Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:13]C(N)=O>C1(C)C(C)=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:13][C:7]2=[O:8]
Reactant: NC(N)=O
Reactant: O=C1OC(=O)c2c(I)cccc21
Solvent: Cc1ccccc1C
Product: O=C1NC(=O)c2c(I)cccc21
Yield: 60.1 %

Procedure:
A solution of 4-iodo-2-benzofuran-1,3-dione (0.55 g, 2.01 mmol) and urea (0.24 g, 3.99 mmol) in xylene (5 mL) was heated to reflux overnight. After cooling, the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 5-10% ethyl acetate/isohexane gave 4-iodo-1H-isoindole-1,3(2H)-dione as a pale yellow solid (330 mg, 60%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].C([O-])(O)=O.[Na+].N#N>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=3)=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CN(C)CCn1cc(Br)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 100 °C
Yield: 20.9 %

Procedure:
To 5-bromo-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.352 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (183 mg, 0.457 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled N2 gas for 10 minutes then Pd(Ph3P)4 (40.7 mg, 0.035 mmol) was added. The mixture was again bubbled N2 gas for 5 minutes then capped and the reaction was heated at 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (3×mL). The organics were combined and washed with brine, dried over Mg2SO4, filtered and concentrated. The resulting amber color oil was dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 7% ACN/H2O, 0.1% TFA to 37% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added to saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then it was transferred into a 40 mL vial with MeCN then added water and freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (35 mg). LC/MS (ES) m/z=477.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.09 (d, J=8.08 Hz, 1H), 7.33 (s, 2H), 7.15-7.30 (m, 4H), 6.06 (br. s., 2H), 4.24-4.33 (m, 4H), 3.95 (s, 2H), 3.24-3.30 (m, 2H), 2.72 (br. s., 2H), 2.24 (br. s., 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][CH2:10][CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: C1=COCCC1
Reactant: OCCSc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Oc1ccc(SCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
17.91 g of 2-hydroxyethyl 4-hydroxyphenyl sulfide prepared by the above process (1) was dissolved in 280 ml of tetrahydrofuran. 0.18 g of p-toluenesulfonic acid was added to the solution. A solution of 17.69 g of 3,4-dihydro-2H-pyran in 140 ml of tetrahydrofuran was added dropwise to the mixture under cooling with ice and then the mixture was stirred at room temperature for 4 h. The solvent was distilled off and the residue was extracted with diethyl ether, washed with an aqueous sodium hydrocarbonate solution and dried over anhydrous magnesium sulfate. The resulting solution was filtered and the filtrate was concentrated and subjected to silica gel column chromatography to obtain 15.38 g (yield: 58%) of the intended compound having the following physical properties:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O-:11][C:12]#[N:13].[K+].C(O)(=O)C.O>C(O)(C)C>[C:5]1([C:3]2[NH:13][C:12](=[O:11])[O:1][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CO)c1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)co1
Temperature: 50 °C
Reaction time: 5 h
Yield: 40.8 %

Procedure:
To a solution of 2-hydroxyacetophenone (10.0 g, 73.4 mmol) and potassium cyanate (11.9 g, 147 mmol) in isopropanol (50 ml) was added dropwise acetic acid (10.1 ml, 176 mmol) at 50° C., and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give 4.83 g (40.9%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH2:6][C:5]([C:14]([O:16]C)=O)=[CH:4][CH2:3]1.Br[CH2:19][Cl:20].C([Li])CCC.CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.C(OCC)(=O)C>[Cl:20][CH2:19][C:14]([C:5]1[CH2:6][N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]([CH3:1])[CH2:3][CH:4]=1)=[O:16]
Reactant: C=CCOC(=O)N1CC(C(=O)OC)=CCC1C
Reactant: ClCBr
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOC(=O)N1CC(C(=O)CCl)=CCC1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.1 %

Procedure:
To a solution of 1-allyl 3-methyl 6-methyl-5,6-dihydro-1,3(2 H)-pyridinedicarboxylate (0.44 g, 1.85 mmol) and bromochloromethane (0.18 ml, 2.8 mmol) in THF (15 ml) was added −90 to −80° C. a solution of n-butyllithium in hexane (1.59M, 1.75 ml, 2.8 mmol) over a 15 minute period. After stirring for additional 40 minutes, the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH 7.0, 10 ml). After ethyl acetate was added and the mixture was separated with a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (25 g) chromatography to give allyl 5-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (253 mg, 53%).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:75]([O:78][CH3:79])[O:76][CH3:77])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][C:59]1[CH:64]=[CH:63][C:62]([S:65]([CH3:68])(=[O:67])=[O:66])=[CH:61][CH:60]=1)=[CH:53][C:52]=2[O:69][CH:70]([CH3:74])[CH2:71][O:72][CH3:73])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(#N)C>[CH3:77][O:76][CH:75]([O:78][CH3:79])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][C:54]([O:58][C:59]2[CH:60]=[CH:61][C:62]([S:65]([CH3:68])(=[O:66])=[O:67])=[CH:63][CH:64]=2)=[CH:53][C:52]=3[O:69][CH:70]([CH3:74])[CH2:71][O:72][CH3:73])=[N:46][CH2:45]1
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)NCC(SCc3ccccc3)C(OC)OC)[nH]c12
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CSc1ccccc1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(C(OC)OC)S3)[nH]c12
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To an ice-cooled and stirred solution of triphenylphosphine oxide (0.43 g) in acetonitrile (8 mL) was added trifluoromethanesulfonic anhydride (0.13 mL), and the mixture was stirred at 4° C. for 30 min, followed by an addition of a solution of N-[2-(benzylsulfanyl)-3,3-dimethoxypropyl]-7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (0.25 g) and thioanisole (0.093 mL) in acetonitrile (5 mL). After stirring at 4° C. for 30 min, the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution, and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated. The resulting precipitate was removed by filtration and washed with ethyl acetate-hexane. The combined filtrate and washings were concentrated and the residue was purified by basic silica gel chromatography (ethyl acetate:hexane=25:75 to 35:65, volume ratio) and then by silica gel chromatography (ethyl acetate:hexane=25:75 to 80:20) to give a colorless oil, which was crystallized from diethyl ether-hexane to give the title compound (21 mg, 10%) as colorless crystals. MS 535 (MH+). mp 109-112° C.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[C:8]=1[F:14].[B:15](OC)([O:18]C)[O:16]C.Cl>CCCCCC.C(OCC)C.O>[Br:6][C:7]1[C:8]([F:14])=[C:9]([B:15]([OH:18])[OH:16])[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1c(Br)cccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
290 ml of a 1.6 molar solution of butyllithium in hexane are added dropwise at −70° C. to a solution of 112 g of 2,6-dibromofluorobenzene [1435-54-7] in 1000 ml of diethyl ether. After the mixture has been kept at the same temperature for 2 hours, 60 ml of trimethyl borate are added, and the mixture is stirred at this temperature for 12 hours. After the mixture has been slowly warmed to room temperature, 300 ml of water are added, and the pH is adjusted to 1 by addition of hydrochloric acid. The organic phase is separated off, the aqueous phase is extracted twice with 100 ml of ether each time, and the combined organic phases are dried under reduced pressure, giving 91 g of 3-bromo-2-fluorophenylboronic acid (mixed with its cyclic anhydride) as a brown solid; 1H-NMR (DMSO-d6): 7.1-7.7 (m) ppm, 19F-NMR (DMSO-d6): −99 ppm.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:35])=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: COc1cc(C=CC(=O)O)ccc1OCc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccc3cnn(CCN4CCCC4)c3c2)ccc1OCc1ccccc1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-benzyloxy-3-methoxy-phenyl)-acrylic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 497 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.85 (m, 2 H), 2.01 (m, 2 H), 3.06 (m, 2 H), 3.55 (m, 2 H), 3.71 (m, 2H), 3.85 (s, 3 H), 4.71 (t, J=6.24 Hz, 2 H), 5.15 (s, 2 H), 6.79 (m, 1 H), 7.12 (m, 1 H), 7.18 (m, 2 H), 7.26 (m, 1 H), 7.35 (m, 1 H), 7.41 (m, 2 H), 7.46 (m, 2 H), 7.55 (m, 1 H), 7.74 (m, 1 H), 8.10 (s, 1 H), 8.41 (s, 1 H), 9.63 (br s, N H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Subsequently, 3.13 g of the 1-benzyl-3-methyl-4-piperidone obtained above was dissolved in 6 ml of ether. The solution was added dropwise to a suspension of 0.44 g of lithium aluminum hydride in 25 ml of ether over 5 minutes while maintaining the temperature at 24°-27° C. Then, the mixture was stirred at 25° C. for 10 minutes, and, 5 ml of water was added thereto under ice-cooling. The mixture was extracted with 30 ml of ether four times. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 3.17 g of an oily matter of 1-benzyl-4-hydroxy-3-methylpiperidine.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])=[CH:26][CH:27]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)C)ccc3OC)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)C)ccc3OC)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate (example 54) (0.50 g, 0.968 mmol) and sodium hydroxide (1M, 1.93 ml, 1.93 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid as a colourless gum, which contained 0.44 mol equivalents of ethyl acetate; 0.48 g (94%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][C:13]2[N:16]=[N:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[C:20]1([C:18]2[N:17]=[N:16][C:13]3[CH2:14][CH2:15][NH:9][CH2:10][CH2:11][C:12]=3[CH:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(-c2cc3c(nn2)CCNCC3)cc1

Procedure:
40 mL hydrogen chloride in dioxane was added to 5.5 g 3-phenyl-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 40 mL dioxane at 5° C. The reaction was stirred over night. The solvent was removed and co-evaporated with ethyl acetate to yield 3.7 g of the desired product. Rt: 4.09 min (method AE), (M+H)+: 226
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH2:24]CC[C:21]2=[O:25])=[CH:17][CH:16]=1.ICC.[Cl-].[NH4+]>O1CCCC1>[CH2:10]([CH:9]1[CH2:8][CH2:24][N:20]([CH2:19][C:18]2[CH:26]=[CH:27][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:21]1=[O:25])[CH3:11]
Reactant: COc1ccc(CN2CCCC2=O)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC1CCN(Cc2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (4.1 mL) in tetrahydrofuran (25 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 18 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., a solution of 1-(4-methoxybenzyl)pyrrolidin-2-one (5.0 g) obtained in Step A in tetrahydrofuran (25 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hr. Iodoethane (2.9 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1[CH2:37][NH2:38]>C(#N)C>[CH3:12][N:9]1[CH:10]=[CH:11][C:7]([CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:2]([CH:3]=2)[NH:38][CH2:37][C:27]2[CH:28]=[CH:29][C:30]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:31][C:26]=2[CH3:25])=[N:8]1
Reactant: Cc1cc(OC(F)(F)F)ccc1CN
Reactant: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole (143 mg, 0.573 mmol) in acetonitrile (10 mL) was added K2CO3 (317 mg, 2.3 mmol) followed by (2-methyl-4-(trifluoromethoxy)phenyl)methanamine (117 mg, 0.573 mmol). The mixture was stirred at 90° Celsius overnight. The reaction was cooled to RT and concentrated to dryness. The resulting residue was dissolved in DCM (50 mL) and washed with water (50 mL). The organic phase was concentrated to give the title compound. MS (ESI): mass calcd. for C20H19F3N4O4, 436.14; m/z found, 437 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CCOCC.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C1COCC1>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of pyridin-3-ylamine (20 g, 212.49 mmol, CAS RN 462-08-8) in a mixture of THF:Et2O (175 mL; 2.5:1 v/v) was added slowly a solution of pivaloyl chloride (26 mL, 212.5 mmol, CAS RN 3282-30-2) in THF (50 mL) and Et3N (44 mL, 318.7 mmol) at 0° C. and left stirring at that temperature for 1 h. After the completion of reaction, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The crude filter cake was washed with n-hexane to yield the title compound. Colorless crystalline solid (32 g, 85%). MS (ESI): m/z=179.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1>[Pd]>[C:11]1([CH2:10][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([CH2:7][OH:8])=[CH:5][CH:6]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccc(C=Cc2ccccc2)cc1
Agent: [Pd]
Product: OCc1ccc(CCc2ccccc2)cc1

Procedure:
Hydrogenating 10 g (48 mmol) of 4-stilbenemethanol (Aldrich; Milwaukee/USA) in 100 ml of 1THF, in the presence of 0.5 g of 5% Pd/C under low pressure and at RT, filtering through ®Celite (filtering aid based on kieselguhr; Johns-Manville Corp., obtainable from Fluka, Buchs, Switzerland) and evaporating the filtrate affords the title compound, approximately 15% of which, according to the 1H-NMR spectrum, consists of p-(2-phenylethyl)toluene: TLC Rf (A)=0.62; 1H-NMR (200 MHz, CDCl3): 2.92 (s, 4H), 4.68 (s, 2H), 7.15-7.35 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].ClCCl>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:22]([C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
For example, 4-amino-benzoic acid methyl ester, is treated with a sulfonyl halide, in this case 4-methanesulfonyl benzenesulfonyl chloride, in a suitable solvent, such as a 1:1 mixture of dichloromethane and pyridine at ambient temperature for 2-24 hours to yield 4-(4-methanesulfonyl-benzenesulfonylamino)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH2:9][NH2:10])([CH3:8])[CH2:5][CH:4]([NH2:11])[CH2:3]1.[CH3:13][C:14]1[O:20]C(C)(C)[O:18][C:16](=O)[CH:15]=1>C1(C)C(C)=CC=CC=1>[C:16]([NH:11][CH:4]1[CH2:3][C:2]([CH3:12])([CH3:1])[CH2:7][C:6]([CH2:9][NH:10][C:16](=[O:18])[CH2:15][C:14]([CH3:13])=[O:20])([CH3:8])[CH2:5]1)(=[O:18])[CH2:15][C:14]([CH3:13])=[O:20]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)NCC1(C)CC(NC(=O)CC(C)=O)CC(C)(C)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To isophoronediamine (139.24 g, 0.819 mol) in xylene (525 ml) at 120° C. was added with stirring 2,2,6-trimethyl-1,3-dioxen-4-one (232.51 g, 1.637 mol) in xylene (525 ml) over 10 minutes, during which the temperature decreased to 103° C. Vigorous effervescence and distillation of acetone (through a Vigreux column) immediately commenced. Pot temperature was increased to 120° C. over 15 minutes, and to 139° C. over a further 30 minutes, with collection of acetone distillate. After cooling to 58° C., supernatant solution was separated from deposited gum, which was dissolved in dichloromethane. Removal of solvent from combined solutions and drying (91° C./100 Pa) gave 1-acetoacetamido-3-acetoacetamidomethyl-3,5,5-trimethylcyclohexane (270.21 g, 98%), (AAMTCH), which was crushed to a light yellow powder, mp 144-147° C. (mixture of E and Z isomers), and identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4]1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[O:3]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4]1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccoc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of zinc chloride (16.0 g, 117 mmol) in diethyl ether (250 ml) was added sodium borohydride (8.9 g, 235 mmol) and the mixture was stirred at room temperature for 2 hrs. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(3-furanyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (20 g, 58.8 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give ethyl (2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (19.7 g, 98%) as a colorless oil.