: C1(CN(C2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)CCC2C=CC(O)=CC=2)CC1.Cl.ClCCN1CCCCC1.[CH:45]1([CH2:48][N:49]([C:67]2[CH:72]=[C:71]([O:73]C)[CH:70]=[CH:69][C:68]=2[CH:75]2[CH2:84][CH2:83][C:82]3[C:77](=[CH:78][CH:79]=[C:80]([O:85]C)[CH:81]=3)[CH2:76]2)[CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)=[CH:54][CH:53]=2)[CH2:47][CH2:46]1>>[CH:45]1([CH2:48][N:49]([CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)=[CH:54][CH:53]=2)[C:67]2[CH:72]=[C:71]([OH:73])[CH:70]=[CH:69][C:68]=2[CH:75]2[CH2:84][CH2:83][C:82]3[CH:81]=[C:80]([OH:85])[CH:79]=[CH:78][C:77]=3[CH2:76]2)[CH2:47][CH2:46]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(OCCN3CCCCC3)cc1)CC1CC1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O)cc1)CC1CC1)C2
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N(CCc1ccc(OCCN3CCCCC3)cc1)CC1CC1)C2
Yield: 47.6 %

Procedure:
Synthesized from 4-{2-{cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, cyclopropylmethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{2-[4-(2-piperidin-1-ylethoxy)phenyl]ethyl}amine (351 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (159 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:6]CO)[CH2:3][CH2:4]O.S(Cl)([Cl:11])=O.[CH2:13]([Cl:15])Cl>>[ClH:11].[Cl:11][CH2:4][CH2:3][NH+:2]([CH3:6])[CH2:1][CH2:13][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)CCO
Reactant: ClCCl
Product: C[NH+](CCCl)CCCl
Product: Cl
Temperature: 0 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
A solution of N-methyldiethanolamine (3 g, 25 mmol) in CH2Cl2 (5 mL) was slowly added dropwise to thionyl chloride (10 mL) in ice-water bath, then stirred at r. t. for 2 days. After evaporated, the residue was dispersed with CH3 CN/Et2O, then was filtered to give N,N-bis(2-chloroethyl)methyl ammonium hydrochloride (4.1 g, 85%).