Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[C:11]#C>C1(C)C=CC=CC=1.II>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][C:10]#[CH:11])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: C#CCO
Agent: II
Solvent: Cc1ccccc1
Product: C#CCOC(=O)CC(=O)CC
Temperature: 115 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
To a solution of methyl 3-ketopentanoate (3) (822 mg, 6.00 mmol) and 2-propynol (686 mg, 12.0 mmol) in toluene (7 mL) is added I2 (46 mg, 0.18 mmol). The mixture is stirred at 115° C. for 6 h, then cooled to room temperature, and extracted with ethyl acetate (100 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is distilled (125-130° C., 2 mm) to give 401 mg (43%) of 4 as a colorless liquid. IR 3345, 2856, 1715, 1456 cm−1; 1H NMR (CDCl3) δ 1.10 (t, J=7.5 Hz, 3H, CH2CH3), 2.52 (t, J=2.4 Hz, 1H, CH≡CCH2), 2.58 (q, J=7.5 Hz, 2H, CH2CH3) 3.51 (s, 2H, CH2), 4.74 (d, J=2.4 Hz, 2H, CH≡CCH2).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:4][CH:3]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:33].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:35]1([CH3:40])[C:34]([C:32]([CH2:31][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:15])[CH2:4][CH:3]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:2]2=[O:1])=[O:33])=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.74 g) was suspended in toluene (24 ml), 2-bromo-2′-methylacetophenone (1.12 g), 1N aqueous sodium hydroxide (12 ml) and tetra n-butylammonium bromide (20 mg) were added, the mixture was stirred for one day at room temperature. The reaction mixture was weakly acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=9:1), to thereby obtain 1.25 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10](=[CH:16][N:17](C)C)[C:11]([O:13]CC)=O.[CH2:20]([NH:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[N:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:11]([OH:13])=[C:10]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=3[Cl:1])[CH:16]=[N:17]2)=[N:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c(Cl)c1

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate and N-benzyl-6-hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.44 (d, J=5.8 Hz, 2 H) 7.13-7.22 (m, 2 H) 7.27 (d, J=4.3 Hz, 5 H) 7.75 (d, J=8.3 Hz, 1 H) 8.00 (s, 1 H) 8.30-8.47 (m, 2H) 8.90 (s, 1 H) 9.20 (t, J=5.3 Hz, 1 H). MS m/z [M+H]+ 430.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]3=[O:15])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCCl
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCCN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 4.94 parts of 1-(4-chlorobutyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.23 parts of 4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4 parts of 1-{4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 160.6° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH2:28][CH2:29][O:30][CH3:31])[C:9](=O)[CH2:10][CH:11]1[S:16](=[O:18])(=[O:17])[C:15]2[S:19][C:20]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:21][C:14]=2[NH:13][C:12]1=[O:26].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(COC)OC>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH2:9][CH2:10][CH:11]1[S:16](=[O:18])(=[O:17])[C:15]2[S:19][C:20]([S:22](=[O:24])(=[O:25])[NH2:23])=[CH:21][C:14]=2[NH:13][C:12]1=[O:26])[CH2:28][CH2:29][O:30][CH3:31]
Reactant: COCCOCCN(CCOC)C(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COCCOC
Product: COCCOCCN(CCOC)CCC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-methoxyethoxyethyl-N-methoxyethyl (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetamide (500 mg, 1 mmol) in dimethoxyethane (5 ml) was added dropwise to a suspension of lithium aluminum hydride (152 mg, 4 mmol) in dimethoxyethane (5 ml) at such a rate that the mixture refluxed gently. When addition was complete, the reaction mixture was refluxed an additional 2 hours. The mixture was cooled in an ice bath and a saturated solution of Rochelle salt was added. The resulting mixture was stirred overnight at ambient temperature, filtered to remove some granular solid, and concentrated to dryness under vacuum. The residue was partitioned between ethyl acetate and 0.5N HCl. The acid fraction was brought to pH 8 by the addition of NH4OH and extracted with ethyl acetate. This ethyl acetate extract was washed with brine and dried over sodium sulfate. After filtration and evaporation of solvent the residue was chromatographed over silica gel eluting with CHCl3 /MeOH/NH4OH (70:30:3) to give 3-[ 2-(N-methoxyethoxyethyl-N-methoxyethylamino)ethyl]-2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine. The free base was converted to the hydrochloride salt hydrate from ethanolic hydrogen chloride and ether, mp 170°-175° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=3[CH2:31][CH2:32][CH3:33])[N:14]=2)=[O:12])[CH:5]=1.CO.[OH-].[Li+].[ClH:39]>O1CCCC1>[ClH:39].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:34])=[O:2])[CH:5]=3)[N:14]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)OC)c3)n2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)O)c3)n2)ccc(C(C)=O)c1O
Reaction time: 30 h

Procedure:
Dissolve 3-{[6-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridine-2-carbonyl]-amino}-benzoic acid methyl ester (700 mg, 1.51 mmol) in minimal amount of tetrahydrofuran (2 mL), add methanol (8 mL), and 2N aqueous lithium hydroxide solution (2.27 mL, 4.54 mmol) and stir 30 hours. Add 1N hydrochloric acid (50 mL), collect resultant white solid by filtration to yield the title compound (493 mg, 1.02 mmol): 1H NMR (DMSO-d6) δ 0.90 (t, 3H), 1.54 (m, 2H), 2.57 (s, 3H), 2.67 (m, 2H), 5.51 (s, 2H), 6.77 (d, 1H), 7.73 (m, 2H), 7.85 (d, 1H), 8.13 (m, 3H), 8.51 (m, 1H), 10.66 (s, 1H), 12.86 (s, 1H), 13.05 (br s, 1H): MS (m/z): 447 (M-HCl−1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].Br[CH:20]([CH2:26]Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[F:17][C:14]([F:15])([F:16])[C:12]1[CH:11]=[CH:10][C:9]2[O:18][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][NH:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(C(F)(F)F)ccc2O1

Procedure:
11.4 g of potassium carbonate was added to 48.7 g of 7B in 320 ml of acetone. Then 18.2 of ethyl 2,3-dibromopropionate was added dropwise to the refluxing mixture. This procedure was repeated thrice. The mixture was refluxed for 17 hours and filtered, and the filtrate was stripped of solvent under reduced pressure. The residue was dissolved in ether; the solution was washed with dilute sodium hydroxide solution, then dried (MgSO4) and stripped of solvent. The residue was washed with petroleum ether and dried. The residue was mixed with ether and filtered. Part of the solvent was evaporated from the filtrate; the remaining solution was cooled. Crystals which formed were filtered and recrystallized from ether to give 7, m.p.: 105°-107°.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][N:29]1[C@H:36]([C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:51]=[C:50]([CH3:58])[CH:49]=3)=[CH:42][CH:41]=2)=[O:38])[C@@H:35]([C:59](O)=[O:60])[CH2:34][C:31]2([CH2:33][CH2:32]2)[CH2:30]1.Cl.NO.CN1CCOCC1>CN(C=O)C>[OH:17][NH:8][C:59]([C@H:35]1[CH2:34][C:31]2([CH2:32][CH2:33]2)[CH2:30][N:29]([CH3:28])[C@@H:36]1[C:37]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:51]=[C:50]([CH3:58])[CH:49]=2)=[CH:44][CH:45]=1)=[O:38])=[O:60]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)O)CC4(CC4)CN3C)cc2)c2ccccc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)NO)CC4(CC4)CN3C)cc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To BOP (120.0 mg, 0.24 mmol) was added to a solution of (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylic acid (140 mg, 0.20 mmol) in DMF (1.0 mL) at 0° C. followed by hydroxylamine hydrochloride (28.0 mg, 0.40 mmol). 4-methylmorpholine (0.07 mL, 0.70 mmol) was then added to the above mixture at 0° C. and stirred at this temperature for 2 h. The product (70 mg) was purified by preparative HPLC. ESI (M+H)+475.4.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9].O.C(=O)(O)O>C(OCC)(=O)C>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1
Agent: O=C(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 113.9 %

Procedure:
After adding 5 ml of trifluoroacetic acid to 340 mg of tert-butyl 4-(((6-cyano-4-(4-(((cyclopropylamino)carbonyl)amino)-3-fluorophenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate, the mixture was stirred at room temperature for 7 minutes. Saturated bicarbonate water and ethyl acetate were added to the reaction solution for extraction. The ethyl acetate layer was washed with saline and dried over sodium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 320 mg of a light yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:48]([CH3:49])[C:34]2=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[C:33]2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:33]4[N:32]=[C:31]([CH3:30])[N:48]([CH3:49])[C:34]4=[N:35][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)nc(C)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.10 mmol), 2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (102 mg, 0.37 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed then heated to 100° C. for 16 hours and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-100% THF/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C30H32ClN4O3S: 563.2 (M+H+); Found: 563.2 (M+H+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31])[CH:24]=O.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:30]([O:29][C:28]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:1])=[CH:22][C:21]=1[O:20][CH2:19][CH2:18][N:9]1[C:8](=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17])([CH3:31])[CH3:32]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)Oc1ccc(C=O)cc1OCCN1C(=O)c2ccccc2C1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(C)C)c(OCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.42 g of potassium tert-butoxide (3.75 mmol) is added portionwise to a suspension of 1.34 g of methyltriphenylphosphonium bromide (3.75 mmol) in 7.5 ml of tetrahydrofuran. The mixture is stirred for one hour at room temperature and is then cooled to 0° C. A solution of 1.20 g (3.4 mmol) of 3-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethoxy]-4-isopropoxybenzaldehyde in 7 ml of tetrahydrofuran is then introduced. The mixture is then stirred at room temperature for 16 hours, after which it is poured into saturated aqueous ammonium chloride solution. This mixture is extracted with dichloromethane, the organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The residue is purified by chromatography on a column of silica (eluent: 80/20 cyclohexane/ethyl acetate). 0.77 g of a yellow oil which crystallizes is obtained:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[C:23]=1[NH2:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[C:23]=1[NH:31][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Reactant: Nc1c(Cl)ccc2c1OCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
Compound 211 (50 mg, 0.17 mmol), 5-chloro-benzo[1,3]dioxol-4-ylamine (38 mg, 0.22 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), X-Phos (8 mg, 0.02 mmol), and NaOtBu (50 mg, 0.52 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAc/H2O, and filtered. The resulting precipitate was washed with EtOAc/H2O, and then suspended in methanolic HCl. The crude product was purified via prep-LC-MS to provide 212 (2 mg, 3% yield) as a white solid. LC-MS (M+H=426, obsd.=426).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].[CH2:7]([O:9][C:10](=[O:13])[CH2:11]Br)[CH3:8].Cl>C1COCC1>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][O:4][CH2:1][C:2]#[CH:3])[CH3:8]
Reactant: CCOC(=O)CBr
Reactant: C#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of prop-2-yn-1-ol (815 g, 14.5 mol) in THF (1 L) is added dropwise to a suspension of NaH (60% content) (500 g) in THF (4 L) at 0° C. under nitrogen atmosphere. The stirring is continued at this temperature for 3 h before a solution of bromo-acetic acid ethylester (2.17 kg, 13.0 mol) in THF (2 L) is added dropwise over 1 h. After addition, the temperature is allowed to warm to RT and the reaction mixture is stirred for another 3 h. HCl (2 M, 8 L) is added into the reaction mixture, the organic layer is isolated and the aqueous layer is extracted with EtOAc (3×5 L). The combined organic layer is washed with brine (2 L), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil is distilled to give the desired product. Yield: 1.6 kg. 1H NMR: (CDCl3) δ 4.31 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.19 (s, 2H), 2.47 (t, J=2.4 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].[Cl-].[NH4+]>C1COCC1.C(Cl)(Cl)Cl>[C:3]1([S:9]([CH:12]([C:13](=[O:15])[CH3:14])[CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CCOC(=O)CBr
Reactant: CC(=O)CS(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOC(=O)CC(C(C)=O)S(=O)(=O)c1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
Under a nitrogen atmosphere, sodium hydride (6.41 g, 0.267 mol) and THF (125 ml) were combined and the suspension was cooled to -15° C. A THF solution (150 ml) of (phenylsulfonyl)acetone (50 g, 0.253 mol) was added to the suspension in a dropwise fashion over an hour. The resultant mixture was stirred for an additional 20 minutes at -15° C. Allyl bromoacetate (47.5 g, 0.265 mol) dissolved in THF (100 ml) was added in a dropwise fashion to the mixture over a period of 30 minutes while maintaining the temperature of the solution below 0° C. The resultant solution was stirred at -5° C. for 15 minutes, allowed to warm to room temperature over a period of an hour, and stirred overnight at room temperature. The reaction solution was poured into saturated aqueous ammonium chloride solution (800 ml) and chloroform (500 ml) and the aqueous layer was separated and extracted with chloroform (2X, 200 ml). The chloroform layers were combined and washed with saturated aqueous sodium chloride (1X, 350 ml), dried over sodium sulfate, filtered and concentrated in vacuo to an oil. The oil was crystallized from a mixture of ethyl acetate and hexane. The collected solid was washed with cold 1:3 ethyl acetate:hexane and dried in vacuo, yielding 52.9 g of the allyl 3-(phenylsulfonyl)-4-oxopentanoate: n.m.r. (90 MHz, CDCl3): δ 2.51 (s, 3), 2.97 (n, 2,), 4.51 (dm, 2, J=6), 4.65 (m, 1), 5.1-5.19 (m,2), 5.58-6.00 (m, 1), 7.4-7.8 (m, 5); m.p. 62-64° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 60 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 480.4 (M+H)+.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.[NH2:26][C@@H:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:36][C@H:37]([O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1)[CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C:28]([OH:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C>[CH2:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][C@@H:37]([O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1)[CH2:36][N:35]([C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:34][CH2:33][CH2:32][CH2:31][C@H:27]([NH:26][C:9]([O:11][CH2:12][CH:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8])[C:28]([OH:30])=[O:29])=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC[C@H](CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OCc1ccccc1)OC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A solution of 9-fluorenylmethyl N-succinimidyl carbonate (203 mg, 0.60 mmol) in DMF (3.0 mL) was added to a solution of 18a (219 mg, 0.37 mmol) in 9% Na2CO3 (803 mg, 0.68 mmol) at 0° C. and stirred overnight at room temperature. The pH was adjusted to 7.0 with 0.1 N HCl. The mixture was concentrated to an oil and purified by flash chromatography (CHCl3, then 95% CHCl3/MeOH) to give 11a (150 mg, 50%) as a colorless oil: 1H NMR δ 1.15-1.94 (m, 14H), 3.10-3.52 (m, 7H), 3.66-3.98 (m, 2H), 4.05-4.21 (m, 2H), 4.24-4.61 (m, 3H), 5.04 (s, 2H), 5.08 (s, 2H), 7.21-7.40 (m, 14H), 7.65 (dd, 2H, J=6.9, 4.2), 7.77 (d, 2H, J=7.2); 13C NMR δ 21.1, 21.7, 24.1, 26.4, 26.5, 28.2, 28.9, 32.1, 32.5, 32.6, 33.2, 34.3, 38.1, 38.5, 51.9, 52.4, 55.5, 64.1, 65.2, 67.4, 67.9, 68.3, 74.9, 79.5, 100.0, 101.5, 120.9, 126.3, 128.2, 128.80, 128.97, 129.10, 129.20, 129.48, 129.57, 129.62, 138.2, 138.5, 142.6, 145.2, 145.4, 158.1, 158.6, 176.8; HRMS m/z calcd for C46H54N3O10 808.3809, found 808.3833.