Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: C1CCNCC1
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Agent: [I-]
Agent: [K+]
Product: Ic1ccc(-c2nnc(CN3CCCCC3)o2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in piperidine (2 ml) and stirred for 18 hours at 20° C. The amine was then removed in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
Reaction SMILES: [H][H].[BrH:3].[CH:4]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=2[OH:18])[C:9]1=[O:20])([CH3:6])[CH3:5]>O.[Pd]>[BrH:3].[OH:20][CH:9]1[C:10]2[C:15](=[C:14]([OH:18])[C:13]([OH:19])=[CH:12][CH:11]=2)[CH2:16][CH2:17][CH:8]1[NH:7][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)NC1CCc2c(ccc(O)c2O)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: O
Product: CC(C)NC1CCc2c(ccc(O)c2O)C1O

Procedure:
In 10 volume parts of water is dissolved 0.180 part of 3,4-dihydro-2-isopropylamino-5,6-dihydroxy-1(2H)-naphthalenone hydrobromide and with the addition of 0.2 part of 5 % palladium-on-carbon, catalytic reduction is carried out in a current of hydrogen gas. The absorption of hydrogen ceases when 9 volume parts of hydrogen has been absorbed. The catalyst is filtered off and the filtrate is freeze-dried. Finally, the residue is recrystallized from ethanol-ethyl ether. The procedure gives colorless prisms of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 169° C.(decomp.)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:15]1(OC)[CH2:19][CH2:18][CH2:17]O1.O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:19][CH:18]=[CH:17]2)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC1(OC)CCCO1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(F)c(-n2cccc2)cc1F
Yield: 79.2 %

Procedure:
5.2 grams (0.03 mol) of 2,5-difluoro-4-aminobenzoic acid, melting at 250°-3°, are dissolved in 60 ml of glacial acetic acid, and 4 grams (0.03 mol) of dimethoxytetrahydrofuran are added. The mixture is heated at the boil for 10 minutes, 20 ml of water are added and the resulting mixture is left to cool. The precipitate formed is filtered off and washed with water to give 5.3 grams of a solid melting at 196°-8° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>C(Cl)(Cl)Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[S:24])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CSC(=S)N1CC(C)(C)SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]L-cysteine methyl ester (5.0 g) in chloroform (90ml), thiocarbonyldiimidazole (3.0 g) was added and the mixture was stirred for 1.5 hr at room temperature. The reaction mixture was washed with 3N hydrochloric acid, water and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 5.10 g(91%) of (4R)-3-[2-(4-methoxy-benzylthio)-2-methylpropyl]-4-methoxycarbonylthiazolidine-2-thion
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:4]1[N:3]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:2]([CH3:1])=[N:6][C:5]=1[CH3:7]
Reactant: Cc1cn(-c2ccccc2C#N)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(C)n(-c2ccccc2C#N)c1Br

Procedure:
Compound 6 (5.18 grams, 26.0 mmol) was dissolved in acetonitrile (150 mL). To this was added N-bromosuccinimide (4.67 grams, 26.0 mmol). This was stirred at reflux for 1 hour before being evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was evaporated in vacuo to give the title compound as a yellow solid. NMR confirmed structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].CC1C=CC(S(O[CH2:35][C@H:36]2[CH2:40][CH2:39][CH2:38][O:37]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:35][C@H:36]5[CH2:40][CH2:39][CH2:38][O:37]5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione was obtained (32%) as a colorless solid: mp>250° C. (toluene/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 1H), 7.17-7.03 (m, 3H), 6.90-6.85 (m, 1H), 6.40-6.28 (m, 1H), 4.99-4.92 (m, 1H), 4.75-4.67 (m, 1H), 4.36-4.25 (m, 1H), 4.01-3.67 (m, 4H), 3.25-3.21 (m, 3H), 2.14-1.85 (m, 3H), 1.79-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.0, 156.9, 155.0, 143.5 (2C), 143.1, 142.6, 132.2, 131.9, 129.3, 129.2, 126.2, 124.1, 123.8, 123.6, 109.8, 109.8, 103.1, 103.0, 94.7 (2C), 80.5, 80.4, 77.1, 76.3, 68.4, 68.2, 58.2 (2C), 45.0, 44.7, 29.3, 29.2, 28.3, 28.2, 25.7; MS (ES+) m/z 393.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added pyrrolidine (24.1 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-(4-nitrobenzyl)pyrrolidine (23.5 g) as orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)([O-])C.[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:15])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (see Tetrahedron Lett. (1980), 21(32), 3019-20 for outline of synthesis, 5 g) was dissolved in dry DMF (75 ml) and potassium tert-butoxide (3.08 g) was added. The mixture was stirred at ambient temperature for 1 hour, then iodomethane (3.9 g) was added, and stirring continued at the same temperature for 2.5 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 100% ethyl acetate in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-methyl-3-oxopiperazine (3.92 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH3:21]C#N>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]([CH3:21])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Reactant: CC#N
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (4.0 g, 12.8 mmol), iodomethane (2.74 g, 9.2 mmol), and K2CO3in CH3CN (60 mL) was stirred at room temperature under a blanket of nitrogen overnight. Upon completion of the reaction, ethyl acetate (200 mL) was added and the organic layer was washed with H2O (200 mL), dried over Na2SO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 5-bromo-3-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid: mp 98-99° C.; 1H-NMR (CDCl3) δ7.7 (d, 1H, J=8,5 Hz), 7.27 (bs, 2H), 7.09 (d, 1H, J=2 Hz), 3.4 (s, 3H), 1.7 (s, 9H); MS (ES) m/z 349([M+Na]+, 20%), 351([M+Na]+, 20%); Anal. Calc. For C13H15BrN2O3: C, 47.73; H, 4.62; N, 8.56. Found: C, 47.46; H, 4.5; N, 8.29.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[NH:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([C:20](=[O:21])[CH:19]([Cl:23])[Cl:18])[CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(C2NCCO2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(Cl)Cl)N1CCOC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Five and eight tenths grams of 2-m-nitrophenyl oxazolidine was dissolved in 50 ml. methylene chloride containing 3.5 g. of triethylamine. Dichloroacetyl chloride 4.4 g. was added dropwise with stirring to the reaction flask and cooled in a water bath at room temperature. When addition was complete, the mixture was stirred at room temperature for about 30 minutes, washed with water, separated and dried over anhydrous magnesium sulfate. The solvent was stripped off under vacuum. There was obtained a yield of 8.6 g. of the title compound, ND30 = 1.5590.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: Nc1nc(-c2cccc(Cc3ccccc3)c2)[nH]c(=O)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2cccc(Cc3ccccc3)c2)[nH]c(=O)c1N
Temperature: 60 °C
Yield: 97.3 %

Procedure:
4-Amino-2-(3-benzylphenyl)-5-nitrosopyrimid-6-one (11.95 g.) was suspended in water (250 ml.), and triethylamine (20 ml.) was added, giving a purple-red solution. Sodium dithionite (12 g.) was added in portions during 30 minutes with shaking and heating at 60° C. After cooling, the mixture was extracted three times with chloroform, and the combined extracts were dried over magnesium sulphate and evaporated to give crude 4,5-diamino-2-(3-benzylphenyl)pyrimid-6-one (11.1 g.), sufficiently pure to use in the above preparation of 8-aza-2-(3-benzylphenyl)purin-6-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:12][O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)[CH:3]=1
Reactant: COc1cc(Br)cn2nccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2nccc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1375 mg, 6.61 mmol), tetrakis(triphenylphosphine)palladium (0) (254 mg, 0.220 mmol), and sodium carbonate (700 mg, 6.61 mmol) were suspended in a mixture of 1,4-dioxane (19.8 ml) and water (2.2 ml). The mixture was sparged with argon for 10 minutes, then heated to 90° C. After 2 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a tan solid contaminated with trace amounts of triphenylphosphine oxide. Analytically pure material could be obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][C@@H:33]([N:36]3[CH2:40][CH2:39][CH2:38][C@@H:37]3[CH3:41])[CH2:32]2)[N:25]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][NH:30][C:29]2[C:24]([CH3:23])=[N:25][C:26]([N:31]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:40][CH2:39][CH2:38][C@@H:37]4[CH3:41])[CH2:32]3)=[CH:27][CH:28]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Product: CCOC(=O)C1(CCCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(3-oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (69 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 113 mg of a crude solid, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[OH-].[K+].[CH:25](=O)[CH3:26].C(O)(=O)C>C(O)C>[CH:25](=[C:15]1[CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13][C:14]1=[O:22])[CH3:26]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC=C1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O

Procedure:
A mixture of 17β-methoxy-5α-androstan-3-one (U.S. Pat. No. 3,301,850, Example 14, 8 g.), potassium hydroxide (2.1 g.) and acetaldehyde (5 ml.) in absolute ethanol (500 ml.) is stirred for 16 hours under nitrogen. The potassium hydroxide is then neutralized with acetic acid and the mixture concentrated to about 100 ml. Water is added and the product is extracted with diethyl ether. After the diethyl ether is removed the steroid is chromatographed over silica gel and then alumina. The appropriate fractions are pooled and concentrated to give both isomers of the product, IR (neat) 1720 and 1690 cm-1 ; MS (m/e) 330; NMR (CDCl3) 0.79, 0.78, 0.83, 1.72, 3.22, 3.35 and 6.75 δ; and UV (ethanol) λ=246 nm (ε=4,300).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC([C@H]2N3C(SC(C([N:28]4[CH2:49][C@H:48]([F:50])[CH2:47][C@H:29]4[C:30]([N:32]4[CH2:39][C:36]5([CH2:38][CH2:37]5)[N:35]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH2:34][C@H:33]4C)=[O:31])=O)=C3C(C)C)=N[C@]2(C2C=NC(Cl)=CC=2)C)=CC=1F>ClCCl>[F:50][C@H:48]1[CH2:49][NH:28][C@H:29]([C:30]([N:32]2[CH2:39][C:36]3([CH2:38][CH2:37]3)[N:35]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH2:34][CH2:33]2)=[O:31])[CH2:47]1
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)C(F)(F)F)C[C@H]2C)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@@H]1C[C@@H](F)CN1)N1CCN(C(=O)C(F)(F)F)C2(CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a dichloromethane (10 ml) solution of the compound (560 mg, 1.32 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure and then saturated aqueous sodium bicarbonate solution (30 ml) was added, followed by extraction with chloroform three times. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (380 mg, 89%) as a pale yellow solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Product: COc1cc(C=Cc2cccc(F)c2)cc(OC)c1C(C)C

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 3-fluorobenzaldehyde in the same way as described in example 21.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-3-trifluoromethylbenzoic acid (395 mg) in methanol (5 mL) was added conc. sulfuric acid (0.4 mL), and the mixture was heated for 6 hours under reflux. The reaction mixture was allowed to stand for cooling down to room temperature, and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, and concentrated to give the title compound (403 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:22][C:23]([F:51])([C:47]([F:50])([F:49])[F:48])[C:24]([F:46])([F:45])[C:25]([F:44])([F:43])[O:26][C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[O:29][C:30]([F:38])([F:37])[CH2:31][O:32][CH2:33][CH2:34][CH2:35]Br>O>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([O:29][C:28]([F:39])([F:40])[C:27]([F:41])([F:42])[O:26][C:25]([F:43])([F:44])[C:24]([F:45])([F:46])[C:23]([F:22])([F:51])[C:47]([F:50])([F:49])[F:48])([F:38])[F:37])=[CH:19][CH:20]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 1 by combining 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10.0 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopropane (6.6 g, 12.0 mmol, Example 10). The product was isolated by addition of water (60 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 180-190° C. at 2 torr; yield 5.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([Br:7])=[N:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:7][C:5]1[S:6][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([F:13])=[CH:15][CH:16]=2)=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1nc(Br)sc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(Br)sc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a mixture of ethyl 5-amino-2-bromothiazole-4-caboxylate (0.50 g, 1.99 mmol) and a catalytic amount of DMAP in pyridine (5 mL) was added a solution of 4-fluorobenzoyl chloride (0.377 g, 2.39 mmol) in pyridine (5 mL) at 0° C. The mixture was allowed to warm to rt, and stirred for 16 hrs. The reaction mixture was quenched with ice-water, and the resulting solids were collected. The solids were purified by silica gel column chromatography eluted with 20% EtOAc in hexane to give 0.70 g (93% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[C:4]([C:23]([O:25][CH3:26])=[O:24])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[C:9]([C:21]#[N:22])[CH:8]=1.C(N(CC)CC)C>O1CCOCC1.[C].[Pd]>[C:21]([C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([C:23]([O:25][CH3:26])=[O:24])=[C:3]([F:27])[CH:2]=2)[CH:12]=[CH:11][C:10]=1[OH:13])#[N:22]
Reactant: COC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)c(Br)c1F
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(-c2ccc(O)c(C#N)c2)cc1F

Procedure:
(4-Benzyloxy-3-cyanophenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 1 M aqueous sodium carbonate solution and the whole was heated at 110° C. for 2.5 days in the presence of tetrakis(triphenylphosphine)-palladium to obtain methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate. Methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate and triethylamine were stirred at room temperature in 1,4-dioxane under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-4-hydroxyphenyl)-3-fluorothiophene-2-carboxylate. FN: 276.