Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]>C(O)C.O.Cl.[Fe]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2cc(N)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
Iron powder (1.010 g, 18.09 mmol) was added to a solution of isopropyl (S)-4-acetyl-3-methyl-7-(4-(methylsulfonyl)phenyl)-6-nitro-3,4-dihydroquinoxaline-1 (2H)-carboxylate (0.86 g, 1.81 mmol) in ethanol (12 mL) and water (2.4 mL). 1 N aqueous HCl (1 drop) was added, and the reaction was heated at 90° C. for 2 h. The mixture was cooled to rt and filtered through a pad of Celite, washing with ethanol. The filtrate was concentrated, and ethyl acetate was added. The solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-6-amino-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 468 [M+Na]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][CH:13]=[C:9]3[N:8]=[C:7]([S:14][CH3:15])[N:6]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN([CH:27]=[O:28])C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:27]=[O:28])=[C:9]3[N:8]=[C:7]([S:14][CH3:15])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(NC2CC2)n2nccc2n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
N-Cyclopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 eq, 3.10 g, 14.00 mmol) was dissolved in anhydrous DMF (50 ml) under nitrogen atmosphere. Phosphorus oxychloride (5.0 eq, 6.4 ml, 69.9 mmol) was added dropwise over 5 minutes. Internal temperature rose to 45° C. The reaction was stirred in an oil bath at 70° C. for 4.5 hours. The mixture was cooled down and added dropwise into a solution of 6N NaOH (150 ml) chilled with an ice bath. The rate of addition was adjusted to maintain the internal temperature of the aqueous NaOH below 16° C. At the end of the addition, the mixture was neutralized by slow addition of 6N HCl to reach pH=5-6. The resulting solid was filtered, washed with water and dried in a vacuum oven overnight. 4-(cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde was isolated as tan solid (9.26 g, 93%). LCMS (ES): >95% pure, m/z 250 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:5][CH:4]=1)=[CH2:2].N1C=CC=CC=1C1C=CC=CN=1.Br[CH:34]([C:39]1[CH:40]=[C:41]([Cl:47])[C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=1)[C:35]([F:38])([F:37])[F:36]>ClC1C=CC=CC=1Cl.Cl[Cu]>[F:38][C:35]([F:36])([F:37])[CH:34]([C:39]1[CH:40]=[C:41]([Cl:47])[C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=1)/[CH:2]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(NN2C(=O)c3ccccc3C2=O)cc1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Nc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 180 °C
Yield: 77.8 %

Procedure:
To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (CI.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M−H]−).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:17][CH2:18][CH3:19])=[CH:8][C:9]2[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=2[CH:16]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:16][C:10]2[CH:11]=[CH:12][C:13](=[O:15])[O:14][C:9]=2[CH:8]=1)[CH3:19]
Reactant: CCOc1cc2oc(=O)ccc2cc1OCCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CO
Product: CCOc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 57 %

Procedure:
Method A (26 h at 60° C.); starting materials: 6-(3-chloropropoxy)-7-ethoxy-2H-1-benzopyran-2-one (see example 70) and 1-phenylpiperazine; yield 57%; fusion point 151° to 153° (from methanol and ethanol). Fumarate: method E; yield 78%; fusion point 170° to 173° C. (from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:5]=1[NH:6][CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:15])[CH3:2]
Reactant: CCOc1cc(OC)ccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2c(OCC)cc(OC)cc2c1=O
Yield: 75.7 %

Procedure:
2-Ethoxy-4-methoxyaniline (2.2 g) and diethyl ethoxymethylenemalonate (2.9 g) were reacted in the same manner as in Experimental Example 1 to give 8-ethoxy-3-ethoxycarbonyl-6-methoxy-4(1H)-quinolone (2.9 g). The compound (1.5 g) was N-ethylated with potassium carbonate (2.1 g) and ethyl iodide (4.0 g) in the same manner as in Experimental Example 9 to give 8-ethoxy-3-ethoxycarbonyl-1-ethyl-6-methoxy-4(1H)-quinolone (compound 78, 1.3 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C(C)C)(C(C)C)[N:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24]1)(C)C>O1CCCC1.C(OCC)(=O)C>[NH:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:29][CH2:30][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:32][CH2:33]2)=[CH:24]1
Reactant: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2ccn([Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2cc[nH]c2)CC1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Tetrabutylammonium fluoride (2.45 ml, 2.45 mmol) was added to a solution of methyl 1-[4-(1-triisopropylsilylpyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (2.5 g, 4.89 mmol) [prepared as described in Step 2 above] in tetrahydrofuran (48 ml) at 0° C. After 30 min., the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, 15-40% ethyl acetate/hexanes) to yield methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (31%) as a clear oil. This material was converted to 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (93%) by proceeding as described in Example 11, Step 1, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-propanol using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.42 (1H, b), 8.56 (1H, s), 8.30 (1H, s), 7.25 (2H, dd, J=5, 9 Hz), 6.99 (2H, dd, J=9 Hz), 4.39 (2H, t, J=7 Hz), 4.16 (2H, s), 4.04-4.12 (1H, m), 3.60-3.67 (1H, m), 3.54 (2H, t, J=8 Hz), 3.34-3.42 (3H, m), 2.36 (2H, b), 1.73-1.80 (4H, m), 1.28 (3H, d, J=6 Hz); ES+ MS: 497 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[C:44]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:64][CH2:63]2)=[C:45]2[CH:51]=[CH:50][N:49]([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[C:55]1([S:52]([N:49]2[C:46]3=[N:47][CH:48]=[C:43]([NH:42][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[C:44]([NH:61][CH:62]4[CH2:63][CH2:64][N:65]([CH2:68][CH2:69][C:70]#[N:71])[CH2:66][CH2:67]4)=[C:45]3[CH:51]=[CH:50]2)(=[O:53])=[O:54])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CCC(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
Racemic 3-methylpentanoic acid (0.180 ml, 1.4 mmol), HATU (0.53 g, 1.4 mmol), and diisopropylethylamine (0.46 ml, 2.7 mmol), were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (0.54 g, 1.3 mmol, prepared as described in Example 118) in DMF (20 ml) at 25° C. The reaction mixture was stirred for 4 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×200 ml). The organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 3-methyl-pentanoic acid {1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amide (0.706 g, 110%) as an off-white solid. LCMS (Method G, ESI): RT=0.73 min, m+H=523.4. This material was used in the next step below without further characterization.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].C(=O)C1C=CC=CC=1>C1COCC1>[CH2:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:10]=[CH2:11]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)[Mg]Cl
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCc1ccc(C#N)cc1
Yield: 81 %

Procedure:
Highly substituted chloro and methoxy aryl bromides can readily be converted into the desired Grignard reagents 3i, j. After the reaction with ClPPh2 and oxidative work-up, the phosphine oxides 2ia, ja are obtained in good yields (entry 15, 16). This type of compound is of interest in relation with P-ligands for asymmetric catalysis.[5] Also functions like a cyano group are tolerated. Thus, the reaction of 4-bromobenzonitrile in THF at −7° C. leads to the desired arylmagnesium reagent (3d) in only 50% conversion using i-PrMgCl whereas over 90% is observed with i-PrMgCl•LiCl (Scheme 3). The addition of benzaldehyde provides the alcohol 2da in 81% yield whereas allylation of arylmagnesium reagent (3d) with allyl bromide leads to the corresponding 4-allylbenzonitrile in 92% yield (entry 5,6 of Table 1). See FIG. 3 for additional information.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[NH:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:28]([CH:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[N:12]2[C:38](=[O:39])[NH:37][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH3:29])=[O:10])=[CH:19][CH:20]=1
Reactant: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Reactant: CCC(N=C=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H]1C(=O)N(C(=O)NC(CC)c2ccccc2)[C@@H]1C(=O)OCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A mixture of compound 59 (41 mg, 0.15 mmol), triethylamine (83 uL, 0.60 mmol), α-ethyl-benzyl isocyanate (29 mg, 0.18 mmol) in methylene chloride (1.2 mL) was stirred overnight. TLC analysis indicated the completion the reaction. Removal of solvents gave the crude material, which was purified by preparative TLC plate (15% EtOAc in hexanes), yielding 38.2 mg of compound 60 (59%): LC-MS purity: 98.1%; 1HNMR (300 MHz, CDCl3): 0.95 (t, 3H), 1.92 (m, 2H), 2.69 (m, 2H), 3.30 (m, 1H), 3.83 (s, 3H), 4.22 (d, 1H), 4.85 (q, 1H), 5.18 (m, 4H), 5.80 (m, 1H), 6.85 (br, d, 1H), 7.45 (m, 9H). Anal. C25H28N2O5, Mol. Wt.: 436.5. Found: ESI-MS: 437.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19].Cl.FC1C=C(C=CC=1)CN1CC2C(C3C=CC(Cl)=CC=3)(C2)C1>>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:19]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: Fc1cccc(CN2CC3CC3(c3ccc(Cl)cc3)C2)c1
Product: O=C(c1cccc(F)c1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Likewise, 3-(m-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane is prepared from 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane and m-fluorobenzoylchloride, then converted as above to 3-(m-fluorobenzyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride, m.p. 241°-244° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[Cl:34])=[CH:6][CH:5]=1)=[O:3].[Cl:36][C:37]1[CH:38]=[C:39]([OH:46])[CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44]>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:36][C:37]1[CH:38]=[C:39]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[O:46][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([C@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26]3)=[O:20])=[CH:14][C:13]=2[Cl:34])=[CH:8][CH:9]=1)=[O:3]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)Cl)cc3)c(Cl)c2)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc([N+](=O)[O-])c(Cl)c4)cc3)c(Cl)c2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-(chlorocarbonyl)phenyl ester obtained was dissolved in 70 ml of benzene and then added dropwise to a solution of 1.04 g of 3-chloro-4-nitrophenol in 50 ml of pyridine. The reaction mixture was stirred overnight at a bath temperature of 65° C., then poured into ice-cold dilute hydrochloric acid and extracted with diethyl ether. The extract was washed four times with 50 ml of 3N hydrochloric acid each time and once with 50 ml of 2N sodium carbonate solution, washed neutral with water, dried and concentrated. The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-[(3-chloro-4-nitrophenoxy)carbonyl]phenyl ester (3.2 g) obtained was chromatographed on silica gel with hexane/dioxan (volume ratio 3:1). The fractions which were pure according to thin-layer chromatography (1.8 g) were recrystallized twice from ethyl acetate; m.p. (C-N) 138° C., cl.p. (N-I) 237.5° C.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[CH2:12]([O:19][CH2:20][CH2:21][SH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O>[CH2:12]([O:19][CH2:20][CH2:21][S:22][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCCOCc1ccccc1
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1SCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 2-nitrobenzonitrile (5.85 g) in DMF (20 mL) was treated with 2-(benzyloxy)ethanethiol (Example 320a, 6.64 g) and a solution of potassium hydroxide (3.76 g) in water (5 mL) was added dropwise under nitrogen. The resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with 50% diethyl ether in iso-hexane) to afford the subtitle compound as a solid (7.08 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH3:21])[CH:20]=1>CN(C)C(=O)C>[N+:22]([C:18]1[CH:17]=[CH:16][C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][C:19]=1[CH3:21])([O-:24])=[O:23]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
14.1 g (150 mmol) of phenol were dissolved in 120 ml of anhydrous N,N-dimethylacetamide, while stirring, 20.6 g (150 mmol) of finely powdered potassium carbonate were added and the mixture was stirred at 70°-80° C. for 30 minutes. After cooling to 20° C., 23.25 g (18.3 ml, 150 mmol) of 5-fluoro-2-nitrotoluene were added dropwise, the mixture was heated at 135°-140° C. for 2 hours and, after cooling, concentrated in vacuo, the residue was introduced into ice and the crystalline product was filtered off with suction, washed with water and dried, 30 g, melting point 43°-46° C.
Reaction SMILES: [I:1]I.[Cl:3][C:4]([Cl:13])([Cl:12])[C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6].O>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:13][C:4]([Cl:3])([Cl:12])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([I:1])[CH:11]=1)=[O:6]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
Iodine (1.2 g, 4.7 mmol) was added portion wise to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1 g, 4.7 mmol) and silver trifluoroacetate (1.1 g, 5 mmol) in dry dichloromethane (24 mL), cooled to 0° C. The reaction mixture was allowed to warm up slowly to 18° C. (water bath) and stirred at the same temperature for 5 h. The solid was filtered, the organic phase washed with Na2S2O5 (5% aq. solution) until decoloration occurs and finally washed with H2O (1×20 mL). The organic phase was dried over Na2SO4 and filtered through a plough of SiO2 (hexane-EtOAc 4:1), to obtain compound 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) as an off-white solid (1.49 g, 94% yield).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:9]=1.CI>CC(C)=O>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:18]([CH3:1])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:9]=1
Reactant: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)cc1N(C)S(C)(=O)=O
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Potassium carbonate (12.5 g) was added to a stirred solution of methyl 4-chloro-2-(N-methylsulphonylamino)benzoate (7.5 g) in acetone. The mixture was stirred for 15 minutes and methyl iodide (8.0 g) was added. The resultant mixture was stirred at room temperature for 1 hour and left to stand overnight. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and washed with sodium hydroxide solution (2M) and water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (4.9 g) as a white solid, m.p. 73-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)=[O:13])[CH2:5]2.CS(O[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][O:28]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2
Reactant: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(O)cn1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(OC[C@@H]2CCCO2)cn1
Temperature: 60 °C

Procedure:
A mixture of N-((R)-5-bromoindan-2-yl)-5-hydroxypyridine-2-carboxamide (1.50 g), (S)-1-(tetrahydrofuran-2-yl)methyl methanesulfonate (0.81 g), cesium carbonate (1.46 g) and DMF (20 ml) was heated to 60° C. for 4 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. This afforded the product with the molecular weight of 417.31 (C20H21BrN2O3); MS (ESI): 417 (M+H+).