Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:13][N:12]([C:14]3[N:15]4[C:19]([N:20]=[C:21]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=35)=[CH:18][CH:17]=[N:16]4)[CH2:11]2)=[O:9])[CH2:4]1)#[CH:2].C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:11][N:12]([C:14]3[N:15]4[C:19]([N:20]=[C:21]5[CH2:27][CH2:26][N:25]([CH3:30])[CH2:24][CH2:23][C:22]=35)=[CH:18][CH:17]=[N:16]4)[CH2:13]2)=[O:9])[CH2:4]1)#[CH:2]
Reactant: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C)CC4)C2)C1
Reaction time: 8 h

Procedure:
To 50 mg (0.14 mmol) of (3-Ethynyl-pyrrolidin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 2 mL of THF and 1 mL of puffer solution (pH 5) was added 11.3 μL (0.15 mmol) of formaldehyde (37% in water) and 35 mg (0.17 mmol) of sodium triacetoxyborohydride. Stirring was continued overnight, the reaction mixture diluted with 1 mL of water, filtered and purified by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([O:19]C)[C:11]([Cl:18])=[CH:12][C:13]=2[O:16]C)[CH2:8][O:7]1)=[O:5])[CH3:2]>C(#N)C.O.C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:13](=[O:16])[CH:12]=[C:11]([Cl:18])[C:10](=[O:19])[C:9]=2[CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(OC)cc(Cl)c(OC)c2CO1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C1CC2=C(CO1)C(=O)C(Cl)=CC2=O
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a stirred solution of 1.0 g (3.7 mmol) of the chloroiso-chroman from step 6 in 20 ml of acetonitrile was added dropwise a solution containing 6.25 g (11.4 mmol) of ceric ammonium nitrate in 20 ml of water. The mixture was stirred overnight and then diluted with 50 ml of CH2Cl2. The organic layer was separated and the aqueous phase was extracted twice with 25 ml CH2Cl2. The combined organic layer was washed once with 50 ml H2O, 50 ml brine and then dried over Na2SO4. After evaporation of solvents, flash chromatography of the residue with a solvent gradient of 5 to 20% ethyl acetate in toluene yielded 495 mg (55%) of the titled compound. (MP: 83.5° C.) 1H NMR (200 MHz, CDCl3) δ: 1.27 (t, 3H, J=7.1 Hz, CH3), 2.58 (ddt, 1H, J=19.0, 8.8, 3.2 Hz, HCHaCHC=O), 2.83 (d multiplets, 1H, HCHeCHC=O), 4.17 (dd, 1H, J=8.7, 3.3 Hz, OCHC=O), 4.20 (q, 2H, J=7.0 Hz, OCH2), 4.44 (dt, 1H, J=18.8, 3.4 Hz, HCHaO), 4.78 (d multipier, 1H, J=18.8, 2.6, 1.7 Hz, HCHeO), 6.95 (s, 1H, C=CH).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14]Br.[NH4+].[Cl-]>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH:11]2[CH2:14][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCBr
Reactant: O=CCC/C=C\c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C(=C\c1ccccc1)\CCC1CO1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
(Z)-5-Phenylpent-4-enal (0.475 g, 2.97 mmol) and dibromomethane (0.626 g, 3.60 mmol) were taken up in THF (20 mL) and chilled to −78° C. under argon n-butyl lithium (1.6M in hexane, 2.0 mL, 3.20 mmol) was added dropwise over 5 minutes. The resulting mixture was warmed slowly to room temperature and stirred overnight. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL), extracted with MTBE (2×30 mL) and solvent removed under reduced pressure. The resulting oil was purified by column chromatography (0-20% EtOAc/n-hexane, silica) to give (Z)-2-(4-Phenylbut-3-enyl)oxirane as a pale yellow oil. 1H NMR (CDCl3): δ 7.32-7.27 (m, 2H), 7.25-7.19 (m, 3H), 6.47 (d, 1H, J=11.7), 5.68 (J1=11.6, J2=7.3), 2.97-2.93 (m, 1H), 2.77-2.74 (m, 1H), 2.55-2.52 (m, 1H), 2.53-2.48 (m, 2H), 1.76-1.67 (m, 2H). Contains ca. 18% (E)-2-(4-phenylbut-3-enyl)oxirane.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=1[CH3:18])(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:5][S:6]([C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=1[CH3:18])(=[O:7])=[O:8]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Reaction time: 24 h

Procedure:
A solution of N-{5-[(tert-butylamino)sulfonyl]-4-methyl-1,3-thiazol-2-yl}acetamide (1.1 g) in TFA (10 ml) was stirred at room temperature for 3d. The mixture was evaporated, redissolved in TFA (10 ml) and stirred for a further 1 d. On evaporation the resulting oil was azeotroped with DCM (×2) and triturated with Et2O to give the subtitle compound as a beige solid. Yield 0.7 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH3:8])[CH2:5][C:6]#N.C1C[O:13]CC1.C1CCCCCCCCCCC1.CC1CCOC1=O>O>[CH3:8][CH:4]([CH2:5][CH2:6][OH:13])[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)C(C)CC#N
Reactant: C1CCOC1
Agent: C1CCCCCCCCCCC1
Agent: CC1CCOC1=O
Solvent: O
Product: COC(=O)C(C)CCO
Temperature: 100 °C
Reaction time: 3.2 h

Procedure:
A mixture of 0.05 mmol RuHCl(H2)(PCy3)2, 0.54 mmol methyl-3-cyano-isobutyrate (prepared by addition of HCN to methyl methacrylate), 17.7 g THF, 15.3 g water, and 0.0596 g cyclododecane (internal standard for gc analysis) was stirred in an autoclave and heated to 100° C. under 7000 kPa H2. After 3.2 hours, the nitrile was completely and cleanly converted to methyl-butyrolactone, which formed by transesterification/cyclization of the intermediate hydroxyester, methyl 2-methyl-4-hydroxybutyrate.
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[OH2:12]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:12])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: O
Reactant: C=CCC1C(=O)C=CC1(C)O
Product: C=CCC1=C(C)C(O)CC1=O
Temperature: 30 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Twenty grams of a 300-mesh activated alumina (Wako Junyaku Co.) for use in column chromatography was suspended in 100 ml of a toluene-ether (1:1 by volume) mixture admixed with 2.4 g of water. To the suspension, was added 4.0 g of 4-hydroxy-4-methyl-5-allyl-2-cyclopentenone. The suspension was stirred at 30° C. for 24 hours and the alumina was separated by filtration. The separated alumina was extracted three times with 50 ml of a toluene-ether (1:1 by volume) mixture. The extract solutions were combined with the filtrate and concentrated. The concentrate was fractionally distilled in vacuo to obtain 2.5 g (62.5% yield) of 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone boiling at 155° C./1 mmHg.
Reaction SMILES: N#N.[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([CH:15]=[CH2:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].B1C2CCCC1CCC2.Br[C:27]1[CH:37]=[CH:36][C:30]2[O:31][C:32]([F:35])([F:34])[O:33][C:29]=2[CH:28]=1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:37]2[CH:27]=[CH:28][C:29]3[O:33][C:32]([F:34])([F:35])[O:31][C:30]=3[CH:36]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A stream of N2 was bubbled through neat 3-vinyl-pyrrolidine-1-carboxylic acid tert-butyl ester (589 mg, 2.99 mmol) for 15 min before adding 9-BBN (0.5 M in THF, 6 mL). The reaction mixture was heated at reflux for 2 h, then cooled to rt. The reaction mixture was then added, via cannula, to a preformed solution consisting of 5-bromo-2,2-difluoro-1,3-benzodioxole (704 mg, 2.97 mmol), Pd(dppf)Cl2.CH2Cl2 (69.7 mg, 0.0953 mmol), and potassium carbonate (559 mg, 4.04 mmol) in DMF/H2O (10 mL/1 mL). The resultant mixture was heated at 60° C. for 18 h, cooled to rt, and poured into water. The pH of the mixture was adjusted to 11 with NaOH (1 N) and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (1.0 g, 98%).
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH2:11][CH3:12])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].C([O-])(=O)C.[Na+]>C1(O)CCCCC1>[CH3:22][O:23][C:24]([CH2:25][N:26]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]2[C:1]1=[O:20])=[O:27]
Reactant: COC(=O)CN
Reactant: CCC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: OC1CCCCC1
Product: CCc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(=O)OC

Procedure:
6.8 g (0.025 mol) of 7-phthalimido-3,6-heptanedione, 3.5 g (0.028 mol) of glycine methyl ester hydrochloride and 2.3 g (0.028 mol) of sodium acetate are stirred in 150 ml of cyclohexanol at 60° C. for 13 hours and the mixture is worked up as in Example 22.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]([O:18]CC)=O)([O-])=O.O.O.[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl>[CH:6]1[C:5]2[N:10]3[CH:14]=[CH:13][CH:12]=[C:11]3[CH2:15][C:16](=[O:18])[NH:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1cccn1-c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cccn2-c2ccccc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
To a solution of 0.8 mmol of 1-(2-nitrophenyl)-2-pyrroleacetic acid, ethyl ester in 3 ml of ethanol is added stannus chloride dihydrate (SnCl2.H2O) in 2 ml of concentrated hydrochloric acid (with cooling in water bath). The mixture is stirred at room temperature for 5 hours and chilled in an ice bath. To the mixture is added slowly saturated sodium carbonate solution. The solid which precipitates is filtered and the solid washed with water and then extracted with ethyl acetate. The ethyl acetate extract is dried (Na2SO4) and the solvent removed to give 0.16 g of solid which is triturated with ether to give 0.11 g of product as an off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:16]([N:18]1[CH2:21][C:20]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[NH2:14][C@H:15]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[C:16]([N:18]1[CH2:21][C:20]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19]1)=[O:17]
Reactant: CCCCCC1(C2CCCCC2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC1(C2CCCCC2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
2.5 ml of trifluoroacetic acid are added, at 0° C., to 0.48 g (0.99 mmol) of tert-butyl[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate dissolved in 10 ml of dichloromethane. After 2 hours, the solvents are evaporated off. The residue is taken up in dichloromethane and washed with 1N sodium hydroxide. The organic phases are combined, dried over MgSO4, filtered and concentrated. 327 mg of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one are obtained with a yield of 86%.
Reaction SMILES: [OH:1][CH2:2][C@:3]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:2]([C@:3]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:1]
Reactant: C[C@@]1(CO)CCCN1C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C[C@@]1(C=O)CCCN1C(=O)OCc1ccccc1
Yield: 92.5 %

Procedure:
To a solution obtained by dissolving 377 mg of the compound [63-2] and 147 mg of pyridine in 7.5 mL of chloroform, 673 mg of Dess-Martin periodinane was added at room temperature, and the mixture was heated under reflux for 1 hour. To the reaction solution, a saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, sequentially, and dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 100/0 to 60/40) to obtain 346 mg of benzyl (2S)-2-formyl-2-methylpyrrolidine-1-carboxylate [63-3] (hereinafter, referred to as the compound [63-3].
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26](OCC)=[O:27])[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:27])[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccn2C)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccn2C)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 6. The product was obtained as a beige powder: 1H NMR (CDCl3) δ 10.14 (1H, br), 8.58 (2H, br), 7.32-7.15 (5H, m), 7.12 (1H, br), 6.88 (1H, br s), 5.97 (2H, br), 4.22 (2H, s), 3.70 (3H, s), 3.67 (2H, q, J˜5 Hz), 3.60 (2H, t, J˜5 Hz), 3.42 (3H, s); ES+ MS: 483 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12](=[CH:35][C:30]4[NH:31][C:32]5[C:28]([CH:29]=4)=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:34][CH:33]=5)[C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2cc(-c3ccc(F)cc3)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
6-(4-Fluoro-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[CH:13](O)[CH3:14].C1(C)C=CC(S(O)(=O)=[O:23])=CC=1.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8](=[O:23])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][CH:13]=[CH2:14]
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CC=CC1=C(C)C(=O)CCC1(C)C
Yield: 2715 %

Procedure:
A solution of 70 g of crude 3-oxo-β-ionol and 1.5 g of paratoluenesulphonic acid in 300 ml of toluene is stirred at reflux temperature for 40 minutes with simultaneous removal of the water formed by means of a water separator. The cooled mixture is treated with 300 ml of ether, the organic phase is washed three times with soda solution and three times with water, dried and concentrated. There are obtained 61 g of crude product which contains more than 90% of 2,4,4-trimethyl-3-(buta-1,3-diethyl)cyclohex-2-en-1-one according to gas-chromatographical analysis. Distillation of the crude product over a 15 cm column gives 45 g of olfactorily-good 2,4,4-trimethyl-3-(buta-1,3-dienyl)cyclohex-2-en-1-one of boiling point 74°-75° C./0.06 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)#[N:9]
Reactant: N#Cc1ccncc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1ccc(-c2cnccc2C#N)cc1

Procedure:
Synthetic Scheme XXVI shows the 6-step preparation of the alkylating reagent 3-(4-bromomethylphenyl)-4-cyanopyridine (66) from 4-picoline (67) (Aldrich). In step 1, 4-picoline was brominated with bromine in fuming sulfuric acid at high temperatures to give 3-bromo-4-picotine (68)- In step 2, the picoline 68 was oxidized to the corresponding carboxylic acid 69 with KMnO4. In step 3, the acid 69 was first converted to its acid chloride with oxalyl chloride and subsequently treated with condensed ammonia to give the amide 70. In step 4, the amide 70 was converted to 3-bromo-4-cyanopyridine (71) by treatment with P2O5 at high temperatures. In step 5, the nitrile 71 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 4-cyano-3-(4-methylphenyl)pyridine (72). In step 6, 72 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 66. ##STR90##
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]([CH3:24])([CH3:23])[C:10]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1)=[O:11].[F:25][CH:26]([F:37])[C:27]1[C:31]([C:32](Cl)=[O:33])=[C:30]([F:35])[N:29]([CH3:36])[N:28]=1.O>ClCCl>[Cl:18][C:17]1[C:12]([C:10](=[O:11])[C:9]([NH:8][C:32]([C:31]2[C:27]([CH:26]([F:37])[F:25])=[N:28][N:29]([CH3:36])[C:30]=2[F:35])=[O:33])([CH3:24])[CH3:23])=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:16]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(C)(N)C(=O)c1ncc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1nc(C(F)F)c(C(=O)NC(C)(C)C(=O)c2ncc(C(F)(F)F)cc2Cl)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 21.7 %

Procedure:
In a 13 ml Chemspeed™ vial is weighted 73 mg (0.726 mmol) of triethylamine. 3 ml of a 0.23 molar solution of 2-amino-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-methylpropan-1-one (0.594 mmole) in dichloromethane is added followed by 3 ml of a 0.26 molar solution of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.66 mmole) in dichloro-methane and stirred at ambient temperature for 15 hrs. 1 ml of water is then added and the mixture is deposited on a basic alumina cartridge (2 g) and eluted twice by 8 ml of dichloromethane. The solvents are removed to yield 57 mg (19%) of pure N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-methyl-1-oxopropan-2-yl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as an oil (M+H=443).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)CCC>>[N:36]1[CH:37]=[CH:38][N:39]=[CH:40][C:35]=1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:20](=[O:29])[C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]4=[O:28])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(c1ccc2c(c1)ncn2-c1cccc(Br)c1)N1C(=O)c2ccccc2C1=O
Product: CC(c1ccc2c(c1)ncn2-c1cccc(-c2cnccn2)c1)N1C(=O)c2ccccc2C1=O

Procedure:
This was prepared analogously from 2-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-isoindole-1,3-dione and 2-tributylstannylpyrazine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=[O:18])[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=[O:18])[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1
Agent: Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Temperature: 0 °C

Procedure:
A stirred mixture of 2-(3-methoxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 25, (12.59 g, 48.7 mmol) in acetic acid (75 mL) and hydrobromic acid (75 mL of a 48% aqueous solution) was heated at reflux temperature for 3 days. The cooled reaction mixture was poured onto ice (500 ml) and stirred until all the ice had melted. The resulting precipitate was collected by filtration and dried in vacuo to give 2-(3-hydroxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 26, as a grey solid (10.95 g, 92%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[CH3:17])[C:7]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:20][C:6]=2[C:5](=[O:27])[N:4]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1.ClCCl>[Cl:16][C:12]1[C:11]([CH3:17])=[C:10]([CH2:9][N:8]2[C:7]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[S:20][C:6]=3[C:5](=[O:27])[N:4]=[C:3]2[CH2:2][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(Cl)cccc1Cn1c(CBr)nc(=O)c2sc(N3CCOCC3)nc21
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1Cn1c(CN2CCCC2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a 20 mL I-CHEM reaction vial was added a solution of 5-(bromomethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (188 mg, 0.400 mmol) in tetrahydrofuran (THF) (4002 μL). The solution was then treated with pyrrolidine (331 μL, 4.00 mmol) and the resulting reaction mixture was allowed to stir at room temperature and was found to have completely converted to the desired material by LCMS in less than 5 minutes. Reaction mixture was placed under a nitrogen stream and warmed to 50° C. to concentrate the reaction to a residue. The residue was then re-dissolved in dichloromethane (DCM) (750 μL) and injected onto a 10 g SNAP silica cartridge for purification [eluting with a gradient: 0-95% THF (1% methanol (MeOH)) into DCM, over 30 column volumes]. Fractions containing the desired material were pooled and concentrated to afford a residue which was subsequently triturated with ethyl acetate and hexanes to afford pure 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-(1-pyrrolidinylmethyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (38 mg, 0.082 mmol, 20.44% yield). LCMS Theoretical m/z MH+=460.99 Found: 461.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (br. s., 4H) 2.37 (br. s., 4H) 2.41 (s, 3H) 3.46-3.52 (m, 4H) 3.52 (s, 2H) 3.62-3.74 (m, 4H) 5.66 (s, 2H) 6.45 (d, J=7.83 Hz, 1H) 7.11 (t, J=8.21 Hz, 1H) 7.33 (d, J=7.33 Hz, 1H).