Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(O)CO.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[C:20]([CH2:33][CH3:34])[N:21]2[CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Tl+2]>C1C=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.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[C:20]([CH2:33][CH3:34])[N:21]2[CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(CC)n1c(CC)nc2c(Cl)ncnc21
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: [Tl+2]
Solvent: c1ccccc1
Solvent: O
Solvent: OCCO
Product: CCCCC(CC)n1c(CC)nc2c(-c3ccc(Cl)cc3Cl)ncnc21
Reaction time: 12 h
Yield: 67.5 %

Procedure:
A solution of 2,4-dichlorobenzeneboronic acid (572 mg, 3.00 mmol) and ethylene glycol (205 mg, 3.30 mmol) in benzene (20 mL) was heated to reflux with azeotropic removal of water for a period of 8 h. The resulting solution was cooled, and treated with 6-chloro-8-ethyl-9-(1-ethylpentyl)purine (see Example 2, Part C above; 562 mg, 2.00 mmol), thallium carbonate (1.03 g, 2.20 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol). The resulting mixture was heated to reflux with stirring for 12 h, then cooled, filtered through celite and evaporated. The resulting residue was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the title compound as a viscous oil (530 mg, 1.35 mmol, 68%). TLC RF 0.31 (20:80 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.94 (1H, s), 7.71 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=1.8 Hz), 7.41 (1H, dd, J=8.4, 1.8 Hz), 4.27 (1H, br), 2.95 (2H, q, J=7.3 Hz), 2.41 (2H, br), 2.11-1.98 (2H, br), 1.42 (3H, t, J=7.3 Hz), 1.37-1.20 (3H, m), 1.09-0.99 (1H, m), 0.84 (3H, t, J=7.7 Hz), 0.82 (3H, t, J=7.7 Hz). MS (NH3-CI): m/e calc'd for C20H25N4Cl2: 391.1456, found 391.1458; 395 (11), 394 (14), 393 (71), 392 (29), 391 (100).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH:28]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[O:29][CH3:30])(C(C)(C)C)(C)C>C1COCC1>[C:33]([O:32][CH2:31][CH:28]([CH2:27][OH:26])[O:29][CH3:30])(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO[Si](C)(C)C(C)(C)C)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)OC
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
1M TBAF (6 mL, 6.0 mmol) was added to a solution of compound 16 (2.4 g, 5.0 mmol) in THF (50 mL). After 30 min, TLC analysis showed that all the starting material had been consumed. Then, the reaction mixture was partitioned between diethy ether (100 mL and sat. NaCl solution (30 mL). The organic extract was dried (MgSO4), concentrated and subjected to silica-gel column chromatography (eluent: hexane/ethyl acetate, 75/25, v/v] to give glycerol derivative 17 (1.42 g, 79%) as an oil
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([OH:10])[CH2:3][CH2:2]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([O:10][C:11](=[O:13])[CH3:12])[CH2:3][CH2:2]2
Reactant: CC(=O)OC(C)=O
Reactant: OC1CCN2CCCC1C2
Product: CC(=O)OC1CCN2CCCC1C2
Temperature: 120 °C
Yield: 87 %

Procedure:
To acetic anhydride (150 ml) (4SR,5RS)-(1-aza-bicyclo[3.3.1]nonan-4-ol (21.34 g, 151 mmol) is added portionwise under cooling. The reaction mixture is heated to 120° C. for 2.5 h, is evaporated and extracted with THF/sat. K2CO3 soln. The aq. layer is reextracted with THF. The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified by bulb-to-bulb distillation (HV, 90° C.) to give 24.07 g (87%) of (4SR,5RS)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([O:7][C:8]([CH3:11])(C)C)=[O:6])=[O:3].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC.C1(C)C=CC=CC=1>C(O)(C)(C)C>[C:5]([O:7][CH2:8][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])[CH2:4][C:2]([CH3:1])=[O:3]
Reactant: CCCCCCCCO
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCCCCCCCOC(=O)CC(C)=O
Yield: 83.2 %

Procedure:
Another procedure involved heating the alcohol and tBAA, (or beta-ketoester) in solvent, in a round-bottom flask with magnetic stirrer, 5-plate Oldershaw column and still head for removal of the t-butanol co-product. For example: a solution of n-octanol (13 g, 0.1 mol), tBAA (16.6 g, 0.105 mol) and 50 mL toluene was heated at reflux until the theoretical amount of t-butyl alcohol was obtained (ca. 15 min. after reflux). The reaction mixture was subsequently concentrated and distilled to give 17.8 g (83.2%) octyl acetoacetate b.p. 95°-110° C. (1.0 mm Hg).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[S:37]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)(=[O:38])=[O:39]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: COC(=O)c1cccc(C)c1S(=O)(=O)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-Chlorosulfonyl-3-methyl-benzoic acid methyl ester. White solid. MS (ESI): 527.14 (MH+)
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[OH:14][N:15]1C(=O)C2=CC=CC=C2C1=O.C(O)(=[O:28])C>>[C:1]([C:4]12[CH2:13][CH:8]3[CH2:7][CH:6]([CH2:12][C:10]([N+:15]([O-:14])=[O:28])([CH2:9]3)[CH2:11]1)[CH2:5]2)([OH:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Yield: 80 %

Procedure:
Into a flask, 1 mmole of 1-carboxyadamantane, 0.1 mmole of N-hydroxyphthalimide and 6 ml of acetic acid were added to mix. The mixture was purged by nitrogen monoxide NO (about 1L) and oxygen O2 (about 1L), and then reacted for 20 hours at 110° C. with stirring. The reaction products were analyzed by gas chromatography, and, as a result, the conversion of 1-carboxyadamantane was 90%, and 1-carboxy-3-nitroadamantane (yield 80%) was formed.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1CCBr)([O-:3])=[O:2].O.[C:16](O)(=O)[CH3:17].[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23]>>[N+:1]([C:4]1[C:5]([NH:14][CH2:16][CH3:17])=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: Nc1c(O)ccc(CCBr)c1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: O
Product: CCNc1c(O)ccc(N(CCO)CCO)c1[N+](=O)[O-]

Procedure:
5.2 g (0.02 mol) of 3-nitro-4-(β-bromoethyl)-aminophenol are heated for 1 hour, at 60° C., in 20 ml of diethanolamine. The reaction medium is poured into 100 g of iced water and the solution is then neutralised with acetic acid. After one night at 0° C., the expected product, which has precipitated, is filtered off. After washing with a small amount of iced water and drying in vacuo, the product is recrystallised from ethyl acetate. It melts at 115° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].Cl.O[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CN(C=[O:33])C>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:26][C:25]2[CH:27]=[CH:28][CH:22]=[CH:23][C:24]=2[OH:33])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CN(C)C=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Product: CCCCN1C(=O)C(Nc2ccccc2O)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 57 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.110 g, 0.33 mmol), 4-hydroxyaniline hydrochloride (0.144 g, 0.99 mmol) and TEA (0.14 ml, 0.991 mmol) in DMF (0.5 ml) was heated at 140° C. for 25 mins in a microwave reactor. The mixture was purified by preparative HPLC (column Ace C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.074 g, 57%); 1H NMR 400 MHz (CDCl3) 7.26-7.20 (m, 2H), 7.18-7.14 (m, 3H), 7.08 (s, 1H), 6.62 (d, 2H), 6.48 (d, 2H), 3.78 (t, 2H), 1.91-1.84 (m, 2H), 1.53-1.45 (m, 2H), 1.02 (t, 3H); Mass Spectrum: M+H 373.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:12]2[NH:11][N:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])=[CH:7][CH:6]=3)[C:13]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Nc3n[nH]c(NCc4ccc(O)cc4)c3C(N)=O)cc2)cc1
Reaction time: 0.25 h
Yield: 12 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in 25.00 mL of DMF along with TEA (211 μL, 2.50 eq.) and stirred on ice for 15 minutes. p-Toluenesulfonyl chloride (145 mg, 1.25 eq.) dissolved in 1 mL of DMF was slowly dripped into to the reaction vessel and continued to stir for 18 hrs allowing the reaction to reach room temperature. Once the reaction was complete, traces of starting material is no longer present and confirmed by HPLC, water was added to the reaction until a white precipitate formed. The white precipitate was then collected via filtration and dried under vacuum for 18 hrs (30 mg, 12% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[C-:11]#[N:12].[K+].O.[I-].[K+]>CC(=O)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:11]#[N:12])=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(F)ccc1CCl
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(F)ccc1CC#N
Yield: 87.2 %

Procedure:
A mixture of 16 parts of 1-(chloromethyl)-4-fluoro-2-methylbenzene, 7.8 parts of a solution of potassium cyanide in a small amount of water, 0.1 parts of potassium iodide and 240 parts of 2-propanone is stirred and refluxed for 22 hours. The reaction mixture is cooled and filtered. The filtrate is evaported. The residue is taken up in water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 13 parts (87.2%) of 4-fluoro-2-methylbenzeneacetonitrile as a residue.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=O)[C:21]1C=CC=[CH:23][CH:22]=1>>[CH:3]1[C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:2]=1[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Yield: 54 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 2-naphthoyl chloride for benzoyl chloride, the title compound was obtained as a white solid in 54% yield: 1H NMR (300 MHz, CDCl3): δ 8.47 (s, 1H), 7.86-8.05 (m, 4H), 7.51-7.62 (m, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.41 (m, 4H), 1.25 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[C:12]1([CH3:11])[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:1]3[C:10]4[C:5]([CH:4]=[CH:3][N:2]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:14][CH:13]=1
Reactant: c1ccc2cnccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(C=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C2OC3c4ccccc4C=CN3c3ccccc32)cc1
Yield: 80 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.064 g, 59 μL, 0.50 mmol) and 4-methylbenzaldehyde (0.090 g, 85 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=90/10) of the crude reaction mixture afforded 6-(p-tolyl)-4bH,6Hbenzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.130 g, 80% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.[Br:18]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:18])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A solution of 51 parts of p-nitrobenzal bromide in 500 parts of carbon tetrachloride is added to a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in 2,000 parts of water at 50° C. The mixture is stirred with a mechanical stirrer for 2.5 hours. The carbon tetrachloride layer is separated, dried and evaporated to give 58 parts (90% yield) of p-nitrobenzotribromide, m.p. 81-3° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:17][N:16]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 70 %

Procedure:
To the solutionof 2-naphthylboronic acid (5.00 g, 29.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in 100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, 58.2 mmol) and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 2 days under argon. The mixture was diluted with DCM. It was filtered through a celite bed. The blue filtrate was washed with water (×2), dried over MgSO4, concentrated, purified by silica column to yield ethyl 3-methyl-1-(2-naphthyl)-1H-pyrazole-5-carboxylate and its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc:hexane), M+H 281; regioisomer, ethyl 5-methyl-1-(2-naphthyl)-1H-pyrazole-3-carboxylate, Rf 0.44 (1:2 EtOAc:hexane). ES-MS: (M+H)+ 281.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:27])[CH2:26][O:25]1>CO.O1CCCC1>[CH2:16]([N:8]([CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:23][C:24]([CH3:27])([OH:25])[CH3:26])[CH2:14][CH2:15]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CO1
Reactant: c1ccc(CN(Cc2ccccc2)CC2CCNCC2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
A mixture of N,N-dibenzyl-N-(piperidin-4-ylmethyl)amine (EXAMPLE 4, Step 3, 3.3 g, 11.21 mmol) and 2,2-dimethyloxirane (12.1 mL, 134.5 mmol) in methanol (40 mL) and tetrahydrofuran (5 mL) was heated at 40° C. with stirring for 17 h. The volatile components were removed and the residue was purified by flash column chromatography on amine gel eluting with hexane/ethyl acetate (50:1) to afford 3.0 g (73%) of the title compound as a colorless amorphous.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8]O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8][Br:35])(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)OCC(CCO)COC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OCC(CCBr)COC(C)=O
Yield: 993.2 %

Procedure:
A mixture of 2-acetoxymethyl-4-hydroxy-but-1-yl acetate (10 g, 49 mmol), triphenyl phosphine (19.25 g, 73 mmol) and carbon tetrabromide (24.4 g, 73 mmol) was stirred for 18 hours at 4° C. in dimethylformamide (150 ml). The solvent was then evaporated, and the residue purified by column chromatography on silica gel, eluting with ether-light petroleum 2:3 to afford 2-acetoxymethyl-4-bromobut-1-yl acetate as a pale oil (130 g, 99%). δH (CDCl3) 1.73-2.56 (3H, m, CHCH2CH2), 2.04 (6H, s, 2×OCOCH3), 3.44 (2H, t, CH2Br), 4.04 (4H, d, 2×CH2OCOCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([NH:22][CH2:23][CH:24]([OH:39])[CH2:25][NH:26][C:27](=[O:38])[C@H:28]([CH3:37])[NH:29]C(OC(C)(C)C)=O)=[O:21])=[C:9]2[CH3:40])=[O:7])=[CH:4][CH:3]=1.O>C(OCC)(=O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([NH:22][CH2:23][CH:24]([OH:39])[CH2:25][NH:26][C:27](=[O:38])[C@H:28]([CH3:37])[NH2:29])=[O:21])=[C:9]2[CH3:40])=[O:7])=[CH:41][CH:42]=1
Reactant: COc1ccc2c(c1)c(CC(=O)NCC(O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)NCC(O)CNC(=O)[C@H](C)N)c(C)n2C(=O)c1ccc(Cl)cc1
Product: Cl

Procedure:
In a manner analogous to that described in Stage 25.3, from 1.44 g (2.38 mmol) of N-tert.-butoxycarbonyl-L-alanine-3-{2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]-acetylamino}-2-hydroxypropylamide, containing 0.21 mol of water, in 40 ml of ethyl acetate, with 40 ml of approximately 5N hydrochloric acid in ethyl acetate (2.5 hours, 0°), there is obtained L-alanine-3-{2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]-acetylamino}-2-hydroxypropylamide hydrochloride in the form of yellowish crystals that decompose at 153° and above (made into a suspension from hot ethyl acetate) and contain 0.17 mol of water; [α]D20 =+5.8°±1.0° (c=1.043; methanol), Rf =0.22 (chloroform:methanol =7:3).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[O:6][C:4](=[O:5])[CH2:3]1.[ClH:19].[CH2:20](O)[CH3:21]>>[CH2:20]([O:6][C:4](=[O:5])[CH2:3][C:2]([CH3:18])([CH3:1])[CH:7]([Cl:19])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10])[CH3:21]
Reactant: Cl
Reactant: CC1(C)CC(=O)OC1CC(=O)c1ccc(Cl)cc1
Reactant: CCO
Product: CCOC(=O)CC(C)(C)C(Cl)CC(=O)c1ccc(Cl)cc1

Procedure:
80.1 g of 3,3-dimethyl-4-(4'-chloro-phenacyl)-γ-butyrolactone were dissolved in 500 ml of ethanol, and dry hydrogen chloride was passed in until the temperature had reached 50° C. A slow stream of hydrogen chloride was then passed through the solution at 50° C., initially with cooling, for 3 hours, and the introduction was then continued until the mixture had reached room temperature again. Distilling off the ethanol in vacuo gave 100 g of 6-(4'-chloro-phenyl)-6-oxo-4-chloro-3,3-dimethyl-hexanoic acid ethyl ester of refractive index nD20 =1.528.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)NCc1ccccc1)=C1SCS1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (15 g) and benzylamine (6.4 ml) in methylene chloride (150 ml) was stirred at room temperature for 4 hrs. The reaction mixture was then washed with dil-HCl and water to remove benzylamine. The solvent was evaporated and the residue was purified with ethyl acetate to give the titled compound as a white solid. (12.2 g, 77%).
Reaction SMILES: [CH:1]1([O:6][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=[C:18]([CH:26]([NH2:33])[C:27]4[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=4)[C:17]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:16]3=4)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:46][C:47](=O)[O:48][C:49]1([CH:52]2[CH2:54][CH2:53]2)[CH2:51][CH2:50]1>ClCCl.C(N(CC)CC)C>[CH:1]1([O:6][C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=[C:18]([CH:26]([NH:33][C:47]([O:48][C:49]4([CH:52]5[CH2:54][CH2:53]5)[CH2:51][CH2:50]4)=[O:46])[C:27]4[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=4)[C:17]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:16]3=4)[CH2:13][CH2:14]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(ON1C(=O)CCC1=O)OC1(C2CC2)CC1
Reactant: Cn1cncc1C(N)C1=Cc2cccnc2C(N2CCN(C(=O)OC3CCCC3)CC2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cncc1C(NC(=O)OC1(C2CC2)CC1)C1=Cc2cccnc2C(N2CCN(C(=O)OC3CCCC3)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
4-{6-[Amino-(3-methyl-3H-imidazol-4-yl)-methyl]-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl}-piperazine-1-carboxylic acid cyclopentyl ester (60 mg, 0.11 mmol) was dissolved in 5 ml of dichloromethane and 0.2 ml of triethyl amine. Carbonic acid bicyclopropyl-1-yl ester 2,5-dioxo-pyrrolidin-1-yl ester (45 mg, 0.19 mmol) was added and the reaction mixture stirred for 18 hours at ambient temperature under a dry nitrogen atmosphere. The reaction mixture was washed with brine and evaporated to a solid. The solid was chromatographed on silica gel using 5% methanol/dichloromethane as eluent to obtain 49 mg of title product.