Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:37][CH2:38][CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:33][C:34]([OH:36])=[O:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH2:3][CH3:4].[CH2:40](O)[CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:40]([O:35][C:34](=[O:36])[CH2:33][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:2][CH2:3][CH3:4])[CH2:37][CH2:38][CH3:39])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: OCC=Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(CC(=O)OCC=Cc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (203 mg) of the compound obtained in Example 65-1 was dissolved in DMF (3.0 ml) and added with cinnamyl alcohol (73.9 μl) and the whole was refluxed overnight under heating. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (19.1 mg) of the subject compound as a brownish-red solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CN1CCOCC1>C(Cl)(Cl)Cl>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(F)cc3)cc2s1
Yield: 8.3 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 4-fluorobenzylamine (29 μL, 0.25 mmol) and PS-NMM (0.22 g, 0.45 mmol) in 4 mL of chloroform. MS (m/z, ES+): 418.3 (M+1, 100%). Yield=9%.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]=[CH2:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([CH:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)[C:8]([O:10][CH2:21][CH:20]=[CH2:19])=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
A mixture of 2,2-bis(p-tolyl)acetic acid (8.52 g), allyl alcohol (6.6 ml) and p-toluenesulfonic acid monohydrate (0.34 g) in toluene (25 ml) was refluxed for 20 hours with continuous removal of water with Dean-Stark apparatus. After being cooled, the mixture was poured into 1N Sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with 1N sodium hydroxide aqueous solution, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give allyl 2,2-bis(p-tolyl)acetate (8.09 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[OH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][CH:41]([OH:40])[CH2:42][CH2:43]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC(O)CC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 80.1 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.2 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with 4-hydroxypiperidine (159 mg, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-hydroxypiperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (80.6 mg, yield 80%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH:12]=[CH2:13])=[N:3][CH:4]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cc(F)cnc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ncc(F)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-nitropyridine (20 g, 90.50 mmol) in 1, 4 dioxane (270 mL) was added tributyl vinyl tin (34.54 g, 108.60 mmol). The reaction mixture was degassed using nitrogen for 30 min. Bis-(triphenylphosphin)-palladium(II)-chloride (3.17 g, 4.5 mmol) was added to the reaction mixture. Reaction mass was stirred at 110° C. for 16 h. The reaction mixture was cooled to 25° C. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-2% EtOAc in hexane to give 5-fluoro-3-nitro-2-vinylpyridine: 1H NMR (400 MHz, DMSO-d6): δ 5.742 (dd, 1H, J=2 Hz, 10.8 Hz), 6.45 (dd, 1H, J=2 Hz, J=16.8 Hz), 7.11-7.17 (m, 1H), 8.489-8.516 (m, 1H), 8.959 (d, 1H, J=2.4 Hz).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:10][CH:9]=1)=[CH:5]OC.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[NH:46][C:45]([NH2:47])=[N:44][CH:43]=2)=[CH:38][CH:37]=1.C[O-].[Na+]>C(O)C>[C:30]([O:29][C:27](=[O:28])[N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[C:3](=[O:2])[N:47]=[C:45]3[NH:46][C:42]([C:39]4[CH:38]=[CH:37][C:36]([Br:35])=[CH:41][CH:40]=4)=[CH:43][N:44]3[CH:5]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])([CH3:32])([CH3:31])[CH3:33]
Reactant: Nc1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC=C(C(=O)OC)c1ccc(CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3cc(-c4ccc(Br)cc4)[nH]c3nc2=O)cc1)C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 52.1 %

Procedure:
To a mixture of 2-(4-{[tert-Butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl)-3-methoxy-acrylic acid methyl ester (5.70 g, 11.92 mmol), 5-(4-bromo-phenyl)-1H-imidazol-2-ylamine (2.84 g, 11.92 mmol) and ethanol (60 mL) was added a solution of sodium methoxide (12 mL, 0.5 M in methanol, 6 mmol). The resulted mixture was refluxed for 18 h, additional 12 mL of sodium methoxide (0.5 M in methanol, 6 mmol) was added and continued to reflex for 20 h. The reaction was concentrated and diluted with EtOAc (300 mL) and washed with water (200 mL), brine (200 mL). The EtOAc solution was concentrated. The crude product was purified by flash chromatography (0%-8% Methanol in dichloromethane) to give desired product (4.05 g, 52%) as brown solid. 1NMR (300 MHz, CDCl3): δ 7.96 (s, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.54 (m, 2H), 7.35(s, 1H), 7.27 (d, J=8.1 Hz, 2H), 5.25 (br.s, 0.5H), 4.70 (br.s, 0.5H), 4.44 (s, 2H), 3.29 (m, 2H), 3.11 (m, 2H), 1.67 (m, 2H), 1.52 (br.d, 9H), 1.44 (s, 9H). LCMS (EI) m/z: 654 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[C:6]3[CH:12]=[N:11][N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].C(Cl)Cl>>[OH:41][C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].[CH:1]1([C:4]2[C:5]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[C:6]3[CH:12]=[N:11][N:10]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c(N4CCNCC4)c(C4CC4)cnc32)cc1
Yield: 102 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (275 mg, 0.593 mmol) was treated with 25% TFA/CH2Cl2 for 30 minutes. The solvent was then removed in vacuo, and the residue was evaporated from toluene (3×10 mL) to provide the crude 5-cyclopropyl-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine TFA salt (220 mg, 102% yield). LCMS (APCI+) m/z 364.1 (M+H)+, Rt=2.61 minutes.
Reaction SMILES: C1(COC([NH:11][C@@H:12]([C:23]([NH:25][C@H:26]([C:39]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)[CH2:43][CH2:42]2)=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=2)=O)C=CC=CC=1.S([O-])(O)(=O)=O.[K+].[H][H]>CO.[Pd]>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([Cl:22])[C:17]=1[OH:21])[CH2:13][C@H:12]([C:23]([NH:25][C@H:26]([C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)[CH2:45][CH2:46]1)=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[O:24])[NH2:11]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](N)Cc1cc(Cl)c(O)c(Cl)c1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
A solution of 6 g (7.9 mmol) of 1-[N2-[N-[(phenylmethoxy)carbonyl]-3,5-dichloro-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in a mixture of 200 ml of methanol and 20 ml of aqueous 1 M potassium hydrogen sulphate solution was hydrogenated in the presence of 0.5 g palladium black as catalyst at room temperature under 3 bar of hydrogen pressure for 40 minutes. The catalyst was filtered off, the reaction mixture was evaporated to dryness in vacuo and the residue adjusted to a pH of about 10 by the addition of 2 ml of concentrated aqueous ammonia solution. The product was extracted several times with isopropanol, the combined isopropanel extracts were evaporated down in vacuo and the residue was purified by column chromatography (LiChroprep, Si60 particle size: 20-40 μm, Messrs. Merck (Darmstadt); eluant: methylene chloride/methanol/ammonia=350/75/75/10 (v/v/v/v)). 2.5 g (51% of theory) of a colourless amorphous solid substance were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[F:15][CH2:16][C:17](=[O:20])[CH2:18][F:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][F:19])[CH2:16][F:15]
Reactant: O=C(CF)CF
Reactant: Cc1ccc(Br)c(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Br)c(C(O)(CF)CF)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 1-bromo-2-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (50 mL) at 0° C. was slowly added i-PrMgCl (12 mL, 23.47 mmol). After stirring for 1 h at 0° C., the reaction temperature was cooled to −70° C. Then a solution of 1,3-difluoropropan-2-one (1.7 g, 18.05 mmol) in dry THF (5 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with 2 N HCl and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (25:1) to give the desired product (2.5 g, yield 53%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J=1.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.02-6.99 (m, 1H), 5.13-5.09 (m, 1H), 5.02-4.94 (m, 2H), 4.87-4.82 (m, 1H), 3.27 (bs, 1H), 2.33 (s, 3H) ppm.
Reaction SMILES: C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][C:12]#[C:13][C:14]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:15]([F:18])([F:17])[F:16])(C)(C)C.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OC)(C)(C)C>[F:16][C:15]([F:17])([F:18])[C:14]([C:20]([F:21])([F:22])[F:23])([OH:19])/[CH:13]=[CH:12]\[CH2:11][C:10]([CH3:25])([CH3:24])[CH2:9][CH2:8][CH2:7][CH2:6][OH:5]
Reactant: CC(C)(CC#CC(O)(C(F)(F)F)C(F)(F)F)CCCCOC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: COC(C)(C)C
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCCO
Yield: 94.8 %

Procedure:
A suspension of 22.13 g of 10-tert-butoxy-1,1,1-trifluoro-6,6-dimethyl-2-trifluoromethyl-dec-3-yn-2-ol, 220 ml of tert-butylmethyl ether and 3.32 g of Lindlar catalyst was hydrogenated at 22° and 1 bar for 1.5 h after which time hydrogen up-take ceased. The suspension was filtered, the filtrate evaporated and the residue, containing pure (Z)-10-tert -butoxy-1,1,1-trifluoro-6,6-dimethiyl-2-trifluoromethyl-dec-3-en-2-ol, was dissolved in 44 ml of isopropanol. The solution was treated with 22.8 g of 50% aqueous H2SO4 and the mixture was heated to 90° for 2 h after which time g.l.c. indicated completion of the reaction. The mixture was evaporated, the residue partitioned between dichloromethane and saturated NaHCO3 solution and the aqueous layer was extracted several times with dichloromethane. The combined ortganic layers were dried over MgSO4 and evaporated to give 17.97 g of the pure title compound as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH:20]=[C:21]2[O:25]C(=O)C)[C@H:17]2[C@H:8]1[C:9]1[CH:10]=[CH:11][C:12]([O:29][C:30](=[O:32])[CH3:31])=[CH:13][C:14]=1[CH2:15][CH2:16]2.C([O-])(=O)C.[Na+].[Br:38]N1C(=O)CCC1=O.O>CN(C)C=O>[C:30]([O:29][C:12]1[CH:11]=[CH:10][C:9]2[C@@H:8]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])([CH3:23])[C:21](=[O:25])[CH:20]([Br:38])[CH2:19]4)[CH2:16][CH2:15][C:14]=2[CH:13]=1)(=[O:32])[CH3:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC1=CC[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3C(CCCCCCl)C[C@]12C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(CCCCCCl)C[C@]2(C)C(=O)C(Br)C[C@@H]12
Yield: 228.4 %

Procedure:
A solution of 6.2 g of 11-(5-chloropentyl)-3,17-diacetoxy-estra-1,3,5(10),16-tetraene in 95 ml of dimethylformamide is mixed at 0° C. first with 9.05 ml of sodium acetate solution (10%) and then with 2.6 g of N-bromosuccinimide, and it is stirred for one hour. Then, it is mixed with water, extracted with ethyl acetate, washed with sodium sulfate solution as well as common salt solution, dried on sodium sulfate and evaporated to the dry state in a vacuum. 15.3 g of crude 3-acetoxy-16-bromo-11-(5-chloropentyl)-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][C:18]2=[O:29])[CH3:16])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][C:18]2=[O:29])[CH3:16])[CH2:10][CH2:9]1
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Reaction time: 2 h
Yield: 105.4 %

Procedure:
A solution of tert-butyl{1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}carbamate (Intermediate 222, 200 mg, 0.48 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL). After 2 hours, the reaction was concentrated to dryness. The residue was partitioned between 15% methanol/chloroform. The aqueous phase was re-extracted 3× with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness giving 160 mg (100%) of the crude product as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: Cc1ccc(C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 111 was prepared from bis(4-methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.24–8.04 (br, 1H), 8.04–7.95 (br, 1H), 7.59–6.92 (m, 10H), 6.90–6.76 (m, 1H), 4.98–4.82 (br, 1H), 4.72 (s, 1H), 3.42–3.25 (m, 2H), 3.25–3.08 (m, 2H), 2.75–2.56 (m, 2H), 2.56–2.40 (m, 1H), 2.35–2.17 (m, 2H), 2.26 (s, 6H), 1.99–1.68 (m, 6H), 1.57–1.44 (m, 1H), 1.12–0.99 (m, 2H), 0.87–0.70 (m, 2H); ESMS m/e: 524.3 (M+H)+; Anal. Calc. for (HCl salt) C34H42ClF2N3O2.0.29CHCl3: C, 69.23; H, 7.16; N, 7.06. Found: C, 68.96; H, 7.35; N, 7.31.
Reaction SMILES: [CH2:1]([O:3][Si:4]([CH:11]([Li])[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[Br:23]Br>>[CH2:1]([O:3][Si:4]([CH:11]([Br:23])[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: BrBr
Reactant: [Li]C([Si](OCC)(OCC)OCC)[Si](OCC)(OCC)OCC
Product: CCO[Si](OCC)(OCC)C(Br)[Si](OCC)(OCC)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To the lithiated carbanion solution prepared in Example 1 above, a slight excess of bromine (1.5 g, 9.4 mmol) at −78° C. was added. The solution was stirred at −78° C. for 30 minutes and then at RT for 2 hrs. The solvent was pumped off and the product was further extracted with dry pentane. The residue was distilled under vacuum resulting in bis(triethoxysilyl)methylbromide (86% yield): boiling point 144–148° C. at 0.04 mm Hg; 1H NMR (300 MHz, CDCl3) δ 0.55–0.58 (t, 1 H, CHSi), δ 1.18–1.23 (q,18H, CH3) δ 2.89–2.92 (d, 2H, CH2Ph), δ 3.78–3.82 (t, 12H, CH2O), δ 7.17–7.20 (d, 2H, ArH), δ 7.36–7.39 (d, 2H, ArH); 13C NMR (75.48 MHz, CDCl3) δ 10.80 (CHSi), δ 18.46 (CH3), δ 29.47 (CHPh), δ 58.66 (CH2O), δ 130.84, 131.10 (CH aromatic); EI-MS (m/z) 508 (5%, M+), 464 (100%, [M+−44]).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([CH:11]=[CH:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[O:10][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:13]1([CH:12]=[CH:11][C:9]2[O:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:19]=[CH:18][C:7]=3[N:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2nc(C=CN3CCCC3)oc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2nc(C=CN3CCCC3)oc2c1

Procedure:
A solution of 6-nitro-2-(2-pyrrolidin-1-yl-vinyl)-benzooxazole (8.5 mmol) and palladium/carbon (10%) (0.85 mmol) in ethanol (100 mL) is hydrogenated with the pressure of 50 psi at room temperature for 18 hours. The mixture is filtered and the filtrate is concentrated in vacuo to afford 2-(2-pyrrolidin-1-yl-vinyl)-benzooxazol-6-ylamine as a solid. 1H NMR (300 MHz, CDCl3): δ 1.82 (m, 4H), 3.2 (broad, 4H), 3.65 (broad, 2H), 4.92 (d, H), 6.49 (d, H), 6.64 (d, H), 7.19 (d, H), 7.60 (d, H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]Br)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(OCC)(=O)C.[Cl-].[Na+]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Yield: 92.3 %

Procedure:
Sodium azide (2.24 g, 34.2 mmol) is added to a stirred solution of 4-(3-bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (4.80 g, 15.6 mmol) in anhydrous DMF (DMF) (40 mL). The resultant mixture is heated in an oil bath at 55° C. under nitrogen for 3 days. At ambient temperature, ethyl acetate (160 mL) and half-saturated aqueous sodium chloride (NaCl) (200 mL) are added to the mixture. The organic layer is separated, washed with half-saturated aqueous NaCl (200 mL), dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a dark oil (3.88 g, 92% yield).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially propionyl chloride the title compound is obtained as colorless solid.