Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)COc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
11 g of 2,4-dichlorophenoxy-acetic acid chloride in solution in 40 ml of methylene chloride were added without exceeding 25° C. to a mixture of 8.6 g of N-(tert-butoxycarbonyl)-1,4-diamino-butane, 120 ml of methylene chloride and 7 ml of triethylamine and the mixture was stirred for 30 minutes, then concentrated to dryness under reduced pressure. The residue was taken up in 200 ml of tetrahydrofuran and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure to obtain 18.53 g of crude product melting at 107° C. which was crystallized from 740 ml of isopropyl ether to obtain 17.43 g of the expected product melting at 110° C. 5.39 g were chromatographed on silica (eluant: hexane-ethyl acetate (6-4)) to obtain 4.48 g of the sought product melting at 114° C.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[N:8]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1>O1CCCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH:12]([C:10]1[N:11]=[C:7]([CH3:6])[N:8]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:9]=1)[OH:13]
Reactant: [Li]C(C)(C)C
Reactant: Cc1nc(C=O)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(C(O)C(C)(C)C)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyllithium (1.7 M in pentane) (1.7 mL, 2.8 mmol) was added slowly to an ambient temperature solution of 2-methyl-1-trityl-1H-imidazole-4-carboxaldehyde in tetrahydrofuran (10 mL) at 0° C. After stirring at ambient temperature for 2 h, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 2,2-dimethyl-1-(2-methyl-1-trityl-1H-imidazol-4-yl)propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichlorobenzoyl chloride (5 g, 23.9 mmol) in 50 mL of dichloromethane at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (2.56 g, 26.3 mmol) and pyridine (4.3 mL, 52.6 mmol). The cold bath was removed and the mixture stirred at ambient temperature for 16 hours, diluted with water and extracted with two portions of dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (SiO2, 20% ethyl acetate/hexanes) to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ: 7.61 (d, J=1.9 Hz, 2H); 7.50 (d, J=1.9 Hz, 1H); 3.60 (s, 3H); 3.40 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCCc1cccnc1)C1CCCN1
Yield: 76.7 %

Procedure:
A solution of 3-(3-pyridyl)-1-propyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.9 mmol) in methylene chloride (40 mL) and trifluoroacetic acid (8 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3×). The combined organic extracts were dried and concentrated to yield 1.60 g (77%) of the free amine as a thick oil, 1H NMR (300 MHz, CDCl3): δ 1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m, 1H); 2.94 (m, 1H); 3.71 (m, 1H); 4.11 (m, 2H); 7.18 (m, 1H); 7.45 (m, 1H); 8.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].[H-].[Na+]>CCN(CC)CC>[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[N:34]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH2:17])=[CH:19][CH:20]=2)[C:33]1=[O:38]
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CC1(C)NC(=O)NC1=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)NC(C)(C)C2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 60 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of 5,5-dimethylhydantoin, and 56 mg of NaH, 32.0 mg of the product was obtained.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: CC=CCC1Cc2ccc(C(C)(C)C)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.58 h
Yield: 92 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 35 minutes while stirring through a solution, cooled to -70°, of 7.35 g of (RS)-2-(2-buten-1-yl)-6-tert-butyl-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.36 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 100 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 6.44 g (92%) of (RS)-2-(2-oxoethyl)-6-tert-butyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[CH3:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[NH:27][N:26]=1.O>CN(C)C=O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:26]=[C:25]([CH3:24])[C:33]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred at 30° C. overnight. The mixture was treated with water and then filtered to provide the desired product. LCMS calculated for C22H21ClN7O (M+H)+: m/z=434.1; Found: 434.2
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccccc1I
Product: COc1ccccc1-n1ccc2ccccc21
Yield: 99.9 %

Procedure:
Using general procedure A, indole (146 mg, 1.25 mmol)) was coupled with 2-iodoanisole (135 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ether 15:1; 15 mL fractions). Fractions 6-10 provided 232 mg (100% yield) of the product as a colorless oil. The 1H NMR spectrum was in accord with that reported by Maiorana et al. Maiorana, S.; Baldoli, C.; Del Buttero, P.; Di Ciolo, M.; Papagni, A. Synthesis 1998, 735.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[C:14]([O:18][C:19]([NH:21][OH:22])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:22][NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)Oc1ccccc1C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino 2-(acetyloxy)benzoate is prepared from acetylsalicyloyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. 1H NMR (250 MHz, DMSO-d6) δ ppm 10.89 (1H, br. s.), 7.97 (1H, dd, 7.8, 1.7 Hz), 7.75 (1H, td, 7.8, 1.8 Hz), 7.46 (1H, td, 7.6, 1.1 Hz), 7.31 (1H, dd, 8.1, 0.9 Hz), 2.27 (3H, s), 1.42 (9H, s).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.I[CH:31]([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:32][CH:31]([O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1)[CH3:33]
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), 2-iodopropane (0.050 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 h at 60° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from hexane/AcOEt to give the title compound (79.5 mg, 72% yield) as colorless prisms: mp 137-139° C.; NMR (300 MHz, CDCl3): δ ppm 1.38 (6H, d, J=6.4 Hz), 4.96-5.09 (1H, m), 7.05 (1H, dd, J=1.9, 7.9 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 8.01 (1H, s). LC-MS (ESI) m/z 441 [M+H]+. Anal. Calcd for C23H19F3N4O2: C, 62.72; H, 4.35; N, 12.72. Found: C, 62.74; H, 4.40; N, 12.81.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][OH:6].[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Na+]>[C:12]([O:6][CH2:5]/[CH:4]=[CH:3]/[C:2]([F:8])([F:7])[F:1])(=[O:13])[CH2:11][C:10]([CH3:9])=[O:14]
Reactant: OCC=CC(F)(F)F
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)CC(=O)OC/C=C/C(F)(F)F
Temperature: 25 °C
Yield: 154.6 %

Procedure:
To a refluxing solution of 4,4,4-trifluoro-2-buten-1-ol (10 g, 79 mmol) and sodium acetate (0.51 g, 6.2 mmol) in anhydrous tetrahydrofuran (27 mL) under nitrogen, a solution of diketene (6.7 mL, 43.1 mmol) in anhydrous tetrahydrofuran (14 mL) was added dropwise over a period of 1 hour. The reaction mixture was heated at reflux for an additional 30 min upon completion of the addition. Then, the reaction mixture mixture was cooled to room temperature and diluted with diethyl ether (100 mL). The resulting solution was washed with a saturated aqueous sodium chloride solution (2×20 mL) and the organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The brown residue was purified by column chromatography using a mixture 4:1 of hexane and ethyl acetate as eluent to afford 14.0 g (84% yield) of trans-4,4,4-trifluoro-2-buten-1-yl acetoacetate as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:17]C1CCCCO1)/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@@H:10]([OH:17])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 75 %

Procedure:
Using the procedure of Example 6 with the resultant compound of Example 12 provided, following silica gel chromatography using a gradient of 15-30% ethyl acetate in hexane, the desired compound (m.p. 108°-109° C., Rf 0.44, 2:1 hexane:ethyl acetate) in 75% yield. 1H NMR (CDCl3) 1.39 (s, 9 H), 2.96 (d, J=8 Hz, 2 H), 3.73 (s, 3 H), 3.75-3.85 (m, 2 H), 4.32 (br, 1 H), 4.79 (br d, 1 H), 6.11 (br d, J=15 Hz, 1 H), 6.94 (dd, J=15, 4 Hz, 1 H), 7.2-7.35 (m, 5 H). Mass spectrum: (M+H)+ =336.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[S:29][C:22]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(-c3ccncc3)sc12
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Tereakis(triphenylphosphine)palladium (54 mg, 0.05 mmole) was added to a solution of 4-(tributylstannyl)pyridine (0.432 g, 1.17 mmole) and 7-chloro-2-iodothieno[3,2-b]pyridine (0.347 g, 1.17 mmole) in DMF (5 ml). The reaction mixture was stirred at reflux for 3 h, cooled to room temperature. The mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (50 ml) and CH2Cl2 (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 30-60% EtOAc in hexane to give pale yellow color solid (0.103 g, 36%); 1H NMR (300 MHz, CDCl3) δ8.61 (1H, d, J=5.1 Hz), 7.95 (1H, s), 7.66 (2H, m), 7.44 (2H, m), 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 481.10.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:36])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)cc1
Yield: 101.3 %

Procedure:
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (0.5 mL) and triethylamine (0.5 mL) was added. To this solution p-anisoyl chloride (60 mg, 0.35 mmol) dissolved in dichloromethane (0.5 ml) was added in one portion. The mixture was filtered and evaporated to afford 148 mg (100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4](Cl)=[N:5][OH:6].[C:13]([C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1)#[CH:14].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=2)[O:6][N:5]=1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1cccc(NCCP(=O)(OCC)OCC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Temperature: 25 °C
Yield: 89.2 %

Procedure:
2,6-Dichloro-N-hydroxybenzimidoyl chloride (370 mg, 1.6 mmol) and diethyl 2-(3-ethynylphenylamino)ethylphosphonate (450 mg, 1.6 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (0.30 mL, 1.6 mmol). The mixture was then heated at reflux for 5 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography on silica gel, eluting with 98:2 methylene chloride:methanol to give diethyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylphosphonate (670 mg) as a pale yellow oil. 1H NMR (CDCl3): 7.30 (m, 2H), 7.21 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.59 (m, 1H), 6.48 (s, 1H), 4.03 (m, 4H), 3.40 (m, 2H), 2.00 (m, 2H), 1.24 ppm (m, 6H). MW=469 confirmed by LC-MS, tr=14.80 min (Method Y) MH+=467-472.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([Br:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:58][C:55]1[N:56]=[CH:57][C:52]([NH:51][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)=[N:53][CH:54]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (200 mg, 0.56 mmol) and triphenylphosphine (195 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-bromopyrazine (200 mg, 1.12 mmol, prepared according to Tetrahedron 1988, 44, 2977-2983) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate eluted to 4/6 hexanes/ethyl acetate) afforded N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (120 mg, 42%) as an off-white foam: [α]23589=−24.6° (c=0.50, chloroform); EI-HRMS m/e calcd for C20H21BrClN3O4S (M+Na)+ 536.0017. found 536.0022.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C[Si](Cl)(C)C>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 1,4 diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at −78° C. was added n-BuLi (2.5 M, 24 mL) over 1 hour. After being stirred for an additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was sired for 3 hours. To the mixture was added TMSCl (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to rt and stirred at rt for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions were combined to give 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (12 g, 66.6%) with LCMS: 361.2 (M+H+, 100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}(trimethyl)silane (6 g, 27%) with LCMS: 433.1 (M+H+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[C@H:10]([OH:21])[CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1>N1C=CC=CC=1.C(OC(=O)CCC)(=O)CCC.CN(C)C1C=CN=CC=1.C(OCC)C>[C:2]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[C@H:10]([O:21][C:11](=[O:20])[CH2:10][CH2:9][CH3:8])[CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:1])[CH2:3][CH2:4][CH3:17]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2=O
Agent: CCCC(=O)OC(=O)CCC
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](OC(=O)CCC)C[C@@H]12
Yield: 80.6 %

Procedure:
A solution of 2.0 g of 3,16α-dihydroxy-1,3,5(10)-estratrien-17-one in 10 ml of pyridine and 5 ml of butyric anhydride is allowed to stand at room temperature for 15 hours with the addition of 100 mg of 4-dimethylaminopyridine. The reaction mixture is diluted with diethyl ether, washed with water, dried over sodium sulfate, and evaporated. The residue is chromatographed on silica gel with a pentane-diethyl ether gradient (0-30% diethyl ether), yielding 1.2 g of 3,16α-dibutyryloxy-1,3,5(10)-estratrien-17-one as an oil.