Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(Br)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 5-bromothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39-7.29 (m, 2H), 7.20-7.05 (m, 3H), 6.96 (d, J=3.6 Hz, 1H), 5.85 (dt, J=2.1, 9.0 & 17.4 Hz, 1H), 5.54 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:35]=[C:34]([NH:33][C:31]4[CH:30]=[CH:29][C:28]5[O:23][CH2:24][CH2:25][O:26][C:27]=5[CH:32]=4)[N:36]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc2c(c1)OCCO2
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3ccc4c(c3)OCCO4)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-guanidine nitrate were converted to I-28 (71%): HRMS Calcd. for C20H15ClN4O3: 395.091, Found 395.0912.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][C:7]([I:15])=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]1=[O:16].[OH2:18].Br>CO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[C:7]([I:15])[CH:6]=[C:5]2[C:10]=1[C:2](=[O:18])[C:3](=[O:16])[NH:4]2
Reactant: O
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1(Br)Br
Agent: Br
Solvent: CO
Product: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O

Procedure:
The crude 3,3-dibromo-4-trifluoromethyl-6-iodooxindole (35.11 g) prepared above was dissolved in MeOH (1200 mL) and H2O (300 mL) was added. The resulting mixture was heated at reflux for 3 hours and then aqueous 48% HBr (10 mL) was added. The solution was then heated at reflux for 27 hours. The MeOH solvent was removed in vacuo to give a brown/yellow solid. The solid was isolated by filtration, washing the collected solid with copious amounts of H2O. The solid was then dried overnight in a vacuum desiccator (NaOH as desiccant) to give the desired isatin as a light brown solid (20.8214 g, 95% (two steps)).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([OH:3])=O.[CH2:15]([CH2:17][NH2:18])[OH:16]>>[OH:16][CH2:15][CH2:17][NH:18][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3]
Reactant: NCCO
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Product: COc1cc(C(=O)NCCO)ccc1B(O)O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate K from 4-carboxy-2-methoxyphenyl boronic acid and ethanolamine. The solvent was removed and then water and EtOAc were added. The phases were separated and the aqueous one was extracted twice with EtOAc. The organics extracts were combined and dried (Na2SO4), and concentrated. The residue was triturated in acetonitrile to give the title compound. tR: 0.42 min (LC-MS 2); ESI-MS: 240.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [O:1]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].[ClH:33].Cl.Cl.[NH2:36][NH:37][C:38]([NH2:40])=[NH:39]>CO>[ClH:33].[ClH:33].[C:28]([NH:31][N:32]=[CH:21][C:20]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[N:36][NH:37][C:38](=[NH:39])[NH2:40])[CH:19]=1)(=[NH:30])[NH2:29]
Reactant: N=C(N)NN
Reactant: COc1ccc(C=O)cc1OCCCCCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(C=NNC(=N)N)cc1OCCCCCOc1cc(C=NNC(=N)N)ccc1OC
Yield: 211 %

Procedure:
Compound 25, FIG. 7E.25: 3,3'-(pentamethylenedioxy)di-p-anisaldehyde (0.748 g), aminoguanidine hydrochloride (0.553 g), and aminoguanidine dihydrochloride (0.01 g) were heated in methanol (5 mL) for 18 hr. Cooling and filtration gave 0.080 g of 3,3'-(pentamethylenedioxy)di-p-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 195°-8° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:11][CH2:12][CH:13]([CH3:17])[CH2:14][CH2:15][Br:16])C(OCC)=O)C.Br.C1C=CC=CC=1>O>[Br:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12][CH2:11][CH2:5][C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(CCC(C)CCBr)C(=O)OCC
Agent: Br
Solvent: O
Solvent: c1ccccc1
Product: CC(CCBr)CCCC(=O)O

Procedure:
30 g of (5-bromo-3-methylpentyl)-malonic acid diethyl ester were heated to the boil, while stirring, with 15 ml of 48% HBr and 15 ml of HBr/glacial acetic acid, whereby the low-boiling products were distilled off. After 7 hours the cooled reaction solution was distributed between benzene and water and the organic phase was evaporated with MgSO4 after drying and distilled off.
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6](=[O:16])[C:7]3[C:12]([C:13]2=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH:3]=[CH:2]1.[H][H]>[Pd].C(O)(=O)C>[CH2:4]1[C:5]2[C:14](=[C:13]([OH:15])[C:12]3[C:7]([C:6]=2[OH:16])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:1][CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)C2CC=CCC12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1c2c(c(O)c3ccccc13)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
300 ml of acetic acid, 64 g of 1,4,4a,9a-tetrahydro-anthraquinone and 0.6 g of a catalyst containing 5% of palladium deposited on charcoal are introduced into an autoclave. The charge is heated to 100° C. and hydrogen is introduced under a pressure of 30 bars. The reaction is continued for 4 hours while maintaining the pressure at between 20 and 30 bars. After cooling, the precipitate obtained is separated by filtration, washed with water and dried. 56 Grams of 1,2,3,4-tetrahydro-9,10-anthracene-diol (melting point 210°-212° C.) are obtained. The yield is 86.7% without taking into account the fraction of product remaining in solution in the acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]4[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:23]=34)[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:30]>>[NH2:30][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]4[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][CH2:24][C:23]=34)[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC1CO1
Reactant: N
Product: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC(O)CN

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazole (500 mg, 1.18 mmol) in 2 N methanolic ammonia (7 mL) is heated in a sealed vial to 100° C. for 5 min in a microwave oven (300 W, active cooling during irradiation). The solvent is evaporated and the residue is purified by prep. HPLC (GROM-SIL ODS-4 HE, 75×30 mm ID, 10 μm, 20-95% acetonitrile in water containing 0.5% formic acid) to afford 1-amino-3-{4-[5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (220 mg) as a colourless resin; LC-MS: tR=0.92 min, [M+1]+=428.38.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].Cl[CH2:30][C:31](=O)[CH3:32]>CN(C)C=O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:28][CH2:30][C:31]([CH3:32])=[N:27][N:26]=1
Reactant: CC(=O)CCl
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Solvent: CN(C)C=O
Product: CC1=NN=C(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A mixture of 1.00 g (2.50 mmol) of the starting material XVIII, 20 ml of dimethylformamide and 0.57 g (6.16 mmol) of chloroacetone was stirred at room temperature for 2 h. After dilution with water the precipitated crystals were filtered off and purified by refluxing in ethyl acetate to yield 0.73 g (67%) of the title compound; Mp.: 203-204° C.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]([F:28])[F:27])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:29]C(=O)C(C)C.[OH-].[Na+].Cl>CO.O>[F:35][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]([F:27])[F:28])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[OH:29]
Reactant: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)n(CC(F)F)c2nccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3n(CC(F)F)c2=O)c1OC(F)F

Procedure:
A solution of isobutyric acid 7-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 2.8) (0.138 g), sodium hydroxide (0.022 g) in methanol (4 ml) and water (1 ml) were stirred at ambient temperature for 3 hours. The reaction mixture was poured into water and neutralised by addition of aqueous hydrochloric acid (2M). The mixture was extracted with ethyl acetate. The organic phase was washed with water, aqueous sodium hydrogen carbonate (saturated) and brine, dried over anhydrous sodium sulfate and concentrated to give Compound No. B25 of Table B (0.095 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][S:7][CH2:8][CH2:9][NH2:10])[N:3]=[CH:2]1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:11]([NH:19][C:20]([NH:10][CH2:9][CH2:8][S:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCSCc1c[nH]cn1)c1ccccc1
Yield: 63.7 %

Procedure:
(i) A solution of 2-(4-imidazolylmethylthio)ethylamine (6.0 g) and benzoyl isothiocyanate (6.0 g) in chloroform (150 ml) was heated under reflux for one hour. Concentration followed by recrystallisation from ethyl acetate-isopropyl acetate afforded N-benzoyl-N'-(2-(4-imidazolylmethylthio)-ethyl)thiourea (7.5 g). An analytically pure sample (from aqueous isopropyl alcohol) had m.p. 126°-128°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=[CH:10][CH3:11].[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=1>CN(C)C=O>[CH2:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[CH:9]=[CH:10][CH3:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCNc1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
1.4 g of anhydrous potassium carbonate and 1.0 g of 1-chloro-2-butene were added to 1.6 g of 3-aminobenzotrifluoride in 30 ml of dimethylformamide, followed by stirring at 70°-90° C. for 2 hours. Potassium carbonate was then removed by filtration, and 100 ml of an aqueous saturated sodium chloride solution were added and extraction was then carried out with toluene. After drying over anhydrous sodium sulfate, the solvent was distilled off, and silica gel chromatography was then done to obtain 1.4 g of the desired compound.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(OC(C)(C)C)=O.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:40]3[CH:41]=[CH:42][C:37]([NH2:36])=[CH:38][CH:39]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1

Procedure:
Compound 59a was prepared from compound 3a and 4-(N—BOC-amino)phenylboronic acid using the methods described in the Example 1, Step G, followed by the TFA deprotection of the resulting product. Mass Spectrum LCMS, ESI (pos.) Calcd. for C27H26N6O: 451.2 [M+H]. found 451.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([O:19][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:15]([F:18])([F:16])[F:17])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](O)C(F)(F)F)COC1(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](Oc2ccc([N+](=O)[O-])cc2)C(F)(F)F)COC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a cooled, stirred solution of (S)-2,2-dimethyl-4-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.99 g) and 1-fluoro-4-nitrobenzene (0.69 ml) in THF (20 ml) at 0° C. was added dropwise potassium bis(trimethylsilyl)amide solution (7.7 ml, 1 M solution in THF). The reaction mixture was stirred for 30 min at 0° C., then allowed to warm to room temperature and stirred for a further 1 h. The mixture was then diluted with dichloromethane and washed with sat. aq. ammonium chloride solution. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(R)-3,3,3-trifluoro-2-(4-nitro-phenoxy)-propyl]-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow viscous oil (2.7 g, 97%). MS (ISP): 435.3 ([M+H]+), 379.3 ([M+H—C4H8]+), 335.4 ([M+H—C4H8—CO2]+).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[CH:10][C:11]=1[CH3:12]>>[Cl:3][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:6]([F:5])[CH:7]=1
Reactant: Cc1ccc(CO)cc1F
Reactant: O=S(Cl)Cl
Product: Cc1ccc(CCl)cc1F
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.892 g, 7.5 mmol) was added to a solution of the product of STEP 1 (1.0 g, 6.4 mmol) dropwise at 0° C. After 30 min, the reaction was quenched with crushed ice carefully, and diluted with H2O. The product was extracted with ether. The organic layer washed with saturated NaHCO3, brine and dried with Na0.2SO4. Ether was evaporated and the residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to give a clear liquid in 10.5 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Cl:22][C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:30][C:24]1[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]=1[Cl:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Yield: 76.2 %

Procedure:
To the mixture of 1.5 g (4.61 mmol) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 1.04 g (6.44mmol) of 2-chloro-4-bromophenol, and 0.89 g (8.76 mmol) potassium carbonate was added 10 mL of anhydrous DMF. The resulting mixture was heated to 110° C. for five hrs. After cooling to room temperature the reaction was treated with 150 mL of ethyl acetate. The organic phase was washed with saturated sodium bicarbonate three times and brine three times and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on a silica gel column with EtOAc/hexane (1:9) to afford 1.8 g (76.3%) of a light yellow solid: 1H NMR (CDCl3/400MHz) 7.69(s, 1H), 7.68(s, 1H), 7.47 (dd,1H, J=2.4 Hz, 8.7 Hz), 7.37 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.38(s, 1H), 5.70(q, 1H, J=6.6 Hz), 4.35 (m, 2H), 1.38(t, 3H, J=7.2 Hz). MS (ESI+) 511 (M+1, 60), 513 (M+3, 100); HRMS (El) m/z calcd for (C19H12BrCl2F3O4) 509.9248, found 509.9274.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[C:10]([C:27]([F:30])([F:29])[F:28])[CH:9]=1>C1COCC1>[CH3:20][N:17]1[CH2:16][CH2:15][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=2[C:27]([F:28])([F:29])[F:30])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Add LiAlH4 (66.5 mg, 1.75 mmol) at 0° C. to the mixture of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperidine-1-carboxylat (151 mg, 0.438 mmol) in THF (3 mL), stir the reaction mixture overnight at room temperature. Quench the reaction with 15% sodium hydroxide solution, filter and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (silica gel, DCM:MeOH=15:1) to afford the desired product (70 mg, 56%). MS: (M+1): 259.1.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH:43]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)CC=O
Reactant: O=C(N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CCN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 44.6 %

Procedure:
The product from Example 31D (80 mg, 0.141 mmol), 3-methylbutanal (18 μl, 0.170 mmol), acetic acid (10 μl, 0.166 mmol), and sodium triacetoxyborohydride (48 mg, 0.226 mmol) were processed as described in Example 27 to provide the title compound (40 mg, 45%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.78 (s, 2H), 7.32-7.11 (m, 10H), 5.32-5.08 (m, 6H), 3.95 (br s, 2H), 2.83 (br s, 2H), 2.71 (dd, 2H), 2.48-2.23 (m, 4H), 1.43 (m, 2H), 1.08 (m, 2H), 0.76 (t, 6H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCNCC1C1CCc2cccc(Cl)c2C1

Procedure:
Using the method of Example 3, 0.5 g (2.78 mmol) of 8-chloro-2-tetralone was treated with N-methylpiperazine, and the resulting product was reduced with sodium borohydride and the product treated with maleic acid to obtain 0.48 g of the title compound as colorless crystals, m.p. 199°-201° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>C(O)C>[CH:1](=[C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 0.67 M solution of the benzaldehyde (20.0 mmol) and cyclohexanone (10.0 mmol) in ethanol (15 ml) is added 10 ml 40% KOH at 10° C. After stirring for 12-24 hr at room temperature, the solution is diluted and filtered. The precipitate is recrystallized from ethanol to afford 2,6-dibenzalcyclohexanone and its derivatives. VIII. 2,6-DIBENZYLIDENECYCLOPENTANONE Derivatives
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CCOC(C)=O>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:3](/[CH:8]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ncccc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-fluoropicolinaldehyde (300 g, 2400 mmol), copper sulfate (572 g, 3600 mmol) and (S)-2-methylpropane-2-sulfinamide (319 g, 2640 mmol) in DCM (3 L) in a 10 L 3-neck round bottom flask was stirred for 3 h at rt. The progress of reaction was monitored by TLC (30% EtOAc in petroleum ether). After completion of reaction, the solid was filtered off and the filtrate was concentrated under vacuum. The residue was purified by column chromatography using silica (60-120 mesh) with 20% EtOAc in n-hexane as eluent to give (S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.89 (s, 1H), 8.64 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 1.29 (s, 9H). MS (ESI pos. ion) m/z: 155.0 (M−O and t-Bu).
Reaction SMILES: [CH2:1]([OH:6])[CH:2](O)[CH2:3][CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:18]1([CH3:33])[CH:23]=[CH:22][C:21]([S:24]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][CH3:31])(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:1]([O:32][CH:29]([CH2:30][CH3:31])[CH2:28][O:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH3:33])=[CH:23][CH:22]=1)(=[O:25])=[O:26])(=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCC(O)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCC(O)CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCC(=O)OC(CC)COS(=O)(=O)c1ccc(C)cc1

Procedure:
Using 1,2-butanediol, pyridine and p-toluenesulfonyl chloride, (RS)-1-p-toluenesulfonyloxy-2-butanol 2b ##STR24## was prepared in the same manner as Example 1 of Production.