Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li].[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]1.[CH2:23]=[O:24].Cl>O1CCCC1.CCCCCC>[CH3:14][C:15]1([CH3:22])[CH2:20][CH:19]([CH2:23][OH:24])[C:18](=[O:21])[CH:17]=[CH:16]1
Reactant: C=O
Reactant: CC1(C)C=CC(=O)CC1
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC1(C)C=CC(=O)C(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of diisopropylamine (7.27 g, 7 mmol) in anhydrous tetrahydrofuran (THF) was added drop wise a hexane solution (1.62 mol/l) of n-butyllithium (44.4 ml, 70 mmol) at −78° C. The solution was warmed to 0° C. and stirred for 1 hr at this temperature. After thus prepared lithium diisopopylamide solution was again cooled to −78° C., 4,4-dimethyl-2-cyclohexen-1-one (7.5 g, 60 mmol) was added dropwise and stirring was continued for 1 hr. Then, gaseous formaldehyde, generated by a thermal decomposition of paraformaldehyde (5 g) over an oil bath, was blown through the solution with a gentle stream of dry nitrogen gas and the reaction mixture was stirred for 2 hr. After standing over night at room temperature, 1N hydrochloric acid was added until the solution became weak acid. The solvent was removed and the residue was extracted with ether. After drying over anhydrous sodium sulfate and removal of the solvent, a mixture of 4,4-dimethyl-6-methylene-2-cyclohexen-1-one and 4,4-dimethyl-6-hydroxymethyl-2-cyclohexen-1-one was obtained (7.03 g). This mixture (3.0 g) was treated in reflxing benzene for 2 hr in the presence of catalytic amount of anhydrous p-toluenegulfonic acid and molecular sieve 3A (4 g). The solution was neutralized with 1N sodium bicarbonate and washed with brine. After drying over anhydrous sodium sulfate and removal of the solvent, crude 4,4-dimethyl-6-methylene-2-cyclohexen-1-one (Yoshixol) was obtained (2.35 g, overall yield 68%). The analytical sample was available. 2-cyclohexen-1-one was obtained (2.35 g, overall yield 68%). The analytical sample was available after purification by column chromatography or kugelrohr distillation but yield was much lowered. This NMR analysis of Yoshixol is following: IR(neat): 1670(C═O), 1620(C═C) cm-1. 1H NMR (60 MHZ, CCL4), d1.15 (s, 6H, C(CH3)2), 2.57 (bs, 2H, CH2), 5.20, 5.93 (2m, 2H, CH2=), 5.87 (d, J=10, 1H, 2-H), 6.63 (d, J=10 Hz, 3-H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CCC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CCC2)cc1
Reaction time: 16 h
Yield: 15.9 %

Procedure:
According to general procedure B, 4-bromo-N-cyclobutylbenzenesulfonamide (117 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide (20 mg, 16%) was provided after purification. MS (ESI) m/z 315. HPLC purity 98.8% at 210-370 nm, 10.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]NC([C@@H]1CCCNC1)=O>>[CH3:15][N:8]([C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCNC1

Procedure:
Prepared from (S)-3-(tert-butoxycarbonylamino)piperidine in the same scale and manner as the (3R) isomer described in Preparative Example 35. Yields were 96% and 93% for the first two steps. Product yield was treated as quantitative for last step and used as reagent in a further reaction (Example 94). LC/MS 1.30 min, [M+1]+ 215.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[CH2:15][NH:16][NH2:17]>>[NH2:10][C:6]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[Cl:12])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2ccc(Cl)cc2Cl)[nH]1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 20.2 g of 2,4-dichlorobenzylhydrazine analogously to the procedure described in Example 45, 11 g of the compound identified above, as colorless crystals of melting point 189°, corresponding to 40% of theory, are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[N:12]O)[CH2:7]1.C1(C)C(S(Cl)(=O)=[O:27])=CC=CC=1.S(=O)(=O)(O)O.C(Cl)Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][CH2:9][NH:12][C:8](=[O:27])[CH2:7]1
Reactant: Cc1cc(C)c(CSC2CCCC(=NO)C2)c(C)c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(CSC2CCCNC(=O)C2)c(C)c1

Procedure:
A solution of 828 mg of 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime and 570 mg of toluenesulfonylchloride in 5 ml of pyridine is stirred at RT for 4 hours and additional 2 hours at 60°. The mixture obtained is distributed between diluted sulfuric acid (2 ml H2SO4 conc. in 15 ml H2O) and CH2Cl2, the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepan-2-one is obtained. 1H-NMR(d-6-DMSO): 7.5 (m,1H,NHCO), 6.8 (s,2H,arom.H), 3.75 (s,2H,C6H5CH2S—),3.2 (m, 1H,CHN), 3.1(m,3H, CH2NH,CHS)AB-system: vA=2.72,vB=2.65(2H,CH2C═O, J=13.4 Hz, J=4.5 Hz) 2.13 2.15,2.3(9H, 3×CH3)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])([CH3:27])[CH3:26]>>[CH:25]([O:28][C:29]1[CH:30]=[C:31]([NH:32][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:22])[CH:33]=[CH:34][CH:35]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: CC(C)Oc1cccc(N)c1
Product: CC(C)Oc1cccc(NC(=O)c2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)c2)c1

Procedure:
The product from Example 33B and 3-isopropoxyaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 467 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:40]([F:43])([F:42])[F:41])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:43])([F:41])[F:42])=[CH:30][CH:29]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(CCc4ccc(-c5ccccc5C(F)(F)F)cc4)ccc32)COC(C)(C)OC1
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: NC(CO)(CO)CN1CCc2cc(CCc3ccc(-c4ccccc4C(F)(F)F)cc3)ccc21

Procedure:
When the product of Step E was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 100%. 1H-NMR (CD3OD/CDCl3) 2.8-2.86 (m, 4H); 2.89 (tr, 2H, J=8.29 Hz); 3.0 (s, 2H); 3.39 (tr, 2H, J=8.29 Hz); 3.48 (d, 2H, J=10.88 Hz); 3.55 (d, 2H, J=10.92 Hz); 6.51 (d, 1H, J=8.6 Hz); 6.86-6.88 (m, 2H); 7.14 (m, 3H); 7.17-7.37 (m, 2H); 7.4 (tr, 1H, J=7.57 Hz); 7.5 (tr, 1H, J=7.01 Hz); 7.68 (d, 1H, J=7.77 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][C:14]=3[CH:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:23].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[OH:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([N:52]4[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][OH:46])[CH2:50][CH2:51]4)=[O:21])=[CH:16][C:14]=3[CH:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:23]
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc2sc(-c3ccc(Cl)c4c3C(=O)NC4)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2c(Cl)ccc(-c3cc4cc(C(=O)N5CCN(CCO)CC5)ccc4s3)c21
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In a similar manner to Step 1 of Example 20, Compound 172 (25.0 mg, 0.0727 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (28 mg, 0.15 mmol), HOBT monohydrate (9.8 mg, 0.073 mmol) and 1-(2-hydroxyethyl)piperazine (38 mg, 0.29 mmol). The reaction mixture was added with water and ethyl acetate, and extracted with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9 and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was added with diisopropylether and stirred for 30 minutes. The solid was collected by filtration, washed with diisopropylether and then dried under reduced pressure to obtain Compound 173 (22.9 mg, yield 69%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])(=[O:40])=[O:39])=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: COc1nccc2c(-c3cc(CN)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1S(=O)(=O)NCc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
A solution of Example 106B (70 mg, 0.177 mmol) in dichloromethane (2.5 mL) was treated with 2-methoxybenzene-1-sulfonyl chloride (43.9 mg, 0.212 mmol) and triethylamine (0.049 mL, 0.354 mmol). The reaction mixture was stirred for 1 hour at ambient temperature and then partitioned between 50% aqueous saturated sodium chloride (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (104 mg, 100% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([NH:23][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc2ccccc12
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1cc(Nc2cccc3ccccc23)cc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
A clean and dry 500 ml round bottom flask equipped with a reflux condenser, magnetic stir bar, and thermometer with adapter was prepared and purged with nitrogen Anhydrous toluene (250.0 ml) was transferred to this flask by cannula. 2-(3-bromophenyl)-1,3-dioxolane (6.0 ml, 0.0397 mol) was added by syringe followed by the manual addition of 1-naphthylamine (5.08 g, 0.0355 mol). The reaction solution was purged with a strong nitrogen flow for 30 minutes. Sodium tert-butoxide (5.60 g, 0.0583 mol) and Pd2dba3 (0.65 g, 0.0007 mol) were then added manually, followed by the addition of tri-tert-butylphosphine (1.30 g, 0.0064 mol) in toluene (−10 ml) via syringe. The vessel was heated to reflux for approximately 5 hours. The reaction was then cooled to room temperature and filtered through a Celite and silica gel pad washing thoroughly with acetone and chloroform. Solvent was removed by rotary evaporation. The crude material was purified by flash column chromatography using ethyl acetate/hexane as an eluent. This provided pure product confirmed by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:3]=1[CH:16]=O.[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CC(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:16]3[N:22]([C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]3[C:9](=[O:15])[NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCN2C(=O)Nc3nccc(Cl)c3C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (4-chloro-3-formylpyridin-2-yl)carbamate (1.2 g, 4.67 mmol), tert-butyl (3-amino-propyl)carbamate (855 mg, 4.91 mmol), and AcOH (0.28 g, 4.67 mmol) were suspended in toluene (50 mL), and stirred overnight at room temperature. The reaction mixture was concentrated. The crude intermediate was dissolved in NMP (8 mL) in a 40 mL sealed tube, and stirred for 30 min. at 160 ° C. The reaction mixture was cooled, and the resulting precipitate was filtered, washed with MeOH, and dried under vacuum. LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)[C:15]([O-:17])=[O:16].[O-]CC.[Na+]>C(O)C>[O:11]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CCOC(=O)CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)CCc1ccccc1
Reaction time: 15 h
Yield: 90.9 %

Procedure:
A mixture of 143 g of ethyl 3-phenylpropionate, 234 g of ethyl oxalate and 154 ml of 28% sodium ethoxide solution in ethanol is heated on a water bath at a bath temperature of 60°-70° C. for 1.5 hours, while distilling off the ethanol under reduced pressure. To the resulting red syrupy residue is added 1.3 liters of 15 v/v % sulfuric acid. The mixture is boiled under reflux with stirring for 15 hours, and the oil layer is separated, neutralized with 10% sodium hydroxide and extracted with ethyl acetate. The aqueous layer is made acidic with diluted sulfuric acid. The resulting oil is extracted with ethyl acetate, washed with water and dried. Removal of the ethyl acetate by distillation under reduced pressure gives 130 g of 2-oxo-4-phenylbutyric acid as an oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[Br:17](O)(=O)=O>O.[Cu]Br>[Br:17][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: [O-][Br+2]([O-])O
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (2.0 g, 12 mmol) in bromic acid (aqueous, 10 mL, 25%) was added sodium nitrite (0.92 g, 13.3 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minutes, and then copper (I) bromide (2.0 g, 13.8 mmol) and bromic acid (aqueous, 20 mL, 25%) was added at 0° C. After addition completed, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with water (200 mL) and the product was extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give the pure product 6-bromo-3,4-dihydronaphthalen-1(2H)-one (1.2 g, 45%). 1H NMR (300 MHz, CDCl3): δ 7.87 (d, J=8.7 Hz, 1H), 7.44-7.42 (m, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.15-2.11 (m, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[CH3:27][S:28]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:30])=[O:29]
Reactant: COc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
15 g (59 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(4-methoxyphenyl)-acetonitrile are dissolved in 200 ml of THF and cooled in an ice bath. After adding 12.4 ml (89 mmol) of triethylamine to the solution, 5.03 ml (65 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is gradually warmed to room temperature, and stirred for 1 hr. The reaction mixture is poured into 300 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from ethyl acetate. 6.8 g (35%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-(4-methoxyphenyl)-acetonitrile are obtained in the form of orange crystals having a melting point of 161-162l° C. (dec.).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17])=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([Cl:4])=[O:17])=[CH:11][CH:10]=1
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCC(C(=O)Cl)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Oxalyl chloride (12 mL of a 2.0M solution in CH2Cl2) was added under nitrogen to a solution of 2-(4'-methoxyphenyl)butyric acid (4.66 g, 24 mmol) in 25 mL of CH2Cl2 and stirred at room temperature overnight. The volatiles were removed under vacuum and the residue was distilled to afford 4.46 g (87%) of pure 2-(4'-methoxyphenyl)butyryl chloride. 1H NMR (CDCl3) δ0.919 (t, 3H, J=7.4 Hz), 1.78-1.92 (m, 1H), 2.13-2.27 (m, 1H), 3.81 (s, 3H), 3.83 (t, 1H, J=7.6 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.7 Hz); 13C NMR (CDCl3) δ11.43, 26.26, 55.14, 64.21, 114.50, 127.86, 129.65, 159.75, 175.48.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:24])[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cccc(F)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc2c(Nc3ccc(Cl)c(Cl)c3)cc(Cl)nc12
Yield: 20 %

Procedure:
Prepared using general procedure 3; 8-Fluoro-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (3.2 g, 9.90 mmol) and 23 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 0.69 g of material (1.98 mmol, 20%). 1H NMR (300 MHz, DMSO): 9.50(s, 1H), 8.17(d, ?H, J=7.67 Hz), 8.04(d, 1H, J=5.25 Hz), 7.79(d, 1H, J=5.65 Hz), 7.71(d, 1H, J=8.88 Hz), 7.61(m, 1H), 7.45(dd, 1H, J=8.88, 2.42 Hz), 6.88(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[C:23]#[N:24])=[C:5]([CH3:25])[O:4][N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[C:23]#[N:24])=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C#N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C#N
Temperature: 25 °C
Yield: 46.5 %

Procedure:
(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (12 mg, 0.036 mmol) was dissolved in CH2Cl2 (3 mL) and BBr3 (1 M solution in DCM, 0.3 mL, 0.28 mmol) was added. The mixture was stirred at room temperature over night. Water and DCM were added and the phases were separated. The organic phase was purified on a silica plug to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (5.4 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:28]([CH3:29])[CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 16.1, Methanesulfonic acid 5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Dimethylamine were converted to yield {5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amine as off-white semisolid, MS: 399 (MH+, 1Br).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:19][CH2:20]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1nc2ccccc2o1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc3ccccc3o2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-benzooxazole following a procedure analogous to that described in Example 19. LC (method 9): tR=1.85 min; Mass spectrum (ESI+): m/z=429 [M+H]+.