Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.Cl.[C:11]([O:15][C:16](=[O:26])[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:11]([O:15][C:16](=[O:26])[NH:17][CH:18]1[CH2:19][CH2:20][CH:21]([CH2:24][NH:25][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:22][CH2:23]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.1 g, 4.83 mmol) was dissolved in DMA (25 mL). To this solution was added tert-butyl-trans-4-aminomethylcyclohexylcarbamate hydrochloride (1.54 g, 5.80 mmol), followed by DIEA (1.98 mL, 11.4 mmol). The reaction was stirred at 25° C. for 18 h. The reaction was worked up by removal of the volatiles in vacuo. The crude was purified via flash chromatography (SiO2, 10-25% EtOAc-Hexanes) to afford 1.32 g (65%) of {4-[(5-bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40](C2CCCCC2)[C:41](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 2-phenylacetaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (dd, J=5.2, 12.0, 1H), 7.65 (t, J=7.1, 2H), 7.38-7.23 (m, 8H), 4.40-4.29 (m, 1H), 3.23 (d, J=10.5, 1H), 3.00 (dd, J=2.6, 9.0, 0.5H), 2.80 (t, J=7.8, 1H), 2.75-2.70 (m, 1H), 2.70-2.61 (m, 1H), 2.61-2.52 (m, 1H), 2.52-2.46 (m, 1H), 2.43 (dd, J=7.6, 8.7, 0.5H), 2.38 (dd, J=2.7, 8.8, 1H), 2.34 (dd, J=2.7, 8.5, 1H), 2.26 (d, J=8.3, 0.5H), 2.24-2.18 (m, 1H), 2.12 (td, J=6.4, 12.4, 0.5H), 1.91-1.82 (m, 1H), 1.76 (dt, J=6.2, 18.7, 0.5H), 1.70-1.61 (m, 0.5H), 1.46-1.26 (m, 2H), 1.23 (dd, J=6.5, 13.5, 3H), 0.97-0.83 (m, 1H), 0.71 (dd, J=2.7, 6.7, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[C:12]([C:10]1[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with N,N-dimethylcarbamoyl chloride (0.014 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL, 16 mmol) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (27 mg, 72%). LCMS calculated for C18H22ClN4O2 (M+H)+: m/z=361.1; Found: 361.0.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:32])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[N:22][C:23]([O:26]C(C)(C)C)=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[C:9]=1[F:31])(=[NH:3])[NH2:2].C(O)(C(F)(F)F)=O.CCO.[C:43]([OH:52])(=[O:51])[C@@H:44]([C@H:46]([C:48]([OH:50])=[O:49])[OH:47])[OH:45]>ClCCl>[C:48]([C@@H:46]([C@H:44]([C:43]([OH:52])=[O:51])[OH:45])[OH:47])([OH:50])=[O:49].[C:1]([NH:4][C:5](=[O:32])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=3)[CH2:16][CH2:15]2)[C:9]=1[F:31])(=[NH:2])[NH2:3]
Reactant: CC(C)(C)Oc1ccc(N2CCN(c3cccc(COC(=O)NC(=N)N)c3F)CC2)cn1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)NC(=O)OCc1cccc(N2CCN(c3ccc(=O)[nH]c3)CC2)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
3-[4-(6 tert-Butoxypyridin-3-yl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate (132 mg) was dissolved in dichloromethane (3.4 ml), and TFA (508 mg) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was mixed with CHCl3/MeOH, and basic silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with EtOH (5 ml), and L-tartaric acid (41.0 mg) were added thereto, followed by stirring at 80° C. for 1 hour, and then stirring at room temperature for 1 hour. The solid was collected by filtration, washed with EtOH, and then dried at 50° C. under reduced pressure to obtain 2-fluoro-3-[4-(6-oxo-1,6-dihydropyridin-3-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate L-tartrate (125 mg).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:30]C1C=CC=CC=1N1CCNCC1>>[Cl:30][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:11][CH2:10]1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=c1c2ccccc2ncn1CCN1CCN(c2ccccc2Cl)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-(2-chlorophenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH2:19][CH3:20])=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:21]=1.Cl.[C:23](=N)(OC)[CH3:24].C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH2:18][CH2:19][CH3:20])[C:23]([CH3:24])=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:21]=1
Reactant: COC(C)=N
Reactant: CCCNc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(C)nc2cc(-c3nc4cc(Cl)ccc4o3)ccc21
Yield: 71.8 %

Procedure:
To a solution of 5-(5-chlorobenzoxazol-2-yl)-2-n-propylaminoaniline (see Working Example 135-1) (200 mg, 0.663 mmol) in ethanol (5 mL) was added methyl acetimidate hydrochloride (123 mg, 0.995 mmol), and this was heated to reflux for 5 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were washed with diethyl ether to yield the title compound (155 mg, 72% yield) as green crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[O:35]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 11; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). NaOH (0.8 g in 1.5 ml water) was added to the solution and the mixture was stirred for 30 min at room temperature. Acetic acid (2 ml) was added. The solvent was evaporated under reduced pressure and the residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 2.0 g (95%). NMR (500 MHz) 0.7–0.8 (m, 6H), 1.0–1.5 (m, 12H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.7 (s, 2H), 7.0–7.3 (m, 6H), 7.4 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[O:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].C(N(CC)CC)C>C(#N)C>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][CH2:14][O:15][S:19](=[O:22])(=[O:21])[NH2:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1cccc(OCc2ccccc2)c1
Yield: 44.3 %

Procedure:
This compound was prepared according to the procedure used in Example 101. Thus, a mixture of 14.7 g (0.06 mole) of 2-(3-benzyloxyphenoxy)ethanol, 17 ml (0.066 mole) of sulfamoyl chloride (3.9M solution in acetonitrile) and 7.0 g (0.069 mole) of triethylamine in 150 ml of acetonitrile gave a viscous, oily residue. The oil was triturated with benzenepetroleum ether (30°-60° C.) and the solid was collected by filtration. The solid was recrystallized from chloroform to yield 8.6 g (44%) of a white solid, mp 107°-109° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.C([N:31]([CH2:35]C)[CH:32]([CH3:34])[CH3:33])(C)C.C(Cl)(=O)[O:38]CC(Cl)(Cl)Cl.C1(N)CC1>O1CCCC1.CN(C)C(=O)C>[CH:32]1([NH:31][C:35]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)=[O:38])[CH2:33][CH2:34]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Agent: NC1CC1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)NC4CC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.8 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (129 mg, 0.359 mmol) and N,N-diisopropylethylamine (184 μL, 1.075 mmol) in tetrahydrofuran (5 mL) was added 2,2,2-trichloroethyl chlorocarbonate (52.0 μL, 0.378 mmol), and the mixture was stirred at room temperature for 30 min. Cyclopropaneamine (150 μL, 2.17 mmol) and N,N-dimethylacetamide (5 mL) were added to the reaction mixture, and the mixture was stirred at 80° C. for 22 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (20.3 mg, 13%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26]C2CCCCO2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:33]C2CCCCO2)[CH2:15][C:14]1=[O:40])=[O:4].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.O.O1CCCC1>>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([OH:33])[CH2:15][C:14]1=[O:40])=[O:4]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC)OC1CCCCO1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC

Procedure:
At 40°, 300 mg. of (5Z,13E)-(8R,11R,12R,15S)-1-(N-methylcarbamoyloxy)-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-9-one was agitated with 9 ml. of a mixture of glacial acetic/water/tetrahydrofuran (65/35/10) for 6 hours. The mixture was then evaporated to dryness under vacuum. After purifying the residue by chromatography on silica gel (ether/ethyl acetate 7+3), 145 mg. of the title compound was obtained as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[K+].O=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.Cl.[CH3:22][NH2:23]>O.O.CO.CCOCC>[C:1]([C:5]1([NH:23][CH3:22])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)#[N:2]
Reactant: CN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CNC1(C#N)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of potassium cyanide (2.79 g, 42.9 mmol) in water (5 mL) was added to a solution of benzyl 4-oxopiperidine-1-carboxylate (10.0 g, 42.9 mmol) and methylamine hydrochloride (2.90 g, 42.9 mmol) in water/methanol (1:1; 10 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 48 h, additional methylamine hydrochloride (1.45 g, 21.4 mmol) was added. After 18 h, the mixture was diluted with ether, and extracted with ethyl acetate (3×). The combined organic extracts were dried over magnesium sulfate and concentrated down to 50 mL volume. HCl gas was bubbled to this solution for 5 min. The solid precipitated out of the solution was filtered and washed with ether (3×), ethyl acetate (3×) and dried under reduced pressure to give the hydrochloride salt of the title compound. MS 274.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:27][O:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:15][C@H:12]([C@@H:11]1[C@:16]2([CH3:24])[C:8]([C:7]3[CH2:6][CH2:5][C@@H:4]4[C@:20]([C:19]=3[CH2:18][CH2:17]2)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]4([CH3:26])[CH3:25])=[CH:9][CH2:10]1)[CH3:13]
Reactant: COCCCN
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COCCCNC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with 3-methoxypropylamine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[N-(3-methoxypropyl)aminomethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:28])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: O=C(CCCCCCCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 16.7 g of benzyl p-hydroxybenzoate and 16.7 g of sebacic acid dichloride to yield di(p-benzyloxycarbonylphenyl)sebacate, m.p. 62.5°-63° C., as white crystals.
Reaction SMILES: [C:1]([O:6][C:7]1[C:16]2[C:11](=[C:12](O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(C(F)(F)F)C(F)(F)F)(=O)C(C)=C.C(C1CCOC1=O)(=O)C(C)=C.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC.C(OC(=O)C)C.O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)C(=O)Oc1cccc2c(O)cccc12
Agent: C=C(C)C(=O)C1CCOC1=O
Agent: C=C(C)C(=O)OC(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)O
Product: Oc1cccc2ccccc12
Temperature: 25 °C
Yield: 90 %

Procedure:
5-hydroxy-1-naphthalenyl methacrylate (a.k.a. hydroxynaphthalene methacrylate or NAMA) monomer (2.60 g, 0.0045 mole), hexafluoroisopropyl methacrylate (iPrHFAMA) monomer (23.20 g, 0.0800 mole), 2-methacryloyl-gamma-butyrolactone (a.k.a. gamma-butyrolactone methacrylate or GBLMA) monomer (3.88 g, 0.0051 mole), azobisisobutyronitrile (AlBN) (0.91 g, 10% the total mole of all monomers), 150 g of tetrahydrofuran (THF) and 72 g of ethylacetate were added to a 250 ml 3-neck round bottom flask equipped with condenser, thermometer, nitrogen inlet and magnetic stirrer bar. The reaction mixture was stirred at room temperature and bubbled with N2 flow for 45 minutes after which is was heated to 67–70° C. and stirred for 14 hours with a blanket N2 flow. After reaction, the solution was then cooled to room temperature and added dropwise to 1200 g of hexane. The resulting slurry was stirred for two hours before filtration. Solid was air dried on the Buckner filter for 1.5 hours, dissolved in acetone (15% wt-wt) and reprecipitated in 1200 g of hexane. The slurry was again stirred for two hours before filtration. The solid was collected and air dried for 2–3 hours before final drying in a vacuum oven at 60° C. overnight. Yield: 90%.
Reaction SMILES: [CH:1]([N:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[CH2:2].[CH2:18]1O[CH2:19]1.[O:21]1CCCC1>>[CH:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:11][CH:12]([CH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[CH:19][CH:18]=1)[OH:21])=[CH2:2]
Reactant: C=CN(Cc1ccccc1)Cc1ccccn1
Reactant: C1CO1
Reactant: C1CCOC1
Product: C=CN(Cc1ccccn1)CC(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution containing 134.6 g (0.6 mole) of the 2-picolylamine substituted monomer of Example 4 in 300 mL of tetrahydrofuran were added dropwise 27.3 g (0.62 mole) of ethylene oxide over a 2 hour period. The reaction mixture was allowed to stir at room temperature for 20 hours and the solvent removed at reduced pressure to give 153.0 g of the hydroxyethylamine substituted monomer. This procedure is repeated, except substituting propylene oxide for the ethylene oxide, to provide the corresponding hydroxypropylamine substituted monomer.
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]=[CH:10][C:11]([CH3:20])=[CH:12][CH:13]=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[CH3:22][C:23]1([CH3:52])[CH2:28][O:27][CH:26]([C:29]([CH3:51])=[CH:30][CH2:31][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:25][CH2:24]1.[O-]CC.[Na+]>ClCCl.[Cl-].[Na+].O>[CH3:22][C:23]1([CH3:52])[CH2:24][O:25][CH:26]([C:29]([CH3:51])=[CH:30][CH:31]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=[CH:9][CH:8]=[C:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:27][CH2:28]1
Reactant: CC(=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C1OCC(C)(C)CO1
Reactant: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C1OCC(C)(C)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.7 g (50 mmol) of the product from step b) were dissolved in 125 ml of dichloromethane. 25.7 g (55 mmol) of 3-(5,5-dimethyl-1,3-dioxan-2-yl)but-2-enyltriphenylphosphonium chloride were added. At 0° C., 20.4 g of a 20% strength ethanolic solution of sodium ethoxide (60 mmol) were added over the course of 1 hour. The mixture was stirred at 0° C. for 1 hour and then 50 ml of semiconcentrated brine were added. The organic phase was separated off, washed once with 50 ml of semiconcentrated brine, dried over sodium sulfate and concentrated in a rotary evaporator at 20° C. down to 20 mbar. The residue (38.2 g) was purified by flash chromatography on silica gel (eluent: cyclohexane/methyl t-butyl ether 4:1). 19.9 g (93.4% of theory) of the title compound were obtained. For characterization, the product was dissolved by heating in 100 ml of ethyl acetate. 50 ml of diisopropyl ether were added to the hot solution and, after cooling to 0° C., the mixture was stirred for 1 hour. The crystals which formed were filtered off, washed with cold ethyl acetate/diisopropyl ether mixture (2:1 vol./vol.) and dried in a stream of nitrogen. Yield: 8.9 g of red crystals. Melting point 157.5 to 158° C. E11 (CHCl3): 2495 (423 nm), 2243 (448 nm).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I-:10].[K+].II.[SH:14][C:15]1[NH:16][CH2:17][CH:18]([OH:21])[CH2:19][N:20]=1>CO.O>[IH:10].[OH:21][CH:18]1[CH2:19][NH:20][C:15]([S:14][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[N:16][CH2:17]1
Reactant: OC1CN=C(S)NC1
Reactant: c1ccc2[nH]ccc2c1
Reactant: [I-]
Agent: II
Agent: [K+]
Solvent: CO
Solvent: O
Product: I
Product: OC1CN=C(Sc2c[nH]c3ccccc23)NC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.36 g of indole in 60 ml methanol is added dropwise to a well-stirred solution of 40 g potassium iodide and 20.3 g of iodine in 120 ml of water at room temperature. This is reacted with a solution of 10.6 g of 2-mercapto-1,4,5,6-tetrahydro-5-pyrimidinol in 1800 ml of 50% aqueous methanol. The reaction mixture is stirred at room temperature for 2 hours and worked up in the manner, described under Example 1 to yield 3-(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 228°-229° (with decomposition) after recrystallization from a mixture of methanol, ethyl acetate and ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7](Br)[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[C:16]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([CH3:16])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(N)c(Br)cc2cn[nH]c12
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(N)c(C)cc2cn[nH]c12
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
To a solution of 500 mg (1.85 mmol) of 6-amino-5-bromo-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 16, in 10 mL of dioxane under an atmosphere of argon is added 767 mg (5.55 mmol) of K2CO3, 106 mg (0.09 mmol) of tetrakis(triphenylphsophine)palladium and 232 mg (1.85 mmol) of trimethylboroxine. The reaction mixture is stirred in a microwave oven at 180° C. for 5 minutes. After filtration over Celite and concentration in vacuo, the residue is purified sequentially by flash chromatography (SiO2, hexanes/ethyl acetate 6:4) and reverse phase chromatography to afford 163 mg of product (43% over two steps) as a pale yellowish solid; LC/MS:206/207 (M+H)+.