Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:17][CH2:18][C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11][N:10]1[CH:14]=[N:15][CH:16]=[C:9]31.[Cu][C:20]#[N:21].N.C(OCC)(=O)C>CN1CCCC1=O>[CH:16]1[N:15]=[CH:14][N:10]2[CH2:11][CH2:12][CH2:13][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:20]#[N:21])=[CH:3][C:4]=4[CH2:18][O:17]3)[C:9]=12
Reactant: Brc1ccc2c(c1)COC21CCCn2cncc21
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)COC21CCCn2cncc21
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.93 mmol of 5-bromo-6′,7′-dihydro-3H,5′H-spiro[2-benzofuran-1,8′-imidazo[1,5-a]pyridine] and 9.63 mmol of copper(I) cyanide in 10 ml of N-methyl-pyrrolidone is heated to 150° C. for 72 h. The reaction mixture is cooled to room temperature and poured into a mixture of 25% aqueous ammonia and ethyl acetate. The mixture is stirred vigorously for 15 minutes and the layers are separated. The aqueous layer is extracted with ethyl acetate and the combined organics are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) followed by crystallization from diethyl ether to afford the title compound as a beige solid. Rf=0.15 (dichloromethane-2M ammonia in ethanol 97:3); Rt=4.66 (gradient II).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11].S(=O)(=O)(O)O.C(NC1C=CC=CC=1)(=O)C>>[CH3:11][C:10]([NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1Cl
Agent: CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(Cl)ccc1Cl
Temperature: 45 °C
Reaction time: 0.83 h

Procedure:
A 2.5 liter flask is charged with 550 g of petroleum distillate (boiling range: 110°-140° C.). With stirring, 162.0 g of 100% 2,5-dichloroaniline are then added and the mixture is warmed to 45° C., whereupon a solution forms. The 108 g of 100% acetic anhydride are added dropwise in the course of about 15 minutes and the temperature is allowed to rise to 65° C. After the reaction mixture has been stirred for 15 minutes at 65° C., the addition of 1265 g of 98% sulfuric acid is commenced, while ensuring that the temperature does not rise substantially above 70°-75° C. After addition of about 20-25% of the sulfuric acid, the precipitated acetanilide starts to dissolve. Hardly any further exothermic reaction ensues when the remainder of the sulfuric acid is added, and the temperature falls to about 60° C. The temperature of the 2-phase mixture is brought to 20°-25° C. by further cooling, and the feed of 128.2 g of 50.2% nitrating acid is commenced immediately at a temperature not higher than 25° C. The addition is complete after about 50 minutes and the reaction mixture is stirred for a further 20 minutes at 20° to 25° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[OH-:10].[Na+].[Cl-]>ClCCl>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:4](=[O:10])[CH:5]([CH3:9])[CH3:6])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: [OH-]
Reactant: Cc1ccc(N)cc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 5-amino-2-methylphenol (30 g, 244 mmol), 10% NaOH (210 mL) and dichloromethane (120 mL) was added at 0° C. slowly isobuyryl chloride (25.5 mL, 244 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. The aqueous layer was separated and extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 37.2 g of N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (78%). 1H NMR (300 MHz, CDCl3 ppm): δ: 1.21 (d, J=7.03 Hz, 6 H), 2.17(s, 3 H), 2.53 (m, 1 H), 2.58 (s, 3 H), 6.81(dd, J=2.05 Hz, 7.91 Hz, 1H), 6.97 (d, J=7.91 Hz, 1H), 7.38 (d, J=2.05 Hz, 1 H), 8.14 (bs, 1 H), 8.58 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][C:10]3(OCC[O:14]3)[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].CC(C)=O.Cl.C([O-])(O)=O.[Na+]>O>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][C:10](=[O:14])[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2c(c1)CC1(CC2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
The title compound was prepared according to the procedure of Pelcman (W02006032851, 1996). A 250 mL flask, equipped with a magnetic stirbar and reflux condenser, was charged with 3′-nitro-7′,8′-dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline] (4.75 g, 20.1 mmol), acetone (65 mL), hydrochloric acid (2N (aq), 42 mL), and water (21 mL). The mixture was heated to 65° C. for 1 h, then to 80° C. for 30 minutes. The mixture was cooled to ambient temperature and neutralized with saturated NaHCO3 (aq) until pH=8. The mixture was extracted with EtOAc (3×) and the combined organic portions were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (30 to 60% EtOAc in hexanes) to afford the title compound (2.5 g, 65%).
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:10][C:11]1[C:19]([N+:6]([O-:9])=[O:7])=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Yield: 49 %

Procedure:
To a 3 liter round bottom flask was charged with 500 ml H2SO4. Fuming nitric acid was added (40 mL) and the mixture gently stirred. 2-Bromo-5-fluorobenzoic acid (60 g, 219 mmol) was added in 5 g portions over 90 minutes at 5-10° C. The mixture was stirred for 60 minutes at which time the reaction was completed. The mixture was poured into 1 liter of an ice/water mixture and extracted with EtOAc (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 minutes. The solid was collected on filter to provide 2-bromo-5-fluoro-3-nitrobenzoic acid as yellow solid (35 g, 49%).
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].Cl>CO>[O:8]([C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(O)c1cccnc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
55.2 g of sodium was added portionwise to 1500 ml of anhydrous methanol. When the reaction was complete 120 g of phenol and 200 g of 2-chloronicotinic acid were added, and the mixture was heated until completely solubilized. The methanol was removed by distillation, and the residue heated to 180°-200° C. for 5 minutes. The molten mass was cooled to about 100° C., and water was added slowly. The solution obtained was acidified with hydrochloric acid. After standing for about 16 hours, the solid obtained was filtered and dried, giving 237.4 g of 2-phenoxynicotinic acid, as white crystals, m.p. 179-181° C. (Kofler micro hot-stage); neutralization equivalent: 215.20 (calculated 216.55).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]([CH3:46])[C:42]([SH:45])=[N:43][N:44]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].[BH4-]>O1CCCC1.C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]2[CH:25]=[CH:26][C:27]([S:45][C:42]3[N:41]([CH3:46])[C:40]([C:37]4[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=4)=[N:44][N:43]=3)=[CH:28][C:9]=2[O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:14][CH:15]=1)[CH3:24]
Reactant: Cn1c(S)nnc1-c1ccc(C(C)(C)C)cc1
Reactant: CCCCCCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)OCC)cc1

Procedure:
A solution of ethyl [4-(2-heptyloxy-4-iodo benzylamino)phenyl]acetate obtained in Step d (4.11 g, 8.07 mmol) in a mixture of tetrahydrofuran (THF) (18 ml) and ethanol (18 ml) is added dropwise to a mixture of 5-(4-tert-butylphenyl)-4-methyl-4H-[1,2,4]-triazole-3-thiol (2.99 g, 12.1 mmol), bis(bipyridine)nickel (II) bromide (106 mg, 0.2 mmol) (Organometallics, 4, (1985), 657-661) and 9.68 g of borohydride polymer supported on Amberlite® IRA400 resin at 2.5 mmol/g (Aldrich) in 18 ml of a mixture of THF and ethanol 50:50. The mixture is heated for 20 hours under reflux, and then filtered at room temperature. The filtrate is concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 7:3 mixture. After evaporation of the solvents, 4.58 g (90%) of the expected compound are recovered in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCN1CCCCC1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)OCCN1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-3-methylbutanoic acid (reported in international publication number WO 2008/083347 A1) (9.18 g, 36.5 mmol) in N,N-dimethylformamide (200 ml) was added N,N-carbonyldiimidazole (6.52 g, 40.2 mmol). The reaction mixture was stirred for 1 hour at room temperature followed by the addition of 1-(2-hydroxyethyl)piperidine (36.3 ml, 47.4 mmol) was added was added to the reaction mixture. The mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed two more times with water and dried over sodium sulfate. The dried organic layer was filtered and concentrated in vacuo. The crude product was purified column chromatography (0 to 10% methanol in dichloromethane) to give 9.45 g (71% yield) of 2-(piperidin-1-yl)ethyl 3-(benzyloxycarbonylamino)-3-methylbutanoate. 1H NMR (CDCl3) δ 7.44-7.26 (m, 5 H), 5.47 (s, 1 H), 5.06 (s, 2 H), 4.19 (t, J=6.0 Hz, 2 H), 2.69 (s, 2 H), 2.50 (t, J=6.0 Hz, 2 H), 2.40-2.32 (m, 4 H), 1.60-1.48 (m, 4 H) 1.46-1.36 (m, 8 H); MS (ESI+) calculated for C20H31N2O4: 362.23, Found: 363.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M83) (0.53 g, 0.83 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a off-white solid (120 mg, 33%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[C:4]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:51]1([C:54](Cl)=[O:55])[CH2:53][CH2:52]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:51]1([C:54]([N:39]2[CH2:40][CH2:41][CH:36]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][O:28][C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[C:8]4[N:13]=[C:12]([N:14]5[C:18]([C:19]([F:21])([F:22])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]5)[CH:11]=[CH:10][CH:9]=4)=[CH:35][CH:34]=3)[CH2:37][CH2:38]2)=[O:55])[CH2:53][CH2:52]1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)C5CC5)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 5 Step C (40 mg, 0.07 mmol) in DCM (1 mL) were added diisopropyl ethyl amine (0.12 mL, 0.70 mmol) and cyclopropanecarbonyl chloride (0.02 mL, 0.21 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then was diluted with sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 636.8 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrCCBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: COC(=O)c1c(C=O)c(C)c(C)n1CCBr

Procedure:
The title compound was prepared as ocherous crystals in 9.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,2-dibromoethane.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20](C(=O)C(F)(F)F)=[CH:19][CH:18]=2)[N:7]=1)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:17]1([N:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:6]([NH:5][C:3](=[O:4])[C:2]([F:30])([F:1])[F:29])=[N:7]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(NC1=NN(c2ccccc2)C(c2ccccc2)C1)C(F)(F)F
Reaction time: 0.03 h

Procedure:
A 5.0 g. amount of 3-amino-1,5-diphenyl-2-pyrazoline (prepared in Example 4) and 25.0 ml. of trifluoroacetic anhydride is heated until solution. After standing for 2 minutes, the precipitate formed is collected by filtration and washed with hexane. The solid is dissolved in dichloromethane and passed through a short column of a hydrous magnesium silicate. The effluent is refluxed and hexane is added to crystallize the product. The product is recrystallized from hexane to give 0.95 g. of the desired product as needles, m.p. 151.5°-153.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22]>CO.C(O)(=O)C>[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: Cn1c(NN)nc2ccccc21
Reactant: CC(=O)c1ccc(C)cn1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1C)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl-5-methylpyridine (1.00 g, 7.40 mmol) and 1-methyl-2-hydrazinobenzimidazole (1.20 g, 7.40 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV234 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water: Yield: 1.54 g (73% of theory).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH:9]=2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(O[Si](C)(C)C)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2cccc(C(C)(C)O[Si](C)(C)C)c2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 51.5 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M Na2CO3 solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example 16-(1); 26.3 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed twice) to give the title compound (18 mg, 49.2%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1.[C:13]([N:20]1[CH2:24][CH2:23][CH:22]=[CH:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:24][C@H:23]2[C@H:22]([C:3]([C:4]3[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)=[N:2][O:1]2)[CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc(C(Cl)=NO)cn1
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1

Procedure:
Chloro oxime 2c (1.12 g; 5.99 mmol), N-Boc-pyrroline (0.5 mL; 2.90 mmol) and sodium bicarbonate (0.61 g) in ethyl acetate (40 mL) were stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to yield crude cycloadduct. 3c was isolated as a white solid after chromatography with 25% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(O[C:33]([N:35]1[CH2:41][CH2:40][CH2:39][C@@H:36]1[CH:37]=O)=O)(C)(C)C.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:1]([CH2:37][C@H:36]3[CH2:39][CH2:40][CH2:41][N:35]3[CH3:33])[C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=3[N:15]=2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2C[C@H]2CCCN2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
N-[2-Amino-5-[(diethylamino)carbonyl]phenyl]-4-ethoxy-benzeneacetamide (85 mg, 0.230 mmol) and N-(tert-butoxycarbonyl)-D-prolinal (0.06 mL, 1.5 eq) were coupled and cyclized following the procedure in example 40E. The solvent was then concentrated. The residue was dissolved in MeOH and 37% formaldehyde in water (formalin) (few drops, excess) was added, followed by sodium cyanoborohydride (43 mg, 3 eq). The solution was then stirred at rt for 1 h. The crude product was directly purified by reversed-phase chromatography (C-18 column) using a gradient of 15–65% CH3CN/H2O and then lyophilized affording the title compound (46 mg, 36% yield) as the corresponding TFA salt; 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 4.85 (m, 1H), 4.66 (m, 1H), 4.49 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.78 (br s, 2H), 3.56 (br s, 2H), 3.27 (br s, 3H), 2.95 (s, 3H), 2.02 (m, 3H), 1.85 (m, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.25 (br s, 3H), 1.11 (br s, 3H); MS (ESI) (M+H)+=449.45; Anal. Calcd for C27H36N4O2+2.4 TFA+1.1H2O: C, 51.47; H, 5.51; N, 7.55. Found: C, 51.46; H, 5.43; N, 7.67.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[C:27]([CH:28]=O)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[S:23]1[C:27]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2sccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5sccc5s4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To 6 mL of a chloroform solution containing 270 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 135 mg of thieno[3,2-b]thiophene-2-carbaldehyde, 54 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 284 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.31 g of 1-(2-(4-((thieno[3,2-b]thiophen-2-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.