Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[OH:20].C(O)(=O)CCCCCC=C.N1CCC[C@H]1C(O)=O.C(C1N=C(C2C=C(O[CH:60]3[CH2:78][CH:77]4[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67]C[CH2:69][CH:70]=[CH:71][CH:72]5[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]4=[O:79])[CH2:73]5)[CH2:61]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:60]1[CH2:78][CH:77]2[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:69][CH:70]=[CH:71][CH:72]3[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]2=[O:79])[CH2:73]3)[CH2:61]1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: C=CCCCCCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 8-chloro-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (46), oct-7-enoic acid and intermediate 5 following the procedure (Step D-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=653 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>>[OH:27][C:26]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:23](=[O:24])[C:22]=1[S:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH3:14])[CH:16]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: Cc1cccc(SC(C(=O)O)C(=O)O)c1
Product: Cc1cccc(Sc2c(O)cc(-c3ccccc3)oc2=O)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methylphenyl)thio]propanedioic acid (1.43 g, 5.07 mmol). m.p. 197°-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3H), 6.89 (s, 1H), 6.93 (t, 1H), 6.97 (s, 1H), 7.14 (t, 2H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH:15]=[O:16])=[CH:9][CH:8]=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:34].F.[F-]>C(OCC)(=O)C>[F:34]/[C:13](/[C:10]1[CH:11]=[CH:12][C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[CH:14]\[CH:15]=[O:16]
Reactant: O=CC#Cc1ccc(-c2ncccn2)cc1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=C/C=C(\F)c1ccc(-c2ncccn2)cc1
Temperature: 110 °C
Yield: 50.3 %

Procedure:
A mixture of 3-[4-(2-pyrimidinyl)phenyl]-2-propynal (210 mg, 1.01 mmol, prepared as described in Reference Example 300) and tetrabutylamonium dihydrogentrifluoride (50 wt % in 1,2-dichloroethane, 1.8 g, 3.0 mmol) was heated to 110° C. for 4 h. The cooled reaction mixture was diluted with ethyl acetate (30 mL), washed with aq. sat. NaHCO3 (30 mL) and brine (30 mL), and filtered through a plug of SiO2 (5 g). The SiO2 plug was rinsed with additional ethyl acetate (30 mL) and the combined filtrates were concentrated. Purification by chromatography (SiO2, 97:3 dichloromethane/ethyl acetate) provided 116 mg (51%) of the title compound as a colorless solid. MS 229 (M+H)+. Also isolated were (2Z)-3-chloro-3-[4-(2-pyrmidinyl)phenyl]-2-propenal (10 mg, 4%, MS 245, 247 (M+H)+) and recovered starting material (15 mg, 7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Li+].[Cl-].I[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1.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]>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2c(F)ccc([N+](=O)[O-])c2F)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. Pd(dba)2 (17 mg, 3 mol %) and P(o-furyl)3 (14 mg, 6 mol %) dissolved in THF (2 mL), followed by the addition of ethyl 4-iodobenzoate (359 g, 1.3 mmol), were then transferred via cannula at -20° C. The resulting mixture was allowed to warm up slowly to 25° C. overnight. The reaction mixture was then quenchend with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:2) furnished compound 17a (281 mg, 92%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH2:27][CH3:28])[CH3:26])=[CH:21][CH:20]=1)=[O:17]>CCO>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:13]=[C:6]2[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)=[CH:20][CH:21]=1)([CH2:27][CH3:28])[CH3:26]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Yield: 80.6 %

Procedure:
4-methyl-3-nitrobenzaldehyde (0.246 g, 1.50 mmol) and anhydrous CuCl2 (0.400 g, 3.00 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.400 g, 1.50 mmol) in anhydrous EtOH (15 mL). After heating at reflux temperature for 2 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 60% EtOAc in heptane, afforded 3-(4-sec-butylphenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.500 g, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[O:4][C:3]1=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[CH:14]2>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[C:5](=[O:7])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:4])=[O:8]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1C(=O)CC(C)(C)C(=O)O

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (7.8 mmol, 1.0 g), 5-chloro-2-methylindole (13.8 mmol, 2.28 g), and AlC3 (9.0 mmol, 1.2 g) were stirred in 100 mL DCE overnight at 65° C. The reaction was cooled and quenched with 10 mL water. The resultant precipitate was filtered and washed with a small amount of DCE giving 1.06 g of the sub-titled compound.
Reaction SMILES: C([C@@H]1C[C@H](O)C[C@@H]1C(N(C1N=C2C=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1)N)=O)C.CC([Si](Cl)(C)C)(C)C.N1C=CN=C1.[Si:45]([O:52][C@@H:53]1[CH2:57][C@H:56]([C:58]([NH:60][NH:61][C:62]2[N:63]=[C:64]3[CH:70]=[CH:69][N:68]([S:71]([C:74]4[CH:80]=[CH:79][C:77]([CH3:78])=[CH:76][CH:75]=4)(=[O:73])=[O:72])[C:65]3=[N:66][CH:67]=2)=[O:59])[C@H:55]([CH2:81][CH3:82])[CH2:54]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>CN(C=O)C>[Si:45]([O:52][CH:53]1[CH2:57][CH:56]([C:58]([NH:60][NH:61][C:62]2[N:63]=[C:64]3[CH:70]=[CH:69][N:68]([S:71]([C:74]4[CH:75]=[CH:76][C:77]([CH3:78])=[CH:79][CH:80]=4)(=[O:73])=[O:72])[C:65]3=[N:66][CH:67]=2)=[O:59])[CH:55]([CH2:81][CH3:82])[CH2:54]1)([C:48]([CH3:49])([CH3:50])[CH3:51])([CH3:46])[CH3:47]
Reactant: CC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)N(N)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4S)-2-ethyl-4-hydroxy-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbo-hydrazide (9.06 g, 20.43 mmol) in DMF (40.9 mL) was added TBDMSCl (3.69 g, 24.51 mmol) and imidazole (3.48 g, 51.1 mmol). The reaction mixture was stirred at ambient temperature for about 4 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (200 mL), filtered, and washed with EtOAc (20 mL). The filtrate was concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-50% EtOAc in DCM to give a scalemic mixture enriched in (1S,2R,4S)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (11.37 g, 100%) as an orange solid: LC/MS (Table 1, Method b) Rt=3.14 min; MS m/z: 558 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2([CH2:12][OH:13])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[C:31](B(O)O)=[CH:30][C:24]=3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:6]1[N:7]=[C:2]([C:31]2[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:23]3[O:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)=[C:25]([C:26]([NH:27][CH3:28])=[O:29])[C:24]=3[CH:30]=2)[CH:3]=[CH:4][C:5]=1[C:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Reactant: OCC1(c2ccc(Br)nc2Cl)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C4(CO)CC4)c(Cl)n3)cc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of (1-(6-bromo-2-chloropyridin-3-yl)cyclopropyl)methanol (100 mg, 0.381 mmol) and (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)boronic acid (160 mg, 0.381 mmol) in 1,4-Dioxane (2 mL) and water (20 μL) was added K2CO3 (105 mg, 0.762 mmol) and Pd(dppf)Cl2 (55 mg, 0.075 mmol). The mixture was heated to 70° C. and stirred overnight. Filtration through a pad of celite removed the solid. After washing with ethyl acetate, the combined filtrate was concentrated in vacuo. Preparative TLC gave 5-(6-chloro-5-(1-(hydroxymethyl)cyclopropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, yield: 37.6%) MS (M+H)+: 559.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>C(O)C>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:16])[C:12]([NH2:14])=[O:13])=[CH:17][CH:18]=1
Reactant: BrCCCCCBr
Reactant: CC(C)(CCCCOc1ccc(O)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CCCCOc1ccc(OCCCCCBr)cc1)C(N)=O
Yield: 60.7 %

Procedure:
A mixture of 3.0 g 6-(4-hydroxyphenoxy)-2,2-dimethylhexanamide, 50 ml ethanol, 2.5 g potassium carbonate and 3.6 g 1,5-dibromopentane was heated under reflux overnight with stirring. The solvent was distilled off under reduced pressure, the residue was extracted with chloroform, the extract was washed with water and worked up as usual. The crude product thus obtained was purified by silica gel column chromatography, affording 2.90 g of 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanamide.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1([CH3:36])[OH:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1([OH:35])[CH3:36])=[O:11]
Reactant: CC1(O)CCCCC1N
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)NC2CCCCC2(C)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (100 mg, 0.358 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (250 μl, 3.41 mmol) was added followed by 2-amino-1-methylcyclohexanol hydrochloride (65 mg, 0.39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (205 mg, 1.07 mmol) and 1-hydroxybenzotriazole (53 mg, 0.39 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution and diethyl ether. The organic was washed with sat. sodium bicarbonate solution, water and brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (5:95 to 50:50) as eluant to give 5-fluoro-N-(2-hydroxy-2-methylcyclohexyl)-2-[3-(methylsulfanyl)phenoxy]nicotinamide (140 mg) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+].OO>O1CCCC1.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:7]=[CH:2]/[CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC/C=C/c1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 170.2 %

Procedure:
In a four necked flask equipped with a stirrer, a reflux condenser and a thermometer which had been replaced by a nitrogen atmosphere, 1-(4-fluorophenyl)-2-(4-bromophenyl)acetylene (3.3 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), sodium hydroxide (2.4 g, 60 mmol) and tetrahydrofuran (60 ml) were charged. Then, to the mixture, a solution of E-1-pentenylcatecholborane (20 mmol) in tetrahydrofuran (50 ml) was dropwise added at room temperature, followed by heat refluxing for 6 hours while stirring. After cooling the reaction mixture to room temperature, 10% aqueous solution of sodium hydroxide (5 ml) and 30% aqueous hydrogen peroxide (2 ml) were added to the mixture, followed by stirring for 1 hour. The mixture was extracted with ethyl ether. The organic layer was washed with saturated aqueous solution of sodium chloride (20 ml each) twice and dried over anhydrous magnesium sulfate. After evaporating the solvent off, the residue was purified by silica gel column chromatography to obtain 1-(4-fluorophenyl)-2-[4-(1-trans-pentenyl)phenyl]acetylene (2.7 g). Yield: 84%.
Reaction SMILES: [N+:1]([C:4]1[CH:59]=[CH:58][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]4[CH:54]=[CH:53][C:52]([N+:55]([O-])=O)=[CH:51][CH:50]=4)[CH:43]=3)[C:16]3[CH:28]=[CH:27][C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:29]6[S:30][C:31]7[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=7[N:33]=6)=[CH:23][CH:24]=5)[C:19]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:18]=4[CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.C(O)C.O.NN>[Pd].O>[NH2:1][C:4]1[CH:59]=[CH:58][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]4[CH:50]=[CH:51][C:52]([NH2:55])=[CH:53][CH:54]=4)[CH:43]=3)[C:16]3[CH:28]=[CH:27][C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:29]6[S:30][C:31]7[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=7[N:33]=6)=[CH:23][CH:24]=5)[C:19]([CH2:38][CH3:39])([CH2:40][CH3:41])[C:18]=4[CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCC1(CC)c2cc(-c3nc4ccccc4s3)ccc2-c2ccc(N(c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)c2cc(-c3nc4ccccc4s3)ccc2-c2ccc(N(c3cccc(Oc4ccc(N)cc4)c3)c3cccc(Oc4ccc(N)cc4)c3)cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-di[3-(4-nitrophenoxy)phenyl]-7-(benzothiazol-2-yl)-9,9-diethyl-fluoren-2-amine (Example 7; 13.68 g, 17.2 mmol) in 300 mL of 1/1 tetrahydrofuran/ethanol mixture under argon was added 10% palladium/carbon (500 mg). The mixture was heated to 60° C., and hydrazine hydrate (12.7 mL, ˜206 mmol) was added slowly over 40 min by addition funnel. The solution became dark, fluorescent green and, after 8 hr, was cooled to room temperature and poured into 1.5 L of distilled water. After a few hours of stirring to evaporate some THF, a fine yellow solid was filtered and purified by column chromatography eluting with ethyl acetate/toluene. The product was further slurried in 100 mL of hot EtOH, filtered at room temperature, and dried in vacuo at 70° C. overnight to give 8.4 g (65%). 1H NMR (400 MHz, CDCl3) δ ppm: 8.08 (m, 2H), 8.01 (dd, J1=8 Hz, J2=1.6 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.48-7.55 (m, 1H), 7.35-7.42 (m, 1H), 7.05-7.18 (m, 4H), 6.52-6.59 (m, 2H), 3.5-3.6 (br. s, 4H), 1.95-2.15 (m, 4H), 0.34 (t, J=7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ ppm: 168.97, 159.73, 154.38, 152.23, 150.91, 149.04, 148.61, 147.69, 144.56, 142.72, 135.98, 135.07, 131.71, 129.98, 127.39, 126.42, 125.11, 124.19, 123.08, 121.68, 121.59, 121.19, 121.00, 119.60, 119.54, 117.90, 116.31, 113.33, 111.70, 56.57, 32.77, 8.73; MS (m/z): 736 (M+); Anal. Calcd. for C48H40N4O2S: C, 78.23%; H, 5.47%; N, 7.60%; S, 4.35%%. Found: C, 78.01%%; H, 5.60%%; N, 7.62%%; S, 4.31%.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[NH:3][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cl)c(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Powdered potassium hydroxide (2.0 g.) was added in portions over 5 minutes to a stirred solution of 3-amino-4-chlorotoluene (2.8 g.) in dimethylformamide (15 ml.) at the ambient temperature and stirring was continued for a further 5 minutes. A solution of 2-chloro-3,5-dinitro-benzotrifluoride (5.4 g.) in dimethylformamide (15 ml.) was then added over 5 minutes, and following the addition, the mixture was stirred for 30 minutes. After acidification with concentrated hydrochloric acid the mixture was poured into water (15 ml.). The precipitated solid was separated from the supernatant liquid by decantation and recrystallised from methylated spirit to yield 2(2-chloro-5-methylanilino)-3,5-dinitrobenzotrifluoride, with a melting point of 127° C.
Reaction SMILES: C(C1C=C(C)C=C(C)C=1N[C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=O)C.[NH2:31][C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[C:40](=[O:44])[CH:41]([CH3:43])[CH3:42]>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:31][C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])=[O:14])(=[O:21])=[O:22]
Reactant: Cc1cc(C)c(N)c(C(=O)C(C)C)c1
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)C(C)C)c1

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that 2′-amino-3′,5′-dimethyl-2-methylpropiophenone was used instead of 2′-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].C[NH:12][CH2:13][CH2:14][C@@H:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CC(OC)(C)C>[CH:19]1[CH:20]=[CH:21][C:16]([C@H:15]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)[CH2:14][CH2:13][NH2:12])=[CH:17][CH:18]=1.[C:1]([C@H:4]([C@@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2]
Reactant: CNCC[C@@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: CO
Solvent: COC(C)(C)C
Product: NCC[C@@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
(D)-Tartrate (10): To a 50 mL round bottom flask was added 1.63 g (5.53 mmol) of (R)-fluoxetine free amine (9). To this was added 20 mL of methanol and the amine was dissolved. To this solution was added 840 mg of (D)-tartaric acid (5.6 mmol). The reaction mixture was stirred for 30 minutes and then methanol was rotoevaporated to dryness. The solid was slurred in 20 mL of TBME and filtered. The white solid was dried in a vacuum oven for 5 hours at ˜40° C. 2.08 g of (R)-norfluoxetine (D)-tartrate was obtained (85%). 99.44% ee, 99.53 A % purity. 1H NMR ppm (δ), DMSO 7.63–7.10 (m, 9H), 5.61 (m, 1H, CH—O), 3.90 (dd, 2H), 2.90 (m, 2H), 2.50 (s, 1H), 2.35–2.08 (m, 2H). 13C NMR ppm (δ), DMSO 175.3, 160.8, 140.8, 129.5, 128.71, 127.5, 126.6, 117.0, 77.0, 72.3, 36.4.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH2:8])=[N:5][N:4]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH:8][C:18](=[O:19])[CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5][N:4]=1
Reactant: Nc1nnc(C(F)(F)F)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnc(C(F)(F)F)o1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 149-150° C. and MS: m/e=347.2 (M+) was prepared in accordance with the general method of example 44a from 5-trifluoromethyl[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.