Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)/[CH2:4][N:5](C=O)C=O.C(O)C.O.Cl>C1(C)C=CC=CC=1>[NH2:5][CH2:4]/[C:3](=[CH:2]/[F:1])/[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: O=CN(C=O)C/C(=C/F)CCc1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine (E)-N-(2-(fluoromethylene)-4-(p-fluorophenyl)butyl)-N-formyl formamide (8.0 g, 32.7 mmol), ethanol (19.9 g), water (29.8 g), and aqueous 12M hydrochloric acid solution (13.1 g). Heat to reflux. After 1 hour, add toluene (29.8 g). Cool to 25° C. Separate the layers. Distill the aqueous layer until the volume is reduced by about two thirds. Cool to 50° C. Add concentrated aqueous hydrochloric acid solution (50 g). Cool to -5° C., filter, rinse with toluene, and dry in vacuo at 60° C. to give a solid. Recrystallize the solid from isopropyl acetate, filter, and dry in vacuo at 43° C. to give the title compound: mp 130°-131.5° C. 1H NMR (D2O, 300 MHz) δ 2.50 (m, 2H), 2.79 (m, 2H), 3.47 (d, J=3.0Hz, 2H), 6.80 (d, J=81.9Hz, 1H), 7.09 (m, 2H), 7.28 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 43.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.065 g, 0.13 mmol) obtained in step 2 and ethanesulfonamide (0.068 g, 0.65 mmol), the title compound (0.033 g, 43%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][C:10]=2[C:27]([F:30])([F:29])[F:28])[CH:7]=1.[OH:31]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:26])=[O:31])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[CH:11][C:10]=2[C:27]([F:28])([F:30])[F:29])[CH:7]=1
Reactant: CSc1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)c1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-(3-chloro-5-pyridyloxy)-5-(4-methylthiobenzenesulfonamido)benzotrifluoride (0.21 g) in acetone (5 mL) was added Oxone™ (0.136 g) in water (1 mL). After 5 hr, the reaction mixture is filtered, and the filtrate is diluted in methylene chloride and extracted with water. The solids from the organic extract were purified by silica chromatography. Trituration with hexane gave the title sulfoxide (0.144 g) as a white solid. mp 156-159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:22][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1c(F)cc(-c2ccc(OC(F)(F)F)cc2)cc1F)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-difluoro-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 39) was reacted with 4-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow amorphous solid. MS: 455.5 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1)[CH2:4][CH3:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O.O=S(=O)=O>[CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]=2[N:8]=[N:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCC(CC)n1nnc2ccccc21
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCC(CC)n1nnc2c([N+](=O)[O-])cccc21
Temperature: 0 °C
Yield: 45 %

Procedure:
Over a 21/2 hour period, 210 grams of the 1-(1-ethylpropyl)benzotriazole is added to a mixture of 100 milliliters of 90% nitric acid and 400 milliliters of 23% oleum with stirring. The mixed acid solution is cooled in an ice-salt bath and the addition rate is such that a temperature of between 5°-10° C. is maintained. The reaction mixture is maintained at 5°-10° C. for an additional 11/2 hours and then at 25° C. for one more hour. The reaction mixture is then poured over 2500 grams of ice with stirring. After 15 minutes of stirring, the brown precipitate is collected by filtration, washed with additional water and air dried. The crude product is then slurried with 500 milliliters of 95% ethanol and then a second time with an additional 400 milliliter of hot 95% ethanol. The slurry is cooled and the product is collected by filtration and dried to yield 108.5 grams (45%) of brown solid, m.p. 129°-132° C. The analytical sample is recrystallized from chloroform-petroleum ether to give a m.p. 132°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[C:5]2[OH:20].Cl[C:22]([F:28])([F:27])C(OC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[N:16][CH:15]=1)=[C:5]2[O:20][CH:22]([F:28])[F:27]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc2ccc(Br)cc2c(OC(F)F)c1Cc1cncnc1
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-hydroxy-3-(pyrimidin-5-ylmethyl)quinolin-2(1H)-one (0.5 g, 1.51 mmol, Intermediate 49: step a) methyl 2-chloro-2,2-difluoroacetate (0.24 mL, 2.26 mmol) and K2CO3 (0.52 mg, 3.76 mmol) in DMF (0.6 mL) was stirred at 80° C. for 2 hours, cooled to room temperature, diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried, filtered, evaporated in-vacuo and purified by chromatography (0-10% MeOH in DCM, gradient) to provide the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][CH:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:16])([CH3:17])[N:7]([C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1=NN(C(=O)CC(C)CC(C)(C)C)C(C)(C)C1c1ccccc1
Temperature: 30 °C
Reaction time: 21 h
Yield: 57 %

Procedure:
To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole (1 ml: 0.25 M in anhydrous tetrahydrofuran, 0.25 mmol) was successively added 3,5,5-trimethylhexanoyl chloride (1.1 ml: 0.25 M in anhydrous tetrahydrofuran; 0.275 mmol) and DIPEA (1.1 ml: 0.285 M in anhydrous tetrahydrofuran; 0.313 mmol) and the resulting mixture was stirred for 21 hours at 30° C. An aqueous 5% NaHCO3 solution and dichloromethane were added to the mixture. The organic layer was separated, successively washed with brine and water, dried over MgSO4, filtered and concentrated in vacuo to give [3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazol-1-yl]-3,5,5-trimethylhexan-1-one as a mixture of diastereomers (55 mg, 57% yield). 1H-NMR (400 MHz, CDCl3) δ 0.88 (t, J=7, 3H), 0.94 (s, 9H), 1.00 and 1.01 (2×d, J=7, 3H), 1.12-1.20 (m, 4H), 1.25-1.39 (m, 3H), 1.47-1.58 (m, 5H), 2.07-2.34 (m, 3H), 2.46-2.55 (m, 1H), 2.63-2.73 (m, 1H), 3.72 and 3.74 (2×s, 1H), 6.98 (br d, J=8 Hz, 2H), 7.28-7.37 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6](OC)=[O:7].[CH3:11][NH:12][CH3:13].C(O)C>>[CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([N:12]([CH3:13])[CH3:11])=[O:7]
Reactant: CNC
Reactant: COCC(=O)CC(=O)OC
Solvent: CCO
Product: COCC(=O)CC(=O)N(C)C

Procedure:
0.17 mol (25 g) of methyl 4-methoxy-acetoacetate and 91 ml 33% dimethylamine in ethanol (about 0.51 mol dimethylamine) were stirred in a pressure reactor for 4 h at 110° C. The reaction mixture was then evaporated to dryness and 27 g of crude product chromatographed over 350 g silica gel with ethyl acetate/methanol 9/1. After drying, 12.4 g of the title compound were obtained.
Reaction SMILES: [BrH:1].[CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[CH2:3]>C1C=CC=CC=1>[Br:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3]
Reactant: Br
Reactant: C=Cc1ccc2ccccc2c1
Solvent: c1ccccc1
Product: CC(Br)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
HBr gas (39.4 g, 486 mmol) was bubbled into a solution of 2-vinylnaphthalene (75 g, 486 mmol) in benzene (100 mL) over a period of 7-8 hours at 55-60° C. The solution was cooled to room temperature, and the benzene with the small excess of HBr was removed under vacuum yielding 105 g (91%) crude of 2-(1-Bromoethyl)-naphthalene. It was used without further purification. C12H11Br; MS: 235.12.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12]([CH3:32])([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.[Br:33]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)C>[Br:33][CH:11]1[C:10]2[C:15](=[CH:16][C:7]([Cl:6])=[CH:8][N:9]=2)[N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)[C:13](=[O:30])[C:12]1([CH3:32])[CH3:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Cc3ncc(Cl)cc32)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(Br)c3ncc(Cl)cc32)CC1
Temperature: 0 °C
Yield: 41 %

Procedure:
A carbon tetrachloride solution (25 ml) of tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 10-2) (1.0 g), N-bromosuccinimide (903 mg) and 2,2′-azobisisobutyronitrile (43.2 mg) was heated at reflux for 40 minutes. After the reaction solution was cooled to 0° C., diethylether was added, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(4-bromo-7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (492 mg).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]#N)[CH2:2][CH3:3].N([O-])=[O:11].[Na+].[OH2:14]>>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]([OH:11])=[O:14])[CH2:2][CH3:3]
Reactant: CCCC(C#N)CCC
Reactant: O
Reactant: O=N[O-]
Agent: [Na+]
Product: CCCC(CCC)C(=O)O
Reaction time: 2 h
Yield: 97 %

Procedure:
By means of the funnel, there were then slowly added 8 g (0.064 mol) of di-n-propyl acetonitrile prepared by the above-described method. The mixture was heated to 80°-82° C. and was kept at this temperature for 2 hours. It was then cooled to 50°-52° C. and, while this temperature was maintained by gentle external cooling, a solution of 6.2 g (0.09 mol) of sodium nitrite in 10 ml of water was introduced under vigorous stirring and by means of the funnel. When the operation of introduction had been completed, the mixture was cooled to 20° C. under a gentle stream of nitrogen and 30 ml of water was added through the funnel. Stirring was maintained for 30 minutes and then the mixture was allowed to decant for 30 minutes into a separation funnel. The organic phase was separated and the aqueous phase was extracted with 10 ml of toluene. This toluenic phase was added to the crude di-n-propyl acetic acid obtained and the toluenic solution was extracted with a solution of 2.8 g of sodium hydroxide in 25 ml of water. After decantation, the toluenic phase was eliminated and the alkali aqueous phase acidified by adding 8 g of 36% by weight hydrochloric acid. After decantation, the organic phase was collected and the aqueous phase extracted with toluene. The two organic phases were combined and three successive washing operations with 8 ml of water carried out. The toluene was distilled at atmospheric pressure and a residue weighing 9 g, representing a yield of 97% of crude di-n-propyl acetic acid was obtained.
Reaction SMILES: [CH:1]1([C:4]2([F:23])[CH2:7][N:6]([C:8]3[N:13]=[C:12](SC)[N:11]=[C:10]([NH:16][C:17]4[NH:21][N:20]=[C:19]([CH3:22])[CH:18]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.O[O:25][S:26]([O-:28])=O.[K+].OS([O-])=O.[Na+].[C:35]([O-])([O-])=O.[K+].[K+]>CO.O>[CH:1]1([C:4]2([F:23])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:26]([CH3:35])(=[O:28])=[O:25])[N:11]=[C:10]([NH:16][C:17]4[NH:21][N:20]=[C:19]([CH3:22])[CH:18]=4)[CH:9]=3)[CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc(Nc2cc(C)n[nH]2)cc(N2CC(F)(C3CC3)C2)n1
Reactant: O=S([O-])OO
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Temperature: 25 °C

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine (130 g, 389 mmol) in MeOH (5.2 L) was cooled to 0° C. A solution of oxone (526 g, 855 mmol) in H2O (5.2 L) was slowly added to the slurry keeping the temperature below 5° C. After addition the reaction was allowed to warm to room temperature overnight. A 10% solution of NaHSO3 (325 ml) and a 10% solution of K2CO3 (2.6 L) was then added to neutralize the reaction mixture, the solution filtered and the filter cake washed with H2O (3.3 L). The solid was slurried in H2O (2.6 L), the solution filtered and the filter cake washed with H2O (3.3 L). The solid was dried under vacuum (72.3 g, 51%). 1H NMR (DMSO): 0.47 (2H, m), 0.60 (2H, m), 1.43-1.46 (1H, m), 2.20 (3H, s), 3.25 (3H, s), 3.97-4.11 (4H, m), 5.93 (1H, br s), 6.47 (1H, br s). 9.88 (1H, s), 12.01 (1H, br s). ES+367
Reaction SMILES: O=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([N:21]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]=3[CH:3]=[C:2]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:30][C:26]=1[CH:27]([OH:29])[OH:28]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=O)CCc2ccccc21)c1ccccc1
Solvent: CC(=O)O
Product: Oc1ccc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)cc1C(O)O
Yield: 50.2 %

Procedure:
A mixture of 3 (2.41 g, 9.1 mmol), 5-aminosalicylic acid (1.40 g, 9.1 mmol) and glacial acetic acid (9 mL) was heated under reflux for 2 hours. After cooling, the precipitate was filtered and washed with acetic acid and water. The solid was recrystallized from acetic acid to afford 1.75 g (50% yield) title product as a yellow solid; MS m/z 380 (M−−H) 9.92 min; 1H NMR (DMSO-d6) δ 2.63 (t, 2H), 2.94 (t, 2H), 4.89 (s, 1H), 7.16 (m, 13H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:6]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:7]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:12]([NH:11][S:8]([C:6]1[CH:7]=[C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])[CH:3]=[CH:4][C:5]=1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])(=[O:9])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(C(=O)N(C)C)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
0.85 g of 5-amino-N-tert.-butyl-2-dimethylaminocarbonyl-benzenesulfonamide (Example e) is dissolved in 3.5 ml of DMF at 0° C., and 0.28 g of propionyl chloride and 0.50 ml of triethylamine are added. After the mixture has been stirred at 5° C. for 1 hour, it is taken up in ethyl acetate and washed successively with dilute hydrochloric acid and water. After the mixture has been dried over MgSO4 and the organic phase has been concentrated, 0.60 g of a highly viscous substance, which is employed in subsequent reactions without further purification (Example k), is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[CH:29][CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)COc1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC(F)(F)F)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-(2,2,2-trifluoro-ethoxy)-benzene in analogy to Example 1a): MS (ISP): 478.1 and 480.1 (M+H)+, 378.2 and 380.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Cl[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:10][C:3]=12
Reactant: COC(=O)Cl
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a stirred solution of 2 (7.0 g, 41.3 mmol) in anhydrous THF (100 mL) at −78° C. under a nitrogen atmosphere was added n-BuLi (24.7 mL, 2.5 M in hexanes, 61.8 mmol). After 1 hour, methyl chloroformate (9.6 ml, 124 mmol) was added and the reaction mixture was stirred for an extra hour at the same temperature, quenched with excess methanol and allowed to warm to room temperature. The solvent was then evaporated and the residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from ethyl acetate to afford title compound 37 (4.3 g, 46% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.75 (dd, J=0.8 and 4.8 Hz, 1H), 8.26 (d, J=0.8 Hz, 1H), 7.74 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][CH:15]([CH3:21])[C:16](OCC)=[O:17].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:16](=[O:17])[CH:15]([CH3:21])[CH3:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C(=O)C(C)C)cc1OC
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl 2-methylpropanoate (1.9 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-4-methyl-3-oxopentanenitrile as a brown oil (0.7 g, 3.4 mmol, 28% yield), MS (EI) for C14H17NO3: 248 (MH+).
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11])(=O)[CH3:2].[CH2:12]([NH:14][NH2:15])[CH3:13]>>[CH2:12]([N:14]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[C:1]([CH3:2])=[N:15]1)[CH3:13]
Reactant: CC(=O)C1C(=O)CCCC1=O
Reactant: CCNN
Product: CCn1nc(C)c2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from 2-acetyl-cyclohexane-1,3-dione and ethylhydrazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12](/[C:13](/Cl)=[N:14]\[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[C:27]#[CH:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[CH:28]=[C:27]([C:26]([O:30][CH2:31][CH3:32])=[O:29])[O:15][N:14]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: O/N=C(/Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Temperature: 80 °C

Procedure:
To (E)-4-(benzyloxy)-N-hydroxybenzimidoyl chloride (7.8 g) in Toluene (78 ml), Ethyl propiolate (7.25 ml) was added and stirred. To this, Et3N (4.58 ml) was added dropwise since reaction was exothermic and the reaction mixture was then heated to 80° C. for 2 hours. The reaction mixture was cooled, diluted with Ethyl acetate and washed successively with 0.1M Aqueous HCl, water and brine. Organic layer was collected and concentrated to obtain dark brown residue which was purified by column chromatography (silica gel, DCM) to obtain pale brown solid which was crystallized from DCM-Petroleum ether to obtain the title compound as off white solid. Yield: 2.83 g (29%); MS (ES+): m/z 324 (M+1); 1HNMR (CDCl3; 300 MHz): δ 7.8 (d, 2H), 7.36-7.47 (m, 5H), 7.28 (s, 1H), 7.1 (d, 2H), 5.14 (s, 2H), 4.48 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6]N1CCN(C2C=CC=CC=2OC)CC1)#N.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O:32]1CCCC1>C(OCC)C>[C:6]([C:5]1[CH:4]=[CH:3][CH:23]=[CH:22][CH:21]=1)(=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: COc1ccccc1N1CCN(Cc2cccc(C#N)c2)CC1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To an ice-cooled solution of 1-(3-cyanobenzyl)-4-(2-methoxyphenyl)piperazine (16.5 g, 53.7 mmol) in 800 mL of tetrahydrofuran was added a solution of phenylmagnesium bromide in ethyl ether (53.6 mL, 3.0M) under nitrogen. The solution was slowly warmed to 25° C. and then brought to reflux. After 8 h of reflux, the reaction mixture was subsequently cooled to 0° C., and ice cold 6N HCl solution (650 mL) was added. The reaction mixture was then stirred at ambient temperature for 8 h. After cooling, the reaction mixture was poured into a separatory funnel and washed with ether. The aqueous layer was then basified with K2CO3 and then extracted with chloroform. The organic extracts were combined, dried (Na2SO4), and concentrated to provide a dark brown oil. This material was purified on a Waters Delta Prep 3000 LC apparatus (10% hexaneschloroform) to afford 19.4 g (93%) of desired benzophenone as a brown oil whose 1H NMR in CDCl3 was consistent with the desired structure.