Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1B(O)O.[C:24]([NH:27][C:28]1[CH:29]=[C:30]([C:41]([O:43][CH3:44])=[O:42])[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2Br)=[CH:32][CH:33]=1)(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.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>[C:24]([NH:27][C:28]1[CH:29]=[C:30]([C:41]([O:43][CH3:44])=[O:42])[C:31]([C:34]2[C:35]([C:7]3[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=3[O:5][CH2:4][C:3]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=3[F:1])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:32][CH:33]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1-c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Temperature: 90 °C

Procedure:
A mixture of 2-[(2,4-difluorobenzyl)oxy]-5-trifluoromethylbenzene boronic acid (66 mg, 0.2 mmol), methyl 4-(acetylamino)-2′-bromo-2-biphenylcarboxylate (110 mg, 0.32 mmol), potassium carbonate (138 mg, 1 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 5 mol %) in 1:1 toluene/ethanol (4 ml) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was chromatographed with ethyl acetate/iso-hexane (2:3) to yield the title compound as a pale yellow gum. (90 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14]
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCOc1ccccc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(2-phenoxyethyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 2-phenoxyethylamine. LC/MS [10.10 min; 478 (M+1)]
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:21])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Ni]>[C:7]([C:11]1[C:12](=[O:21])[C:13]2[C:18]([C:19](=[O:20])[C:10]=1[OH:9])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[NH:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)c2c(-c3ccccc3)noc21
Agent: [Ni]
Solvent: CCO
Product: N=C(C1=C(O)C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 50.1 %

Procedure:
To a solution of 3-phenyl-4,9-dihydronaphtho-[2,3-d]isoxazole-4,9-dione (m.p. 133°-135°C, 2.0 g) in ethanol (200 ml) is added Raney nickel prepared from 50 % Raney-Nickel alloy (3 g). The mixture is subjected to catalytic reduction procedure at room temperature (20°-30°C) under atmospheric pressure. After completion of hydrogen absorption, the catalyst is removed by filtration and the ethanol is evaporated. The residue is chromatographed on alumina and eluted with methylenechloride-methanol (95:5). The yellowish crystals obtained are washed with ether-ethyl acetate and recrystallized from 80 % acetic acid to give 2-benzimidoyl-3-hydroxy-1,4-naphthoquinone (1.01 g) as pale yellow scales, m.p. 258°-259°C, which is identical with the product of the part [A] above.
Reaction SMILES: C([Si](CC)(CC)[O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][Si](CC)(CC)CC)[C@H:7]([CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C@H:6]1/[CH:30]=[CH:31]/[C@@H:32]([O:45][Si](CC)(CC)CC)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[C@H:7]([CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C@H:6]1/[CH:30]=[CH:31]/[C@@H:32]([OH:45])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=1
Reactant: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O[Si](CC)(CC)CC)C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
The product of Example 11 (0.8 g) was dissolved in 10 ml acetone and 2 ml water, followed by addition of 0.1 g p-toluenesulfonic acid monohydrate. The reaction solution was stirred at room temperature for 1 hour and concentrated until two separate layers were observed. 30 ml ethyl acetate was added for extraction and phase separation. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and subjected to vacuum evaporation for removal of the solvent until dryness. The crude Travoprost was purified by column chromatography and then concentrated under reduced pressure to provide 0.44 g of Travoprost. UPLC (ACQUITY UPLC HSS C18) analysis of the product showed that no isomer and impurities were detectable and the purity was higher then 99.9%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH2:2]2.CC1C=C(OC)C=CC=1C=C[C:13]([O-])=[O:14].C(N(CC)CC)C.C(Cl)(=O)C=CC1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH:6]2[CH2:13][OH:14]
Reactant: C1=CC2CCC1C2
Reactant: COc1ccc(C=CC(=O)[O-])c(C)c1
Agent: O=C(Cl)C=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCC1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(exo-rich) 5-norbornene-2-methanol (15 g, 0.121 mol) that was synthesized in (2) of Example 1, triethylamine (Aldrich, 61.2 g, 0.605 mol), and 20 ml of THF were put into the two-neck flask having the volume of 250 ml, and then agitated in the ice-water bath at 0° C. Cinnamoyl chloride (22.1 g, 0.133 mol) was dissolved in 60 ml of THF and then slowly added to the above reactant by using the additional flask. After 10 min, the reactant was heated to normal temperature and the agitation was additionally performed for 1 hour. The solution was diluted with ethyl acetate, moved to the separatory funnel, washed by using water and NaHCO3 several times, and subjected to the distillation under reduced pressure to remove the solvent. The purification was performed by using the column chromatography (hexane:ethyl acetate=20:1) to obtain the product (yield: 88%). The molar ratio (mol %) of the exo isomer and the endo isomer of the product was 58:42.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:30][CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30]([CH2:31][CH3:32])[C:42]([NH:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:43])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:17]1[C:21]([C:22]2[C:27](=[O:28])[CH:26]=[CH:25][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[N:23]=2)=[CH:20][CH:19]=[N:18]1.I[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1>CC#N.CCOC(C)=O.O.[Cu-]=O>[S:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[N:17]1[C:21]([C:22]2[C:27](=[O:28])[CH:26]=[CH:25][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)[N:23]=2)=[CH:20][CH:19]=[N:18]1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccn[nH]1
Reactant: Ic1cccs1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccs1
Temperature: 90 °C
Reaction time: 24 h
Yield: 2.9 %

Procedure:
To a mixture of copper (I) oxide (0.028 g, 0.20 mmol), salicylaldoxime (0.11 g, 0.78 mmol), Cs2CO3 (0.64 g, 2.0 mmol) and 3-(1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.30 g, 0.98 mmol) in MeCN (8 mL) was added 2-iodothiophene (0.16 mL, 1.5 mmol), and the mixture was stirred at 90° C. for 1 day. The mixture was diluted with AcOEt and water, and filtered. The filtrate was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (20/80-100/0 AcOEt/hexane) to give yellow crystals. The crystals were purified by preparative HPLC and recrystallized from AcOEt/hexane to give the title compound (11 mg, 3% yield) as off-white crystals: 1H NMR (300 MHz, CDCl3): δ ppm 6.75 (1H, d, J=7.9 Hz), 6.95 (1H, dd, J=5.5, 3.8 Hz), 7.01 (1H, dd, J=3.8, 1.3 Hz), 7.23 (1H, dd, J=5.5, 1.3 Hz), 7.31 (1H, d, J=8.7 Hz), 7.40 (1H, brs), 7.42 (1H, d, J=1.9 Hz), 7.51-7.57 (1H, m), 7.62 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=1.9 Hz), 8.21 (1H, d, J=7.9 Hz). LC-MS (ESI) m/z 389 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:19][CH:18]=3)[C:41]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:8]2)=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: Oc1ccccc1-c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)Oc3ccccc3-c3[nH]c4ccccc4c32)cc1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
7.7 g of 4,4'-bisdimethylaminobenzophenone was dissolved in 50 ml of chloroform, and the solution was stirred. Phosphorus oxychloride (5 g) and 10 ml of chloroform were added thereto, and the mixture was stirred for 30 minutes at room temperature (about 20°-30° C.). Then, 6 g of 2-(2'-hydroxyphenyl)indole was added thereto, and the mixture was stirred at room temperature for 3 hours. The mixture was heated under reflux for an additional 2 hours. The heated mixture was cooled to room temperature, and poured into ice water, and neutralized with an aqueous solution of sodium hydroxide. Furthermore, 200 to 300 ml of chloroform was added for extraction. The chloroform layer was washed with water, dried, and distilled under reduced pressure to remove the chloroform. The remaining oily substance was dissolved in a small amount of methanol by heating, and the solution was cooled. The crystals precipitated were separated by filtration, and dried to obtain 4 g of the objective compound having a melting point of 165° to 168° C.
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:20]([CH3:31])[CH2:21][CH2:22][NH:23][C:24](OC(C)(C)C)=[O:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=O)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C>[CH3:31][C@H:20]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:24](=[O:25])[NH:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@H](C)CCNC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@H](C)CCNC3=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 1-((R)-3-tert-butoxycarbonylamino-1-methyl-propyl)-1H-indole-2,6-dicarboxylic acid diethyl ester (6.0 g, crude) in CH2Cl2 (27 mL) is added TFA (18.1 mL). The reaction mixture is stirred for 1 hour and the solvent is removed under vacuum. To a solution of the residue in ethanol (90 mL) is added K2CO3 (4.6 g, 33.3 mmol) and the reaction mixture is heated to reflux for 2 hours. The cooled reaction mixture is poured into ice water and extracted with EtOAc. The combined extracts are washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (3.65 g, crude) as a brown oil.
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2([OH:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:11][C:10]=1[F:30])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:30][C:10]1[CH:11]=[C:12]([C:16]2([OH:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[CH:13]=[C:14]([F:15])[C:9]=1[OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)c(O[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)c(O)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-(4-((tert-butyldimethylsilyl)oxy)-3,5-difluorophenyl)-4-hydroxypiperidine-1-carboxylate D1e (1.0 g, 2.25 mmol) in tetrahydrofurane (10 mL) is treated with a solution of tetra-n-butylammonium fluoride in tetrahydrofurane (1.0 M; 3 mL, 1.33 mmol). The mixture is stirred at room temperature for 4 hours. Concentration and purification by flash chromatography (hexanes/ethyl acetate gradient) affords tert-butyl 4-(3,5-difluoro-4-hydroxyphenyl)-4-hydroxypiperidine-1-carboxylate D1f as an oil. 1H-NMR (400 MHz, CDCl3) δ=7.01 (d, J=7.2 Hz, 2H), 4.03 (br. s, 2H), 3.19 (br. t, J=11 Hz, 2H), 1.89 (br. t, J=11 Hz, 2H), 1.67 (d, J=12.5 Hz, 2H), 1.58 (s, 1H), 1.48 (s, 9H); 19F-NMR (376 MHz, CDCl3) δ=−134.41. No MS spectrum could be obtained.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[OH:16][C:15](=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (12.5 g) in tetrahydrofuran (188 mL) was cooled to 0° C. A solution of malononitrile (10.3 g) in tetrahydrofuran (65 mL) was added dropwise thereto over a period of 1 hour. After stirring the reaction mixture at room temperature for 1 hour, it was again cooled to 0° C., and then a solution of 2-phenylacetyl chloride (24.2 g) in tetrahydrofuran (52 mL) was added dropwise thereto over a period of 80 minutes. After stirring the reaction mixture at room temperature for 49 hours, water (26 mL) was added to the reaction solution. The solvent was distilled off under reduced pressure, diethyl ether (130 mL) and 1 mol/L hydrochloric acid (130 mL) were added to the residue and extraction was performed with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (31.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:15])[Cl:14])=[CH:7][C:5]([NH2:6])=[C:4]([F:16])[CH:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:14])[Cl:15])=[CH:7][C:5]([N:6]2[C:20](=[O:21])[C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=3[C:17]2=[O:22])=[C:4]([F:16])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OCC2CC2(Cl)Cl)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OCC2CC2(Cl)Cl)c(Cl)cc1F
Temperature: 0 °C

Procedure:
8.9 g (0.031 mol) 4-Chloro-2-fluoro-5-(2,2-dichlorocyclopropylmethoxy) aniline was dissolved in 12.5 ml acetic acid and 3.85 g 3,4,5,6-tetrahydrophthalic anhydride added. The mixture was heated under reflux for 3 hours, then poured into ice-water and extracted with ether. The ether phase was neutralised with aqueous sodium hydrogen carbonate, washed with saturated brine, dried over magnesium sulphate and the solvent removed. The residue was chromatographed on silica gel using a mixture of 9 parts hexane and 1 part ethyl acetate as eluent.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH:15]=[C:16]2[C:17](=[O:19])[CH3:18])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]1.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl>N1C=CC=CC=1>[CH3:25][Si:26]([CH3:29])([CH3:28])[O:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH:15]=[C:16]2[C:17](=[O:19])[CH3:18])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C
Temperature: 0 °C

Procedure:
30 g. of 11β-hydroxy-1,4,16-pregnatriene-3,20-dione is combined in 300 ml. of absolute pyridine with 30 ml. of trimethylchlorosilane and agitated for 24 hours at room temperature. The mixture is then stirred into ice water, the thus-precipitated sediment is vacuum-filtered, washed out with water, and taken up in methylene chloride. After evaporation, 36.5 g. of crude 11β-trimethylsilyloxy-1,4,16-pregnatriene-3,20-dione is obtained. A sample recrystallized from diisopropyl ether melts at 196°- 197.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3]1.[C:12]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:21][CH3:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](=[N:19][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[S:21][CH3:22])[CH2:6][CH2:7]1
Reactant: CN1CCC(CCCO)CC1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSC(=NC(=O)OC(C)(C)C)N(CCCC1CCN(C)CC1)C(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL round bottom flask were added 3-(1-methyl-piperidin-4-yl)-propan-1-ol (0.23 g, 0.0014 mol), 1,3-di-Boc-2-methylisothiourea (0.42 g, 0.0014 mol), PPh3 (0.42 g, 0.0016 mol) and THF (anhydrous, 8.0 mL). The resultant, stirred stirring solution was cooled to 2.0° C. To the resultant solution was then added DEAD (0.27 mL, 0.0016 mol) drop wise. The reaction was aged cold for 30 min, warmed to room temperature and aged for 14 h. The THF was removed via rotovap and the residue taken up in MTBE (10 mL). The resultant solution was extracted with saturated aqueous NaHCO3 (2×10 mL) and diluted with hexanes (20 mL). After 10 min, the resultant slurry was filtered and the filtrate concentrated via rotovap. The residue was taken up in hexanes (25 mL) and filtered after 10 min. The filtrate was concentrated to yield N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′-di-Boc-methylisothiourea.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[C:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
In 10 ml of toluene was added 600 mg (1.11 mmoles) of (4-bromophenyl)perfluorohexyl sulfone, and 20 mg (0.17 mmoles) of Pd(PPh3)4. To this clear colorless solution was added 170 mg (1.12 mmoles) of 4-methoxyphenylboronic acid in 2 ml of methanol, 240 mg (2.26 mmoles) of Na2CO3 in 1 ml of water. The mixture was stirred under nitrogen at 80° C. overnight. Isolation in accordance with the procedure of Example 9 gave after flash chromatography (silica gel, 50% CHCl3 /hexane) 343 mg of the biphenyl (0.60 mmoles, 54.6%). Elemental analyses: Found: C: 40.29; H: 2.03; calculated for C19H11F13O3S: C: 40.30; H: 1.96 Mp: 101.5°-103° C. SHG: not active. 1H nmr (CD2Cl2): 8.05 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.6Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 3.87 (s 3H).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[CH3:7][C:8]([CH3:13])=[CH:9][C:10](O)=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:7][C:8]1([CH3:13])[NH:6][C:2]([CH3:5])([CH3:1])[CH:3]=[N:4][C:10](=[O:11])[CH2:9]1
Reactant: CC(C)=CC(=O)O
Reactant: CC(C)(N)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)C=NC(=O)CC(C)(C)N1

Procedure:
4.4 g 2-methyl-1,2-propanediamine, 6.0 g 3,3-dimethylacrylic acid and 8 ml toluene were mixed and heated at 140°-150° C. overnight. The mixture was cooled and poured into 80 ml of 5% Na2CO3 solution; then extracted 3 times with 50 ml aliquots of chloroform. The combined chloroform solutions were dried and concentrated. Upon recrystallization from hexane-benzene a yellow crystalline solid, m. pt 129°-132° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]=[CH2:21])=[CH2:19]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[O:15][C:18]([O:17][CH3:16])([CH3:19])[CH2:20][CH2:21]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=C)OC
Solvent: c1ccccc1
Product: COC1(C)CCc2cc(OCc3ccccc3)ccc2O1

Procedure:
A mixture of 40 g. of p-(benzyloxy)phenol, 33.6 g. of 2-methoxybutadiene, and 30 ml. of benzene was sealed in a glass tube under N2. The tube was heated at 160°-165° for 20 hours, cooled and opened. The yellow solution was chromatographed on silica gel with 97.5:2.5 benzene-ethyl acetate to give (±)-6-benzyloxy-2-methoxy-2-methylchroman, identical with the material prepared as described in Example 44, as 34.5 g. of pale yellow oil.