Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].Cl.Cl[CH2:17][C:18]1[S:22][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:20][CH:19]=1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH:8]1([NH:7][C:5](=[O:6])[C:4]2[CH:11]=[CH:12][C:13]([F:14])=[C:2]([O:1][CH2:17][C:18]3[S:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:20][CH:19]=3)[CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=C(NC1CC1)c1ccc(F)c(O)c1
Reactant: ClCc1cnc(Nc2ccccn2)s1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(F)c(OCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
To a suspension of NaR (16 mg, 60% in oil) in DMF (1 mL) was added a solution of 3-hydroxy-4-fluoro-N-cyclopropylbenzamide (58.5 mg, 0.3 mmol) in DMF (1 mL) at RT. After 10 min, (5-chloromethylthiazol-2-yl)pyridin-2-ylamine hydrochloride (Example 10A) (52.4 mg, 0.2 mmol) was added. The mixture was stirred at RT for 1 h and poured onto ice. The mixture was neutralized with 1 N KHSO4 solution and the precipitates were collected, washed with water and ethyl acetate to give the title compound as a light yellow solid (25.2 mg, 33%). MS m/z 385 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([F:11])=[CH:9][CH:10]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (191 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (130 mg, 48%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.O[NH:49][C:50](=[NH:52])[CH3:51]>CN(C=O)C.O>[CH3:51][C:50]1[N:52]=[C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:26]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:25]=[CH:24][CH:23]=2)[O:21][N:49]=1
Reactant: CC(=N)NO
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C)no3)c1)C2=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (180 mg, 0.49 mmol) obtained in Step 1 of Example 56 was suspended in DMF (3.0 mL), and the mixture was stirred at 100° C. for 6 hours after adding 1-hydroxybenzotriazole (200 mg, 1.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (280 mg, 1.46 mmol), and N-hydroxyacetamidine (108 mg, 1.46 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-5-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (183 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[S:4][N:3]=1.Br[C:15]1[N:30]=[C:18]2[C:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=[CH:22][N:17]2[N:16]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[O-]C1C=CC=CC=1.[Na+]>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:13][CH:10]4[CH2:9][CH2:8][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:12][CH2:11]4)[N:30]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-c2cccn3nc(Br)nc23)cc1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(Cl)cc5)cccn4n3)CC2)n1

Procedure:
Through a suspension of 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-amine (40 mg, 202 μmol), 2-bromo-8-(4-chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (74.7 mg, 242 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.34 mg, 16.1 μmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (8.35 mg, 8.07 μmol) and sodium phenoxide (35.1 mg, 303 μmol) in dry dioxane (3 mL) was bubbled argon for 5 minutes. The mixture was then irradiated at 150° C. for 60 minutes. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as an off-white foam (42 mg, 49%).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH3:5][NH:6][CH2:7][CH2:8][NH:9][CH3:10]>O>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([CH3:10])[CH2:3][C:1]1=[O:2]
Reactant: CNCCNC
Reactant: O=CC=O
Solvent: O
Product: CN1CCN(C)C(=O)C1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To 10 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of distilled water is rapidly added 6.1 g (69.0 mmoles) of N,N'-dimethylethylenediamine. The solution is heated rapidly to reflux and heating maintained for 5 minutes. The dark brown solution is allowed to cool to room temperature and is then evaporated at 60° C. under water pump vacuum to a viscous brown oil. The oil is distilled in a short path distillation apparatus to yield 8.2 g (93 percent yield) of 1,4-dimethylpiperazin-2-one in the form of a yellow oil. Purity is greater than 99 percent by capillary gas chromatograph.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCN(C)CC5)cnc43)cc2OC)cn1
Temperature: 120 °C
Reaction time: 19 h
Yield: 134.4 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (1.40 g, 2.79 mmol) in dimethylsulfoxide (15 mL) was added 1-methylpiperazine (0.44 g, 4.40 mmol), copper(I) iodide (0.16 g, 0.84 mmol), L-proline (0.19 g, 1.67 mmol), and potassium carbonate (0.96 g, 6.97 mmol). The mixture was degassed under vacuum/backfilled with N2 (×3), and then it was heated to 120° C. As the mixture warmed, it became dark blue/black in color. After 19 h, the brown mixture was allowed to cool to room temperature and was diluted with 5N ammonium hydroxide solution (100 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 1.78 g of a brown oil. Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-10% 2M ammonia in methanol/dichloromethane elute) afforded 0.60 g (45%) of the product as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 7.92 (s, 1H), 7.69-7.61 (m, 2H), 6.91-6.84 (m, 2H), 6.80 (dd, J=8.2, 2.0 Hz, 1H), 6.74 (dd, J=8.5 Hz, 1H), 5.34 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.25-3.18 (m, 4H), 2.68-2.61 (m, 4H), 2.38 (s, 3H) ppm; (M+1)=475.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:34])[NH:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[N:26]=[C:25]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:33])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:36]>CO>[CH:1]1([NH:5][C:6](=[O:34])[NH:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[N:26]=[C:25]([C:27]([O-:29])=[O:28])[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:33])[CH2:4][CH2:3][CH2:2]1.[Na+:36]
Reactant: COC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)[O-])n3)CC2)cc1F)NC1CCC1
Yield: 79.4 %

Procedure:
Methyl 6-((4-(4-(3-cyclobutylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)picolinate (400 mg, 0.852 mmol) and sodium hydroxide (35 mg, 0.852 mmol) were combined and heated to reflux for 18 hours in methanol. The reaction mixture was concentrated at reduced pressure to afford the title compound (323 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]C)=[CH:6][C:5]([B:10]2[O:14]C(C)(C)C(C)(C)O2)=[C:4]([C:19]([O:22]COCC)([CH3:21])[CH3:20])[CH:3]=1.Cl.O>C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[B:10]([OH:14])[O:22][C:19]([CH3:20])([CH3:21])[C:4]=2[CH:3]=1
Reactant: CCOCOC(C)(C)c1cc(Cl)c(CC)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1Cl)C(C)(C)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of 2-(4-chloro-2-(2-(ethoxymethoxy)propan 2-yl)-5-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.77 g, 4.8 mmol) in THF (24 mL) was added 6N HCl (24 mL). The reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with EA. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE-EA (20:1) to give 5-chloro-3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (540 mg; yield 53.6% over 2 steps) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 2.36 (s, 3H), 1.46 (s, 6H) ppm; MS: m/z=210.9 (M+1, ESI+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1I.[C:12](#[N:17])[CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C.O>C(#N)C.[Cu](I)I>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:16]#[C:15][CH2:14][CH2:13][C:12]#[N:17]
Reactant: C#CCCC#N
Reactant: FC(F)(F)c1ccccc1I
Agent: I[Cu]I
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CCCC#Cc1ccccc1C(F)(F)F
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 15.0 grams (0.055 mole) of 2-trifluoromethylphenyl iodide, 4.8 grams (0.061 mole) of 4-pentynenitrile, 30.6 mL (0.22 mole) of triethylamine, 0.4 gram (0.0006 mole) of bis(triphenylphosphine)palladium(11) chloride, and 0.1 gram (0.0006 mole) of copper(11) iodide in 50 mL of acetonitrile was stirred at ambient temperature for 5 hours. After this time, gas chromatographic analysis (GC) of the reaction mixture indicated that the reaction was about 60% complete. The reaction mixture was warmed to 40°-45° C., where it was stirred for 16 hours. After this time the reaction mixture was poured into 300 mL of water, and the mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with aqueous dilute hydrochloric acid and then were dried with magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 - methylene chloride and petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.4 grams of 5-(2-trifluoromethylphenyl)-4-pentynenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CC(C)=O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[CH:2]([OH:1])[CH3:3])=[CH:24][CH:23]=1
Reactant: CC(O)c1c(O)cccc1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)-3-nitrophenol (0.300 g, 1.638 mmol) in acetone (5 mL) was added potassium carbonate (0.25 g, 1.802 mmol). The mixture was stirred at room temperature for 15 min, and 4-methoxybenzyl chloride (0.22 mL, 1.638 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hrs and at 60° C. for 3 hrs. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1). The purified compound was washed with diisopropyl ether to give 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanol as a white solid (0.201 g, yield; 41%).
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH2:28][NH:27][CH2:26][CH2:25]5)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH2:28][N:27]([CH3:34])[CH2:26][CH2:25]5)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CCNC4)cc3nccn23)cn1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2cc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-6-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 52; 10 mg, 0.024 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (49 mg, 0.49 mmol) and sodium triacetoxyborohydride (16 mg, 0.073 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=424.3 (M+H).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9]1)C1C=CC=CC=1.[C:29]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O>>[Si:22]([O:21][CH2:20][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:12][N:8]([C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: Cc1ccccc1[C@H]1CN(Cc2ccccc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CCCCC(=O)[O-]
Product: CCOC(=O)CCCCC(=O)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2C)C1

Procedure:
Using the (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-methylphenyl)pyrrolidine obtained in Reference Example 127 which is described later, the elimination of benzyl group and amidation with monoethyl adipate were carried out in that order in the same manner as in Reference Example 16 and Reference Example 50 to produce ethyl 6-[(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-methylphenyl)pyrrolidin-1-yl]-6-oxohexanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCCCN(C)C)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 3-hydroxy-4-nitro benzoic acid methyl ester. (394 mg, 2.0 mmol), triphenyl phosphine (525 mg, 2.0 mmol), arid 3-(dimethylamino)-propanol (237 μL, 2.0 mmol) in dry tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (394 μL, 2.0 mmol in 1 mL of tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with hydrochloric acid (30 mL of a 1M solution) and extracted with ethyl acetate (2×50 mL). The aqueous solution was basified with 10% aqueous sodium carbonate (50 mL) and the product was extracted with ethyl acetate (3×100 mL). The ethyl acetate was washed with brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product (86% yield). 1H-NMR (400 MHz, CDCl3) δ7.81 (d, 1H), 7.78 (s, 1H), 7.65 (d, 1H, 4.23 (t, 2H), 3.91 (s, 3H),2.44 (t, 2H), 2.22 (s, 6H), 2.05 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Into a solution of crude methyl 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate in THF-methanol (10-5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (136 mg) as a yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)(Cl)Cl>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:20]([NH:19][CH3:18])=[O:21])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1.4 grams (0.06 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in 25 ml of chloroform, under an argon atmosphere, was added dropwise 5 ml of methyl isocyanate. Upon completion of addition the reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to give 1.4 grams of 2-[2-chloro-4-(methylaminocarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 227°-229° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](C(=O)C1C=CC=CC=1)[CH:11]=[C:10]2[CH2:24][CH2:25][N:26]([CH3:28])[CH3:27].[OH-].[K+]>CO>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:24][CH2:25][N:26]([CH3:27])[CH3:28]
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(C3CCC=CO3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(C3CCC=CO3)cc12
Yield: 56.2 %

Procedure:
To 5-(2,3-dihydropyran-2-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (Example 18e, 0.048, 0.129 mmol) was added a 5% solution of KOH in MeOH (5 mL) followed by methanol (5 mL). The solution was heated at reflux for 3 hours. At this time, the solution was allowed to cool, and was filtered and concentrated by reduced pressure. The crude product was purified by column chromatography [7% NH3 (2M in MeOH) in CH2Cl2 ] to yield the title compound as a yellow oil (19.6 mg, 56%); HRMS-FAB+ for C17H22N2O: calc. MH+ :271.1810; found MH+ :271.1826.
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.[CH:27]([C:30]1[CH:34]=[C:33]([CH2:35][S:36](Cl)(=[O:38])=[O:37])[O:32][N:31]=1)([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:34]=[C:33]([CH2:35][S:36]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:37])=[O:38])[O:32][N:31]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1cc(CS(=O)(=O)Cl)on1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: CC(C)c1cc(CS(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)on1

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 (3-isopropyl-isoxazol-5-yl)-methanesulfonyl chloride. Light yellow solid. MS (ESI): 502.16 (MH+)