Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[SH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][S:15][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:28]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Methyl 3-fluoro-4-nitrobenzoate (8.72 g, 43.8 mmol) was added to a suspension of 2-ethylhexyl 3-sulfanylpropanoate (10.5 g, 48.2 mmol) and potassium carbonate (9.08 g, 65.7 mmol) in DMF (50 mL) at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give the title compound (14.4 g, yield 83%).
Reaction SMILES: [C:1]([C:3]1([CH3:26])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])#[N:2].CCN(CC)CC.[NH2:34][OH:35].Cl.[CH3:37][O:38][C:39]([C:41]#[C:42][C:43]([O:45][CH3:46])=[O:44])=[O:40]>CCO>[NH2:2]/[C:1](=[N:34]\[O:35]/[C:42](/[C:43]([O:45][CH3:46])=[O:44])=[CH:41]/[C:39]([O:38][CH3:37])=[O:40])/[C:3]1([CH3:26])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C#N)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)/C=C(/O/N=C(\N)C1(C)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1)C(=O)OC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 1-benzyl 4-tert-butyl 2-cyano-2-methylpiperazine-1,4-dicarboxylate (C-41) in EtOH was added to a solution of Et3N (3.2 eq) and NH2OH HCl (3 eq) in EtOH. The mixture was stirred 2 hr at 40° C. After evaporation of the solvent, the residue was diluted with AcOEt, washed with water, dried over Na2SO4, filtered and concentrated. The residue was further dissolved in chloroform and dimethylacetylenedicarboxylate (1.5 eq) added to the stirred solution. Reaction was refluxed over night. The mixture was evaporated and the residue was purified by flash chromatography on silica gel (petroleum ether/AcOEt, 65:35) affording (C-42).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:54][CH2:53][CH2:52][CH2:51][N:48]2[CH2:47][CH2:46][N:45]([CH3:44])[CH2:50][CH2:49]2)=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (140 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 3-(4-methylpiperazino)-1-propaneamine (74 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 39%).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:2]=1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:29][C:25]1([CH3:30])[CH2:24][NH:23][CH2:28][CH2:27][N:26]1[C:12]([C:9]1[N:10]=[CH:11][N:7]([C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)[N:8]=1)=[O:14]
Reactant: Cc1cccc(-n2cnc(C(=O)O)n2)c1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-n2cnc(C(=O)N3CCNCC3(C)C)n2)c1

Procedure:
This intermediate was prepared from 1-m-tolyl-1H-[1,2,4]-triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[C:11](O)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15].Cl>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:11]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[O:21])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C[Mg]Cl)cc1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: Cl
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)Cc1ccc(F)cc1

Procedure:
4-Fluorobenzyl magnesium chloride (4.6 g, 25 mmol) in ether is added to phthalic acid (7.4 g, 50 mmol) in ether. The reaction mixture is stirred under reflux for 2 hours, is cooled with ice and is hydrolysed with HCl to yield 2-(4-fluorobenzylcarbonyl)benzoic acid.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH2:25][C:26]#[N:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH2:25][CH2:26][NH2:27])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.6 %

Procedure:
To a mixture of NaBH4 (6.0 g) in THF (100 ml) was added dropwise trifluoroacetic acid (18 ml) at 0° C. (ice bath). 4-Bromo-2-cyanomethylphenyl benzyl ether (10 g) was added and the mixture stirred at ambient temperature for 18 hours. The reaction was quenched with water (100 ml), the pH adjusted to 13 with 2N aqueous NaOH solution, and extracted with diethyl ether. The diethyl ether extracts were dried (MgSO4) and evaporated to give 2-(2-aminoethyl)-4-bromophenyl benzyl ether (11.0 g) as a yellow gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 3.00 g of 5-{4-(6-bromo-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 60) and 40 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.75 g of the title compound, melting at 204-205° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1C=CC=CC=1.O>[CH2:10]([NH:17][CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)CCCC(=O)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCCC(NCc2ccccc2)C1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
3,3-Dimethylcyclohexanone (3 g, 23.77 mmol) and benzylamine (2.73 mL, 24.96 mmol) were dissolved in benzene (20 mL) and stirred at reflux with continuous removal of H2O for 3 hours. The reaction mixture was allowed to cool to RT and the solvent was evaporated. The imine intermediate was dissolved in DCM (100 mL) and cooled to 0° C. Sodium triacetoxyborohydride (95%, 6.36 g, 28.53 mmol) and acetic acid (1.5 mL, 26.15 mmol) were added. After about 20 minutes the ice bath was removed, and the suspension stirred at RT overnight. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed once more with saturated aqueous NaHCO3, dried (Na2SO4), filtered and evaporated. The remaining yellow oil (5 g) was purified by SiO2 chromatography (300 g SiO2, DCM/(DCM:MeOH:NH4OH 60:10:1) 100 to 87% DCM) to give 1 g of racemic benzyl-(3,3-dimethyl-cyclohexyl)-amine as a light yellow oil (19% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[O:21]>>[OH:21][CH:20]([CH:9]1[C:8](=[O:11])[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:10]1)[C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C=O
Reactant: Cc1cccc2c1C(=O)CO2
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)C1Oc2cccc(C)c2C1=O

Procedure:
A solution of 4-methyl-2,3-dihydro-1-benzofuran-3-one (26c) (200 mg, 1.35 mmol) in ethyl glyoxylate 50% in toluene (0.40 mL, 2.02 mmol) was heated at 100° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/5 to 80/20) to provide ethyl 2-hydroxy-2-(4-methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl)acetate (26d) (200 mg, 0.8 mmol) which was dissolved in a mixture of cyclohexane (2 mL) and dichloromethane (0.5 mL) before adding silver oxide (560 mg, 2.4 mmol) and tert-butyl bromide (0.54 mL, 4.8 mmol). The mixture was stirred at room temperature for 60 hours, with addition of silver oxide and tert-butyl bromide every hour of working day until the reaction stopped evolution. The mixture was filtered over Celite®, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide ethyl 2-(tert-butoxy)-2-(4-methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl)acetate (26e) (73 mg, 0.238 mmol) which was dissolved in a mixture of dimethylformamide (1.5 mL) and tetrahydrofuran (0.2 mL) under argon atmosphere. This mixture was cooled at −78° C. and a 1.0 M solution of potassium t-butoxide in tetrahydrofuran (0.26 mL, 0.262 mmol) was added. After 1 hour stirring at −78° C., a solution of N-phenyl-bis(trifluoromethanesulfonimide) (98 mg, 0.274 mmol) in dimethylformamide (0.07 mL) and tetrahydrofuran (0.3 mL) was slowly added and the mixture was further stirred at the same temperature for 90 minutes. The reaction was quenched by addition of saturated sodium carbonate solution (5 mL) and the mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide ethyl 2-(tert-butoxy)-2-{4-methyl-3-[(trifluoromethane)sulfonyloxy]-1-benzofuran-2-yl}acetate (26f) (60 mg, 0.137 mmol, 17% over 3 steps).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+]>CN(C)C=O.O>[F:16][C:13]1[CH:14]=[CH:15][C:7]2[NH:6][C:3](=[O:4])[CH2:2][O:10][C:9](=[O:11])[C:8]=2[CH:12]=1
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COC(=O)c2cc(F)ccc2N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2.52 g(13.75 mmol) of bromoacetyl bromide was added for 10 min below 40° C. to the solution having 1.94 g(12.5 mmol) of 2-amino-5-fluorobenzoic acid dissolved in 4 ml of dimethyl formamide. The mixed solution was stirred for 30 min, and the solution having 1.12 g of sodium hydroxide dissolved in 28 ml of water was added. The mixture was slowly heated to 60° C. for 1 hr, then maintained at about 60° C. for 1 hr, and cooled to 5° C. Finally, a crystalline solid of 7-fluoro-4,1-benzooxazepine-2,5-(1H, 3H)-dione of melting point 186° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH2:16][CH2:17][CH:13]([N:12]([CH3:18])[CH3:11])[CH2:14]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CN(C)C1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(C#N)cc2Cl)C1

Procedure:
0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml (0.58 g, 5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF are combined with 231 mg (5.30 mmol) 55% sodium hydride dispersion at ambient temperature with stirring and under an argon atmosphere. After stirring at ambient temperature for 3.5 h the reaction mixture is poured into water and extracted with ethyl acetate after thorough mixing. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]=[S:5]1(=[O:29])[C:10]2[CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]2[CH2:26][CH2:27][CH2:28][CH:7]2[NH:6]1>C1COCC1>[O:4]=[S:5]1(=[O:29])[C:10]2[CH:11]=[C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([N:2]([CH3:3])[CH3:1])=[O:24])=[CH:20][CH:21]=3)[CH:13]=[CH:14][C:9]=2[N:8]2[CH2:26][CH2:27][CH2:28][CH:7]2[NH:6]1
Reactant: CNC
Reactant: O=C(O)Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1

Procedure:
The procedure is as in Step A of Example 3 but replacing the ammonia gas with 2M dimethylamine in THF and 3-{4-[5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl}propanoic acid by the compound obtained in Step B. Purification is carried out by chromatography on a silica column, eluting with a mixture of CH2Cl2/MeOH 99/1, followed by crystallisation from water.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:27]1[C:31]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:20]([N:27]1[C:31]([C:32]([OH:43])([C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][CH:10]=2)[CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Reactant: O=C(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2cncn2Cc2ccccc2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
9,9 g of p-tert-butylaminocarbonylphenyl bromide is dissolved in 200 ml of dry tetrahydrofuran and cooled to -70° C. To the solution is added dropwise n-butyl lithium (5,3 g) in hexane and the mixture is stirred for one hour. 1-benzyl-5-[4-(4-fluorophenyl)-1-oxobutyl]-1H-imidazole (10,4 g) in 200 ml of tetrahydrofuran is added to the mixture at -70° C. and the mixture is allowed to warm to room temperature and stirring is continued over night. Saturated ammonium chloride is added to the mixture and the solution is extracted with ethyl acetate. Ethyl acetate fractions are combined and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:10]1[C:11]2[C:6](=[CH:5][C:4]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1

Procedure:
A solution of 8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.17 g, 0.63 mmol) and NCS (0.10 g, 0.76 mmol) in THF (20 mL) were stirred under nitrogen at room temperature overnight according to Method C. The solution was concentrated onto Florosil and purified on a silica column (20% ethyl acetate-hexanes) to yield 0.16 g (84%) of the. title compound as a yellow solid. An analytical sample was further prepared by preparative reverse phase HPLC to yield a light yellow solid: mp 120–124° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.06 (2H, d, J=8.80 Hz), 7.34 (1H, d, J=8.91 Hz), 7.67 (1H, dd, J=1.69 Hz, J=15.48 Hz), 7.78 (2H, d, J=8.78 Hz), 8.01 (1H, d, J=1.54 Hz), 10.62 (1H, s); MS (ESI) m/z 301/303 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=2)[C:7]=1[Br:30].[CH3:32]C([O-])(C)C.[K+].CI.[H-].[Na+]>C1COCC1>[Br:30][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:16]3[N:17]([CH3:32])[C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:2])=[O:31]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.410 g, 0.853 mmol) in THF (20 mL) at 0° C. was added KOt-Bu (0.105 g, 0.938 mmol) followed by MeI (0.064 mL, 1.02 mmol). The reaction was warmed to rt and let stir for 1 h. It appeared by TLC and MS that all the starting material was gone; however, two polar acids (one N—Me and one N—H) had been generated due to hydrolysis in these basic conditions. After concentration, the residue was taken up in DMF (20 mL). Added NaH (0.075 g, 60% by wt., 1.88 mmol) followed by excess MeI to convert all intermediate to one acid (N—Me). After 1 h, the reaction mixture was concentrated and then diluted with EtOAc (200 mL) and 1 N HCl (20 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by preparatory plate chromatography (10% MeOH:CHCl3) to afford the product (0.232 g, 57%) as a yellowish-orange foamy solid, mp>73° C. (decomp.); 1H NMR (DMSO-d6) δ 0.73 (t, J=7.0 Hz, 3H), 1.11-1.20 (m, 4H), 1.50-1.58 (m, 2H), 2.66 (t, J=7.3 Hz, 2H), 3.58 (s, 3H), 4.93 (s, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H), 7.42-7.48 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.68 (dd, J=1.7, 8.7 Hz, 1H), 7.99 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 11.95-14.75 (bs, 1H); IR (neat) 3050, 2955, 2925, 2850, 1725, 1670, 1600, 1480, 1470, 1430, 1370, 1325, 1275, 1220, 1190, 1145, 1095, 1015, 980, 925, 895, 830, 800, 765, 735, 700, and 665 cm−1; mass spectrum [(+) ESI], m/z 480/482 (M+H)+;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])O[C:9](=[O:10])[C:2]=12.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[OH:16][CH2:15][CH2:14][CH2:13][N:12]1[C:7](=[O:11])[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10]
Reactant: NCCCO
Reactant: O=C1OC(=O)c2ncccc21
Solvent: ClC(Cl)Cl
Product: O=C1c2cccnc2C(=O)N1CCCO
Temperature: 155 °C
Yield: 70.1 %

Procedure:
To a suspension of 4.0 g (27 mmol) furo[3,4-b]pyridine-5,7-dione in 10 ml chloroform a solution of 2.03 g (27 mmol) of 3-aminopropanol in 7 ml chloroform was added and the mixture was heated to reflux for 30 minutes. Now the solvent was slowly evaporated and the mixture was gradually heated to 150-160° C. while the vacuum was maintained. After two hours the mixture was cooled to room temperature and the brownish crude product was purified by flash chromatography (silica gel, ethyl acetate/MeOH 15:1) to afford 3.9 g (70%) of the desired product as a white powder. 1H-NMR (CDCl3): 1.89-1.95 (m, 2H), 2.25 (s, br, 1H), 3.64-3.68 (m, 2H), 3.90-3.96 (m, 2H), 7.60-7.66 (m, 1H), 8.14-8.20 (m, 1H), 8.93-8.99 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])O.[K+]>C(#N)C>[ClH:10].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
A suspension of 1-acetylpiperazine (0.627 g), 2-chloro-4′-fluoroacetophenone (0.844 g), and potassium hydrogen carbonate (0.735 g) in acetonitrile (12 ml) was stirred at ambient temperature for 3 days. After removal of the solid by filtration, the filtrate was evaporated under reduced pressure to give a residue, which was chromatographed on silica gel (100 ml) eluting with 0%-5% methanol in dichloromethane. The objective compound of the free form was taken up into ethyl acetate (2 ml) and to the solution was added a solution of hydrogen chloride in ethyl acetate (4N, 2 ml). The resulting precipitate was collected by filtration, washed with diisopropyl ether, and dried in vacuo to give 1-acetyl-4-(4-fluorophenylcarbonylmethyl)-piperazine hydrochloride (1.47 g).
Reaction SMILES: [CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:18]S(C(F)(F)F)(=O)=O)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([CH:36]=[O:37])C.[CH3:38]O>>[CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:18][CH3:38])[O:10][C:9]1=[C:36]=[O:37])[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CN(C)C=O
Reactant: CCCN(C(C)C)[C@H]1COc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CCN(CC)CC
Product: CCCN(C(C)C)[C@@H]1Cc2c(OC)cccc2OC1=C=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman (4.0 g, 10.5 mmol), triethylamine (2.3 g, 23.1 mmol) and a mixture of DMF/MeOH (18 mL, 6:2) was mixed in a three necked round-bottom flask. The flask was evacuated followed by inlet of CO-gas (repeated two times). Finally 1,3-bis(diphenylphosphino)propane (0.l 1 g) and palladium(II)acetate (0.07 g) was added. The mixture was stirred at 70° C. for 17 hours. The reaction mixture was diluted with diethyl ether, washed with 2M NH3 and dried (MgSO4). Removal of solvent in vacuo gave a brown oily residue which was purified by flash chromatography (SiO2, CH2Cl2 /EtOAc; 10:1) to give the title compound in 82% yield (2.5 g).