Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49](O)(=[O:53])[CH:50]([CH3:52])[CH3:51]>>[C:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:44][CH2:45]1)(=[O:53])[CH:50]([CH3:52])[CH3:51]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)C(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (0.4 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using isobutyric acid as the acylating agent. LCMS: m/e 712.8 (M+H)+, 4.46 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.88 (d, J=8.2 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.77-3.54 (m, 4H), 2.97 (dt, J=13.4, 6.6 Hz, 2H), 2.86-2.71 (m, 3H), 2.70-2.51 (m, 4H), 2.46 (br. s., 1H), 2.15 (dd, J=17.1, 6.4 Hz, 1H), 2.08-1.82 (m, 5H), 1.75 (s, 3H), 1.73-1.18 (m, 16H), 1.22 (s, 3H), 1.11 (d, J=6.7 Hz, 6H), 1.10 (s, 3H), 1.05 (s, 3H), 0.97 (s., 3H), 0.97 (s., 3H),
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[OH:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:11]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH2:10]
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=C(c1cc(F)ccc1O)n1ccnc1
Yield: 18.2 %

Procedure:
Thionyl chloride (17.8 g, 0.15 mole) was added dropwise over 30 minutes to 1H-imidazole (41.1 g, 0.60 mole) in dried methylene chloride (200 ml) with stirring and ice-cooling. After stirring for additional 30 minutes, 2-hydroxy-5-fluoroacetophenone (15.4 g, 0.10 mole) in dried methylene chloride (50 ml) was added dropwise over 30 minutes. After stirring for 1 hour, methylene chloride (200 ml), water (400 ml) and an aqueous saturated solution of sodium bicarbonate (200 ml) were added to the reaction mixture and the mixture was stirred for 5 minutes. Then, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate to obtain the title compound (3.71 g, 18.2%), m.p. 164°-166° C.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[C:11]([CH:25]=[C:26]([C:28]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:29]=3[CH:30]=[CH:31][N:32]4[Si](C(C)C)(C(C)C)C(C)C)[CH:27]=2)[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O:21]C(=O)C)=[N:18][CH:19]=2)=[O:13])=CC=1.BrC1C=C(C=C(OCC2C=CC(OC)=CC=2)C=1)C(C1C=CC(COC(=O)C)=NC=1)=O.CC1(C)C(C)(C)OB(C2C=CC=C3C=2C=CN3[Si](C(C)C)(C(C)C)C(C)C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)C1C=CC=CC=1C1C=CC=CC=1N(C)C>[OH:8][C:9]1[CH:10]=[C:11]([C:12]([C:14]2[CH:19]=[N:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)=[O:13])[CH:25]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[CH:27]=1
Reactant: COc1ccc(COc2cc(C(=O)c3ccc(COC(C)=O)nc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: COc1ccc(COc2cc(Br)cc(C(=O)c3ccc(COC(C)=O)nc3)c2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1ccc(CO)nc1)c1cc(O)cc(-c2cccc3[nH]ccc23)c1

Procedure:
Acetic acid 5-[3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-benzoyl]-pyridin-2-ylmethyl ester. To the mixture of acetic acid 5-[3-bromo-5-(4-methoxy-benzyloxy)-benzoyl]-pyridin-2-ylmethyl ester (145 mg, 0.308 mmol) and chloro(di-2-norbornylphosphino)(2′dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (15 mg) in dioxane (6 mL) under nitrogen was added a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (129 mg, 0.324 mmol) in dioxane (6 mL), followed by 2M K3PO4 (0.3 mL, 0.6 mmol). The resulting solution was heated at reflux for 24 hr. The reaction mixture was then diluted with methylene chloride and the organic phase washed with brine, dried, and concentrated. After removal of the solvents, the crude product was purified by flash chromatography (3:1 hexane/EtOAc) to afford the titled product which was carried to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of methyl 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanoate (293 mg, 1.0 mmol) in dichloromethane (25 mL) was added Dibal-H (3 mL of a 1.0 M solution in dichloromethane, 3.0 mmol). The mixture was then stirred at 0° C. for 2 hours before being quenched with a saturated aqueous sodium potassium tartrate solution (10 mL). The biphasic mixture was then rapidly stirred for approximately 45 minutes, until the aqueous and organic layers clarified. The aqueous and organic layers were then separated and the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a pale yellow residue, which was purified by silica gel flash chromatography (1:1 hexanes:ethyl acetate) to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol as a colourless oil in a yield of 138 mg (52%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.45 (m, 2H), 1.56 (m 2H), 2.71 (br s, 1H (OH), 3.54 (t, 2H, J=6.9 Hz), 4.56 (m, 1H), 5.22 (br s, 1H(NH)), 7.16-7.26 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:7][CH:8]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[N:15][NH:14][C:12]([C:11]1[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)=[N:19][CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: NNC(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(3-trifluoromethyl-phenylamino)-nicotinic acid-hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.30 (s, 1H), 10.58 (s, 1H), 8.53 (s, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J=8.1 Hz), 7.84 (m, 3H), 7.54 (t, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.03 (q, J=4.5 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:46][CH:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:50]3[CH2:51][CH2:52][C@@H:47]([OH:46])[CH2:48][CH2:49]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(O[C@H]3CC[C@@H](O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) and triphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.37 g, 28%) as an amorphous solid.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]Br)(C)(C)C.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:32])=[C:10]([CH2:30][O:41][C:38]2[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:42])[F:43])=[CH:36][CH:37]=2)[CH:11]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CBr)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(COc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107 %

Procedure:
General procedure for parallel synthesis using the DynaVac Carousel apparatus. A 50 mL glass tube with screw cap and nitrogen inlet was charged with 3-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.040 g, 0.080 mmol), 4-trifluoromethylphenol (0.019 g 0.12 mmol), anhydrous DMF (0.5 mL), and then cesium carbonate (0.039 g, 0.12 mmol). The mixture was stirred at ambient temperature for 16 h. MS analysis of the reaction indicated formation of the intermediate ester product [MS (ES) m/e 582 (M+1)]. The reaction mixture was poured into ether (30 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated. The residue was diluted with CH2Cl2 (1 mL) and trifluroacetic acid (0.25 mL) was added. The mixture was stirred at ambient temperature for 1.5 h and was concentrated. The crude product mixture was purified by mass-directed reverse phase HPLC to provide the title compound (0.045 g, 64%). MS (ES) m/e 526 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][OH:22]>C1COCC1>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][OH:22])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: OCCC1CCCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCCCC2CCO)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 85.2 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 1.0 ml of THF and 30 mmol of 2-piperidinethanol were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 3.71 g of yellow powder were obtained.
Reaction SMILES: C[Mg]Br.CC[O:6][CH2:7][CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:20]([CH2:30][CH:31]2[CH2:35]C[C:33](=O)[CH2:32]2)[C:21]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:22])[CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17]>O1CCCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:20]([CH2:30][CH:31]2[CH2:32][CH2:33][C:7]([OH:6])([CH3:8])[CH2:35]2)[C:21]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:22])[CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
3.0M solution of methylmagnesium bromide in ether (2.53 mL, 7.59 mmol) cooled to 0° C. was treated dropwise with a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 0.10 g, 0.237 mmol) in tetrahydrofuran (1 mL). The resulting solution was stirred at 0° C. for 30 min, quenched with a saturated aqueous ammonium chloride solution (3 mL), and partitioned between a saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxy-3-methyl-cyclopentyl)-N-pyrazin-2-yl-propionamide (37 mg, 35%) as a yellow foam: mp 78-84° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H24ClN3O4S (M+H)+ 438.1249. found 438.1254.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:47]([O:49][C:50]([C:52]1([NH2:55])[CH2:54][CH2:53]1)=[O:51])[CH3:48].CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.C1COCC1.CO>[CH2:47]([O:49][C:50]([C:52]1([NH:55][C:3]([C:5]2[C:6]([OH:29])=[C:7]3[C:12](=[CH:13][N:14]=2)[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:22])[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8]3)=[O:4])[CH2:54][CH2:53]1)=[O:51])[CH3:48]
Reactant: CCOC(=O)C1(N)CC1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)c2ncc3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (34 mg, 0.25 mmol), CH2Cl2 (3 mL), and EDC (54 mg, 0.28 mmol), and the resulting mixture was stirred for 10 min. 1-Amino-cyclopropanecarboxylic acid ethyl ester HCl salt (41 mg, 0.25 mmol) and Hunig's base (0.1 mL, 0.56 mmol) were added, and the mixture was stirred for 48 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-45% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound. MS: (+) m/z 484.37 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[CH3:38]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31]5[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=5)=[CH:30][C:25]=4[N:24]=[C:23]3[CH3:38])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCN
Product: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCNCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.
Reaction SMILES: C1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)CC1.C1(C2C3C(=CC=CC=3)NC=2[Si](C)(C)C)CC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: c1ccc2c(C3CC3)c[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)c1[nH]c2ccccc2c1C1CC1
Agent: [F-]
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
3-Cyclopropyl-1H-indole (Ind-11) 3-Cyclopropyl-2-trimethylsilanyl-1H-indole (1.56 g, 6.0 mmol)) was dissolved in tetrahydrofuran (40 ml), tetrabutylammonium fluoride×3H2O (2.79 g, 8.84 mmol) was added and the mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated, water (90 ml) and diethyl ether (70 ml) were added and the mixture was stirred for 10 min. The phases were separated. The aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic phases were dried with sodium sulfate and concentrated. Ind-11 was isolated as a brown oil in a yield of 99% (1.04 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 61 was prepared from 1-(4-fluoro phenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 494.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:12])[CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[F:13].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([O:11][CH2:10][CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:13])[CH:4]=1)[OH:12])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OCC[C@H](O)c1ccc(Cl)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
(S)-1-(4-Chloro-3-fluorophenyl)propane-1,3-diol (10.5 g, 51.3 mmol) was dissolved in dichloromethane (200 mL), and imidazole (8.73 g, 128 mmol) was added. The mixture was then cooled to 0° C., and tert-butyldimethylsilyl chloride (9.67 g, 64.1 mmol) was added. The mixture was agitated for 1 hour, diluted with dichloromethane to 250 mL and washed with water, sodium bicarbonate solution, dried and evaporated. Purified by chromatography on silica gel, eluted with 5-10% ethyl acetate/hexanes to give (S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propan-1-ol (8.40 g, 26.3 mmol, 51.3% yield) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]([CH3:70])[C:66](=[O:71])[CH:65]=1>ClCCCl>[CH3:70][N:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][C:66]1=[O:71]
Reactant: Cn1ccc(N)cc1=O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol) in 1,2-dichloroethane (30 mL) was added diisopropylethylamine (0.59 g, 4.6 mmol), diphenylphosphinic chloride (Aldrich) (0.54 g, 2.3 mmol) respectively. The mixture was stirred at room temperature for 0.5 h, then 4-amino-1-methyl-pyridin-2-one (Molbridge) (0.07 g, 0.57 mmol) was added. The reaction mixture was heated and stirred at 60° C. for 10 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (5-10% of MeOH in EtOAc) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a off white solid (32 mg, 10%).