Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[N:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](O)=[O:48])=[CH:42][CH:41]=1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:16]3[CH2:17][CH2:18][N:19]([C:47](=[O:48])[CH2:46][C:43]4[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=4)[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccncc1)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 8.5 g (27.2 m mole) of 8-chloro-11-(1-piperazinyl)-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (Preparative Example 7) in 256 mL of anhydrous DMF at room temperature and under an argon atmosphere was added 2.98 g (27.2 m mole of 4-methylmorpholine, 7.81 g (27.2 m mole) of DEC, 3.68 g (27.2 m mole) of HOBT, and 3.72 g (27.2 m mole) of 4-pyridylacetic acid. The mixture was stirred at room temperature for 22 hours. The mixture was poured into 3300 mL of CH2Cl2 and washed with 500 mL of water. The aqueous layer was extracted with 500 mL of CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a solution of 1.5% (10% NH4OH in MeOH) in CH2Cl2. The product was obtained as a white amorphous solid, M.S. (Mass Spec) M+=433.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:42]O.[Li+].[OH-].C1[CH2:50][O:49]CC1>>[C:1]([O:5][C:6]([CH2:8][CH:9]([CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)=[CH:32][CH:33]=1)[C:50]([OH:49])=[O:42])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(CCOc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)CC(CCOc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a 0° C. solution in THF (200 mL) of N-[2-tert-butyloxycarbonylmethyl-4-(4-(4-cyanophenyl)phenoxy)butanoyl]-(S)-(-)-4-benzyl-2-oxazolidinone (7.05 g, 12.7 mmol) was added 30% aqueous H2O2 (3.0 mL, 50.8 mmol) and 1M aqueous LiOH (20.3 mL, 20.3 mmol) and the reaction mixture was stirred for one hour. The reaction mixture was quenched with saturated aqueous NaHSO3 and diluted with dichloromethane. The aqueous phase was made basic with aqueous 2N NaOH and extracted twice with dichloromethane. The organic extracts were discarded and the aqueous phase was cooled to 0° C. and acidified with aqueous 2N HCl. The aqueous phase was extracted with dichloromethane and THF/dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (dichloromethane/10% THF/1% methanol) gave 2-tert-butyloxycarbonylmethyl-4-[4-(4-cyanophenyl)phenoxy]butanoic acid (2.6 g, 52%).
Reaction SMILES: [OH:1][C:2]1[C:7](C)=[C:6]([O:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25].[Cl:27]C1C(O)=C(C(=O)C)C=CC=1O>>[Cl:27][C:7]1[C:2]([OH:1])=[C:3]([C:24](=[O:26])[CH3:25])[CH:4]=[CH:5][C:6]=1[O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=2)[N:12]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone, employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (57%). LC-MS (m/e): 483 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:20][C:21]([C:23]1([CH3:26])[CH2:25][O:24]1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:26][C:23]([OH:24])([CH3:25])[C:21]([NH:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:11]=1[CH3:10])=[O:22]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: Cc1c(NC(=O)C2(C)CO2)cccc1[N+](=O)[O-]
Product: Cc1c(NC(=O)C(C)(O)COc2ccc(F)c(Cl)c2)cccc1[N+](=O)[O-]

Procedure:
3-(3-Chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1 starting from 3-chloro-4-fluorophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.27 (3H, s), 3.99 (1H, d, J=9.8 Hz), 4.23 (1H, d, J=9.8 Hz), 6.15 (1H, s), 6.92-6.97 (1H, m), 7.17-7.20 (1H, m), 7.29-7.35 (1H, m), 7.41-7.46 (1H, m), 7.66-7.69 (1H, m), 7.72-7.75 (1H, m), 9.72 (1H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=O)[CH3:15].[I-].[Na+].C(=O)(O)[O-].[Na+]>C(O)CCC>[N:17]1[CH:14]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)=[CH:15][CH:18]=1
Reactant: CC(=O)N1CCNCC1
Reactant: NS(=O)(=O)c1ccc(CCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: NS(=O)(=O)c1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reaction time: 66 h
Yield: 69.6 %

Procedure:
A mixture of 4-(2-chloroethyl)benzenesulphonamide (2.00 g), 1-acetylpiperazine (1.17 g), sodium iodide (1.37 g) and sodium bicarbonate (0.84 g) in n-butanol was heated under reflux with stirring for 66 hours. The mixture was cooled slightly and filtered. The filtrate was allowed to stand and the solid that crystallised out was filtered off and recrystallised from ethyl acetate/methanol to give the title compound (1.10 g), m.p. 203°-204.5° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=3)[CH:27]2[CH3:38])[C:20]=1[CH3:39]>CN(C)C=O>[ClH:25].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=3)[CH:27]2[CH3:38])[C:20]=1[CH3:39]
Reactant: Nc1ccc(F)cc1
Reactant: COCc1nc(Cl)nc(N2CCc3cc(OC)ccc3C2C)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(OC)ccc3C2C)c1C
Product: Cl
Yield: 53.1 %

Procedure:
After 4-fluoroaniline(0.32 ml, 3.3 mmol) and triethylamine(0.46 ml, 3.3 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (1.0 g, 2.3 mmol) in dimethylformamide(5 ml), 0.56 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[ClH:33].C(O)C.C(=O)([O-])[O-].[NH4+:41].[NH4+]>ClCCl.CO>[ClH:33].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[NH:41])[NH2:32])=[CH:29][CH:30]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Yield: 33 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]-5-(isoindolin-2-yl-sulfonyl)benzimidazole and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 33% of theory, C24H24N6O2S (460.6); Rf value: 0.32 (silica gel; dichloromethane/methanol=4:1); EKA mass spectrum: (M+H)+=461.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1c[nH]cn1
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(Cn2ccnc2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of imidazole (0.07 g) in dimethylformamide (1.5 ml) was stirred with 60% sodium hydride (0.04 g) at ice-bath temperature under nitrogen until the reaction was complete. The reaction mixture was then treated with a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.27 g) in dimethylformamide (3 ml) and stirred at room temperature for 2 hours. The solution was then diluted with ethyl acetate and washed several times with water. The organic layer was then dried and evaporated under reduced .pressure. The crude reaction product was chromatographed on silica-gel (44 g). Elution with 2% methanoldichloromethane gave 1 -hexyl-3-(1H-imidazol- 1 -ylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone which crystallized as a white solid. That the expected product was obtained was confirmed by the spectral data: MS: m/e 353 (M+); NMR (CDCl3): δ3.90 (s, 3H, OCH3), 5.18 (s, 2H, CH2 -Im), 6.99, 7.14, 7.72 (s, 3H, CH=) wherein Im represents imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[CH2:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:17].CN([CH:21]=[O:22])C>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:21](=[O:22])[C:7]([CH3:6])([CH3:17])[S:8](=[O:9])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=C1CS(=O)(=O)c2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Product: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Reaction time: 1 h

Procedure:
A solution of 6-bromo-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 240; 1.00 g; 3.83 mmol) in anhydrous DMF (4 mL) was treated with sodium hydride (337 mg; 8.43 mmol) and stirred for 1 h. The resulting mixture was treated with iodomethane (715 μl; 11.5 mmol) and stirred for 15 min. The reaction was quenched with water, then partitioned between AcOEt and brine. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated to give a residue which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as an orange oil. Methyl 4-bromo-2-(isopropylsulfonyl)benzoate was also isolated and denominated as Intermediate 242.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].C([Li])CCC.[CH:15](N1CCCCC1)=[O:16]>O1CCCC1.CCCCCC>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:15]=[O:16])=[CH2:5]
Reactant: C=Cc1ccccc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccccc1C=O
Temperature: -65 °C

Procedure:
To a solution of 2-bromostyrene (115 mmol) in dry tetrahydrofuran (200 ml) at -65° C. under nitrogen was added dropwise n-butyllithium (115 mmol) in hexane. The reaction mixture was stirred at -65° C. for an additional hour and a solution of N-formylpiperidine (125 mmol) in tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was cooled to 0° C. and then quenched with saturated ammonium chloride (50 ml). The reaction mixture was extracted with diethyl ether (2×50 ml) and the combined organic phases were washed with 3N hydrochloric acid (2×50 ml), saturated aqueous sodium bicarbonate (50 ml), and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield the Compound 2a which was directly used in the next reaction.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(Cl)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)cc1Cl
Reaction time: 1 h

Procedure:
Concentrated nitric acid (10 ml) in acetic acid (30 ml) was added dropwise to a cooled solution of 3-chlorophenol (10 g) in acetic acid (10 ml). After 1 hour at -5°, the mixture was poured onto ice, extracted with ether, dried over sodium sulfate and evaporated. The residue was then pun fled by column chromatography eluting with hexane-ethyl acetate (85:15) to give the title compound (9 g). M.p. 120°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[CH2:17][C@H:16]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])[CH2:15][CH2:14][C@@H:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br-].[CH2:41]([Zn+])[CH2:42][CH3:43]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([N:18]([CH3:19])[C@@H:16]1[CH2:15][CH2:14][C@H:13]([NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)[C@H:12]([CH2:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:41][CH2:42][CH3:43])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:17]1)([CH3:22])[CH3:21]
Reactant: CCC[Zn+]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N(C)C(C)C)CC[C@@H]2NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
(1S,2R,4R)-N-[2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide, Example 3, was dissolved in THF (1 ml) prior to the addition of propyl zinc bromide (0.32 ml), Pd(PPh3)4 (3 mg). The mixture was stirred under microwave conditions (150° C.) for 5 min. After cooling, the crude reaction was filtered and the filtrate was concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the two fractions, one of which contained the title compound (8 mg). MS found: (M+H)+=594.5
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].O=P(Cl)(Cl)[Cl:15].C([O-])([O-])=O.[Na+].[Na+]>>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[Cl:15][CH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(Cl)nc1C
Product: COC(=O)c1cccnc1CCl
Temperature: 25 °C

Procedure:
Methyl 2-methylpyridine-3-carboxylate 1-oxide (2.93 g, 17.53 mmol) was taken up in POCl3 (17 mL, 182 mmol) and heated to reflux for 3 hours. The mixture was then cooled to room temperature and poured into ice-water. The resulting dark solution was neutralised with solid Na2CO3 and the products extracted into EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (2-30% EtOAc-hexanes) gave methyl 6-chloro-2-methylpyridine-3-carboxylate as a pale yellow oil (A) and methyl 2-(chloromethyl)pyridine-3-carboxylate (B) as an orange oil.
Reaction SMILES: [OH-].[NH4+:2].[Cl-].[NH4+:4].[C-:5]#N.[Na+].[S:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1>>[NH2:2][C:11]1([C:5]#[N:4])[CH2:12][CH2:13][S:8][CH2:9][CH2:10]1
Reactant: [NH4+]
Reactant: O=C1CCSCC1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: N#CC1(N)CCSCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Using the procedure of Stage 1 of Example 1, 8 ml of ammonium hydroxide, 1.58 g of ammonium chloride, 1.23 g of sodium cyanide and 2.51 g of tetrahydro-4H-thiopyran-4-one were reacted and the mixture was stirred for 18 hours at ambient temperature. Extraction was carried out 3 times with methylene chloride, followed by washing with salt water and drying to obtain 2.88 g of the expected product (white crystals) melting at 51-52° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Fe]>[CH3:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1c([N+](=O)[O-])cc(C)c2ncccc12
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(N)cc(C)c2ncccc12

Procedure:
To a solution of 5,8-dimethyl-6nitroquinoline (1.41 g) in ethanol (17.4 mL) under argon is added iron (Fe) (1.21 g) and glacial acetic acid (2.56 g). The mixture is refluxed for two hours. More Fe (1.23 g) and glacial acetic acid (2.49 g) are added to the reaction, which is allowed to reflux for an additional hour. The reaction is poured into a beaker of ice and adjusted to pH 10 by careful addition of a saturated solution of potassium carbonate. The product is extracted with methylene chloride and the organic layer is dried over sodium sulfate, filtered, and rotary evaporated to give 5,8-dimethyl-6-aminoquinoline.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=O)C)([O-:3])=[O:2].Cl.IC>CO>[CH3:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2
Agent: Cl
Solvent: CO
Solvent: CI
Product: CNc1ccc2c(c1[N+](=O)[O-])CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
A mixture of N-(1-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (800 mg, 3.88 mmol) in a 10 M solution of hydrochloric acid in MeOH were heated to reflux for 4 h. After concentration, the residue was basified with 2 N aqueous solution of NaOH to pH 9, then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (30 mL), dried, and concentrated. The residue was dissolved in DMF (20 mL), cooled to 0° C., and NaH (60% dispersion in mineral oil, 0.155 mg, 3.88 mml) was added in one portion. Iodomethane (582 mg, 3.88 mmol) was added dropwise. The resulting mixture was stirred at the same temperature for another 2 h. The reaction mixture was quenched by ice (20 g) and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (20 mL), dried, and concentrated to give a yellow solid (190 mg). ESI MS: m/z 207 [M+H]+.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccncc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccncc2)cc([N+](=O)[O-])c1O
Temperature: 79 °C
Yield: 36.5 %

Procedure:
A mixture of 1-phenyl-2-(pyridin-4-yl)ethanone (Intermediate 36) (100 mg, 0.507 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (107 mg, 0.507 mmol), urea (91.3 mg, 4.587 mmol), and concentrated hydrochloric acid (0.3 mL) in ethanol (1 mL) was refluxed at 79° C. for 80 h. After being cooled down to room temperature, the mixture was evaporated, and purified by preparative HPLC to give Compound 74 (80.1 mg, yield 38.3%). 1H NMR (DMSO-d6 400 MHz): δ 10.41 (s, 1H), 9.57 (s, 1H), 8.34 (d, J=6.4 Hz, 2H), 8.02 (s, 1H), 7.50-7.42 (m, 4H), 7.39 (d, J=7.2 Hz, 2H), 7.34 (d, J=1.6 Hz, 1H), 7.06 (d, J=6.4 Hz, 2H), 5.39 (d, J=3.2 Hz, 1H), 4.15-4.10 (m, 2H), 1.38-1.35 (m, 3H); MS (ESI): m/z 433.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1cccc(Cl)c1
Product: Cc1c2n(c3c(-c4cccc(Cl)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (59 mg, 72%), MS (ISP) m/z=329.4 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.[CH:42]([N-]C(C)C)(C)[CH3:43].[Li+].ICC>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:37]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:42][CH3:43])[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C(=O)O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid (70 mg, 0.12 mmol) in dry THF (50 mL) was added lithium diisopropylamide (0.17 mL, 0.35 mmol) dropwise with cooling to −78° C. After the reaction mixture was stirred at −78° C. for an additional 1 h, iodoethane (40 μl) was added. The reaction was warmed to RT over 4 h followed by quenching with saturated ammonium chloride (10 mL). Solvent was removed and the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (37 mg, 50%). MS m/e 609.2 (M+H)+.