Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.Cl>CCOCC>[Br:8][C:4]1[N:3]=[C:2]([CH:19]([OH:20])[C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a stirred solution of 2,6-dibromopyridine (100 g) in dry ether (1 l) under nitrogen at -70° was added dropwise during 2 hr a solution of n-butyllithium (270 mL, 1.7M in hexane). After an additional 0.5 hr, a solution of p-chlorobenzaldehyde (65 g) in dry ether (500 mL) was added during a 1 hr period. The reaction mixture was allowed to warm to ca. 0° and then poured into aqueous hydrochloric acid (1 l, 4N). The ether layer was separated and the aqueous layer was extracted with two additional portions (300 mL) of ether. The combined ether layers were washed with water (500 mL), dried (Na2SO4) and concentrated to give a syrup. The crude product was chromatographed on silica gel using the Waters Prep 500 (trademark of Waters Associates Inc., Milford, MA 01757) with methylene chloride to provide α-(6-bromo-2-pyridyl)-4-chlorobenzyl alcohol (93.8 g), m.p. 64.5°-65°.
Reaction SMILES: OC1C=CC(C([O-])=O)=CC=1.[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C(C)=CC=CC=1.[OH:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[CH:31][CH:30]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[CH2:12]([O:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[CH:31][CH:30]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])c1ccc(O)cc1
Agent: [Cl-]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1C
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 73 %

Procedure:
Sodium p-hydroxybenzoate (64 g) and 51 g of benzyl chloride were added to 300 g of xylene, and 1.3 g of tetrabutyl ammonium chloride as a phase transfer catalyst and 2 g of methyl ethyl ketone were added. The mixture was refluxed for 8 hours Benzyl p-hydroxybenzoate was obtained in a yield of 73%, and the ratio of benzyl p-benzyloxybenzoate formed was 13%.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:15]1=2)=O)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].B.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:15]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH3:2]
Reactant: CCN(CC(=O)N1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CCN1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of tert-butyl ethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (1.01 g, 2.65 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran; 7.94 mL, 7.94 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched via the slow dropwise addition (to avoid excessive bubbling) of MeOH (5 mL). The quenched reaction was then diluted with ethyl acetate and washed with water (2×) and saturated sodium carbonate (2×). The organic phase was dried, filtered, and concentrated, giving a red-orange oil (925 mg, 95%). 1H NMR (DMSO-d6) δ 7.59-7.41 (m, 1H), 7.39-7.32 (m, 1H), 7.24-7.13 (m, 1H), 3.69-3.62 (m, 2H), 3.58-3.48 (m, 2H), 3.45-3.35 (m, 2H), 3.28-3.16 (m, 2H), 3.15-3.08 (m, 2H), 1.32, 1.24 (2s, 9H), 1.04 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 390 (M+Na, 70), 368 (MH+, 12), 312 (47), 268 (100).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.C(Cl)(=O)[C:10]([Cl:12])=O.[N+](=C)=[N-].Cl>ClCCl.CCOCC>[Cl:12][CH2:10][C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCOC1
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CCl)C1CCOC1
Yield: 88.1 %

Procedure:
(RS)-3-Tetrahydrofuroic acid (3.48 g) in dichloromethane (40 ml) was treated with oxalyl chloride (11.43 g) as described in Example 1 (a). The resultant acid chloride in dichloromethane (40 ml) was then treated with excess diazomethane (60 mM) in ether (100 ml), followed by hydrogen chloride. The solution was washed once with brine, dried and concentrated. Flash chromatography on silica gel, eluting with 40% ethyl acetate/hexane afforded the title compound as a pale yellow oil, (3.924 g, 88%); νmax (CH2Cl2) 1735 and 1716 cm-1 ; 2.17 (2 H, dt, J 7.0, 7.5 Hz), 3.47-3.58 (1 H, m), 3.77-4.04 (4 H, m) and 4.18 (2 H, s); [mass spectrum: +ve ion (ammonia) MNH4+ (166)].
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2[CH2:19][CH2:20][CH2:21][CH2:22][C:14]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([N:6]2[C:16](=[O:17])[C:15]3[CH2:19][CH2:20][CH2:21][CH2:22][C:14]=3[C:13]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Yield: 61.8 %

Procedure:
4-Chloro-2-fluoro-5-nitroaniline (19 g) and 3,4,5,6-tetrahydrophthalic anhydride (15.2 g) were dissolved in acetic acid (50 ml) and refluxed for 6 hours. After being allowed to cool, the resultant mixture was poured into water and extracted with toluene. The toluene layer was washed with water, an aqueous sodium hydrogen carbonate solution and water in order, dried and concentrated. The residue was crystallized from ethanol to give 20 g of N-(4-chloro-2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 157°-157.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+:13]>C(O)C>[S:8]([C:5]1[CH:4]=[CH:3][C:2]([O-:1])=[CH:7][CH:6]=1)(=[O:9])(=[O:10])[NH2:11].[K+:13]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1ccc([O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxybenzenesulfonamide (200 mg, 1.15 mmol) in ethanol (1 mL) was added potassium hydroxide solution (0.5M in ethanol, 2.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give the title compound as a pale orange crystal (quantitative yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][N:9]=1)=[O:6].[OH-].[K+]>C(O)C.O>[CH3:14][C:13]([C:11]1[O:10][N:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]2=[O:6])[CH:12]=1)([CH3:16])[CH3:15]
Reactant: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1CCN(c2cc(C(C)(C)C)on2)C1=O

Procedure:
To a solution of 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide in 10 ml of ethanol was added 2 g of powdered potassium hydroxide in 5 ml water and 5 ml ethanol. The mixture was refluxed for 30 minutes, cooled and poured into 40 ml water. A gummy solid was collected by filtration and recrystallized from pentane to afford 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methyl-2-pyrrolidinone as a solid. mp 89°-90° C.
Reaction SMILES: [F:1][CH:2]1[CH:11](OC)[NH:10][C:9](=O)[C:8]2[N:7]=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]1=2.O=P(Cl)(Cl)[Cl:19]>C(#N)C>[Cl:19][C:9]1[N:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[N:7]=[CH:6][C:5]([C:15]#[N:16])=[CH:4]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1NC(=O)c2ncc(C#N)cc2C1F
Solvent: CC#N
Product: N#Cc1cnc2c(Cl)ncc(F)c2c1
Temperature: 75 °C
Yield: 56.3 %

Procedure:
A pressure bottle was charged with 5-fluoro-6-methoxy-8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (2.27 g, 10.26 mmol), acetonitrile (41.1 ml) and POCl3 (3.35 ml, 35.9 mmol). The bottle was sealed and the reaction was heated at 75° C. for 17 h. Upon cooling to RT the mixture was concentrated and the crude material was purified by silica gel chromatography, using a gradient of 0-20% 90/10 DCM/MeOH in DCM. 8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (1.2 g, 5.78 mmol, 56.3% yield) was isolated as a white solid. LC/MS (ESI+) m/z=208.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.C(OCC1C=CC=CC=1)C1C=CC=CC=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Solvent: c1ccc(COCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(OCCN2CCCC2)cc1

Procedure:
The synthesis begins with bromination1 of 2-bromo-5-methoxy-toluene to provide the benzyl bromide 1-Bromo-2-bromomethyl-4-methoxy-benzene. Alkylation of ethyl benzoylacetate2 with the benzyl bromide followed by decarboxylation leads to the ketone 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one, which is protected3 as the ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane. Metal-halogen exchange of ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane provides an aryl-lithium species, which adds readily to either 4-benzyloxy-benzoate or 4-benzoxy-benzontrile4 and furnishes the diketone 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one upon acidic work-up. The diketone undergoes a titanium mediated McMurry type coupling5 to provide the alkene 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene, which possesses the carbon framework of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine with all the functional groups in place. A palladium catalyzed hydrogenation achieves the reduction of the olefinic double bond and deprotection of the benzyl ether in one pot. The introduction of the N-ethyl-pyrrolidino side-chain is achieved under Mitsunobu conditions to afford 1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine, the key precursor to cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine. This compound is converted to cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol with HBr as described in U.S. Pat. No. 5,552,241.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a mixture of 0.51 g of 2,6-dichloro-4-(3,3,-dichloro-2-propenyloxy)phenol, 0.27 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.29 g of m-chlorobenzyl chloride dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.50 g of 3,5-dichloro-4-(3-chlorobenzyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (69% yield), m.p. 87.0° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](N(OC)C)=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:28]([Mg]Br)=[CH:29][CH3:30]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:23])[CH:28]=[CH:29][CH3:30])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:11]=[CH2:12])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC=C[Mg]Br
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 5, 32.5 g, 80.73 mmol) in THF (400 mL) under nitrogen at 0° C. was added prop-1-enylmagnesium bromide (323 ml, 161.45 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then quenched with 400 mL 10% citric acid, diluted further with 100 mL water and extracted with ether. The organics were concentrated and the resulting oil was dissolved in ether and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (5%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oil (27 g, 87%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1)#[N:21]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[N:23][CH:24]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cn1
Yield: 46 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (196 mg) was reacted with 2-cyanopyridine-5-boronic acid pinacol ester as in General Procedure 4B to give the title compound as a yellow solid (46% yield). M.p.>200° C., LCMS: m/z=342.20 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.23 (2H, s), 5.27 (2H, s), 7.23 (1H, m), 7.32 (4H, m), 7.49 (2H, m), 8.03 (1H, d, J=8.3 Hz), 8.18 (2H, m), 8.95 (1H, d, J=2.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[OH:13].[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23](O)[C:24]#[CH:25])[CH2:19][CH2:18]1)[CH2:15][CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl-].[Na+]>C1COCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH:14]([CH:17]1[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]1)[C:15]#[CH:16]
Reactant: C#CC(O)C1CCC(CCC)CC1
Reactant: Oc1cc2c(c(F)c1F)OCCC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(Oc1cc2c(c(F)c1F)OCCC2)C1CCC(CCC)CC1
Reaction time: 19 h

Procedure:
5.0 g (26.9 mmol) of 7,8-difluorochroman-6-ol are initially introduced in 65 ml of THF together with 5.33 g (29.6 mmol) of 1-(4-propylcyclohexyl)-prop-2-yn-1-ol and 8.45 g (32.2 mmol) of triphenylphosphine, and 6.79 ml (34.9 mmol) of DIAD are added over the course of 30 min with ice-cooling. After 19 h at RT, semi-saturated sodium chloride solution is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride solution, and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-pentane:MTBE=2:1), giving 7,8-difluoro-6-[1-(4-propylcyclohexyl)prop-2-ynyloxy]chroman as a pale-brown oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si](CC)(CC)CC)[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:34][CH3:35])([OH:36])[CH2:44][CH3:45])[CH2:12][C@@H:11]([OH:46])[CH2:10]1
Reactant: CCC(CC)(CCCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)CCCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98.2 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7-diene (180 mg), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (6 ml), followed by reflux under heating for 5 hours. After adding ethyl acetate, the mixture was washed with saturated brine, a saturated aqueous sodium bicarbonate solution and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the resulting residue was purified by column chromatography (ethyl acetate) to give the titled compound (0.10 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C:38]1[C:39](=[O:67])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:54][C@H:53]([CH2:55][NH:56][C:57]([C:59]4[S:60][C:61]([Cl:64])=[CH:62][CH:63]=4)=[O:58])[O:52][C:51]3=[O:65])=[CH:46][C:45]=2[Cl:66])[CH:41]=[CH:42][CH:43]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.O.[Cl-].[Na+].C(OCC)(=O)C>[Cl:64][C:61]1[S:60][C:59]([C:57]([NH:56][CH2:55][C@@H:53]2[O:52][C:51](=[O:65])[N:50]([C:47]3[CH:48]=[CH:49][C:44]([N:40]4[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][OH:36])[C:39]4=[O:67])=[C:45]([Cl:66])[CH:46]=3)[CH2:54]2)=[O:58])=[CH:63][CH:62]=1
Reactant: CC(C)(C)[Si](OCc1cccn(-c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2Cl)c1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC[C@H]1CN(c2ccc(-n3cccc(CO)c3=O)c(Cl)c2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 3 h

Procedure:
367 mg (1.41 mmol; 1 molar in THF) of tetrabutylammonium fluoride are added to a solution of 515 mg (0.703 mmol) of the compound from Example 6A in 8 ml of THF. After 3 h at RT, the mixture is diluted with water, saturated aqueous sodium chloride solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried over sodium sulphate. After filtration, the mixture is freed from the solvent and the residue is purified by chromatography on silica gel (dichloromethane/methanol 20:1). This gives 278 mg (78% of theory) of the desired product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(NCCO)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NCCO)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.014 g, 15%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.00 (br. s., 1H), 7.86 (d, 1H), 7.63 (s, 1H), 7.33-7.52 (m, 3H), 6.86 (d, 1H), 4.71 (d, 1H), 3.65 (t, 1H), 3.39-3.57 (m, 5H). LCMS: m/z 525.3 (M+1).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[S:13][C:14]1[N:18]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:17]=[N:16][N:15]=1)([O-])=O.C[O-].[Na+].O>CO>[CH3:25][S:22]([NH:21][CH2:20][CH2:19][N:18]1[C:14]([SH:13])=[N:15][N:16]=[N:17]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)NCCn1nnnc1S
Reaction time: 1 h

Procedure:
5-(2,4-Dinitrophenylthio)-1-(2-methanesulfonamidoethyl)tetrazole (4.46 g, 11.5 mmol) was added to 60 ml of 5% sodium methoxide in methanol. After 1 hour, water was added and the solid material was removed by filtration. The filtrate was concentrated in vacuo and 3N hydrochloric acid was added to the residue to bring the pH to 1.4. The acidic solution was filtered and the filtrate was extracted twice with ethyl acetate. The extracts were combined and concentrated to give a residue which crystallized upon addition of ethyl acetate to give 1-(2-methanesulfonamidoethyl)tetrazole-5-thiol, mp 131°-132°.
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[CH:11][CH:10]=2)[S:3]1.Cl.C([OH:33])C>>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:33])[NH:6][C:5]2=[O:7])=[CH:14][CH:13]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=N)NC2=O)cc1
Reactant: CCO
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 95.7 %

Procedure:
A mixture of 2-imino-5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl}-4-thiazolidinone (18.8 g), 2N-HCl (200 ml) and ethanol (200 ml) was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure. The residue was neutralized with saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4). The solvent was distilled off, whereby 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione (18.0 g, 95.7%) was obtained. Recrystallization from ethanol afforded colorless needles. m.p. 113°-114° C. Elemental Analysis for C22H20N2O4S, Calcd.: C, 64.69; H, 4.93; N, 6.86. Found: C, 64.48; H, 4.91; N, 6.75.