Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[C:26]([OH:28])[C:25]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:23]=3[CH2:34][CH3:35])[C:12]=2[CH2:36][CH2:37][CH3:38])[CH:5]=1.[OH-:40].[Li+].CO.[O:44]1[CH2:49]COCC1>>[CH2:34]([C:23]1[CH:24]=[C:25]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:36][CH2:37][CH3:38])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[C:49]([OH:44])=[O:40])[CH3:35]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3nccs3)cc2CC)cccc1Oc1cccc(C(=O)OC)c1
Reactant: [OH-]
Reactant: C1COCCO1
Agent: [Li+]
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(-c3nccs3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 69 %

Procedure:
2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxyl-2-propylphenoxy}benzoic acid methyl ester (107 mg, 0.196 mmol) was dissolved in a 1:1 solution of methanol/dioxane (3 mL) and treated with 1 N lithium hydroxide solution (1 mL) at 60° C. for 2 h. The mixture was concentrated in vacuo and the residue diluted with water, washed twice with diethyl ether, and the aqueous layer acidified with 1 N hydrochloric acid. The resulting solution was extracted twice with methylene chloride and the combined organic layers dried (magnesium sulfate), filtered, and concentrated in vacuo. Trituration (hexane) of the residue provided 72 mg (69%) of the title compound as a tan powder. 1H NMR (CDCl3) δ 8.22 (dd, J=8, 2 Hz, 1H), 7.70 (d, J=4 Hz, 1H), 7.41 (dt, J=8, 2 Hz, 1H), 7.35 (s, 1H), 7.18 (m, 3H), 6.82 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.55 (s, 1H), 4.22 (t, J=6 Hz, 2H), 4.21 (t, J=6 Hz, 2H), 2.57 (m, 4H), 2.35 (quintet, J=6 Hz, 2H), 1.49 (hextet, J=8 Hz, 2H), 1.18 (t, J=7 Hz, 3H}, 0.86 (t, J=7 Hz, 3H); MS ES+ m/e 534 (p+1); IR (KBr, cm−1) 2957, 1695, 1599, 1457. Anal. Calcd for C30H31NO6S: C, 67.52; H, 5.B6; N, 2.62. Found: C, 67.44; H, 5.95; N, 2.55.
Reaction SMILES: C([CH2:4][NH:5][C:6]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:7]=1[C:8](O)=O)(O)=O.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].C(O[C:25](=[O:27])[CH3:26])(=O)C>>[C:25]([N:5]1[C:6]2[C:7](=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=2)[C:8]([O:18][C:16](=[O:19])[CH3:17])=[CH:4]1)(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNc1ccc(Br)cc1C(=O)O
Agent: [Na+]
Product: CC(=O)Oc1cn(C(C)=O)c2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2-(N-carboxymethylamino)-5-bromobenzoic acid (0.84 g, 3.4 mmol) and anhydrous sodium acetate (0.6 g, 7.3 mmol) were dissolved in 8 ml acetic anhydride. After stirred for 5 hours at 60° C., the reaction mixture was cooled down to room temperature. Sodium acetate was filtered off. The filtrate was evaporated, and the residue was dissolved in 100 ml ethyl acetate. 100 ml water and 20 ml saturated sodium bicarbonate were added to the solution, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 ml×2). The combined organic phases were washed with saturated sodium bicarbonate (100 ml×2), dried and evaporated to obtain a white solid (1-acetyl-5-bromo-3-acetoxyindole) (1.3 g, 25.4%).
Reaction SMILES: CS(O[CH2:6][CH:7]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.[H-].[Na+]>C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH:7]1[CH2:8][C:9]2([CH2:11][CH2:10]2)[O:12][CH2:6]1
Reactant: CS(=O)(=O)OCC(CC1(O)CC1)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1CCC(OC2COC3(CC3)C2)OC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
A mixture of 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (1.3 g, 4.63 mmol) and NaH (0.15 g, 6 mmol, Aldrich) in 20 mL of THF was stirred at rt for 4 hrs. The reaction mixture was quenched with 5 mL of methanol. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:10 (v/v) EtOAc/petroleum ether) to give the title compound as colorless oil (380 mg, 42%).
Reaction SMILES: O[CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[N:12]=2)[CH2:7][CH2:6][C:5]1=[O:16].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:15][O:14][C:11]1[N:12]=[C:13]2[C:8]([CH2:7][CH2:6][C:5](=[O:16])[N:4]2[CH2:3][CH:2]2[CH2:17][O:18]2)=[CH:9][CH:10]=1
Reactant: COc1ccc2c(n1)N(CC(O)CO)C(=O)CC2
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(n1)N(CC1CO1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
A solution of 1-(2,3-dihydroxypropyl)-7-(methyloxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2.325 g, 9.226 mmol) in DCM (40 ml) and triethylamine (1.915 ml, 13.839 mmol) at 0° C. under argon was treated with methanesulfonyl chloride (0.714 ml, 9.226 mmol) and stirred at 0° C. for 0.5 h. The reaction mixture was then treated with water (100 ml), extracted with DCM (3×100 ml). The organic extracts were dried (MgSO4), and evaporated. The residue was then dissolved in methanol (50 ml) and treated with potassium carbonate (6.366 g, 46.130 mmol) and stirred at rt for 15 min. The reaction mixture was then treated with water (100 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), evaporated and chromatographed (0-100% ethyl acetate:Hexane) to give the product as a yellow oil (428 mg, 20%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][CH:14]1[CH2:20][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH:17]([CH3:28])[N:16]([CH3:29])[CH2:15]1>CN(C)C=O>[CH2:21]([N:19]1[CH2:20][CH:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:15][N:16]([CH3:29])[CH:17]([CH3:28])[CH2:18]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CC1CN(Cc2ccccc2)CC(N)CN1C
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)CN1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (2.2 g) in N,N-dimethylformamide (40 ml), N,N'-carbonyldiimidazole (2.2 g) is added, and the mixture is heated at 60° C. for 3.5 hours. A solution of 6-amino-1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepine (3.0 g) in N,N-dimethylformamide (10 ml) is added to the mixture, and the mixture is stirred at 25° C. for 2 hours. The solvent is evaporated under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with 10% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution 10% methanol-acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.9 g) which is one isomer with lower polarity in two isomers produced in the above reaction, m.p. 203-205° C. (recrystallized from isopropyl alcohol).
Reaction SMILES: [CH3:1][O-].[Na+].[F:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:16][N:15]=1.C=O.[BH4-].[Na+]>CO.O.ClCCl>[F:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:1])=[CH:24][CH:23]=2)=[CH:16][N:15]=1
Reactant: C[O-]
Reactant: Nc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CNc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
Sodium methoxide (1M in methanol, 0.23 ml) was added to a solution of compound 5 (15.8 mg, 0.046 mmol) in methanol (5 ml) followed by the addition of paraformaldehyde (6.6 mg, 0.23 mmol). The reaction mixture was refluxed for 1.5 hour then cooled to 0° C. with an ice bath. Sodium borohydride (10.4 mg, 0.27 mmol) was added with caution. The mixture was refluxed again for 1 hour and cooled down. Dichloromethane and water was added. Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by PTLC (3% MeOH in DCM as developing solvent) to give product 6 (12 mg, Yield: 73%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.2 Hz), 7.76 (1H, d, d, J1=8.6 Hz, J2=2.4 Hz), 7.35 (2H, d, J=8.6 Hz), 6.92 (1H, d, J=16.4 Hz), 6.80 (1H, d, J=16.4 Hz), 6.76 (2H, d, J=8.6 Hz), 4.53 (2H, d, t, J1=47.6 Hz, J2=4.2 Hz), 4.49 (2H, t, J=4.8 Hz), 3.85 (3H, m), 3.70 (5H, m), 2.88 (3H, s). HRMS (EI) m/z calcd. for [C20H25FN2O3]+ 360.1849.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C@H:3]([CH2:7][OH:8])[CH:4]([CH3:6])[CH3:5].[CH3:10]I.[F:12][P-:13]([F:18])([F:17])([F:16])([F:15])[F:14].[H+]>ClCCl>[OH:8][CH2:7][CH:3]([N+:2]([CH3:10])([CH3:9])[CH3:1])[CH:4]([CH3:6])[CH3:5].[F:12][P-:13]([F:18])([F:17])([F:16])([F:15])[F:14]
Reactant: CC(C)[C@@H](CO)N(C)C
Reactant: CI
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: CC(C)C(CO)[N+](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
58.5 g (0.5 mol) valinol are dissolved in 115 g (2.5 mol) formic acid and cooled to 0° C. 1.2 mol formaldehyde are added to this mixture and heated until carbon dioxide formation is complete on the boiling water bath. The solution is acidified with hydrochloric acid and the solvents removed by vacuum. The residue is dissolved in 50 ml water, made basic with 25% sodium hydroxide solution and extracted with diethyl ether. The extracts are dried via sodium sulfate and the solvent removed under vacuum. Distillation (33 mbar/80° C.) yields 53.7 g (82%) N,N-dimethylvalinol as a colourless oil. 50 g (0.38 mol) N,N-dimethylvalinol are dissolved in 100 ml dichloromethane, mixed with 56.8 g (0.4 mol) methyl iodide and stirred at room temperature for 12 h. The solvent is removed under vacuum, the residue is dissolved in 200 ml water and mixed with ice cooling with 0.4 mol hexafluorophosphoric acid in an aqueous solution. The reaction mixture is washed repeatedly with water and the solvent removed under vacuum. The yield of (1-hydroxymethyl-2-methyl-propyl)-trimethylammonium-hexafluorophosphate is 107 g. The enantiomer excess in the product is >95%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:14].CO.O1CCCC1.[BH4-].[Na+]>CC(C)=O>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:14]
Reactant: COc1cc(C)c2c(c1C)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cc(C)c2c(c1C)C(O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 4,7-dimethyl-6-methoxy-1-indanone (7.0 g) in a mixed solvent of methanol (100 ml) and tetrahydrofuran (50 ml) was added sodium borohydride (1.2 g) at 0° C. and then the mixture was stirred at room temperature for 1 hour. Acetone (10 ml) was added and the solvent was distilled off under reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added and the organic layer was washed with water and saturated saline. The organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain 4,7-dimethyl-6-methoxy-1-indanol (7.0 g) (Compound A-14). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C.C(OCC)C>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][N:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CCCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Temperature: 25 °C

Procedure:
10g of (-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxy-phenoxymethyl)-piperidine hydrochloride in 250 ml 99.9% ethanol was mixed with 50 ml 1-bromopentane and 20 g potassium carbonate. The mixture was refluxed for 3 hours and was subsequently cooled to room temperature. 25 ml acetone and 25 ml diethylether was added to the solution. The precipitate was filtered off and the filtrate was evaporated in vacuo. 20 ml 4N NaOH was added to the residue, and the resulting mixture was extracted 3 times with diethyl ether. The combined ether phases were dried over potassium carbonate, filtered, the filtrate was acidified with conc. hydrochloric acid to pH 2, and the filtrate was evaporated in vacuo. The resulting oil was dissolved in acetone and crystals precipitated by addition of ether and after cooling at 4° C. over night. The title compound was filtered off and dried giving 10.1 g of the title compound. M.p. 153.6° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15](/[N:17]=[CH:18]\[N:19](C)C)=O)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C(O)(=O)C.O.[NH2:27]N>>[Br:1][C:2]1[S:3][C:4]([C:15]2[NH:17][CH:18]=[N:19][N:27]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: CN(C)/C=N\C(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(Cc2nc(Br)sc2-c2nnc[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottomed flask were placed 2-bromo-4-(4-chlorobenzyl)-N-[(1Z)-(dimethylamino)methylene]-1,3-thiazole-5-carboxamide and acetic acid (50 mL, 900 mmol). Hydrazine hydrate (490 uL, 10 mmol) was added and the mixture was stirred for 1 h at 50° C. The mixture was allowed to cool to rt, then was concentrated under reduced pressure to obtain 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole as a yellowish off-white crystalline solid. The crude material was used in the next step without further purification. LC/MS (FA) ES+ 357.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32]C(=O)OC(C)(C)C)=[CH:27][CH:26]=3)=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O.C(#N)C>C(Cl)Cl>[NH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[O:24][C:20]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:18])[CH3:19])(=[O:16])=[O:15])=[CH:10][CH:9]=4)[N:4]=3)=[N:21][N:22]=2)=[CH:26][CH:27]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)o3)n2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CN)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]carbamate (45 mg, 0.08172 mmol) in CH2Cl2 (1 mL) was treated with TFA (1 mL, 12.98 mmol) and stirred at room temperature for 1 h. The solution was concentrated under reduced pressure then azeotroped with methanol/ CH2Cl2 (×2), dissolved in CH2Cl2/MeOH and passed through a carbonate cartridge. The eluent was concentrated then crystallised from hot acetonitrile giving a yellow crystalline solid (18 mg, 41% yield); 1H NMR (400 MHz, DMSO) d 1.20 (d, 6H), 1.97 (br s, 2H), 3.47 (m, 1H), 3.85 (s, 2H), 7.63 (d, 2H), 7.89 (br s, 2H), 7.98 (d, 2H), 8.11 (d, 2H), 8.40 (d, 2H) and 9.06 (s, 1H) ppm; MS (ES+) 451.41
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].[K+].C1OCCOCCOCCOCCOCC[O:28]C1>O.CS(C)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:28][CH:3]([CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: OCCCCCCc1nc2ccccc2[nH]1
Reactant: Clc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(CCCCc1nc2ccccc2[nH]1)Oc1ccccn1
Temperature: 150 °C
Yield: 268.5 %

Procedure:
218 mg of the compound obtained in Example 16a, 115 mg of 2-chloropyridine, 200 mg of KOH and 50 mg of 18-crown-6-ether were added to 15 ml of DMSO and the mixture was heated to 150° C. for 8 hours. The reaction mixture was cooled, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 150 mg of the title compound (yield: 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:13])=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:5](=[O:7])[C:4]2[C:8]([F:13])=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:14](=[O:17])[CH2:15][CH3:16])[CH:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: CCC(=O)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1cc(F)c(C(=O)O)cc1N
Product: CCC(=O)Nc1cc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)c(F)cc1OC

Procedure:
Compound 79 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxy-6-fluorobenzoic acid, propionyl chloride and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 66%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].O>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH2:12][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, 1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (49a) (1.55 g, 8.8 mmol) was dissolved in anhydrous tetrahydrofuran (48 mL) and sodium hydride (60% in mineral oil, 0.42 g, 10.6 mmol) was added portionwise, maintaining the temperature between −5 and 0° C. After 30 minutes stirring at the same temperature, ethyl trifluoroacetate (1.5 mL, 10.6 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Water (10 mL) was added and tetrahydrofuran was removed in vacuo. The resulting aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide 1-(3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,4-trifluorobutane-1,3-dione (49b) (2.39 g, 8.8 mmol, 100%) which was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: COC(=O)/C=C/CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/CN=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To the solution of NaN3 (2.80 g, 43.01 mmol) in 100 ml of DMF at −20° C. was added methyl 4-bromocrotonate (5.00 ml, 85%, 36.10 mmol). After stirred at −20° C. for 30 min, the mixture was stirred at 0° C. for 4 h, evaporated, suspended with EtAc/Hexane (1:1), filtered, evaporated and chromatographic purification on SiO2 column eluted with EtAc/Hexane (1:25 to 1:10) to afford HRMS for 4.08 g (80%) of the title product. 1H NMR (CDCl3) 6.88 (m, 1H), 6.06 (ddd, 1H, J−=1.7, 3.4, 15.6 Hz), 3.97 (dd, 2H, J=1.2, 4.96 Hz), 3.73 (s, 3H); 13C NMR 166.23, 140.86, 123.49, 51.95, 51.36; ESI MS m/z+ 182.5 (M+Na+H2O); HRMS m/z+ (C5H7N3O2+H2O+Na) calcd 182.0542. found 182.0548.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(Cl)(Cl)Cl.[BH3-]C#N.[Na+]>Cl.CO>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reactant: C1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC(N2CCCC2)CC1(C)C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A solution of 4a (11.05 g, 38.1 mmol) and pyrrolidine (8.13 g, 0.114 mol) in 11.5 mL of 5N HCl in methanol (57.1 mmol) and 100 mL chloroform was stirred at ambient temperature overnight and the volatiles were removed in vacuo. The residue was dissolved in 100 mL methanol and 5N HCl methanol was added until the mixture became acidic (bromocresol green). To the solution was added NaCNBH3 (2.40 g, 38.7 mmol) and the reaction was maintained at pH 3-5 by the dropwise addition of 5N HCl in methanol. After stirring overnight the volatiles were removed in vacuo. The residue was diluted with ether and 1N NaOH. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by HPLC using 1% Et3N in 1:1 hexanes:EtOAc as the eluent provided 8.75 g of the oily product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH2:23][C:24]([O:26]CC)=[O:25])=[CH:18][CH2:17][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH2:17][CH2:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1=CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1=CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
To a solution of ethyl {6-[(3-phenoxybenzyl)oxy]-3,4-dihydronaphthalen-1-yl}acetate (0.622 g, 1.50 mmol) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) was added 2 M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr and further at 70° C. for 5 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) and recrystallized from ethyl acetate-hexane to give the title compound (0.198 g, yield 34%) as colorless needle crystals.