Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: Ic1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCCCC#Cc1cccc2ccccc12
Yield: 68.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4.0 mL (0.027 mole) of 1-iodonaphthalene, 0.1 gram (0.0003 mole) of copper(I)iodide, and 0.19 gram (0.0003 mole) of bis(triphenylphosphine)palladium(II) chloride in 75 mL of diethylamine was stirred, and 2.6 mL. (0.027 mole) of 4-pentyn-1-ol was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. Gas chromatographic (GC) analysis of the reaction mixture indicated that the reaction had not gone to completion. An additional 0.5 mL of the 4-pentyn-1-ol was added, and the reaction mixture was stirred for an additional six hours. GC analysis of the reaction mixture indicated that the reaction was complete. The reaction mixture was passed through a column of silica gel. Elution was accomplished using methylene chloride. The eluate was concentrated under reduced pressure, yielding 3.9 grams of 5-(naphth-1-yl)-4-pentyn-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.Cl.[NH2:32][CH:33]1[C:54](=[O:55])[N:35]2[C:36]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])=[C:37]([Cl:40])[CH2:38][S:39][C@H:34]12>C(OCC)(=O)C.CC(C)=O.O1CCCC1.O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([NH:32][CH:33]2[C:54](=[O:55])[N:35]3[C:36]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=4)=[O:42])=[C:37]([Cl:40])[CH2:38][S:39][C@H:34]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CCCCCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 90.2 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 3.24 g.), N,N-dimethylformamide (0.951 g.), and phosphoryl chloride (2.00 g.) in ethyl acetate (20 ml.), and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (4 g.) in a mixture of acetone (20 ml.), water (20 ml.) and tetrahydrofuran (40 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.78 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=2)[OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:32]=[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47](O)=[O:48])[C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[C:34](=[O:40])[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=1)[CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:48])=[O:32]
Reactant: COc1cc(CC[C@@H](O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc(OC)c1OC
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cc(OC)c(OC)c(OC)c1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of alcohol 14 (650 mg, 1.5 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 382 mg, 1.5 mmol, followed by 1,3-dicyclohexylcarbodiimide (370 mg, 1.8 mmol), and 4-(dimethylamino)-pyridine (128 mg, 1.0 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-30% EtOAc/hexanes) to give (1R)-3-(3,4,5-trimethoxyphenyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (776 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.30-6.80 (m, 4H), 6.37 (s, 2H), 5.82 (t, J=6.1 Hz, 1H), 5.33 (d, J=5.2 Hz, 1H), 4.54 (s, 2H), 3.85 (s, 6H), 3.83 (s, 3H), 3.38 (d, J=12.6 Hz, 1H), 3.16 (td, J=12.8, 3.1 Hz, 1H), 2.60 (m, 2H), 2.45-2.05 (m, 3H), 1.70 (m, 6H), 1.50 (s, 9H), 1.45 (m, 2H), 1.25 (s, 3H), 1.23 (s, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.1, 168.2, 167.6, 158.5, 153.6, 141.7, 137.0, 130.1, 120.9, 120.2, 114.6, 113.7, 105.7, 82.7, 66.2, 61.2, 56.5, 51.7, 47.1, 44.6, 38.2, 32.9, 32.4, 28.4, 26.8, 25.3, 23.9, 23.5, 21.6, 9.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>[Pt]>[CH:4](=[O:5])[C:3]1[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:1]
Reactant: OCc1ccccc1O
Agent: [Pt]
Product: O=Cc1ccccc1O

Procedure:
DiBella, U.S. Pat. No. 3,673,257, patented June 27, 1972, points out that o-hydroxybenzyl alcohol (saligenin) can be oxidized in the presence of a platinum catalyst to produce salicylaldehyde. However, DiBella states that the reported processes are generally unsatisfactory for use on a commercial scale, because they require the use of large amounts of the catalyst if the necessary reaction rate is to be attained, give low yields of salicylaldehyde, and under certain conditions salicylic acid rather than salicylaldehyde is formed. In U.S. Pat.No. 2,676,189 Britton and Head state that when saligenin was oxidized under a variety of conditions using a platinum or platinum oxide catalyst, it was not possible to convert more than fifteen percent of the saligenin to salicylaldehyde. Marchand and Genet report in U.S. Pat. No. 3,321,526 that when saligenin was oxidized in the presence of boric acid and a platinum catalyst a 12.5% yield or salicylaldehyde was obtained, whereas when a palladium catalyst was used under the same conditions the yield of salicylaldehyde was 83.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Solvent: CCO
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.8 %

Procedure:
72.15 g (0.3 mol) of 2-(4-chlorophenoxy-methyl)-2-tert.-butyl-oxirane and 24.15 g (0.35 mol) of 1,2,4-triazole were heated under refulx in 120 ml of ethanol for 48 hours. The mixture was then concentrated, and the residue was taken up in 200 ml of ethyl acetate and the solution heated. The solution was thereafter cooled in an ice bath, and the solid material was filtered off under suction and was washed with ethyl acetate. The filtrate was concentrated and the residue was dissolved in ether/hexane, and the solution was treated with gaseous hydrogen chloride. The precipitate was filtered off under suction and washed with ether, and the free base was obtained by the addition of ethyl acetate/1 N sodium hydroxide solution. 60.2 g (65% of theory) of 2-(4-chlorophenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 84°-87° C. were obtained.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH:7]([O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:31]([NH:30][C@H:29]([C:28]([O:27][CH:7]([CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:6]([OH:45])=[O:5])=[O:44])[CH:41]([CH3:42])[CH3:43])([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of t-butyl-2,3-bis-(N-CBz-L-valyloxy)-propionate (7.2 g, 11.4 mmole) in dichloromethane (25 ml) was added trifluoroacetic acid (25 ml) and the solution was stirred for five hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 5.9 g=90%
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:31]#[N:32]>O1CCCC1.C(OCC)(=O)C.[Cu]I.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:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:31]#[N:32])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol), tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) and copper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 0.28 mmol) were added and the reflux was continued for 1 hour. The reaction mixture turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC[C@@H]1CCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCO2)cc1
Reaction time: 2 h
Yield: 65 %

Procedure:
To (S)-(tetrahydrofuran-2-yl)methanol (2.0 g, 20 mmol) in CH2Cl2 (10 mL) at about 0° C. was added p-toluenesulfonyl chloride (4.2 g, 22.00 mmol), followed by drop-wise addition of triethylamine (5.6 mL, 40.0 mmol). The resulting solution was kept at 0° C. for 2 hours, and then at room temperature for another 2 hours. The reaction mixture was concentrated to dryness and diethylether (200 mL) and water (100 mL) were added. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to yield the title compound (2.3 g, 13.00 mmol, 64%) as a colorless oil, which was used in the next step without purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N+:14]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][O:23][C:19]1[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCBr)c1

Procedure:
43 ml of 1,3-dibromopropane are added to a suspension of 29 g of potassium carbonate and 0.5 g of potassium iodide in 170 ml of acetone and the mixture is refluxed. A solution of 19.4 g of 3-nitrophenol is then added dropwise in the course of 2 hours and the mixture is refluxed for a further 15 hours. The reaction mixture is filtered hot and evaporated. Chromatography of the residue on silica gel with toluene gives 3-(3-bromopropoxy)-nitrobenzene as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[O:11][CH2:6][C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To a suspension of 4-chloro-2-hydroxybenzoic acid (10.0 g, 57.9 mmol) and K2CO3 (20.8 g, 151 mmol) in DMF (115 mL) is added benzyl bromide (14.5 mL, 122 mmol) and the mixture is stirred at 85° C. for 7 h. The mixture is allowed to cool to RT and is partitioned between EtOAc and 1N HCl. The organic phase is washed with 1N HCl and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1.C(#N)C>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of 35.3 grams of 1-hexadecyl-sn-glycerol, 37.3 grams of triphenylchloromethane and 22.44 grams of dry triethylamine in a mixture of 470 ml dry tetrahydrofuran and 120 ml dry acetonitrile was refluxed for 15 hours under a nitrogen atmosphere. After cooling to room temperature the reaction mixture was filtered. The filtrate poured on ice (500 grams) and then extracted thrice with 200 ml chloroform. The organic phase was washed successively with 500 ml water, 500 ml of 0.15 N HCl, 500 ml saturated aqueous NaHCO3, and again with water. The extract was dried over Na2SO4 and the solvent was removed under reduced pressure. The obtained yellow residue was dissolved in 500 ml warm hexane and the obtained clear solution was refrigerated (5±3° C.) overnight. During this time, precipitation occurred. After filtration of the precipitate, the solvent from the filtrate was removed under reduced pressure, yielding 58.3 grams of 1-hexadecyl-3-trityl-sn-glycerol. The yield was 95%.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1.C(#N)C.CCCCCC>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
20 grams of (S)-1-hexadecyl-glycerol and 21.29 grams of triphenylchloromethane were dissolved in 369 ml dry tetrahydrofuran (THF) and 93 ml dry acetonitrile. 17.75 ml triethylamine was added and the reaction mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, poured on ice (100 grams), transferred to a separatory funnel and extracted with methyl tert-butyl ether. The organic phase was washed consecutively with 200 ml water, twice with 200 ml dilute (1.5%) sulfuric acid, 200 ml water, 200 ml saturated aqueous sodium bicarbonate, and again with 200 ml water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 36.86 grams of crude product as a residue. This residue was dissolved in hot hexane (200 ml) and the resulting solution was cooled at 4° C. overnight. The precipitated product was filtered, yielding 30.71 grams of (R)-1-hexadecyl-3-trityl-glycerol.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:37])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:37])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCN(C)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCN(C)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
85 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-nonyl-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is dissolved in 3 ml of methanol and mixed with 25 mg of sodium borohydride. After 30 minutes of stirring at room temperature, the solvent is drawn off in a vacuum for the most part, the residue is mixed with common salt solution, extracted 3 times with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Preparative thin-layer chromatography with methylene chloride/methanol=9/1+0.5% triethylamine as a mobile solvent provides 33 mg of 11β-fluoro-7α-{5-[methyl-nonyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol as a foam.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.C1CCCCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)CC(O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Ethyl acetate (5.8 ml) was dissolved in tetrahydrofuran (80 ml), to which was then added 1.5M lithium diisoprypylamide/cyclohexane solution (43 ml) in nitrogen atmosphere at −70° C., and then the mixture was stirred for 15 min. 4-Bromobenzaldehyde (10.151 g)/tetrahydrofuran (10 ml) solution was added to the reaction mixture, which was then stirred for 30 min. A saturated aqueous solution of ammonium chloride was added thereto, and then it was extracted with in ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (11.906 g, yield; 80%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[OH:24])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])=[CH:16][CH:17]=1
Reactant: OC1CCCCC1c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCCCC1c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of oxalyl chloride (0.45 mL, 5.2 mmol) in dry dichloromethane (15 mL) at −78° C. is added a solution of DMSO (0.73 mL, 10.3 mmol) in dichloromethane (10 mL) dropwise, and the resulting mixture is allowed to stir at −78° C. for 30 minutes. Then a solution of 2-(4-Fluoro-phenyl)-cyclohexanol (500 mg, 2.57 mmol) in dichloromethane (5 mL) is added and stirred for 15 minutes. Then triethylamine (2.87 mL, 15.4 mmol) is added and the reaction is allowed to slowly warm up to 20° C. and stirred for 16 hours. The mixture is poured into ice-water (30 mL) and organic layer is washed with water (10 mL×5), then brine (10 mL×1) and dried over anhdrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 30%) to give 342 mg of the desired product.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]ncc12
Product: Clc1ncnc2[nH]ncc12

Procedure:
31.1 g. of 4-hydroxypyrazolo[3,4-d]pyrimidine are heated at reflux with 200 ml. of phosphorous oxychloride for 12 hours. The excess phosphorous oxychloride is distilled off and the residue is boiled with benzene. After distilling off the benzene and trituration with petroleum ether, there remain 15.8 g. of 4-chloropyrazolo[3,4-d]pyrimidine as light yellow crystals, m.p. 94°-96°. This product is pure enough for further use.