Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:37]=[CH:38][CH:39]=1)[CH2:31]CS([O-])(=O)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:37]=[CH:38][CH:39]=1)[CH2:31][N:16]1[CH2:17][CH2:18][N:13]([C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH2:14][C:15]1=[O:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)([O-])CCc1cccc(OCc2ccccc2)c1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (430 mg, 10.8 mmol as 60% dispersion in mineral oil) was triturated with hexanes, then suspended in 5 mL of DMF. After cooling to 0° C., 4-(benzyloxy)carbonyl-2-piperazinone was added (1.68 g, 7.18 mmol). After 15 minutes, a solution of the product from Step H (2.096 g, 7.18 mmol) in 2 mL of DMF was added, followed by a 1 mL DMF rinse. The reaction was warmed to room temperature, stirred for 30 minutes, then poured into EtOAc. The organic layer was washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (60% EtAOAc/hexane) to produce the titled product as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:20][CH:8]([N:9]=[C:10]2[NH:13][CH2:14][CH:15](OC)OC)[CH2:7]3)=[CH:4][CH:3]=1.Cl>O1CCCC1>[Br:1][C:2]1[CH:12]=[C:11]2[C:5](=[CH:4][CH:3]=1)[CH:6]1[CH2:20][CH:8]([CH2:7]1)[N:9]1[C:10]2=[N:13][CH:14]=[CH:15]1
Reactant: COC(CNC1=NC2CC(C2)c2ccc(Br)cc21)OC
Agent: Cl
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)-c1nccn1C1CC2C1
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Into a 1000-mL round-bottom flask was placed 5-bromo-N-(2,2-dimethoxyethyl)-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine (33.4 g, 98.46 mmol, 1.00 equiv), tetrahydrofuran (340 mL), and hydrogen chloride (340 mL, 10%). The resulting solution was heated to reflux for 2 h, concentrated under vacuum and extracted with 2×150 mL of ethyl acetate. The pH value of the combined aqueous layers was adjusted to 8-9 with sodium hydroxide (2 mol/L). The resulting solution was extracted with 3×300 mL of dichloromethane. The organic layers were combined, washed with 2×150 mL of water and 1×150 mL of brine, dried over anhydrous sodium sulfated and concentrated under vacuum. The crude product was decolorized by the addition of active carbon, stirring for 30 min. The solids were filtered out and the filtrate was concentrated under vacuum to afford 15 g (55%) of 9-bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10](OCC)=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC.O>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc2ncsc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: OCc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Ethyl benzothiazole-6-carboxylate (2.10 g, 10.0 mmol) prepared in the Step 36-1-2 was dissolved in dichloromethane (80 ml), and under an ice cooling, a solution (1.5 mol/L) (20 ml, 30.0 mmol) of diisobutylaluminum hydride in hexane was slowly added thereto. The mixture was stirred at a room temperature for one hour, and then ethyl acetate (10 ml) and a saturated sodium bicarbonate solution were added to the mixture. Ethyl acetate and water were added thereto, the resulting mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (0.61 g, 37%) as a yellowish-brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[N:28]=[C:27](Cl)[N:26]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:26]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(Oc2ccc(C(C)(C)C)cc2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(C(C)(C)C)cc3)n2)ccc1-n1cnc(C)c1
Yield: 39 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-(4-tert-butyl-phenoxy)-2-chloro-6-methyl-pyrimidine in a yield of 39%. MS ISP (m/e): 444.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 d, 1H), 7.55 (d, 1H, 7.42 (d, 2H), 7.18 (s, 1H), 7.08 (d, 2H), 7.03 (d, 1H), 6.91 (dxd, 1H), 6.82 (s, 1H), 6.21 (s, 1H), 3.59 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH2:24]([N:26](CC)CC)[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:26][CH2:24][CH3:25])=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c([N+](=O)[O-])c1Cl
Product: CCNc1c(C(=O)OCC)c(C)nc(N2CCN(C)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 73 %

Procedure:
32.7 g. of 4-chloro-2-methyl-5-nitro-6-[(N-methyl)-piperazino]pyridine-3-carboxylic acid ethyl ester (0.1 mol.) and 12 g. of triethylamine are treated with stirring in 100 ml. of alcohol at reflux temperature with 6 g. of ethylamie for 1 hour. After this time, the solution is evaporated and dissolved in 100 ml. of ether. The precipitated triethylamine hydrochloride is filtered off and the filtrate cooled to -30°. 4-Ethylamino-2-methyl-5-nitro-6-[(N-methyl)piperazino]-pyridine-3-carboxylic acid ethyl ester precipitates, yield 73%, m.p. 59°-61° (methanol).
Reaction SMILES: I.[N+:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10]([NH2:13])(=[O:12])=[O:11])([O-])=O>C(OCC)(=O)C>[NH2:2][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1sccc1[N+](=O)[O-]
Agent: I
Solvent: CCOC(C)=O
Product: Nc1ccsc1S(N)(=O)=O
Temperature: 90 °C
Yield: 65 %

Procedure:
A 57% aqueous solution of hydriodic acid (15 mL) was added to neat 3-nitro-thiophene-2-sulfonamide (1.02 g, 4.90 mmol) at room temperature. The reaction mixture was heated at 90° C. for 1 hour, cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with a solution of sodium thiosulfate and the pH was adjusted to pH˜8 with sodium bicarbonate. The mixture was extracted with 10% methanol in ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography, using a gradient of 30-70% ethyl acetate in hexanes as the eluent, gave 65% yield of the title compound.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][C@@H:25]1[NH:26][CH2:27][CH2:28][N:29]([C:2]2[NH:3][C:4]3[C:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=4)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=3[N:6]=2)[CH2:30]1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1

Procedure:
2-Chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (350 mg, 1 mmol, Example 51b) reacted with (S)-(+)-2-methylpiperazine (150 mg. 1.5 mmol, Aldrich) under the conditions of Example 3c to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 415 (M+1).
Reaction SMILES: Cl[C:2]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:4]=2[CH:3]=1.[CH2:23]([N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1)[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[CH2:23]([N:25]1[CH:29]=[C:28]([C:2]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([OH:22])([C:18]([F:21])([F:19])[F:20])[C:4]=3[CH:3]=2)[CH:27]=[N:26]1)[CH3:24]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(O)c1cc(Cl)cc2c1-c1ccccc1C2(O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1cc(-c2cc(C(=O)O)c3c(c2)C(O)(C(F)(F)F)c2ccccc2-3)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Under an argon atmosphere, an optically active form (0.100 g) of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid, 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.133 g), tripotassium phosphate (0.191 g), palladium(II) acetate (0.0034 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0123 g), dioxane (3 ml) and water (0.6 ml) were mixed, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, hydrochloric acid and ethyl acetate were added, and the mixture was partitioned in a separatory funnel. The organic layer was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was treated with hexane/ethyl acetate mixed solution (hexane:ethyl acetate=1:2, 2 ml). This slurry was filtered, and the obtained solid was dried to give the title compound (0.075 g, 63%). 1H-NMR (DMSO-D6) δ: 13.60 (1H, s), 8.43 (1H, s), 8.18-8.15 (1H, m), 8.01 (1H, d, J=0.7 Hz), 8.00 (1H, d, J=1.6 Hz), 7.97-7.95 (1H, m), 7.70-7.66 (1H, m), 7.53-7.48 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17 (2H, q, J=7.3 Hz), 1.43 (3H, t, J=7.3 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:38][C:39]([CH2:41]Cl)=[CH2:40]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:3]([N:10]1[CH2:24][CH2:25][CH2:26][N:27]([S:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:29])=[O:30])[CH2:41][C:39](=[CH2:38])[CH2:40][N:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(CCl)CCl
Reactant: O=S(=O)(NCCCN(CCCNS(=O)(=O)c1ccccc1)Cc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C1CN(S(=O)(=O)c2ccccc2)CCCN(Cc2ccccc2)CCCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 24 h
Yield: 77.4 %

Procedure:
In a 500 mL three-necked round-bottomed flask equipped with a rubber septum and a gas inlet, 0.92 g of a 60% (w/w) dispersion of sodium hydride in mineral oil (0.55 g NaH, 23 mmol) was washed with hexane (3×15 mL) under N2. A solution of 5.78 g (11.5 mmol) of N-benzylbis(3-benzenesulfonamidopropyl)amine in 220 mL of DMF was added slowly with stirring. The resulting clear solution was stirred under N2 while a solution of 1.44 g (11.5 mmol) of 3-chloro-2-chloromethyl-l-propene in 8 mL of DMF was added dropwise over 10 h. Stirring at room temperature under N2 was continued for an additional 24 h. The solvent was removed by rotary evaporation evaporation using a hot water bath. A solution of the residue in 50 mL of CHCl3 was washed with water (3×30 mL) and saturated aq. NaCl (2×30 mL) then dried (MgSO4). Removal of the drying agent by filtration and concentration of the filtrate by rotary evaporation gave the crude product as a thick yellow oil. The oil was dissolved in 100 mL of 1:1 (v/v) ethyl acetate/hexane and filtered through a pad of 16 g of basic alumina (Act 1, 80-200 mesh) washing with an additional 50 mL of 1:1 ethyl acetate/hexane. Concentration of the combined filtrates under vacuum afforded 4.93 g (77 %) of 9-benzyl-3-methylene-1,5-dibenzenesulfonyl-1,5,9-triazacyclododecane as a bubbly film that was converted to the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][C:20]=3[CH3:25])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1Cl
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnc2c(Br)cnn2c1Nc1ccc(F)cc1C
Yield: 99.9 %

Procedure:
In the same manner as in Example 1, step 4 and using ethyl 3-bromo-7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (3.5 g, 11.4 mmol) obtained in Example 22, step 1 and 4-fluoro-2-methylaniline (1.53 mL, 22.8 mmol), the title compound (4.48 g, 99%) was obtained.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
Cs2CO3 (214 g, 0.66 mol) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (100 g, 0.66 mol) and cyclopentyl bromide (98 g, 0.66 mol) in anhydrous DMF (500 ml). The reaction mixture was stirred at RT for 16 h then treated with a further portion of cyclopentyl bromide (98 g, 0.66 mol) and Cs2CO3 (214 g, 0.66 mol). After a further 6 h at RT, the mixture was filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (300 ml) and washed with NaOH solution (10%; 2×150 ml). The organic layer was dried (MgSO4), concentrated in vacuo, and distilled (150° C., 10-2 mbar) to afford the title compound (130 g) as a viscous colourless oil. δH (CDCl3) 1.5-2.0 (8H, br m, CH2)4), 3.87 (3H, s, OMe), 4.80 (1H, br m, OCHCH2), 6.90 (1H, d, J 8.7 Hz, ArH ortho to OMe), 7.30-7.45 (2H, m, 2×ArH meta to OMe), and 9.77 (1H, s, ArCHO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 60 %

Procedure:
4-(3-Chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (78.3 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolid-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]=[O:18])=[C:13]([CH3:21])[CH:12]=1.[CH3:22][NH:23][C:24](=[O:27])[CH2:25]O>O1CCCC1>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]2[N:23]([CH3:22])[C:24](=[O:27])[CH2:25][O:18]2)=[C:13]([CH3:21])[CH:12]=1
Reactant: Cc1cc(Cl)ccc1OCC=O
Reactant: CNC(=O)CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCC1OCC(=O)N1C
Reaction time: 24 h
Yield: 11 %

Procedure:
4.6 g (0.0325 mole) of boron trifluoride etherate was added to a solution containing 4.6 g (0.025 mole) of (4-chloro-2-methylphenoxy)acetaldehyde and 2.5 g (0.028 mole) of N-methylglycolamide in 40 ml of tetrahydrofuran. After 24 hours at ambient temperature, the reaction mixture was concentrated under reduced pressure, extracted with ether, washed with water and dried. Purification by silica chromatography gave 0.7 g of 2-(4-chloro-2-methylphenoxymethyl)-3-methyl-4-oxazolidinone as a light yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([O:23][C:24](=[O:39])[C:25]1[CH:37]=[C:36](I)[CH:35]=[C:27]([C:28]([N:30]([CH3:34])[CH2:31][CH2:32][CH3:33])=[O:29])[CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([O:23][C:24](=[O:39])[C:25]1[CH:37]=[C:36]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:35]=[C:27]([C:28]([N:30]([CH3:34])[CH2:31][CH2:32][CH3:33])=[O:29])[CH:26]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OCc2ccccc2)c1
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCN(C)C(=O)c1cc(C(=O)OCc2ccccc2)cc(-c2ccncc2)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
Add pyridine-4-boronic acid (2.361 g, 19.21 mmol) and 2 N sodium carbonate (19.21 mL, 38.42 mmol) to a solution of 5-iodo-N-methyl-N-propyl-isophthalamic acid benzyl ester (6.000 g, 13.72 mmol) in ethylene glycol dimethyl ether (206 mL) under nitrogen at room temperature. Add tetrakis(triphenylphosphine)palladium (0) (0.634 g, 0.549 mmol) and reflux for 20 h. Cool to room temperature and concentrate. Add ethyl acetate, separate the organic layer and extract the aqueous layer with ethyl acetate (4×). Wash the combined organic layers with H2O, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate) to give the title compound (56%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)[CH3:2].[C:19]1([SiH2]C2C=CC=CC=2)C=CC=C[CH:20]=1>O1CCCC1.[C-]#[O+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[CH2:1]([N:4]([CH2:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:19][CH3:20])[CH3:2]
Reactant: c1ccc([SiH2]c2ccccc2)cc1
Reactant: CC(=O)NC[C@H]1COCCN1C(=O)OC(C)(C)C
Agent: [Rh]
Agent: [C-]#[O+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 3-((N-ethylacetamido)methyl)morpholine-4-carboxylate (INTERMEDIATE 86A, Step 2, 0.04 g, 0.14 mmol) and diphenylsilane (0.052 ml, 0.28 mmol) in tetrahydrofuran (1.345 ml) at rt was added carbonyltris(triphenylphosphine)rhodium(I) hydride (6.42 mg, 6.98 μmol). After a brief surge of gas evolution, the now yellow reaction was stirred for 30 min and then quenched with 1N aqueous hydrogen chloride. The mixture was extracted with ether, and the aqueous layer was basified with 50% aqueous sodium hydroxide. The aqueous layer was the extracted with ethyl acetate (×4), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (0.038 g, yield: almost quantitative) (INTERMEDIATE 86A, Step 3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8]O)([O-:3])=[O:2].CCN(CC)CC.CS(Cl)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[Li+].[I-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][N:25]=[N+:26]=[N-:27])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCc1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 3-nitrophenethyl alcohol (2 g, 11.97 mmol), Et3N (3.0 mL, 20.8 mmol) in CH2Cl2 (40 mL) was added methanesulfonyl chloride (1.0 mL, 12.9 mmol) at 0° C. After stirring for 0.5 hr, more CH2Cl2 was added. The solution was washed with water and brine, dried over Na2SO4 and concentrated. The residue was dissolved in DMF (30 mL), sodium azide (0.8 g,12.3 mmol), lithium chloride (0.53 g, 12.5 mmol) and catalytic amount of sodium iodide were added. The mixture was stirred at room temperature overnight. Most of DMF was then removed under vacuum and the residue was washed with water and brine, dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (eluent: hexane:ethyl acetate v/v 4:1) to give a pale yellow oil (1.8 g) as desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 117 °C
Reaction time: 2 h

Procedure:
7 g (0.02 moles) of (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and toluene (25 ml) are warmed gently to form a solution. A slight excess (1.05 molar equivalents) of 2-morpholinoethanol (3 g, 0.021 moles) and toluene (25 ml) are added. The reaction mixture is stirred for half an hour and then heated to reflux at an initial pot temperature of 117° C. (which increases a few degrees during reflux) under a Dean-Stark trap for 80 hours. The reaction mixture is cooled, washed with water (2×15 ml), 10% aqueous sodium bicarbonate (2×15 ml) and finally with water (15 ml). The toluene layer is stripped to a volume of about 20 ml in vacuo, n-hexane (30 ml) is added and the resulting slurry is aged at room temperature for 2 hours. The product is filtered, washed with n-hexane (ca. 10 ml) and dried in vacuo at 60° C. to yield 2-(morpholin-4-yl)ethyl (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.