Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:38][C:39](O)=[O:40])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:29].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]([NH:17][CH3:18])[C:39](=[O:40])[CH2:38][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:21]([O:20][CH3:19])[CH:22]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OCCNC)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OCC(NC)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-methylaminoethoxy)benzoate (510 mg, 2.01 mmol) in DMF (13 mL) was added pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (900 mg, 1.87 mmol) and Et3N (0.420 mL, 3.01 mmol), and the resulting mixture was stirred for 2 days. The mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over Na2SO4. After being evaporated, the residue was purified by column chromatography on silica-gel with CHCl3:MeOH (50:1, v/v) to give 880 mg (85%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-N-methylaminoethoxy]benzoate as a colorless amorphous solid. 1H-NMR (CDCl3) d 1.37-1.41 (m, 3 H), 2.28 (s, 3 H), 3.03 and 3.18 (s, 3 H), 3.56 (s, 2 H), 3.65 (s, 2 H), 3.75-3.87 (m, 6 H), 4.06-4.24 (2 H, m), 4.33-4.39 (m, 2 H), 6.68-8.08 (series of m, 12 H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40]>C(Cl)Cl>[C:39]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][N:19]=2)[C:15]([NH:14][CH2:13][C@H:12]([OH:30])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:29])[CH2:24][CH2:25]1)(=[O:40])[CH3:38]
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccnc(NC2CCNCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(piperidin-4-ylamino)isonicotinamide (70 g), and Et3N (40 g) in DCM (2000 mL) was added Ac2O (17 g) dropwise over 1 h at 0° C. After addition, the mixture was warmed to 20° C. and stirring was continued for another 1 h, at which time TLC showed the reaction was completed. The reaction mixture was washed with water (500 mL), and the organic phase dried and concentrated. The residue was then purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give crude product. Five batches were run in parallel and produced a combined crude product weight of 400 g. This crude was further purified by preparative HPLC to give the pure product (310 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 7.94-7.92 (d, 7.0 Hz, 1H), 7.14-7.05 (m, 4H), 6.87 (s, 1H), 6.76-6.74 (m, 1H), 4.44 (m, 1H), 4.10 (m, 1H), 3.96-3.94 (m, 2H), 3.75 (s, 2H), 3.52 (m, 2H), 3.33-3.32 (m, 1H), 2.92-2.86 (m, 5H), 2.67 (m, 2H), 2.13-2.00 (m, 5H), 1.44-1.37 (m, 2H); LCMS (m/z): 452.3 [M+H]+
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14](Cl)=[N:13][C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[C:10]([Cl:16])[CH:11]=2)[N:6]=1.[O:18]1[CH2:22]CCC1>CO>[Cl:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[Cl:16])[N:13]=[C:14]([O:2][CH3:1])[C:5]([O:18][CH3:22])=[N:6]2
Reactant: C[O-]
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Reaction time: 72 h
Yield: 95 %

Procedure:
A solution of sodium methoxide (25% wt/v in methanol, 190 mL, 880 mmol) was added dropwise to a stirred suspension of 2,3,6,7-tetrachloroquinoxaline (106 g, 400 mmol) in methanol (1400 mL) at room temperature under nitrogen. After 3 days, a solution of sodium methoxide (25% wt/v in methanol, 40 mL, 190 mmol) was added, followed by tetrahydrofuran (300 mL). The reaction mixture was heated under reflux for 5 minutes, cooled, concentrated to a small volume under reduced pressure and poured into water (500 mL). The precipitate was collected by filtration and washed with water to afford the title compound (97 g, 95%) as a pink solid, mp 144-146° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
A solution of 5-fluoro-2-hydrazinyl-pyridine (0.59 g, 4.65 mmol), isobutyric acid (528 mg, 6 mmol), and HOBt hydrate (153 mg, 1 mmol) in DCM (10 mL) was treated with EDC (1.15 g, 6 mmol). The reaction mixture was stirred at RT for 40 min, poured onto sat. aq. sodium bicarbonate (40 mL), extracted with four portions of DCM, dried (Na2SO4), evaporated and purified by FCC using 10-30% EtOAc/DCM to give the title compound (0.42 g, 46%). LCMS (method 2): Rt 2.46 min, m/z 198 [MH+].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)(=[O:26])=[O:25])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 40 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A 500-mL round-bottomed flask was charged with a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (16 g, 79.60 mmol, 1.00 equiv) in DCM (200 mL), 4-nitrobenzene-1-sulfonyl chloride (17.6 g, 79.64 mmol, 1.00 equiv) and pyridine (9 mL). The resulting solution was stirred at 40° C. for 16 hours. The reaction progress was monitored by TLC (EtOAc: PE=1:2). Upon completion, the reaction was then quenched by the addition of aqueous NaHCO3 (200 mL). The resulting mixture was extracted with dichloromethane (4×100 mL). Combined organic layers were washed with brine (1×30 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10-1:2) affording tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate as yellow solid (23 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]#[C:11][CH2:12][OH:13])[N:5]=1)([O-])=O.CO.NN>C(OCC)(=O)C.[Ni].O>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[N:5]=1
Reactant: O=[N+]([O-])c1ccn(CC#CCO)n1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccn(CCCCO)n1
Yield: 96.7 %

Procedure:
The 4-(3-nitro-pyrazol-1-yl)-but-2-yn-1-ol (prepared in example 52, 113 mg, 0.62 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. While stirring, a 50% slurry of raney nickel in water (1.3 mL) was added followed by hydrazine (400 μL). Immediate effervescence was observed. The reaction continued to stir and bubble for 25 min. The reaction was passed through a plug of celite and concentrated in vacuo to afford 4-(3-amino-pyrazol-1-yl)-butan-1-ol (93 mg, 98%) as a clear oil: ESI-LRMS m/e calcd for C7H13N3O [M+] 155.11, found 156.32 [M+H+].
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24](O)=[O:25])[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.[C:38]([C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)#[N:39]>>[ClH:36].[NH2:16][C@H:15]([C:24](=[O:25])[N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:38]#[N:39])[CH2:14][CH2:13][CH2:12][NH:11][S:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[O:35])=[O:34]
Reactant: N#C[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: N#C[C@@H]1CCCN1C(=O)[C@@H](N)CCCNS(=O)(=O)C1CCCCC1

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, cyclohexanesulphonyl chloride and (S)-2-cyano-pyrrolidine hydrochloride, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: FC(F)(F)C(NC1C=CC(C#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=CC=1)=O.I[C:22]1[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[N+:28]([C:24]1[CH:23]=[C:22]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: O=C(Nc1ccc(C#CCCCCO)cc1)C(F)(F)F
Product: O=[N+]([O-])c1cccc(C#CCCCO)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 39, using 3-iodonitrobenzene as a substrate. ES/MS calcd. for C11H12NO3+ 206.1. Found m/z=206.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[F:11][S:12]([O:15][CH3:16])(=[O:14])=[O:13]>>[F:11][S:12]([O-:15])(=[O:14])=[O:13].[CH2:1]([O:5][C:6]1[CH:10]=[CH:9][S:8][N+:7]=1[CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccsn1
Reactant: COS(=O)(=O)F
Product: CCCCOc1ccs[n+]1C
Product: O=S(=O)([O-])F

Procedure:
3-n-Butoxyisothiazole (7.2 g, 0.046 mol) and 8 ml of methyl fluorosulfonate were heated to 70° for 1 hr. After cooling, the solid was washed with ether and dried to yield 8.7 g of 3-n-butoxy-2-methylisothiazolium fluorosulfonate a low melting solid. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:15]1[CH:32]=[CH:31][C:18]([C:19]([N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=1[Cl:33].Cl>N1C(C)=CC(C)=CC=1C>[Cl:33][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][C:15]=1[O:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:19]([N:21]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)N(C(=O)c1ccc(Br)c(Cl)c1)C1CCCCC1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2Cl)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-3-chloro-N-cyclohexyl-N-isopropylbenzamide (1.43 g, 4.0 mmol) in 2,4,6-collidine (20 mL) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[C:6](=[O:10])[N:7]=[CH:8][CH:9]=1>O1CCCC1>[C:1]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1N=CC=N1
Solvent: C1CCOC1
Product: CC(=O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23.6 parts by weight of acetyl chloride in 100 parts by volume of tetrahydrofurane were added dropwise over the course of 60 minutes to a suspension of 25.8 parts by weight of imidazol-2-one in 350 parts by volume of dry tetrahydrofurane. at 0° C. The mixture was stirred for 3 hours at room temperature, dry air was subsequently blown through the solution for some time, the solvent was then removed in vacuo and the residue was recrystallized from boiling nitromethane.
Reaction SMILES: [CH:1]1([NH:4][S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22]>CC(C)=O>[CH:1]1([N:4]([S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:3][CH2:2]1
Reactant: CC(=O)OCCBr
Reactant: CCCS(=O)(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCS(=O)(=O)N(CCOC(C)=O)C1CC1
Yield: 85.2 %

Procedure:
A mixture of propane-1-sulfonic acid cyclopropyl amide (1.3 g, 8 mmol), K2CO3 (2.4 g, 14.4 mmol) and acetic acid 2-bromo-ethyl ester (9.5 g, 16 mmol) mmol) in 10 ml acetone was heated for 6 h to 120° C. in the microwave (Biotage). After cooling the mixture was filtered and the solvent evaporated to obtain 1.7 g of product as an oil which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Br)c1
Temperature: 110 °C

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene (2.5 g, 11.4 mmol), phenol (1.28 g, 13.6 mmol), and cesium carbonate (4.44 g, 13.6 mmol) were combined in dimethylsulfoxide (140 mL) and heated to 110° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>O1CCOCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: NCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCNS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4,6-trichlorobenzenesulfonic acid chloride (3.00 g, 11 mmol) in 1,4-dioxane (50 ml) was added dropwise to a solution of 5-aminovaleric acid hydrochloride (1.50 g, 10 mmol) in 1 N sodium hydroxide solution (30 ml). The reaction mixture was stirred for 18 h at room temperature, and 1,4-dioxane was then distilled off in vacuo. The aqueous phase was extracted with ethyl acetate (3×50 ml) and then adjusted to pH 1 with concentrated hydrochloric acid. The acidic aqueous phase was extracted with ethyl acetate (3×60 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][C:22]([C:24]1([CH3:27])[CH2:26][O:25]1)=[O:23]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[O:10][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[CH3:11])=[O:23]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1(C)CO1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C(C)(O)COc1ccc(C#N)c(Cl)c1

Procedure:
3-(3-Chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitrophenyl)propionamide was prepared as described in Example 64c starting from 2-chloro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.15 (1H, d, J=10.1 Hz), 4.39 (1H, d, J=10.1 Hz), 6.51 (1H, s), 7.10 (1H, dd, J=8.8 Hz, J=2.4 Hz), 7.37 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=8.8 Hz), 8.05-8.12 (2H, m), 8.18 (1H, d, J=2.3 Hz), 9.56 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) in DMF (10 mL) was added cesium carbonate (5.04 g, 15.46 mmol) and 2-iodopropane (2.58 mL, 25.8 mmol). The mixture was heated at 100° C. overnight. After cooling to RT, H2O (300 mL) was added and the aqueous layer was extracted with EtOAC (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered, and solvent was removed in vacuo. The resulting crude material was reconstituted in MeOH (1.0 mL) and purified by HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C12H21BN2O2, 237. found 237.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].CI>C1COCC1>[F:19][C:20]1[C:28]([CH3:1])=[C:24]([C:23]([O:29][CH3:30])=[CH:22][CH:21]=1)[C:25]([OH:27])=[O:26]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(F)cc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: COc1ccc(F)c(C)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 229.6 %

Procedure:
Diisopropyl amine (478 g, 4.725 mol) and anhydrous THF (2.8 L) were charged to a 10 L 4-neck flask equipped with gas inlet, addition funnel, thermometer and mechanical stirrer. The solution was degassed with N2 for 5 min then cooled to −78° C. with dry ice acetone bath under N2 flow. A solution of n-BuLi in n-hexane (1.8 L, 2.5 M, 4.5 mol) was added to the stirring mixture at −20° C.˜−10° C. over 40 min. After the addition, the reaction was stirred at −20° C. for 40 min A solution of 5-fluoro-2-methoxybenzoic acid 60 (297.5 g, 1.75 mol) in anhydrous THF (1.3 L) was added to the reaction mixture at −55° C.—45° C. with stirring over 60 min. The resulting brown mixture was stirred at −15˜−25° C. for 3.5 h. The reaction mixture turned to red brown. Another para-reaction same with above reaction was set at same time. A 20 L four-neck flask equipped with gas inlet, addition funnel, thermometer and mechanical stirrer was charged with neat MeI (1500 g, 10.5 mol) and anhydrous THF (2.6 L). The mixture was degassed with N2 for 5 min and cooled to −20˜−15° C. with dry ice acetone bath under small N2 flow. The obtained solution from the above two para-reactions was transferred to the 20 L flask containing MeI at −15˜−5° C. with stirring over 20 min. The resulting cloudy mixture was stirred at −20˜−15° C. for 2 h and brought to ambient temperature over 1.5 h. The obtained brown suspension was stirred at 25-30° C. for 16 h. The reaction was then quenched with aqueous HCl (5.0 L, 2N) at 20-25° C. and diluted MTBE (3.0 L). After being stirred for 5 min at 20° C., the two phase mixture was separated, and the upper layer was concentrated to dryness under vacuum to give black oil. The aqueous layer was extracted with EtOAc (5×1.5 L) and all the organic layers were combined with the black oil. The resulting solution was washed with water (2×μL) and brine (3×1 L). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduce pressure to afford crude 3-fluoro-6-methoxy-2-methylbenzoic acid 61 (740 g, >100%) as brown crystal solid that was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=9.8, 8.5 Hz, 1H), 6.75 (dd, J=9.8, 3.7 Hz, 1H), 3.86 (s, 3H), 2.34 (d, J=2.4 Hz, 3H); MS (ESI) m/z 185.12 (M+H).
Reaction SMILES: [CH3:1][O-].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:10][CH:11]=1)([O-:6])=[O:5].CI>CO>[CH3:1][N:10]1[CH:11]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[C:9]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C[O-]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.5 g. of sodium methoxide in 25 ml. of methanol is cooled to 10° C. and a mixture of 7.0 g. of ethyl 4-nitro-2-pyrrolecarboxylate in 15 ml. of methanol is added. After 10 minutes, 18.6 g. of methyl iodide is added. The dark-colored solution is warmed to 35° C. for 0.5 hours, then cooled and allowed to stir at room temperature for 16 hours. Chilling and filtration affords a solid which is collected by filtration and recrystallized from ethanol to yield the product.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([NH2:38])[CH:32]=1.N1C=CC=CC=1>C1COCC1.CN(C=O)C>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([NH:38][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:32]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
(4-Adamantan-1-yl-phenoxy)-acetic acid (143.2 mg, 0.5-mmol) was dissolved in THF (5 mL), and oxalyl chloride (178.5 mg, 0.11 mL, 1.5 mmol) and one drop of DMF were added to the solution. After the mixture was stirred for 1 h at room temperature, 3-amino-4-hydroxy-benzoic acid methyl ester (125.4 mg, 0.75 mmol) and pyridine (0.05 mL) were added, and the resulting. Solution was stirred at room temperature overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4-anh), and concentrated. The residue was purified by (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester as a white solid (183.2 mg, 84.1% yield).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=1.[ClH:32].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:32].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:29](=[O:30])[C:26]4[CH:27]=[CH:28][C:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)=[CH:24][CH:25]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccccn4)cc3)cn12

Procedure:
The title compound was obtained as white solid by conducting the operations similar to those of Example 1, using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(2-pyridyl)benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure, to provide the title compound as white solid.