Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[S:19](=[O:21])=[O:20])[CH:9]([CH3:18])[C:10]=1[C:11]1[CH2:15][CH:14]([CH2:16][Cl:17])[O:13][N:12]=1)[C:4](Cl)=[O:5].[CH:22]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:30])[CH2:24][C:23]2=[O:31].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C[Si](C#N)(C)C>[CH3:1][C:2]1[C:3](=[CH:7][C:8](=[S:19](=[O:21])=[O:20])[CH:9]([CH3:18])[C:10]=1[C:11]1[CH2:15][CH:14]([CH2:16][Cl:17])[O:13][N:12]=1)[C:4]([CH:24]1[C:25](=[O:30])[CH:26]2[CH2:29][CH:22]([CH2:28][CH2:27]2)[C:23]1=[O:31])=[O:5]
Reactant: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)Cl
Reactant: O=C1CC(=O)C2CCC1C2
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen and at 0-5° C., 0.7 g (2 mmol) of 2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methyl-sulfonylbenzoyl chloride in 40 ml of acetonitrile was added dropwise to 0.28 g (2 mmol) of bicyclo[3.2.1]octane-2,4-dione and 0.4 g (4 mmol) of triethylamine in 40 ml of acetonitrile, and the mixture was stirred at room temperature for 4 hours. 1 drop of trimethylsilyl cyanide and 0.05 g of potassium carbonate were then added, and the mixture was stirred at 40° C. for 2 hours and then at room temperature for 12 hours. Following this, the solvent was removed, the residue was taken up in ethyl acetate and the solution was extracted repeatedly with 5% strength potassium carbonate solution. The combined extracts were then adjusted to pH 2-3 using 10% strength hydrochloric acid and extracted repeatedly with methylene chloride. These combined organic extracts were then washed with water and dried, and the solvent was removed. The oily yellow residue was chromatographed over silica gel (mobile phase: methylene chloride/methanol=99/1 to 97/3). This gave 0.4 g (44% of theory) of the title compound of melting point 98-103° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=2)[CH2:10][CH3:11])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1cccc(C)c1)C(=O)O
Product: CCC(Oc1cccc(C)c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 98.5 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.71 g of (2RS)-2-(3-methylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[CH2:12][N:11]([CH3:23])[CH2:10]2)=[CH:5][CH:4]=1.[BrH:24]>>[BrH:24].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[CH2:12][N:11]([CH3:23])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)C(c1ccc(Cl)cc1)CN(C)C2
Agent: Br
Agent: Cl
Product: CN1Cc2cc(O)c(O)cc2C(c2ccc(Cl)cc2)C1

Procedure:
The free base isolated from 1.80 g. of rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride is stirred for 3 hours with 30 ml. of 48% hydrogen bromide solution at 150° (bath temperature). After concentration and recrystallization from methanol-ether, there is obtained rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-6,7-isoquinolinediol hydrobromide, m.p. 280°-281°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2.Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1Br
Product: COC(=O)c1ccc(Cn2ccc3cc(Br)c([N+](=O)[O-])cc32)c(OC)c1
Yield: 65 %

Procedure:
5-Bromo-6-nitroindole was reacted with methyl 4-bromomethyl-3-methoxybenzoate using the procedure described in part (a) of Example 1 to give methyl 4-(5-bromo-6-nitroindol-1-ylmethyl)-3-methoxybenzoate (HH) in 65% yield and as a bright yellow solid; partial NMR: 3.89 (s,3H,OCH3), 3.94 (s,3H,OCH3), 5.35 (s,2H,NCH2), 6.53 (dd,1H,H3 -indole), 7.38 (d,1H,H2 -indole), 7.89 (s,1H,H4 -indole), 8.03 (br s,1H,H7 -indole).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)O.Cl>>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: OC(CCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Product: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1

Procedure:
A mixture of 100 parts of α-(4-bromobutyl)-4-fluoro-α-(4-fluorophenyl)benzenemethanol and 714 parts of concentrated hydrochloric acid was stirred and refluxed for 5 hours. The reaction mixture was cooled and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated, yielding 92 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene] as a residue (int. 50).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:23])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+].C=O.C(O)(=O)C.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:26])[CH2:19][C:18]3=[O:23])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3=O)cn2)c1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C(=O)C1
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of 1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazin-2-one (332e) (500 mg, 1.32 mmol) in methanol (20 mL) was added Na(OAc)3BH (2.0 g, 13.2 mmol), formaldehyde (30% aq., 8 mL), and acetic acid (2.7 mL, 45 mmol). The mixture was stirred for 4 h. The pH of the reaction mixture was adjust to 11˜13 by adding NaOH (1M). It was then extracted with methylene chloride three times. The combined organic exact was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica-gel column eluting with 50:1 methylene chloride/methanol to afford 332f as a gray solid (312 mg, 60%). MS: [M+H]+ 393. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J=2.5 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.45 (dd, J=9 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 3.64 (m, 2H), 3.53 (s, 3H), 3.22 (s, 2H), 2.74 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][O:18][C:16]([C:15]1[CH:14]=[C:13]([CH:22]=[CH:21][CH:20]=1)[CH2:12][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:17]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C(O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2cccc(C(=O)O)c2)c1
Reaction time: 16 h
Yield: 99.2 %

Procedure:
A mixture of 3-mercaptobenzoic acid (154 mg, 1.00 mmol), methyl 3-(bromomethyl)benzoate (229 mg, 1.00 mmol) and K2CO3 (414 mg, 3.00 mmol) in DMF (1 mL) was stirred for 16 h, then solvent removed. The resulting residue was purified by silica gel chromatography to give 300 mg (90%) of the product.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47]>C1COCC1.C(O)C>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47].[NH2:1][CH2:4][C@@H:5]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CN=[N+]=[N-])c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CN)c1ccccc1
Temperature: 60 °C

Procedure:
The product from step (b) (2.79 g) in dry THF (80 ml) was treated with triphenylphosphine (3.47 g) and water (12 ml) and the mixture heated at 60° C. for 2 h. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate which was washed with water and dried (MgSO4). The solvent was evaporated and the residue purified by chromatography (silica, ethyl acetate and then 10% 7M ammonia in methanol/dichloromethane as eluent) to give an oil. This was dissolved in ethanol (10 ml), treated with fumaric acid (70.3 mg) and heated until a clear solution was obtained. The mixture was evaporated and the residue triturated with ether to give after filtration and drying in vacuo the final compound (222 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7].S(Cl)(Cl)=O.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:12]([F:14])([F:17])([F:16])([F:13])[F:15])[CH:11]=1)[C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7]
Reactant: CN(C)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Yield: 90.8 %

Procedure:
3-Dimethylamino-5-pentafluorosulfanylbenzoic acid (1.0 g) was dissolved in methylene chloride (60 ml). Thionyl chloride (5 ml) was added while stirring and the mixture was stirred at RT for 2 h. To complete the reaction, the mixture was subsequently heated to reflux for 3 h. After cooling, the solvent was drawn off, the residue was dissolved in methylene chloride (50 ml), and N,O-dimethylhydroxylamine hydrochloride (315 mg) and Hünig's base (1 ml) were added. After stirring for one hour, the solvent was drawn off, and the residue was taken up with ethyl acetate and washed 5 times with water. The organic phase was dried with magnesium sulfate, filtered and concentrated. 980 mg of the title compound were obtained, which were converted directly in the next stage.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:37])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([C:27](=[O:36])[C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:44]([S:47](Cl)(=[O:49])=[O:48])[CH2:45][CH3:46].CC1CCCO1>CN(C1C=CC=CN=1)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[C:19]3[C:11]([C:9]([C:4]4[C:3]([F:37])=[C:2]([NH:1][S:47]([CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])[CH:7]=[CH:6][C:5]=4[F:8])=[O:10])=[CH:12][N:13]([C:27](=[O:36])[C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[C:14]3=[N:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 12.5 °C
Yield: 116.9 %

Procedure:
Compound 7 (800 g; 1.44 mol) and dimethylamino pyridine (7.2 g; 0.059 mol), under nitrogen, were added to a 5 L three-necked-round bottom flask cooled in an ice water bath. Anhydrous pyridine (1.8 L) was charged and the mixture was stirred at 10-15° C. until a homogeneous solution was obtained. Propane-1-sulfonyl chloride (308 g; 2.16 mol) was added drop-wise from an addition funnel while keeping the reaction temperature <20° C. and the reaction mixture was stirred at 20-25° C. for 3 h. The reaction mixture was added to a mixture of 2-methyl-THF (7 L) and water (10 L) in a flask and the organic layer was separated, washed with 1N HCl (2 L) followed by brine (2 L), and dried. The residue was azeotroped with toluene to remove the residual water to provide crude compound 9 (1116.4 g) which was used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCC(=O)c1ccncc1
Solvent: CCO
Product: CCC(=NNC(=O)c1ccccc1)c1ccncc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 4.05 gm (0.03 mole) of 4-propionylpyridine, 4.08 gm (0.03 mole) of benzhydrazide and 100 ml of Ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with Skellysolve B and dried to yield 5.36 gm (71%) of the title compound having a melting point of 177.6° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[OH-].[Na+].[N+](C1C=CC=C(C(O)C)C=1C(O)=O)([O-])=O.O.NN>C(O)=O.C(OCC)(=O)C.CCCCCC>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:4](=[O:5])[O:3][CH:2]2[CH3:1]
Reactant: CC1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CC1OC(=O)c2c(N)cccc21
Yield: 90.4 %

Procedure:
2.37 g (12.2 mmol) of 3-methyl-7-nitro-3H-isobenzofuran-1-one (Example 4) are heated in 5 ml of 30% sodium hydroxide solution (49 mmol) for 1 hour at 90° C. until 2-nitro-6-(1-hydroxyethyl)-benzoic acid can be demonstrated almost quantitatively by TLC (mobile phase: ethyl acetate/hexane 3:1 plus 1 drop of formic acid). 1.2 ml (24.5 mmol) of hydrazine hydrate are then slowly added dropwise and the temperature is maintained for a further 4 hours. The cooled reaction mixture is then adjusted to a pH of 2 and is extracted with ethyl acetate. 1.8 g (90.4%) of crude 7-amino-3-methyl-3H-isobenzofuran-1-one are obtained; 1H-NMR (CDCl3): 7.37 ppm, t, 1H; 6.63 ppm, d, 1H; 6.61 ppm, d, 1H; 5.44 ppm, q, 1H; 5.22 ppm, b, 2H; 1.58 ppm, d, 3H.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]([F:37])([F:36])[C:12]1[CH:13]=[C:14]([C:22]2[CH:27]=[CH:26][C:25](/[C:28](/[CH3:35])=[CH:29]/[C:30](OCC)=[O:31])=[CH:24][CH:23]=2)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>>[F:10][C:11]([F:36])([F:37])[C:12]1[CH:13]=[C:14]([C:22]2[CH:23]=[CH:24][C:25](/[C:28](/[CH3:35])=[CH:29]/[CH2:30][OH:31])=[CH:26][CH:27]=2)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1

Procedure:
The colourless solid (E)-3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous to that described in example 50b.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].I[CH:12]([CH3:14])[CH3:13].CC[O-].[Na+].CC(O)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)c1cc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To 1H-pyrazole-3-carboxylic acid ethyl ester (23.1 g, 165 mmol) in THF (330 mL) was added 2-iodopropane (33.0 mL, 330 mmol) followed by NaOEt (21% in EtOH, 65.0 mL, 174 mmol). This solution was then heated to reflux for 16 h. The reaction was then allowed to cool to room temperature. AcOH (10.5 mL, 183 mmol) was added and the reaction was stirred for 5 min. H2O (400 mL) was added to the solution, and this mixture was extracted with EtOAc (3×150 mL). The combined organic was washed with sat. aq. NaHCO3, then brine. The organic was dried over MgSO4, filtered, and concentrated to give the product (28.70 g, 96%) as a brown oil containing a 98:2 mixture of regioisomers by 1H NMR.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27].N1CCCCC1>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])/[C:13](=[CH:22]/[C:21]2[CH:24]=[CH:25][C:18]([OH:17])=[C:19]([O:26][CH3:27])[CH:20]=2)/[C:12]([CH3:16])=[N:11]1
Reactant: COc1cc(C=O)ccc1O
Reactant: CC1=NN(c2nc3ccccc3s2)C(=O)C1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: COc1cc(/C=C2/C(=O)N(c3nc4ccccc4s3)N=C2C)ccc1O

Procedure:
1 g (4.32 mmol) of 2-(1,3-benzothiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one and 1.97 g (12.96 mmol) of 4-hydroxy-3-methoxybenzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and the orange-yellow precipitate is filtered off, then washed with water and a small amount of cold methanol and dried under reduced pressure.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 61 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-fluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 61% yield: mp 154-155° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.34-7.21 (m, 5H), 7.12-7.07 (m, 2H), 6.99-6.88 (m, 2H), 6.16 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.29-4.16 (m, 1H), 3.97-3.82 (m, 1H), 3.39-3.25 (m, 1H), 2.82-2.66 (m, 2H), 2.61 (s, 3H), 2.06-1.91 (m, 1H), 1.89-1.69 (m, 2H), 1.57-1.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.9, 162.7, 161.6, 156.9, 151.9, 138.0, 134.6, 130.6, 128.8, 127.9, 127.6, 119.6, 115.3, 48.0, 44.1, 44.0, 36.7, 24.8, 21.2, 17.4; MS (ES+) m/z 438.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11]1([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH:5]([C:21](=[O:22])[NH:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])[C:4](=[O:9])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C(=O)NS(=O)(=O)c2ccccc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5,5-dimethyl-1,3-cyclohexanedione with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5,5-DIMETHYL-2-(N-BENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 101°-103° C. (corr.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Br)[C:5]=1[NH2:12].[C:14](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:14])[C:5]=1[NH2:12]
Reactant: COC(=O)c1cc(Cl)nc(Br)c1N
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)nc(C)c1N
Temperature: 25 °C
Yield: 26.5 %

Procedure:
3-Amino-2-bromo-6-chloroisonicotinic acid methyl ester (500 mg), potassium carbonate (829 mg), tetrakis(triphenyl phosphine)palladium(0) and trimethylboroxine (276 mg) were suspended in dioxane (15 mL). Water (1.5 mL) was added and the mixture was degassed using subsequent evaporation and flushing with nitrogen (5×). The reaction mixture was stirred under reflux for 7 hours. After cooling to room temperature, the mixture was quenched with water and extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.25) to afford 100 mg of the title compound of the formula
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:2]=[CH:1][O:3][CH2:4][CH2:5][O:6][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCCCCBr
Reactant: C=COCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=COCCOCCCCCCC(=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
2-Hydroxyethyl vinyl ether (0.42 mol) was added dropwise to a flask, in which sodium hydride (0.42 mol) had been dispersed in anhydrous toluene (60 ml), under a nitrogen atmosphere. After the drop addition, ethyl 7-bromoheptanoate (0.42 mol) was added dropwise. Thereafter, tetrabutylammonium iodide (2 g) was immediately added to stir the mixture at 100° C. for 3 hours. The reaction mixture was poured into water, and the resultant-organic layer was washed with water and then combined with an extract from ether. The combined layer was dried over anhydrous sodium sulfate. After the solvent was removed, the resultant residue was distilled under reduced pressure to obtain 52 g of CH2═CHOCH2CH2O(CH2)6COOC2H5 (yield: 50.7%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]
Reactant: O=C(Cl)c1ccccc1O
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2O)n1
Reaction time: 2 h

Procedure:
To a cooled, stirred mixture of 2 g. of 1,2,4-triazole-3-carboxamide and 5.4 g. salicyloyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 22 hours. The mixture is filtered and the solid is collected and washed successively with diethyl ether, cold water, diethyl ether and dried in vacuo for 4 hours. The solid is extracted with hot, dry acetonitrile. The filtrate is reduced to about half volume by evaporation in vacuo over a warm water bath and filtered to separate a small amount of solid which separates for 2 hours. Further evaporation of the resulting filtrate to a very small volume results in the separation of a solid which is collected, washed with acetonitrile and dried yielding 210 m.p. 125°-135° C. (dec.).