Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[CH2:12][OH:13])=[CH:6][C:5]=1[CH3:15].Br[CH2:17]Br>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:14])[CH2:12][O:13][CH2:17]2)=[CH:6][C:5]=1[CH3:15]
Reactant: BrCBr
Reactant: Cc1cc(NC(=O)CO)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N2COCC2=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 21.5 %

Procedure:
Sodium hydride (81 mg, 1.80 mmol) was added to a solution of N-(4-bromo-3-methyl-phenyl)-2-hydroxy-acetamide (200 mg, 0.819 mmol) in DMF (4.0 ml), and the mixture was stirred at room temperature for 50 minutes. Further, dibromomethane (0.114 ml, 1.64 mmol) was added to the reaction solution, and the mixture was heated with stirring at 110° C. for two hours. Cooling to room temperature and subsequent purification by silica gel column chromatography (hexane-ethyl acetate) gave 3-(4-bromo-3-methyl-phenyl)-oxazolidin-4-one (45 mg, 21%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][C:8]1([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]2[CH:17]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCBr
Reactant: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Product: COC(=O)C1(CCCCl)Sc2cc(C)ccc2OCC1=O

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (4.1 g) is treated with 1-bromo-3-chloropropane in the same manner as described in Reference Example 25 to give methyl 4-(3-chloropropyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (2.0 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([F:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:39](#[N:41])[CH3:40]>>[F:22][C:12]1[CH:11]=[C:10]([O:9][CH2:8][C:7]2[S:6][C:5]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:4][C:3]=2[CH2:2][N:41]2[CH2:24][CH2:25][CH:26]([C:29]([F:32])([F:31])[F:30])[CH2:40][CH2:39]2)[CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1
Reactant: CC#N
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CBr)cc2F)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CN3CCC(C(F)(F)F)CC3)cc2F)no1
Reaction time: 8 h

Procedure:
To a mixture of 136 mg of 3-{4-[4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 17 mL of acetonitrile was added 48.6 mg of 4-trifluoropiperidine hydrochloride and 70 mg of potassium carbonate. The resulting mixture was stirred overnight and then concentrated under reduced pressure. It was then taken into dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 98/methanol 2) to give 51.6 mg of 3-{2-fluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as a white solid.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16](/[CH:18]=[N:19]/[OH:20])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][O:23][C:24](=[O:31])[CH2:25][C:26](=[CH2:30])[C:27]([OH:29])=[O:28].Cl>C1COCC1>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([C:18]2[CH2:30][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:31])([C:27]([OH:29])=[O:28])[O:20][N:19]=2)[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Reactant: C=C(CC(=O)OC)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: COC(=O)CC1(C(=O)O)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 146 g) was added to a mixture of (E)-1-(5-(benzyloxy)-2-bromophenyl)-N-hydroxymethanimine (27.2 g), 4-methoxy-2-methylene-4-oxobutanoic acid (12.8 g), and THF (270 mL) at 0 C. The obtained mixture was stirred at 0 C for 1 hour and at room temperature overnight. To the reaction mixture, 1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with bline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then, the obtained residue was washed with hexane/diethyl ether to obtain the title compound (26.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:12])[O:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Yield: 106.5 %

Procedure:
A solution of 3'-chloro-4'-nitroacetophenone (3 g), ethylene glycol (9.3 g), and p-toluenesulfonic acid monohydrate (0.5 g) in toluene (30 ml) was refluxed for 6 hours. Water formed in the reaction was removed by means of Dean Stark apparatus. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated to give an oil of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (3.9 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccccc2)cc1F
Temperature: 110 °C
Yield: 155.2 %

Procedure:
A solution of 4-bromo-2-fluorobenzaldehyde (0.15 g, 0.74 mmol), tributyl(phenyl)stannane (0.27 mL, 0.81 mmol) and Pd(PPh3)4 (0.043 g, 0.037 mmol) in PhCH3 (2.5 mL) was heated in a sealed reaction tube to 110° C. for 12 h. Additional tributyl(phenyl)stannane (0.20 mL, 0.61 mmol) and Pd(PPh3)4 (0.043 g, 0.037 mmol) were added and the solution was further heated to 110° C. for 2 h. The solvent was removed in vacuo. The residue was purified via column chromatography (SiO2, 5:1 hexanes/EtOAc) to provide 0.23 g (>100% yield) of 3-fluorobiphenyl-4-carbaldehyde, which was used without further purification: MS (EI) for C13H9OF: 201 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:12])[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of methanesulphonyl chloride (23.7 ml) in dry dichloromethane (25 ml.) was added dropwise to a solution of hex-5-yn-1-ol (Lancaster Synthesis, 25 g) and triethylamine (47.3 ml) in dichloromethane (300 ml), stirred under a nitrogen atmosphere at -70°. The resulting mixture was allowed to warm to room temperature over 16 hours. The mixture was then washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. Hex-5-ynyl methanesulphonate was obtained as an oil (43.6 g) and was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]2[CH2:11][C:12](=[O:14])[O:17][C:16](=[O:18])[CH2:15]2)=[CH:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)CC(CCc1ccc(O)cc1)CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CCC2CC(=O)OC(=O)C2)cc1

Procedure:
A solution of 3-[2-(4-hydroxyphenyl)ethyl]glutaric acid (600 mg) in acetic anhydride (15 ml) is heated in a bath at 120° C. for 2.0 hours. It is evaporated in vacuo and the residue is crystallized from dichloromethane-hexane to afford 495 mg of 3-[2-[4-(acetyloxy)phenyl]ethyl]glutaric anhydride, melting point 97°-99° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: CCc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(CC)cc2C1=O
Yield: 50 %

Procedure:
A solution of 11.8 g of 6-ethyl-1-indanone, 15.4 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 7.92 g (50%) of (RS)-2-(2-buten-1-yl)-6-ethyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.O>[CH3:39][C:38]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)=[O:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(Tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.0 g) was dissolved in the solvent described in Table 1 to form a solution and the solution was cooled to 0° C. Triethylamine (1.02 g) was then added followed by 4-dimethylaminopyridine (DMAP) (0.02 g). After the reaction mixture was stirred for 10 minutes at the same temperature, acetic anhydride (0.83 g) was added to the solution. The reaction was monitored by Thin Layer Chromatography (TLC) (petroleum ether/ethyl acetate=10/1 or 5/1) until the reaction was completed. After the reaction was completed, cold water was added to the reaction mixture and the mixture was stirred for 15 minutes. It was then cooled to −5° C. and further stirred for 3 hours before collecting the crystal as prasugrel free base. Solid precipitate was collected. The yield of prasugrel was calculated and the results were shown in Table 1.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=O)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=O)C.[CH3:27][NH:28][NH2:29].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:20]([C:6]12[C:4](=[O:3])[N:28]([CH3:27])[N:29]=[C:11]1[CH2:10][CH2:9][NH:8][CH2:7]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNN
Reactant: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1N=C2CCNCC2(Cc2ccccc2)C1=O
Temperature: 65 °C
Reaction time: 7.5 h
Yield: 84.8 %

Procedure:
To a solution of 3-benzyl-4-oxo-piperidine1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1935.97 g, 5.36 mol) in toluene (9700 mL) was added methylhydrazine (299.2 mL, 5.63 mol), followed by acetic acid (325 mL, 5.68 mol) slowly at about 8° C. The reaction mixture was heated slowly to about 65° C. and stirred for about 7.5 hours. After cooling to room temperature, the organic layer was washed with 10% sodium bicarbonate, water and saturated NaCl solution and concentrated in vacuo to a low volume. The reaction was repeated at same scale twice. The concentrated product solutions from the three reactions were combined and mixed with IPE (50 L), cooled to about 0° C., HCl gas was introduced repeatedly and stirred at room temperature overnight until the deprotection was complete. The mixture was concentrated in vacuo to about half of the original volume, methylene chloride (24 L) was added, followed by NH4OH (22 L). The mixture was then extracted with methylene chloride and concentrated to a low volume (6 to 7 L). Hexane (20 L) was added and the mixture was cooled to about 15-20° C. The free base product was collected as crystals and dried under vacuum (2985 g total, yield 84.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)F
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(F)F
Yield: 62.2 %

Procedure:
Using the procedure of Step F of Example 9, 4.1 g of the acid of Step C and 4.5 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain 4.7 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propynyl]-cyclopropane-carboxylate after elution with a 6-4 mixture of petroleum ether (B. Pt. 40°-70° C.)-isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]#[N:17])[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18]C#N.O>CO>[NH2:17][CH2:16][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12][C:11]([CH3:18])([OH:15])[CH2:10]1
Reactant: CC#N
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC(=O)C1
Solvent: O
Solvent: CO
Product: CC1(O)CCCC(CN)(c2ccc(Cl)c(Cl)c2)C1
Yield: 81 %

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-3-oxo-cyclohexanecarbonitrile (1.0 g, 3.7 mmol) according to General Procedure Y, followed by General Procedure E (Scheme 31). The crude product was dissolved in MeOH (4 ML) and subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give (±) 3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.57 g, 81%).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH2:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:18][CH:19]=[CH2:20])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCOCCCCCl
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(O)ccc1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOCCCCOc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
2-Acetyl-7-hydroxyfluorene 22.4 g, allyl(4-chlorobutyl) ether 18 g and potassium carbonate 20 g were added to dimethylformamide 150 ml and stirred at 90° C. for 8 hours. The reaction mixture was poured into 6N hydrochloric acid 300 ml to obtain a solid matter. The solid matter was filtered and dried, and then it was recrystallized from ethanol to obtain 22 g of 2-acetyl-7-(allyloxybutyloxy)fluorene. The melting point was 77° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:35])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])CCC>O1CCCC1>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH:6][C:26]1[C:25](=[O:35])[C:24](=[O:23])[C:27]=1[NH:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31]
Reactant: NCc1c(Cl)cccc1Cl
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2c(Cl)cccc2Cl)c(=O)c1=O
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To 2,6-dichlorobenzylamine hydrochloride of Example 4, Step 2 (1.06 g 5.0 mmol) in tetrahydrofuran (10 mL) was added triethyl amine (0.505 g, 5.0 mmol) followed by 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1.20 g, 5.0 mmol, Example 3) and stirring was continued at room temperature for approximately 16 hours. The reaction mixture was freed of solvent and the residue was triturated successively with water and with diethyl ether, and then dried. The resulting light yellow solid was recrystallized from acetonitrile three times to provide 0.755 g (44%) of the title compound as a white solid: mp 239°-241° C. (dec); 1H NMR (DMSO-d6): δ7.57 (m, 1H), 7.55 (m, 1H), 7.52 (br m, 1H),m 7.43 (m, 1H), 7.30 (s, br, 1H), 5.07 (d, 2H), 1.65 (q, 2H), 1.28 (s, 6H), 0.80 (t, 3H) ppm. IR (KBr): 3250, 1785, 1660 cm-1 ; MS (m/z) 340/342/344 (M+). HPLC indicates a major component (99.7%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][S:9][C:8]=2[CH:15]=1)([O-])=O.[NH2:16]C1C=C2C(C(C(N(C(OC(C)(C)C)=O)C)=O)=CN2C(OC(C)(C)C)=O)=CC=1>>[NH2:16][C:5]1[CH:4]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12]([NH2:14])=[O:13])[C:7]=2[CH:6]=1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1cn(C(=O)OC(C)(C)C)c2cc(N)ccc12
Reactant: NC(=O)c1csc2cc([N+](=O)[O-])ccc12
Product: NC(=O)c1csc2ccc(N)cc12

Procedure:
Obtained as a mixture from the reaction of a mixture of 6-nitro-benzo[b]thiophene-3-carboxylic acid-amide and 5-nitro-benzo[b]thiophene-3-carboxylic acid-amide (Example IXXX (9)). The crude product is further reacted directly in Example XI (42).
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].C([O:9][C:10](=O)[C:11]#[CH:12])C.[OH-].[K+]>>[CH2:3]([C:2]1[NH:6][C:10](=[O:9])[CH:11]=[CH:12][N:5]=1)[CH3:4]
Reactant: C#CC(=O)OCC
Reactant: CCC(=N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCc1nccc(=O)[nH]1
Yield: 22.6 %

Procedure:
To a hot (60° C.) solution of propionamidine hydrochloride prepared in step 2 (54.3 g, 0.5 mol) and propynoic acid ethyl ester (53.9 g, 0.55 mol) in absolute alcohol (1 L) was added dropwise a solution of KOH (70 g, 80%, 1 mol) in absolute alcohol (300 mL) during 3 hours. The temperature was kept between 60° C. and 70° C. during the addition. The solvent was removed in vacuo and the residue was dissolved in water. The aqueous solution was acidified to pH 5 with HCl (6 M), extracted with ethyl acetate for at least 15 times. The organic layer was dried over Na2SO4 and then filtered. The filtrate was evaporated under reduced pressure and the residue was recrystallized with acetonitrile to afford 2-ethyl-3H-pyrimidin-4-one as light yellow crystals (14 g, 23%).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[Si](C)(C)[CH3:16]>CCOCC>[O:13]=[C:11]([CH3:16])[CH2:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Product: CC(=O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of indole-N-acetic acid (KNK, 10 g, 57 mmol) in dry ether (150 mL) was added dropwise at 0° C. a solution of MeLi (75 mL, 1.4M in ether as LiBr complex). The reaction mixture was then stirred at r.t. for 2 hrs. Chlorotrimethylsilane (70 mL, 0.57 mol) was added dropwise at 0° C. Then the cooling bath was removed and 1N HCl (70 mL) was added at r.t. The aqueous portion was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatography usine 30% ethyl acetate in hexanes gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1.CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1CO
Temperature: 80 °C
Yield: 114.6 %

Procedure:
To a solution of 2-methyl-5-nitrobenzoic acid (3.0 g, 16.6 mmol, Acros) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0 M borane-tetrahydrofuran complex (33.1 ml, 33.1 mmol, Aldrich). The solution was heated to 80° C. for 1.5 h. To the solution at ambient temperature was slowly added methanol (20 ml) and then heated to 80° C. for 30 min. The solvent was removed in vacuo to leave an oil. The residue was dissolved in methanol (approximately 30 ml) and the solvent removed in vacuo to give (2-methyl-5-nitrophenyl)methanol as a yellow solid (3.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=550.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19]CC3C=CC(OC)=CC=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[N:34]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Reactant: Fc1cccc(CCl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Temperature: 45 °C
Yield: 53 %

Procedure:
To a solution of Intermediate 3 (250 mg, 0.81 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloromethyl-6-fluoro-pyridine from Step A (118 mg, 0.81 mmol), potassium carbonate (224 mg, 1.62 mmol) and 18-crown-6 (40 mg). The slurry was heated at 45° C. for eighteen hours. After cooling the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white solid. (180 mg, 53% yield). MS (M+H): 418