Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.S(=O)(=O)(O)O>CO>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCC=Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 94.1 %

Procedure:
3-(4-Trifluoromethylphenyl)acrylic acid (3.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 3.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white powder was dissolved in tetrahydrofuran (40 ml), 1M diisobutylaluminum hydride/toluene solution (34 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 1 hr. Saturated Rochelle salt water, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (2.64 g) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[CH:33]([NH:36][C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (54.58 g, 224 mmol) in dry DMF (200 mL) was added 1,1′-carbonyldiimidazole reagent grade (70 g, 432 mmol) portionwise with stirring. After the evolution of CO2 had ceased, the resulting solution was stirred at RT for 10 minutes. The solution was cooled to 0° C., and isopropylamine (38.5 mL, 449 mmol) was added with stirring. The reaction was stirred at 0° C. for 10 minutes and at RT for 24 hours. The reaction was diluted slowly with water (1 L) with stirring in an ice-water bath and then allowed to age for 1 hour. The precipitate was collected by filtration, washed with water, and dried in vacuo to generate tert-butyl cis-4-(isopropylcarbamoyl)cyclohexyl-carbamate as a white solid (39.11 g, 61% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6](=[O:37])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][OH:25])([OH:14])[CH:10]([C:26]2([CH3:34])[O:33][CH:27]2[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH:9]1[O:35][CH3:36])=[O:4].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].O>ClCCl>[Cl:1][CH2:2][C:3]([NH:5][C:6](=[O:37])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][S:46]([CH3:45])(=[O:48])=[O:47])([OH:14])[CH:10]([C:26]2([CH3:34])[O:33][CH:27]2[CH2:28][CH:29]=[C:30]([CH3:31])[CH3:32])[CH:9]1[O:35][CH3:36])=[O:4]
Reactant: COC1C(NC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC1C(NC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2COS(C)(=O)=O)C1C1(C)OC1CC=C(C)C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
In dichloromethane (3 ml) were dissolved 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (514 mg) and triethylamine (0.33 ml). To the solution was added dropwise at -20° C. methanesulfonyl chloride (96 μl). The mixture was stirred for 10 minutes, to which was added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (550 mg; yield 98%) as a colorless powdery product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[N:31][CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M89) (0.29 g, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (170 mg, 76%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1.[CH2:13]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)/C=C\C(O)=O.CN[C@@H]1CC2C(=CC=CC=2)NC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1)[C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN[C@H]1CNc2ccccc2C1
Agent: O=C(O)/C=C\C(=O)O
Solvent: Cc1ccccc1
Product: CN(C(=O)OCc1ccccc1)[C@H]1CNc2ccccc2C1
Reaction time: 0.5 h

Procedure:
A mixture of (R)-1,2,3,4-tetrahydro-N-methyl-3-quinolinamine of crude material prepared above (V, EXAMPLE 4, 15.0 g), approximately 84.4 mmol) in toluene (50 ml) is stirred at −40° while N-(benzyloxycarbonyloxy)succinimide (24.2 g, 97.1 mmol) in toluene (150 ml) is added over one hr. After 30 min at −40°, GLC analysis indicated that all of (V) had been consumed. The mixture is quenched by the addition of sodium bicarbonate (10% aqueous solution, 300 ml) and warmed to 0°, followed by the addition of methanol (100 ml). This is stirred overnight and then extracted with ethyl acetate. Drying over magnesium sulfate and solvent removal gives a liquid which is purified by flash chromatography (230-400 mesh silica gel; hexane/ethyl acetate, 4/1) which crystallized from ethyl acetate/hexane to give the title compound, mp=80°; NMR (CDCl3) 2.88, 2.80-3.04, 3.30, 3.83, 4.57, 5.16, 6.51, 6.64, 6.96-7.02 and 7.35 δ; [a]25D=−50.1° (CH3OH, c=0.816); IR (mineral oil) 1680 and 1606 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:11](=O)(O)[O-:12].[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:12][CH3:11]
Reactant: Cc1cccc(CBr)c1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1cccc(C)c1Br
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-3-methylbenzylbromide (5.2 g, 0.0197 mol) in methanol (30 ml) was added saturated sodiumbicarbonate (5 ml) and the mixture was refluxed overnight. The mixture was neutralised with acetic acid and the solvent was evaporated under reduced pressure. Chromatography of the residue on silica gel using hexane: methylene chloride (7/3) as eluent gave 4.2 g (99%) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](O)=[O:18].C(O)(=O)C>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][N:11]([CH:17]=[O:18])[C:12]=1[CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.00 g) was dissolved in tetrahydrofuran (10 mL) at room temperature. A mixed anhydride of formic acid and acetic acid (0.489 g) and acetic acid (0.0140 g) were successively added to the solution. After stirring the reaction mixture at room temperature for 5 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=4:1) to give 4-benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one (1.07 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)(C(C)(C)C)(C)C.[F-].[CH2:25]([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O:23][CH3:25])=[O:22])=[CH:15][CH:14]=2
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2cc(CC(=O)[O-])ccc2[nH]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(2-(t-butyldimethylsilyl-oxyethyl)-indole-5-acetate (400 mg; 1.15 mmol) in ca. 4 ml of THF was added a 1 M tetrabutylammonium fluoride in THF (1.2 mL; 1.05 eq) at 0° C. After 15 minutes, the reaction was allowed to warm to room temperature and stirred for an additional 3 hours. It was con-centrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), concentrated and chromatographed (silica gel, hexane:ethyl acetate 4:1) to yield 241 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:15]O>C(O)(=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:14])[N+:13]=1[O-:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OO
Reactant: CCCCCCOc1cccc(C)n1
Solvent: CC(=O)O
Product: CCCCCCOc1cccc(C)[n+]1[O-]
Reaction time: 3 h

Procedure:
To a solution of 8.60 g (44 mmol) of 6-hexyloxy-α-picoline dissolved in 43 ml of acetic acid was added 6.4 ml of hydrogen peroxide, the mixture was stirred at 70° to 80° C. for 3 hours, further 4 ml of hydrogen peroxide was added, and the mixture was stirred at the same temperature for 3 hours. After concentration under a reduced pressure to a half amount, water was added and the mixture concentrated under a reduced pressure (repeated for three times). A crude in an amount of 5.50 g was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:23]=[C:22](B(O)O)[C:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:22]2[C:16]3[O:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=3[CH:14]=[C:13]([Cl:12])[CH:23]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: CC1(C)Oc2cc(Cl)cc(B(O)O)c2O1
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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)cc3c2OC(C)(C)O3)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.7 grams (0.012 mole) of 5-chloro-2,2-dimethylbenzodioxolan-7-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-(5-chloro-2, 2-dimethylbenzodioxolan-7-yl)pyridine.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[Br:19])[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br>C(O)(=O)CC>[Br:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][NH:10][CH2:11]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cccc(Br)c3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Brc1cccc2c1CNC2
Yield: 92.5 %

Procedure:
The procedure of Reference Example 6-(3) was followed using 9.61 g of 2-(p-toluenesulfonyl)-4-bromoisoindoline, 10 g of phenol, 120 ml of 48% hydrobromic acid, and 20 ml of propionic acid. Purification of the crude product by vacuum distillation gave 5.0 g of 4-bromoisoindoline.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]([O:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[N:12]=1)([CH3:9])[CH3:8].Br[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32](C1CCCCO1)[N:31]=[C:30]2[C:42]1[N:47]=[C:46]([N:48]2[CH2:53][CH2:52][CH:51]([NH:54]C(=O)OC(C)(C)C)[CH2:50][CH2:49]2)[CH:45]=[N:44][CH:43]=1>[Cu]I.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([O:10][C:11]1[N:12]=[C:13]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][N:31]=[C:30]3[C:42]2[N:47]=[C:46]([N:48]3[CH2:49][CH2:50][CH:51]([NH2:54])[CH2:52][CH2:53]3)[CH:45]=[N:44][CH:43]=2)[CH:14]=[N:15][CH:16]=1)([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Reactant: CC(C)Oc1cncc(B2OC(C)(C)C(C)(C)O2)n1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Product: CC(C)Oc1cncc(-c2ccc3[nH]nc(-c4cncc(N5CCC(N)CC5)n4)c3c2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of CuI (Aldrich, 26.6 mg, 0.27 mmol), cesium carbonate (Aldrich, 351 mg, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene (14.9 mg, 0.03 mmol), palladium(II) acetate (Strem Chemicals, 3.0 mg, 0.01 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (Combi-Phos, 142 mg, 0.54 mmol), and tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 150 mg, 0.27 mmol) in a 5 mL conical microwave vial was sealed, evacuated and back-filled with N2 3×. DMF (2.7 mL) was added, and the reaction mixture was stirred at 80° C. for 16 h. The resulting reaction mixture was cooled to RT, filtered, and concentrated to dryness. The crude product was purified by HPLC (5 to 80% 0.1% TFA:Water:0.1% TFA:ACN over 25 min). The fractions were combined, washed with sat. aq. NaHCO3 and extracted with 20% IPA in chloroform. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to a tan oil. The oil was dissolved in MeOH/DCM before adding 6 N HCl in IPA and stirring at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure before resolubilizing with MeOH and passing through a MeOH washed plug of Si-propylsulfonic acid. The compound was released with 2M NH3 in MeOH (30 mL) to afford 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine as a dark tan solid. MS (ESI, pos. ion) m/z: 431 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:7]=1[CH2:15][N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:5])C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:21]([O:20][C:18]([CH:17]1[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[CH2:15][C:7]2[N:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[S:10][C:6]=2[C:4]1=[O:5])=[O:19])[CH3:22]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C(C)(C)C)sc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2sc(C(C)(C)C)nc2CN1Cc1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-tert-butyl-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (12.8 g, 26.7 mmol) in 350 mL of anhydrous THF was cooled to 0° C. with an external ice bath and 53 mL of 1 N potassium tert-butoxide was added slowly. The reaction was stirred at 0° C. for 2 h and then allowed to warm to room temperature and stirred for 2 h. The reaction was diluted with ethyl acetate and washed with a solution of 200 mL saturated ammonium chloride and 50 mL 1 N HCl. The organic fraction was washed with brine, dried over anhydrous sodium sulfate and concentrated to 11.5 g of product. MS (ESI+): m/z 433.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:13](=O)[CH3:14])[C:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[N:24][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[C:13]=1[CH3:14])[CH3:2]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)CC(C)C
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(CC(C)C)nn(-c2ccccn2)c1C
Yield: 84.9 %

Procedure:
Combine 3-acetyl-6-methyl-4-oxoheptanoic acid ethyl ester (3.0 g, 13.1 mmol) and pyridin-2-yl-hydrazine (1.72 g, 15.72 mmol) in glacial acetic acid (25 mL) and stir at room temperature for 68 hr. Concentrate to an oil and partition the residue between ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 90:10 hexanes:ethyl acetate, to give (3-isobutyl-5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-acetic acid ethyl ester (3.35 g, 85%). 1H-NMR (400 MHz, CDCl3) δ 8.38 (m, 1H), 7.77 (m, 2H), 7.13 (m, 1H), 4.12 (q, 2H), 3.41 (s, 2H), 2.98 (d, 2H), 2.27 (s, 3H), 1.82 (m, 1H), 1.22 (t, 3H), 0.80 (d, 6H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]I>O1CCCC1>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:2][CH3:1]
Reactant: CN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Solvent: C1CCOC1
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
5.1 g of methylamine is condensed in a solution of 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 35 ml of anhydrous tetrahydrofuran at -78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at -20° C., it was allowed to reach room temperature to be able to evaporate excess methylamine. Then, the reaction solution is added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.7 g of 11β-fluoro-3-hydroxy-7α-[5-(methylamino)-pentyl]-estra-1,3,5(10)-trien-17-one is obtained as crude product.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)C(=O)OC(C)(C)C)[CH3:2].O1CCOCC1.O.[OH-].[Na+]>Cl>[CH2:1]([NH:3][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:2]
Reactant: CCN(CCCN1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNCCCN1CCOCC1
Reaction time: 0.75 h
Yield: 22.3 %

Procedure:
3-(4-Morpholinyl)propan-1-amine (35.0 g, 243 mmol) was dissolved in tetrahydrofuran (THF, 250 mL), di-tert-butyl dicarbonate (58.0 g, 266 mmol) and N,N-diisopropylethylamine (DIPEA, 84 mL, 484 mmol) were added, and the solution was stirred overnight. The solvent was removed and the residue partitioned between ethyl acetate (EA) and 1.2M hydrochloric acid (300 mL). The pH was raised to 7 with saturated aqueous sodium bicarbonate and the layers separated. The aqueous layer was extracted twice with EA (150 mL each), and the EA layers were combined, washed with brine, and dried over magnesium sulfate. The solvent was removed, giving tert-butyl 3-(4-morpholinyl)propylcarbamate (39 g). Tent-butyl 3-(4-morpholinyl)propylcarbamate (3.5 g, 14.3 mmol) was dissolved in THF (30 mL), and sodium hydride (60% dispersion in mineral oil, 1.03 g, 25.8 mmol) was added in portions. After stirring for 5 min, ethyl iodide (13.4 g, 86.0 mmol) was added and the mixture was heated to 60° C. for 7 hr then stirred at room temperature overnight. Water (5 mL) was added and the solvent removed. The residue was dissolved in EA, and the solution was washed with brine, dried over magnesium sulfate, and the solvent removed to give crude tert-butyl ethyl[3-(4-morpholinyl)propyl]carbamate (2.5 g). Purification by silica gel chromatography eluting with 92:8 dichloromethane/methanol (DCM/MeOH) gave purified tert-butyl ethyl[3-(4-morpholinyl)propyl]carbamate (1.4 g). Purified tert-butyl ethyl[3-(4-morpholinyl)propyl]carbamate (350 mg, 1.3 mmol) was dissolved in 4.0M hydrogen chloride in dioxane (5 mL, 20 mmol) and stirred for 45 min. Water was added and the solution made basic with 2M aqueous sodium hydroxide. The product was extracted into EA, and the EA extract washed with brine and dried over magnesium sulfate. Removal of the EA gave N-ethyl-3-(4-morpholinyl)propan-1-amine (50 mg).
Reaction SMILES: [OH:1][C:2]([CH3:40])([CH3:39])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:7][CH2:6]1.C[Si]([N:45]=[N+:46]=[N-:47])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[OH:1][C:2]([CH3:39])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:47][N:46]=[N:45][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 100 °C
Reaction time: 120 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), trimethylsilylazide (0.54 mL), dibutyltinoxide (0.086 g) and toluene (3 mL) was stirred at 100° C. for 5 days. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.9 mL) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.075 g, 45%).