Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=CC=1.C[O:22]C1C=C(C=CC=1)C(O)C1OC2C=CC=CC=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[O:22][C:12]2[CH:13]=[CH:14][CH:15]=[CH:10][C:11]=2[CH:16]=1
Reactant: COc1cccc(C(O)c2cc3ccccc3o2)c1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Product: COc1cccc(C(Cl)c2cc3ccccc3o2)c1

Procedure:
The compound 12 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:38])[F:39])=[CH:33][CH:32]=4)(=[O:36])=[O:35])=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 298 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 4-trifluoromethyl benzene sulfonyl chloride. The compound of example 298 was used directly without isolation, for the preparation of compound of example 299.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH2:16][OH:17])[C:13]([OH:15])=O)(=[O:10])=[O:9].[F:18][C:19]([F:33])([F:32])[C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH2:16][OH:17])[C:13](=[O:15])[N:29]1[CH2:30][CH2:31][N:26]([C:21]2[C:20]([C:19]([F:33])([F:18])[F:32])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:28]1)(=[O:9])=[O:10]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1Cl
Product: O=C([C@H](CO)NS(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, (S)-2-(2-chloro-benzenesulfonylamino)-3-hydroxy-propionic acid was reacted with 1-[3-(trifluoromethyl)pyrid-2-yl]-piperazine to give 2-chloro-N-{(S)-1-hydroxymethyl-2-oxo-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-ethyl}-benzenesulfonamide as a colorless foam. MS: 493.0 ([M+H]+)
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1CCCCC1.C(OCC)C>[CH2:13]([C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[C:9](/[C:10](=[O:12])[CH3:11])\[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCCCCCc1ccc(/C=C(/C(C)=O)C(=O)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
Benzoylacetone (0.65g, 0.004 moles), parahexylbenzaldehyde (0.76g, 0.004 moles) and piperidine (3 drops) were stirred in ethyl ether (10ml) for 20 hrs. An additional 200mg benzoylacetone was added and the solution stirred for 48 hrs. The solution was concentrated to an oil with a gentle stream of Nitrogen. The product was purified by silica gel chromatography. The structure assignment was supported by NMR, infrared and uv spectra and elemental analysis (334.5).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH2:14])[CH3:8].[C:16]([C@H:19](OS(C)(=O)=O)[CH2:20][CH3:21])(=[O:18])[NH2:17]>C(#N)C>[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH:14][C@@H:19]([C:16](=[O:18])[NH2:17])[CH2:20][CH3:21])[CH3:8]
Reactant: CCOC(=O)CCCN
Reactant: CC[C@@H](OS(C)(=O)=O)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCCN[C@H](CC)C(N)=O
Temperature: 60 °C

Procedure:
A mixture of powdered caesium carbonate (9.0 g, 27.4 mmol, 5 equiv.), ethyl-4-aminobutyrate (IVb) (1.85 g, 11.0 mmol, 2 equiv.) and methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) (1.0 g, 5.5 mmol, 1 equiv.) in acetonitrile (20 ml, 20 vol.) is heated to 60° C. for 16 hours. The mixture is then filtered and the cake rinsed with acetonitrile (50 ml). Combined filtrates are concentrated to dryness under reducd pressure. The crude methyl-(R)-4-(1-carbamoylpropylamino)butyrate is used directly in the next step.
Reaction SMILES: [Mg].II.[CH3:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][CH:10]=1.[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14](O)=[O:15].Cl>C(OCC)C>[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:4])[CH:10]=1)=[O:15]
Reactant: Cc1cccc(Br)c1
Reactant: O=C(O)C(F)(F)C(F)F
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(C(=O)C(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring a solution of magnesium (14.1 g, 579 mmol) and iodine (one crumb) in diethyl ether (100 ml), 3-methylbromobenzene (90.0 g, 526 mmol) in diethyl ether (200 ml) was dropwise added at room temperature. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. The reaction solution was cooled to −78° C. and a solution of 2,2,3,3-tetrafluoropropionic acid (25.61 g, 175.4 mmol) in diethyl ether (100 ml) was dropwise added, and the mixture was heated under reflux for 4 hrs. To the reaction solution was dropwise added 1N hydrochloric acid under ice-cooling. The diethyl ether layer was separated, and the aqueous layer was extracted with diethyl ether. The recovered diethyl ether solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>C(#N)C>[Br:46][CH2:10][CH2:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(C(=C(CCBr)c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
33.0 g of (Z)-1,2-diphenyl-1-(4-methoxyphenyl)-1-buten-4-ol are dissolved in 500 ml of dry acetonitrile. Then 39.3 g of triphenylphosphine and 49.8 g of carbon tetrabromide are added while stirring. The stirring is continued for 1 h at room temperature. The solvent is evaporated and the evaporation residue is dissolved in hot petrol ether. The insoluble material is removed by filtration. The mother liquor is evaporated, and the evaporation residue is recrystallized from methanol. The yield of the product is 26.7 g (68%) having m.p. 116°-8° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][C:9]([CH3:21])=[C:8]([CH3:22])[C:7]=3[C:5]=2[N:6]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:30][CH2:31][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][C:9]([CH3:21])=[C:8]([CH3:22])[C:7]=4[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COc1cc(C)c(C)c2c1Cc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: Cc1cc(OCC(=O)O)c2c(c1C)-c1nc(SCCC(c3ccccc3)c3ccccc3)sc1C2
Yield: 53 %

Procedure:
Using ethyl [(2-mercapto-4,5-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 53%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[O:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccoc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)nc23)CC1
Yield: 60.9 %

Procedure:
Beginning with 1.0 gm (4.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.68 gm (5.2 mMol) 3-furoyl chloride, 0.85 gm (61%) of the title compound were prepared as an ivory crystalline solid essentially by the procedure described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[O:8])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22](N(C)C)OC(C)(C)C)[CH3:21]>O1CCOCC1>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:15][C:14]1[NH:13][C:12](=[O:16])[CH:11]=[CH:10][C:9]=1[C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(=O)[nH]c2C=CN(C)C)cc1
Reaction time: 0.5 h

Procedure:
A mixture containing 50 g of 5-(4-methoxybenzoyl)-6-methyl-2(1H)-pyridinone, 400 ml of p-dioxane and 40 ml of bis(dimethyamino)-t-butoxymethane was refluxed with stirring for 5 and 1/2 hours. The reaction mixture was allowed to cool and the separated crystalline product was collected, washed with ethanol and dried in a vacuum oven at 80°-85° C., to yield 65.8 g of 6-[2-(dimethylamino)ethenyl]-5-(4-methoxybenzoyl)-2(1H)-pyridinone, m.p. 216°-218° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10].[OH-].[Na+]>>[OH:7][NH:6][C:9](=[O:10])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)Cl
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)NO

Procedure:
DE3245503 discloses a process for producing methoxymethylamine via butyl N,O-dimethylcarbamate as an intermediate. According to this prior art process, the starting material hydroxylamine sulfate is allowed to react with butyl chloroformate in the presence of sodium hydroxide to form butyl hydroxycarbamate which is then subjected to the steps of extraction with dichloromethane and of drying, and after the solvent is distilled off, said butyl hydroxycarbamate is dimethylated with dimethyl sulfate in an aqueous solution of sodium hydroxide, followed by hydrolysis with hydrochloric acid, whereby methoxymethylamine hydrochloride is obtained in 65% yield.
Reaction SMILES: [CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].FC(F)(F)C(O[I:25](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[C:6]([I:25])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(I)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 135 %

Procedure:
To 8.88 g of 2-ethyl-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone in 50 ml carbon tetrachloride and 50 ml chloroform, were added [bis(trifluoroacetoxy)iodo]benzene (6.82 g) and iodine (4 g). The reaction solution was stirred at room temperature for 4 hours. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The solution was extracted with 50 ml water and dichloromethane (100 ml×3). The organic layer was concentrated in vacuo and the resulting residue was purified by lo column chromatographic separation (hexane/ethylacetate=1:1) to yield 8.7 g of 2-ethyl-4-iodo-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.5 Hz, 3H), 1.51 (s, 3H), 1.93 (q, J=7.5 Hz, 2H), 3.11 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 8.34 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1701, 1552, 1314, 1148, 747, 551.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Oc1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3OC(F)(F)F)cc2)no1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-trifluoromethoxyphenol (25 μL, 0.187 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-trifluoromethoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (30 mg, 74%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.4 Hz, 2H), 7.54-7.63 (m, 3H), 7.26-7.41 (m, 3H), 6.97-7.07 (m, 1H), 5.29 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8]([C:12](OC(C)(C)C)=[O:13])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(OCC)(OCC)OCC>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[O:13])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 40 °C
Yield: 63.9 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath. The mixture was then cooled to −5° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once. The temperature increased to 15° C. The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour. The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified. The solid was dissolved by warming and poured into 500 g of ice. The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved. The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution. The dichloromethane phase was washed with 150 mL of sodium bicarbonate and both bicarbonate solutions discarded. The dichloromethane solution was washed with 3 times with 100 mL of water each time. The dichloromethane solution was evaporated to dryness and the dark residue recrystallized twice from hot ethyl acetate after decolorizing with Darco to give golden yellow needles. The brown precipitate was recrystallized from 350 mL of hot ethyl acetate after decolorizing with Darco to give a yellow-red solid. All the recrystallized solids were combined and recrystallized from 500 mL of hot ethanol to give 37.4 g (63.9%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6-166.3° C., lit. 163-164° C.). The evaporated residues from the ethyl acetate and ethanol mother liquors were recrystallized from 500 mL of ethanol to give 10.1 g (17.1%) of a second crop of dirty yellow needles.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[OH-].[Na+]>O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCCCCOc1ccc2ccccc2c1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-[(2-naphthalenyl)oxy]butanol (2.4 g), 1,6-dibromohexane (5.3 ml), TAB (1 g) and 50% sodium hydroxide solution (24 ml) was stirred at room temperature for 19 h. The mixture was diluted with water (100 ml) and extracted with ether (2×150 ml). The combined organic fractions were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane followed by hexane-ether (19:1→8:1) gave the title compound as a colourless oil (2.34 g), t.l.c. (ether-hexane 1:1) Rf 0.85.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[Li+].[OH-]>CO.O>[C:13]([N:8]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(C(=O)O)c1C1CC1
Yield: 91.5 %

Procedure:
To a solution of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (921 mg, 4.14 mmol) in methanol (15 mL) and water (15 mL) was added LiOH (119 mg, 4.97 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (789 mg, 92%), which was used without further purification.
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=O)[C:9](=[O:14])[NH:8]3)[N:3]=[CH:2]1.Cl.[F:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[C:19]([NH:23][N:24]=[C:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]4[N:3]=[CH:2][S:1][C:12]4=3)[NH:8][C:9]2=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: NNc1cccc(F)c1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=NNc1cccc(F)c1
Temperature: 70 °C
Yield: 60.2 %

Procedure:
6H-1-Thia-3,6-diaza-as-indacen-7,8-dione (Procedure A, 50 mg, 0.25 mmol) was combined with 3-fluorophenylhydrazine hydrochloride (50 mg, 0.3 mmol) in 2 ml of ethanol and heated at 70° C. for 6 hrs. The product was collected by filtration of the hot solution, washing with ethanol and diethyl ether, to give 47 mg (60%) of the title compound as a brown solid. 1H NMR (DMSO-d6): δ 6.82 (t, J=8.7 Hz ,1H); 7.10 (d, J=8.6 Hz, 1H); 7.37 (m, 2H); 7.41 (dd, 1H); 7.97 (d, J=8.6 Hz, 1H); 9.25 (s, 1H); 11.2 (s, 1H). ES-MS m/z 311 (M−1)−.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]=[N:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27]([F:26])([F:37])[F:38])=[O:31])[CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc(-c2ccc(N3CCNCC3)nn2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccn3)nn2)CC1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a stirred mixture of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine (0.240 g, 1.000 mmol) and triethylamine (0.7 mL) in dichloromethane (15 mL) at room temperature was added 2-trifluoromethylbenzoyl chloride (0.210 g, 1.000 mmol). After 15 minutes, the mixture was washed with citric acid and NaHCO3. The organic layer was separated, dried over anhydrous MgSO4 and evaporated to yield solid residue, which was crystallized from ether to afford the title compound as a white solid in 23% yield (0.097 g). 1H NMR (300 MHz, CDCl3) δ 8.6 (d, J=4.4 Hz, 1H), 8.5 (d, J=8.0 Hz, 1H), 8.3 (d, J=9.5 Hz, 1H), 7.8 (m, 1H), 7.7 (d, J=7.7 Hz, 1H), 7.6 (t, J=7.3 Hz, 1H), 7.5 (t, J=7.5 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.28 (m, 1H), 7.0 (d, J=9.5 Hz, 1H), 4.1-3.6 (m, 6H), 3.35-3.31 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 159.3, 153.9, 151.4, 148.9, 137.0, 134.4, 132.3, 127.3, 126.8, 123.6, 120.3, 113.1, 46.5, 44.9, 44.6, 41.3. MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[CH3:12].[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][C:24]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][S:11][C:5]=4[N:4]=[C:3]3[CH3:12])=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: Cc1nc2sccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1nc2sccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-methylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.58-1.74 (m, 12H), 1.93-1.98 (m, 3H), 2.08-2.18 (m, 2H), 2.39 (s, 3H), 7.39 (d, J=6.0 Hz, 1H), 7.59 (d, J=6.0 Hz, 1H), 10.89 (s, 1H) ppm; MS (DCI/NH3) m/z 358 (M+H)+; Elemental Analysis: Calculated for C19H23N3O2S.0.8H2O: C, 61.37; H, 6.67; N, 11.30. Found: C, 61.50; H, 6.86; N, 11.38.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][N:12](C=O)C.[C-]#N.[Na+]>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[C:3]([F:10])[C:4]=1[F:9]
Reactant: CN(C)C=O
Reactant: Nc1ccc(Br)c(F)c1F
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(N)c(F)c1F
Yield: 55 %

Procedure:
A stirred mixture of the crude 4-bromo-2,3-difluoroaniline, 36 g of cuprous cyanide and 908 mL of DMF is heated 7 hours at reflux under an N2 atmosphere. After cooling, 900 mL of 10% aqueous NaCN is added and 45 minutes later 2 L of H2O. The black solution is extracted three times with CH2Cl2 (total volume 4 L). The CH2CL2 extract is washed with H2O, saturated NaHCO3 and H2O (500 mL of each) and then stripped in vacuo. The resulting black oil is purified by dry-column chromatography on silica gel using CH2CL2 as eluent. There is obtained 31.17 g (55% overall yield) of 4-amino-2,3-difluorobenzonitrile, m.p. 108°-110° C., with the expected ion at 156 in the mass spectrum and consistent NMR and IR spectral data.