Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].Br[CH:23]([CH2:25][CH3:26])[CH3:24].O>CN(C=O)C.C(OCC)C>[CH3:24][CH:23]([CH2:25][CH3:26])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21]
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Reactant: CCC(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 19.58 g (174.5 mmol) of potassium tert-butoxide were initially charged in 200 ml of DMF, the mixture was cooled to 0° C., 30 g (145.4 mmol) of tert-butyl(4-methylphenyl)acetate, dissolved in 50 ml of DMF, were added slowly and the mixture was then stirred at 0° C. for 30 min. 18.95 ml (174.5 mmol) of 2-bromobutane were then slowly added dropwise, and the solution was stirred at 0° C. for another 4 h. 200 ml of water and 200 ml of diethyl ether were then added to the reaction solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 15.5 g (59.1 mmol, 40.6% of theory) of a colorless liquid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[S:8][CH:7]=[C:6]([C:9]([O:11]CC)=[O:10])[CH:5]=1.Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[Br:3][C:4]1[S:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1
Reactant: CCOC(=O)c1csc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
7.4 g (185 mmol) of sodium hydroxide pellets are added to a solution of 8.7 g (37 mmol) of ethyl 5-bromothiophene-3-carboxylate in 100 ml of tetrahydrofuran, 10 ml of methanol and a few drops of water. After stirring at room temperature for 18 hours, the reaction medium is taken up in ethyl acetate and washed with water. The aqueous phase obtained is acidified to pH 1 with aqueous hydrochloric acid solution and then extracted with dichloromethane. The organic phase obtained is dried over magnesium sulfate, filtered and concentrated under vacuum. 7 g (92%) of 5-bromothiophene-3-carboxylic acid are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.C(Cl)Cl.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>O>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCOC(=O)COCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)COCCOS(=O)(=O)c1ccc(C)cc1
Yield: 55 %

Procedure:
A mixture of ethyl (2-hydroxyethoxy)acetate (0.50 g, 3.37 mmol), triethylamine (1.4 ml) and methylene chloride (8 ml) was stirred under ice-cooling. Then, p-toluenesulfonyl chloride (0.96 g, 5.06 mmol) was added in small portions and the resulting mixture was stirred under ice-cooling for another 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate: n-hexane= 1:5) to obtain 0.56 g of ethyl [2-(toluene-4-sulfonyloxy)ethoxy]acetate as a colorless oil.
Reaction SMILES: O=C(OCC(OC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)CCCCCCC/C=C\CCCCCCCC.CCCCCCCC/C=C\CCCCCCCC([O:83][C@@H:84]1[CH2:97][C:96]2[C@@:87]([CH3:110])([C@@H:88]3[C@@H:93]([CH2:94][CH:95]=2)[C@@H:92]2[CH2:98][CH2:99][C@H:100]([C@@H:101]([CH2:103][CH2:104][CH2:105][CH:106]([CH3:108])[CH3:107])[CH3:102])[C@@:91]2([CH3:109])[CH2:90][CH2:89]3)[CH2:86][CH2:85]1)=O.N#N.CCC(C(O[C@@H]1[C@@H]2[C@@H](CC[C@H]3OC(=O)C[C@H](O)C3)[C@@H](C)C=CC2=C[C@H](C)C1)=O)(C)C>C(Cl)(Cl)Cl.CO.C(O)C(N)(CO)CO.Cl>[CH3:108][CH:106]([CH2:105][CH2:104][CH2:103][C@H:101]([C@@H:100]1[C@:91]2([CH3:109])[C@H:92]([C@H:93]3[C@H:88]([CH2:89][CH2:90]2)[C@:87]2([CH3:110])[C:96]([CH2:97][C@H:84]([CH2:85][CH2:86]2)[OH:83])=[CH:95][CH2:94]3)[CH2:98][CH2:99]1)[CH3:102])[CH3:107]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 52.5 °C
Reaction time: 24 h

Procedure:
A 3:2:1 molar mixture of Phosphatidylcholine: Triolein: Cholesteryl Oleate (PC:TO:CO) was dissolved in chloroform/methanol 2:1 (V/V) and the solvent removed under a stream of nitrogen. The lipids were then re-dissolved and lyophilised from t-butanol for 24 hours (EF4 Modulyo Freeze Dryer, Edwards High Vacuum, Crawley, United Kingdom), then re-suspended in 0.01M Tris-HCl buffer (pH 8.0) to give a final concentration of 7 to 8 % w/v for extrusion. The lipid dispersions were sonicated under a stream of N2 for two hours using a 250W sonicator, centrifuged at 10,000 rpm for 60 minutes (MSE Superspeed 75 Ultracentrifuge, MSE Ltd, London, United Kingdom) and then transferred to the Extruder vessel (Lipex Biomembranes Inc, Vancouver, Canada) which was maintained at 50-55° C. throughout. The lipid mixture was successively extruded through polycarbonate filters of pore size 0.1 and 0.05 μm using two stacked filters and at least four extrusions under 60 psig pressure provided by a nitrogen source8. Samples of lipid microemulsion were diluted with Tris-HCl buffer to give a cholesterol concentration of approximately 1 mmol/l and heated to 55° C. in a stirring water bath. Aliquots of peptide dissolved in DMSO were added under the surface of the stirring microemulsion, control experiments were performed with DMSO alone. The volume of DMSO added in each case was kept below 20 μl/ml of microemulsion mixture. The peptide-microemulsion complex was incubated at 55° C. for 15 minutes then dialysed overnight against 5 liter PBS. The resulting non-naturally occurring LDL (nLDL) were filter sterilised (0.2 μm) and stored at 4° C. under N2 before use.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21].Cl>ClCCl.CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O>[CH3:20][NH:21][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94 %

Procedure:
A suspension of 3-bromo-5-nitrobenzoic acid (7.10 g, 28.9 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (5.04 mL, 57.7 mmol) and a few drops of N,N-dimethylformamide, producing gas evolution. After 2 hours, the mixture was concentrated to give an oil, which was dissolved in tetrahydrofuran and added dropwise to a stirred solution of methylamine in tetrahydrofuran (2.0 M, 28.9 mL, 57.7 mmol) at 0° C. After stirring overnight, the mixture was treated with water, ethyl acetate and 0.2 N aqueous hydrochloric acid. The layers were separated after mixing, and the organic phase was washed with 0.2 N aqueous hydrochloric acid, then with saturated aqueous sodium chloride. The solution was dried over sodium sulfate and concentrated under vacuum to provide a yellow solid (7.0 g, 94%). 1H NMR (300 MHz, DMSO-d6) δ9.92 (m, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 2.81 (d, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:37]=[CH:38]\[CH2:39][OH:40])CCC.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.CS(C)=O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:40][CH2:39]/[CH:38]=[CH:37]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 65, 0.6 g), (Z)-3-tributylstannanylprop-2-en-1-ol (Intermediate 12, 0.81 g), tris-(dibenzylideneacetone)dipalladium (0.1 g) and tri-tert-butylphosphonium tetrafluoroborate (0.07 g) in dioxane (18 mL) and DMSO (2 mL) was stirred at room temperature for 30 minutes. The resultant mixture was diluted with ethyl acetate and washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether with a gradient of 30-50% to give methyl (1aRS,7bSR)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-[methoxycarbonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.55 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])C>O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[O:11])[C:13]([F:16])([F:15])[F:14])=[N:3][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Reaction time: 0.29 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2,5-Dibromo-pyridine (4 g, 6.87 mmol) in dry tetrahydrofuran (30 mL) and dry toluene (40 mL) is added drop wise n-Butyl litihum (1.62 g, 25.31 mmol) at −78° C. After stirring for 15-20 minutes, added trifluoro-acetic acid ethyl ester (3.56 g, 25.31 mmol) at −78° C. then stirred at −78° C. for another 30 minutes. The reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 20% ethyl acetate in hexane to afford the title compound (1.2 g). 1HNMR (400 MHz, DMSO-d6) δ: 7.72 (d, J=8.32 Hz, 1H), 7.85-7.88 (dd, J1=8.32 Hz, J2=2.44 Hz 1H), 8.52 (d, J=2.36 Hz, 1H). LC-MS (m/z): [M+H]=255.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 55.6 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (150 mg, 0.3 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 143, step C) (87 mg, 0.27 mmol), and p-toluenesulfonic acid (135 mg, 0.71 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (121 mg, 0.15 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.70, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.39-7.47 (m, 2H), 7.32-7.39 (m, 1H), 7.24 (d, J=8.79 Hz, 1H), 7.18 (t, J=8.06 Hz, 2H), 6.92 (t, J=7.05 Hz, 1H), 6.66 (d, J=2.38 Hz, 1H), 6.53 (d, J=5.31 Hz, 1H), 6.44-6.49 (m, 1H), 4.24 (q, J=6.90 Hz, 2H), 4.05 (q, J=6.96 Hz, 2H), 3.30-3.34 (m, 2H), 3.08-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.87 Hz, 2H), 2.54-2.59 (m, 4H), 1.41 (t, J=6.87 Hz, 3H), 1.23 (t, J=6.96 Hz, 3H). MS (ESI): 797 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:9])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCC(F)(F)CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours, A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](Cl)(C)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N>N1C=CC=CC=1.O>[C:25]([NH:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.37 mmol) of 7-amino-3-β-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidine are initially introduced in 5 ml of dry pyridine. 0.47 ml (3.7 mmol) of trimethylsilyl chloride is added dropwise to this solution under an argon atmosphere. After the mixture has been stirred at room temperature for half an hour (monitoring by TLC), 0.25 ml (2.0 mmol) of benzoyl chloride is added dropwise, and this reaction mixture is stirred at room temperature for 4 hours. It is then cooled down to 0-5° C. and 1 ml of water is added followed, 5 min later, by 2 ml of aqueous ammonia (25%); this mixture is then stirred for a further 30 min. The solvent is stripped off and the residue is then evaporated with toluene. The residue is taken up in 15 ml of a saturated solution of NaHCO3, and this mixture is extracted one with 25 ml of methylene chloride and several times with ethyl acetate. The combined organic phases are dried using Na2SO4.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:73]([NH2:79])[C:74]1[O:78][CH:77]=[CH:76][CH:75]=1>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:79][CH2:73][C:74]4[O:78][CH:77]=[CH:76][CH:75]=4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccco1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Yield: 94.8 %

Procedure:
A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), 1-hydroxybenzotriazole (14 mg, 0.1 mmol), and furfuryl amine (10 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. overnight, diluted with CH2Cl2 (3 mL), and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow oil. Et2O (5 mL) was added to dissolve the oil, and concentration afforded the title compound as a pale yellow solid (42 mg, 95% yield). LC/MS (ESI) retention time: 1.74 min, m/z 633 (MH+); 1H NMR (400 MHz, CDCl3 ) δ 1.29-1.44 (m, 3 H) 1.46-1.57 (m, 1 H) 1.69-1.81 (m,3 H) 1.86-1.97 (m, 1 H) 1.98-2.11 (m, 3 H) 2.27-2.37 (m, 1 H) 2.38-2.49 (m, 4 H) 2.61-2.78 (m, 2 H) 2.78-2.89 (m, 1 H) 3.66 (s, 4 H) 4.38 (s, 1 H) 4.66 (d, J=5.29 Hz, 2 H) 5.06 (s, 1 H) 6.22-6.41 (m, 2 H) 6.64 (t, J=5.04 Hz, 1 H) 6.81 (s, 1 H) 7.33-7.50 (m, 5 H) 7.51-7.61 (m, 1 H) 7.85 (d, J=8.31 Hz, 1 H) 7.97 (s, 1 H); 13C NMR (101 MHz, CDCl3) δ 26.20, 27.02, 33.27, 36.73, 37.04, 41.92, 49.45, 61.67, 66.94, 107.54, 108.90, 110.48, 116.84, 120.05, 121.19, 127.05, 127.95, 128.21, 129.24, 130.08, 130.96, 131.24, 133.24, 134.00, 135.18, 136.39, 142.15, 151.57, 167.74, 168.88.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C#CC(C)(O)c1cc(CO)on1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(C)(O)c1cc(COS(=O)(=O)c2ccc(C)cc2)on1
Temperature: 25 °C

Procedure:
To a solution of 2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol (500 mg, 2.99 mmol) in DCM (5 mL) at 0° C. under an atmosphere of nitrogen was introduced triethylamine (333 mg, 3.29 mmol) and p-toluenesulfonyl chloride (627 mg, 3.29 mmol) in one portion. After warming to RT for 3 hr, the reaction mixture was diluted with DCM (10 mL) and washed with brine (5 mL). The organic extract was dried (Na2SO4), filtered and the filtrate adsorbed onto silica gel in vacuo. Purification by silica gel flash column chromatography (heptane/EtOAc gradient of increasing polarity) furnished the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 1.84 (3H, s), 2.26 (3H, s), 2.66 (1H, s), 2.86 (1H, br. s), 5.14 (2H, s), 6.41 (1H, s), 7.36 (2H, d, J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz); LC-MS: m/z=+321.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of Compound 45 (1.0 g, 3.2 mmol) in dichloromethane was added slowly to a stirred solution of piperazin (826 mg g, 9.59 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water sonicated briefly and filtered. The solid was dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.1 g (96%) yellow solids. M.P. 162° C. 1H NMR (DMSO-d6): δ 2.70 (s, 1H), 2.94 (m, 4H), 3.53 (m, 4H), 5.47 (s, 2H), 7.19-7.25 (m, 3H), 7.42 (m, 2H), 7.51 (dd, J=4.3, 9.3 Hz, 1H), 7.54 (td, J=2.4, 8.0 Hz, 1H), 7.58 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 363 (M+1).
Reaction SMILES: N(CCO)CCO.CCOCC.[C:13]([CH2:17][C:18]([OH:20])=[O:19])(=[O:16])[CH2:14][CH3:15].[N+]([O-])([O-])=O.[Ag+:25]>O>[C:13]([CH2:17][C:18]([O-:20])=[O:19])(=[O:16])[CH2:14][CH3:15].[Ag+:25]
Reactant: CCC(=O)CC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: OCCNCCO
Product: CCC(=O)CC(=O)[O-]
Reaction time: 0.25 h
Yield: 423.5 %

Procedure:
Diethanolamine (0.22 g) was dissolved in water (0.5 mL), and to this was added an ether solution (3 mL) containing propionylacetic acid (0.25 g). Next, the mixture was stirred at 15° C. while an aqueous solution (1 mL) containing silver nitrate (0.34 g) was added dropwise, and this was further stirred for 15 minutes. The white precipitate that settled was filtered off to obtain silver propionylacetate (yield 1.89 g). FIG. 3 shows the infrared absorption spectrum (IR) of the silver propionylacetate that was obtained. IR:1714 cm−1, 1505 cm−1.