Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2c(C)nc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoacetate (2 ml) and the mixture heated to 80° C. for 2 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: [Br-:1].[Li+].C1COCC1.Cl[CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1>O>[Br:1][CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Yield: 88.9 %

Procedure:
A mixture of 4-trifluoromethylbenzyl bromide (5.68 g, 23.8 mmol) and triethyl phosphite(10.4 g, 63 mmol) was heated at reflux under nitrogen for 5 hours. The excess triethyl phosphite was removed by distillation and the crude product was purified by distillation at 95° C. (0.07 mm Hg.) to give 6.27 g, 89% of the product as an oil. D.C.I.M.S.[MH+,297].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)(O)[O-].[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>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[CH:3]=2)=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccc(Br)c4)ccc3c1)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)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: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cccc(-c5ccc(Cl)cc5)c4)ccc3c1)n2C1CCCCC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
In dried vial with a Teflon lined screw cap, a solution of Compound 482 (156 mg, 0.31 mmol), 4-chlorophenylboronic acid (73 mg, 0.465 mmol), and Palladium Tetrakis (37 mg, 0.031 mmol) in toluene (9 mL), methanol (2 mL), and saturated sodium bicarbonate in water (900 μL) was degassed, flushed with argon, and sealed. The reaction was stirred for 16 h at 90° C. The completed reaction was then evaporated to dryness, purified via HPLC, and converted to the HCl salt using the standard procedure (as described in Compound 516) to produce the title compound (73 mg, 42% yield).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C-:17]#[N:18].[Na+].C(O)(=O)C>CO>[F:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]#[N:18])[CH2:12][CH2:11]1
Reactant: [C-]#N
Reactant: FC1(F)CCNCC1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC(c1ccccc1)N1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
Benzaldehyde (1.284 ml, 12.63 mmol), 4,4-difluoropiperidine (1.53 g, 12.63 mmol), and NaCN (0.619 g, 12.63 mmol) were combined in MeOH (20 ml). Acetic acid (0.759 ml, 13.26 mmol) was added dropwise over 30 min via syringe pump and the mixture heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and CH2Cl2, the aqueous portion extracted 2×CH2Cl2, and the organic portion dried (Na2SO4) and concentrated in vacuo. The resulting material was used without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1nc2ccnn2c(O)c1C#N
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccnn2c(OCc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
80 mg of sodium hydride (60%) was added to 400 mg of 7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 6 ml of DMF, followed by stirring at room temperature for about 10 minutes, and then 350 mg of benzyl bromide was added thereto, followed by stirring at about 50° C. overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, about 50 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 490 mg of 7-benzyloxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 51) having a melting point of 194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(OC)nc1C
Yield: 64 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)=[C:37]([OH:55])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)=[C:37]([O:55][CH3:3])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccc(F)cc2)C(c2cccc(F)c2F)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(c2ccc(F)cc2)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/4.2 v/v, 31 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-4-(4-fluorophenyl)-3-hydroxy-1H-pyrrol-2(5H)-one (0.5 g, 1.2 mmol, 1 eq) and MeOH (10 ml); yield 0.160 g (60%); MS m/z: 436.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 10.5 (b, 1H), 7.88 (s, 1H), 7.72 (s,1H),7.59-7.56 (m, 1H), 7.26-7.00 (m, 4H), 6.91-6.86 (m,3H),6.38 (bs, 1H), 4.20 (s, 3H); HPLC (METHOD [A]): rt 15.20 min (97.35%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9](O)=[C:8]2[C:3]=1[CH2:4][CH:5]=[C:6]([CH3:13])[CH2:7]2.[H-].[Na+].[CH3:16]I.CN([CH:21]=[O:22])C>C(OCC)(=O)C>[CH3:16][O:1][C:2]1[CH:11]=[CH:10][C:9]([O:22][CH3:21])=[C:8]2[C:3]=1[CH2:4][CH:5]=[C:6]([CH3:13])[CH2:7]2
Reactant: CN(C)C=O
Reactant: CC1=CCc2c(O)ccc(O)c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c2c1CC=C(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of hydroquinone 3 (17.00 g, 96.6 mmol) in DMF under N2 was added unwashed 60% sodium hydride in mineral oil (8.90 g, 222.5 mmol). The resultant reaction mixture was warmed to room temperature over a 30 min period and subsequently treated with methyl iodide (14.3 mL, 230 mmol). After stirring the reaction mixture for 1 hr at room temperature the reaction mixture was diluted with ethyl acetate (1.5 L) and washed with brine (3×500 ml). The organic solution was dried over sodium sulfate, filtered, concentrated, and the residue purified on silica gel (elution with 20% ethyl acetate\hexane) to afford 4 as a light yellow oil which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Clc1ccc2c(c1)CCN2
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Product: Clc1ccc2[nH]ccc2c1

Procedure:
Ikan et al. [Israel J. of Chemistry, Vol. 2 (1964), p. 37-42] and Terent'ev et al. [Proc. Acad. Sci. USSR, Vol. 118 (2) (1958), p. 49-52] describe the dehydration of 5-chloro-indoline with chloranil to obtain 5-chloro-indole but due to the expense of chloranil, the process is not commercially feasible. French Pat. No. 1,576,807, DOS No. 1,770,977, Chem. Abs., Vol. 72 (1970), p. 121360n and Bader et al. [J.A.C.S., Vol. 83 (1961), p. 3319] tried to avoid this difficulty with partial success by heating indoline and its derivatives to high temperatures in the presence of palladium, platinum of Raney nickel catalysts, sometimes in the presence of a hydrogen acceptor. For example, indoline can be dehydrated at 100 to 150° C. in aromatics with a good yield of indole with hydrogen in the presence of finely divided palladium. Hunt et al. [J. Chem. Soc., (C) (1966), p. 344-345] teach reacting 5-methoxy-indoline in refluxing mesitylene in the presence of palladized carbon to obtain a 90% yield of 5-methoxy-indole.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1Cl.FC1C=CC(C=O)=CC=1[C:23]([F:26])([F:25])[F:24].[CH2:27](S([O-])=O)C.[Na+]>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:27])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCS(=O)[O-]
Agent: [Na+]
Product: CCS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared analogously to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-3-trifluoromethylbenzaldehyde and by replacing sodium methanesulfinate with sodium ethanesulfinate.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13](/[C:12](=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)/[C:11]([O:17][CH2:18][CH3:19])=[O:16])(=[O:14])[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc(C#N)cc1)C(C)=O

Procedure:
A solution of 4-cyanobenzaldehyde (2 g, 15.3 mmol), ethyl acetoacetate (1.98 g, 15.3 mmol), piperidine (65 mg, 0.76 mmol), and p-toluenesulfonic acid (131 mg, 0.76 mmol) in toluene (100 ml) is stirred under an argon atmosphere at reflux for 72 hours in a flask equipped with a Dean-Stark trap. The crude reaction mixture is concentrated in vacuo to afford an oil which is chromatographed over silica gel with cyclohexane/ethyl acetate 20:1 as eluent.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[C:3]#[CH:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>>[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([NH:1][CH:2]([CH3:5])[C:3]#[CH:4])=[O:11]
Reactant: O=C(Cl)CCCCl
Reactant: C#CC(C)N
Product: C#CC(C)NC(=O)CCCCl

Procedure:
The compound 3-amino-1-butyne was treated with γ-chlorobutyryl chloride giving 3-(γ-chlorobutyramido)-1-butyne, m.p. 50°-51°C., which was ring-closed to N-(1-methylpropargyl)-pyrrolidin-2-one with the boiling point 71°C. at 0.8 mm Hg. Treatment of this product with formaldehyde and pyrrolidine yielded a reaction product which was isolated and purified as the sesquioxalate. It melted at 117°-119°C. after recrystallization from ethanol-ether.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29])(=[O:22])=[O:21].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])(=[O:22])=[O:21])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Oc2ccc(N)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-(4-tert-butyl-phenoxy)-phenylamine (0.1 g, 0.41 mmol). 5-chlorosulfonyl-2-methylbenzoic acid (0.097 g, 0.41 mmol) and pyridine (0.1 ml, 1.24 mmol) in 2 ml anhydrous tetrahydrofuran was heated at 60° C. for 2 hr. The reaction mixture was cooled to room temperature and diluted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 25 ml 1N aqueous hydrochloric acid solution and 25 ml brine, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure. The crude product was purified by preparative thick layer chromatography (silica gel), eluting with 9:1 chloroform/methanol to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:21]([F:31])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]([F:31])[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:25])[CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCC(=O)NCc2cc(F)c(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an N,N-dimethylformamide (DMF) (10 ml) solution of (4-tert-butylphenoxy)acetic acid (330 mg, 1.50 mmol) and N-[4-(aminomethyl)-2,6-difluorophenyl]methanesulfonamide hydrochloride (491 mg, 1.80 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (431 mg, 2.25 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol) and triethylamine (607 mg, 6.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=10/1 to furnish the title compound. Further, the title compound was recrystallized from ethyl acetate and hexane to furnish 199 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH2:12]([Zn+])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Brc1ccc2sccc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(Cc2ccc3sccc3c2)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
5-Bromobenzothiophene (2.13 g, 10 mmol) was dissolved in a THF solution of benzyl zinc(II) bromide (0.5M, 10 mL, 20 mmol) in a microwave reaction tube. Pd(PtBu3)2 (255 mg, 0.5 mmol) was added to this solution. The mixture was purged with N2 gas for 3-5 minutes and heated at 100° C. for 30 minutes under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (150 mL), washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give the desired product (65% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.40 (d, J=5.6 Hz, 1H), 7.18-7.30 (m, 7H), 4.10 (s, 2H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[CH3:21]OC(OC)(C)C.CO.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH:4]=[CH:3]2)[CH:11]=1
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC2=CC[C@H]3[C@@H]4CC=C[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Yield: 44.5 %

Procedure:
To a partial solution of androsta-4,16-dien-3-one (1.00 g, 3.70 mmol) in 2.2-dimethoxypropane (5.0 mL, 41 mmol) and 5 mL DMF were added methanol (0.2 mL) and p-toluenesulfonic acid monohydrate (26.4 mg, 0.139 mmol). The mixture was refluxed 5 h, after which it was cooled and sodium bicarbonate (152.5 mg) was added. The suspension was partitioned between 50 mL of ice water and 50 mL of ethyl acetate. The organic layer was washed with two 50 mL portions of water+50 mL of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residual oil was taken up in 50 mL of hot hexane and filtered through a 12 mm×30 mm column of silica gel 60 using 150 mL of hot hexane. The combined filtrates were concentrated under reduced pressure and recrystallized from acetone/methanol to give white crystals (468.0 mg, 1.645 mmol, 44%), m.p. 83-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:11]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1cc(F)cc(F)c1

Procedure:
Quantities: 3,5-difluorophenol (5.0 g, 0.038 mol), 1-bromodecane (8.84 g, 0.04 mol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:13](=[O:15])[NH:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCN)OCC
Reactant: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)C(NC(=O)OCc1ccccc1)C(O)C(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoic acid (368 mg, 1.31 mmol) in anhydrous tetrahydrofuran (5 ml) was added hydroxybenzotriazole (177 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol). The resulting solution was stirred at room temperature under nitrogen for 30 minutes. A solution of 1-amino-3,3-diethoxypropane (183 mg, 1.25 mmol) in tetrahydrofuran (2 ml) and N,N-diisopropylethylamine (0.228 ml, 169 mg, 1.31 mmol) were added and stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (75 ml) and water (40 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×75 ml). The combined extracts were washed with 2% cold hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to provide [1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 79%) as a white solid.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].C1([C+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[S:36][CH2:35][CH2:34][S:33]2)=[CH:28][CH:27]=1.C(Cl)Cl.CCOCC>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]2[S:33][CH2:34][CH2:35][SH+:36]2)=[CH:30][CH:31]=1
Reactant: Cc1ccc(C2SCCS2)cc1
Agent: F[B-](F)(F)F
Agent: c1ccc([C+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(C2SCC[SH+]2)cc1
Yield: 14 %

Procedure:
A 3.30 g (0.01 mole) sample of triphenylcarbenium tetrafluoroborate is added to a solution 3.92 g of 2-(4-methylphenyl)-1,3-dithiolane in 35 ml of acetonitrile under nitrogen at 5° C. Methylene chloride is added then ether. The yellow solid is collected and washed with ether. There is obtained 0.7 g (14% yield) of 2-(4-methylphenyl)-1,3-dithiolanium fluoroborate, m.p. 119°-120° C.