Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].ClCCCl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: C1COCCN1
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a stirred solution of 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (236 mg, 0.00100 mol) in 1,2-dichloroethane (8 mL, 0.1 mol) at room temperature was added morpholine (0.23 mL, 0.0026 mol) followed by acetic acid (0.15 mL, 0.0026 mol) dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride was added in one portion. The reaction mixture was stirred at 0° C. for 2 h then warmed to room temperature overnight. Workup involved addition of 1N NaOH to bring pH to ˜10. The reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to a orange oil. Purification was accomplished using ISCO chromatography on silica gel using hexane-ethyl acetate and methylene chloride-methanol to give 4-(1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine as a yellow solid (0.24 g, 78%). 1H NMR (400 MHz, CDl3). δ 6.70 (s, 1H, J=7.92 Hz), 6.51 (d, 1H, J=7.88), 3.70 (m, 9H), 3.29 (q, 1H, J=14.41, 8 Hz), 2.74 (q, 1H, J=14.28, 7.48 Hz), 2.55 (m, 6H), 2.31 (m, 1H), 2.10 (m, 2H), 1.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:24])([CH3:23])[C:9](=O)[CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:13])=[CH:4][C:3]=1[O:25][CH3:26]>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:12](=[S:13])[NH:11][CH:10]=2)([CH3:24])[CH3:23])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C(C)(C)C(=O)CNC(=S)Nc2ccc(F)cc2)ccc1F
Solvent: CC(=O)O
Product: COc1cc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)ccc1F
Yield: 94.4 %

Procedure:
A solution of 1-(3-(4-fluoro-3-methoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl)-thiourea (45 g, 0.119 mol) in AcOH (500 mL) was heated at reflux overnight. The cooled reaction mixture was concentrated and triturated with Et2O to give 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (40.5 g, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.90 (t, 3H), 6.81 (s, 1H), 6.61 (m, 2H), 6.50 (m, 2H), 3.76 (s, 3H), 1.46 (s, 6H); MS (ESI) m/z 361 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.CS(C)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[CH2:30]([NH:37][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])cc3O2)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CNCc1ccccc1)CO2
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A 3 L three necked flask equipped with a heating mantle, thermocouple and mechanical stirrer is charged with [7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (356.8 g, 0.977 mol), DMSO (1 L) and benzylamine (261.7 g, 2.44 mol). The slurry is heated to maintain an internal temperature of 90° C. Heating is continued for 18 h, and then the solution is allowed to cool to 30° C. over 2 h. Water (400 mL) is added over 15 min. then seed crystals (˜100 mg) are added resulting in rapid formation of a precipitate. The slurry is stirred for 30 min prior to additional water (2 L) being added over 1.5 h. The slurry is stirred for 4 h, the solids are collected by vacuum filtration, washed with water (2 L) and suction dried under nitrogen giving the title compound (302.87 g, 103%) as a yellow powder (94% ee). Yield is high due to trapped water, m.p. 98° C. (dried sample). LCMS (Basic Method): 2.05 min, 301 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 7.77-7.70 (m, 1H), 7.47-7.18 (m, 6H), 7.10-7.06 (m, 1H), 4.47 (dd, J=2.5, 11.5 Hz, 1H), 4.37-4.29 (m, 1H), 4.15 (dd, J=7.1, 11.5 Hz, 1H), 3.73 (s, 2H), 2.82-2.70 (m, 2H), 2.43 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH2:55]>ClCCl>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:55][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[F:48])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1F
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4F)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D (53 mg, 0.1 mmol), N,N-diisopropylethylamine (0.052 mL, 0.3 mmol), 2-Fluoro-phenylamine (0.014 mL, 0.15 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour, then concentrated under vacuum to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li+].[Cl-].Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.C([Cu])#N>C1COCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:19]2[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: BrC1C=CCCC1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C2C=CCCC2)ccnc1Cl
Temperature: -50 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
2-Chloro-3-nitropyridine (18) (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. After cooling down to −50° C., 3-bromo-cyclohexene (192 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 0.05 mL, 0.05 mmol) were added and the reaction mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished 2-chloro-4-cyclohex-2-enyl-3-nitro-pyridine (20) (173 mg, 73%) as a colourless solid.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][Cl:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:37].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCN(C)C)cc4)cc3)n(C)c(=O)c12
Yield: 46 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (311 mg), 3-dimethylaminopropyl chloride hydrochloride (249 mg) and potassium carbonate (322 mg) in DMF (5 ml) was stirred at 60° C. for 18 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration to provide the title compound as colorless solid (185 mg).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].CN1CCOCC1.Cl.C(C(NCCCN(C)C)=N)C.[C:38]([C:41]1[N:42]=[C:43]([CH:46]2[CH2:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]2[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[NH:44][CH:45]=1)(O)=[O:39]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:38]([C:41]1[N:42]=[C:43]([CH:46]2[CH2:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]2[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[NH:44][CH:45]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1c1nc(C(=O)O)c[nH]1
Reactant: COC(=O)CN
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)c1c[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00036 mole), glycine methylester, hydrochloride (0.00047 mole), 4-methylmorpholine (0.00055 mole), and N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride (0.00047 mole) were added to compound 117 (0.00036 mole) dissolved in DCM (30 ml) at 0° C. The mixture was allowed to warm to room temperature under nitrogen, and stirred overnight. The mixture was extracted with water, saturated NaHCO3, 2N citric acid, then saturated NaHCO3, dried, filtered, and concentrated, yielding 0.100 g (69%) of 1,1-dimethylethyl 2,3-dihydro-2-[4-[[(2-methoxy-2-oxoethyl)amino]carbonyl]-1H-imidazol-2-yl]-1H-indole-1-carboxylate (compound 118).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]-2-methyl-propan-2-ol (66 mg, 0.104 mmol) in TFA (0.5 mL) and DCM (1.0 mL) was stirred at room temperature. After 1.5 hours, the reaction mixture was concentrated under reduced pressure to give an oil. The oil was dissolved in EtOH (1 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C28H28ClN3O4 505.18 observed m/e: 506.23 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 7.87 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.56 (qt, 1H), 4.96 (t, 1H), 4.54 (t, 1H), 4.10-4.00 (m, 3H), 3.51 (dd, 1H), 2.63 (m, 1H), 2.59 (m, 1H), 1.95 (dd, 1H), 1.58 (dd, 1H) and 1.25 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.Cl[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]>O.CN(C)C=O>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:6]1[C:5](=[O:24])[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:7]1
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nn(CCN(C)C)c1=O
Reaction time: 4 h
Yield: 63 %

Procedure:
4-Acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one (20.0 g), potassium carbonate (9.0 g) and 30 ml of a toluene solution of N-(2-chloroethyl)dimethylamine (0.34 g/ml) and dimethylformamide (150 ml) were stirred at 80° C. for 18 hours. A second equivalent of the amine was added and heating continued for an additional four hours. The mixture was cooled, poured into water and the suspension extracted with ethyl acetate. The combined organic extracts were dried and evaporated in vacuo. Following purification by dry column silica gel chromatography and recrystallization, the title compound was obtained (63 percent yield), m.p. 149°-150° C.
Reaction SMILES: [CH2:1]([C:3]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:34]#[C:35][CH2:36][O:37]S(C)(=O)=O)[C:18]4[S:22][C:21]([N:23]5[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].O[N:48]1[C:52](=[O:53])[C:51]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:50]2[C:49]1=[O:58].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:58]=[C:49]1[C:50]2[C:51](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52](=[O:53])[N:48]1[O:37][CH2:36][C:35]#[C:34][C:17]1[C:18]2[S:22][C:21]([N:23]3[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]3=[O:32])=[N:20][C:19]=2[CH:33]=[C:15]([C:12]2[CH:11]=[N:10][C:9]([N:6]3[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:8][CH2:7]3)=[N:14][CH:13]=2)[CH:16]=1
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCOS(C)(=O)=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCON4C(=O)c5ccccc5C4=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 60 °C

Procedure:
Ethyl 4-ethyl-1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(3-methylsulfonyloxyprop-1-ynyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (368 mg, 0.55 mmol), N-hydroxyphthalimide (134 mg, 0.82 mmol), potassium iodide (9 mg, 0.05 mmol) and potassium carbonate (152 mg, 1.10 mmol) were dissolved in anhydrous DMF (5 mL) under argon and heated to 60° C. for 3 h. The cooled mixture was diluted with water, extracted into EtOAc (4×30 mL) and the organic phase washed with water then brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. A yellow solid was obtained and the mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 50-80% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a pale yellow oil, 233 mg (58%). MS: 737.13 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH:20]1[C:25]([C:26]2[C:31](=[O:32])[C:30]3[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:29]=3[O:28][CH:27]=2)=[CH:24][CH:23]=[C:22]([OH:38])[CH:21]=1>C(O)C>[C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH:24]1[C:25]([C:26]2[C:31](=[O:32])[C:30]3[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:29]=3[O:28][CH:27]=2)=[CH:20][CH:21]=[C:22]([OH:38])[CH:23]=1
Reactant: CC(=O)NC(CCc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Solvent: CCO
Product: CC(=O)N[C@@H](CCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 2-acetamido-4-(4-nitrophenyl)butyric acid (57.65 g) in hot 95% ethanol (1000 ml) add d-(+)-α-methylbenzylamine (25.2 g) in hot 95% ethanol (125 ml), cool the solution slowly and keep at room temperature 18 hours. Collect the solid and wash with cold 95% ethanol, and dry to give an orange-yellow solid. Recrystallize this solid from 95% ethanol treated with charcoal to give 2(S)-acetamido-4-(4-nitrophenyl)butyric acid, d-(+)-α-methylbenzyl amine salt [α]D26 =+45.6 (MeOH), m.p. 211°-213° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.C1C(=O)N([I:19])C(=O)C1>CN(C=O)C>[I:19][C:6]1[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(C)c1I
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
To a stirred solution of ethyl 3-methylpyrazole-5-carboxylate (3.11 g, 20.17 mmol) in DMF (50 mL) under Ar at 0° C. was added NIS (5.90 g, 26.2 mmol). The reaction mixture was stirred 20 hr at rt and quenched with 500 mL of water. The resulting precipitate was collected to afford the title product (5.61 g, 20.03 mmol, 99% yield) as a white solid. tR: 3.75 min (HPLC 1); tR: 0.78 min (LC-MS 2); ESI-MS: 281 [M+H]+ (LC-MS 2)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH:20]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])([CH3:22])[CH3:21]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
3.0 g of 3-hydroxy-4-nitrobenzaldehyde, 30 ml of acetonitrile, 5.9 g of caesium carbonate and 4.1 ml of 2-iodopropane are successively introduced into a three-necked round-bottomed flask under argon. The reaction mixture is heated at 70° C. for 17 h. After cooling to ambient temperature, the mixture is filtered through a sintered glass filter and the filtrate is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 50 ml of ethyl acetate and 15 ml of water, and then separated by settling out. The aqueous phase is separated and the organic phase is washed with 10 ml of water. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure, so as to obtain 3.6 g of 3-isopropoxy-4-nitrobenzaldehyde in the form of a dark brown liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[CH2:23][O:22]2)=[CH:16][CH:15]=1)=O)([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[C:1]1(=[O:3])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[CH2:23][O:22]3)=[CH:16][CH:15]=2)[O:2]1
Reactant: CC1(C)CON(Cc2ccc(NC(=O)Cc3ccccc3C(=O)O)cc2)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CC1(C)CON(Cc2ccc(Nc3cc4ccccc4c(=O)o3)cc2)C1=O
Temperature: 25 °C
Yield: 109.8 %

Procedure:
A solution of 0.57 gram (0.0015 mole) of 2-[[4-[(2-carboxyphenylmethyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone in 100 mL of toluene was cooled in an ice bath, and, with stirring, 0.33 gram (0.0016 mole) of dicyclohexylcarbodiimide was added in one portion. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. The resultant solid was collected by filtration to yield 0.60 gram of 2-[[4-[(1H-2-benzopyran-1-one-3-yl)amino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 175°-177° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14](O)=[C:13]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:12]=1)(=[O:9])=[O:8])[CH3:6].O>CN(C)C=O>[CH2:5]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:13]=2[CH:12]=1)(=[O:9])=[O:8])[CH3:6]
Reactant: CCS(=O)(=O)Oc1ccc(O)c(C(C)(C)CO)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCS(=O)(=O)Oc1ccc2c(c1)C(C)(C)CO2
Temperature: 5 °C
Yield: 69.9 %

Procedure:
Thionyl chloride (4.3 g) was added dropwise to dimethylformamide (13 ml) maintained at about 5° C. To this was quickly added 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl ethanesulphonate (9.5 g) from Example 2 in dimethylformamide (13 ml). The reaction mixture was then heated to 100° C. and maintained at that temperature for 4-5 hours, after which it was cooled and poured into water (100 ml). The oil was extracted with diethyl ether, washed with water, dried over magnesium sulphate and evaporated down to give 6.2 g of a brownish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]([C:10]2[C:11](F)=[N:12][C:13]([F:29])=[C:14]([Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:15]=2)=[O:9])[CH:7]=1.BrB1C2CCCC1CCC2>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:31][C:11]1=[N:12][C:13]([F:29])=[C:14]([Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[C:10]1[C:8]2=[O:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)c2cc(Br)ccc2OC)c(F)nc1F
Agent: BrB1C2CCCC1CCC2
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(=O)c3cc(Br)ccc3oc2nc1F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
(5-Bromo-2-methoxyphenyl)(2,6-difluoro-5-(tributylstannyl)pyridin-3-yl)methanone (6.48 g, 10.50 mmol) was dissolved in DCM (60 mL) under nitrogen and cooled in a dry ice bath to −78° C. 9-Bromo-9-borabicyclo[3.3.1]nonane, (1 M in DCM, 11.02 mL, 11.02 mmol) was added dropwise over 5 minutes and the reaction stirred for another 5 minutes. The flask was removed from the cold bath and stirred at ambient temperature for 20 minutes then saturated sodium bicarbonate (50 mL) was added to quench. Water (200 mL) and dichloromethane (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to dichloromethane gradient) gave 7-bromo-2-fluoro-3-(tributylstannyl)-5H-chromeno[2,3-b]pyridin-5-one.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[CH2:22][CH2:23][CH3:24].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:21]1([CH2:22][CH2:23][CH3:24])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3)[CH3:31]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 5-benzyloxytryptophol (4.72 g, 17 mmol) and ethyl butyrylacetate (3.16 g, 20 mmol) in methylene chloride (75 ml) is treated dropwise with boron trifluoride etherate (3 mL) and stirred under nitrogen at room temperature overnight. The reaction mixture is diluted with methylene chloride (250 mL) and sequentially washed with 5% aqueous sodium bicarbonate (2×100 mL) and water (2×50 mL). The organic phase is dried (MgSO4), filtered, and evaporated to afford 7.0 g of a crude dark oil. Purification by flash column chromatography (ethyl acetate:hexane, 1:9 eluent) on silica gel (50:1 ratio, 230-400 mesh) affords the title compound (5.5 g, 79%) as a slightly amber oil homogeneous by TLC.