Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18]C)=[O:17])[C:6]2=[O:20].C(OC([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=O)(C)(C)C.C([O-])(O)=O.[Na+].CN(C=O)C>C(#N)C.C(OCC)(=O)C>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:3]=[CH:4]3)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(N2CCNCC2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (200 mg, 0.69 mmol), N-(tert-butoxycarbonyl)-piperazine (256 mg, 1.38 mmol) and NaHCO3 (259 mg, 14.64 mmol) in ACN (8.6 mL) was heated in a microwave at 120° C. for 20 min. DMF (2 mL) was added to the mixture and the reaction was heated in a microwave at 120° C. for 20 min. Then the reaction was heated in a microwave at 130° C. for 30 min twice. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (30 mL). After extraction of the aqueous phase with ethyl acetate (2×30 mL), the organic phases were combined washed with brine, dried with magnesium sulfate, filtrated, and concentrated. The residue was dissolved in TFA (1 mL) and agitated for 1 hour prior to evaporation of the solvent. The residue was dissolved in THF (1 mL) and an aqueous 4M NaOH solution (0.79 mL) and heated in a microwave at 120° C. for 10 min. More aqueous 4M NaOH solution (0.5 mL) was added and the reaction was heated in a microwave at 120° C. for 10 min. The mixture was evaporated and the residue purified by preparative HPLC. The title compound EXAMPLE 34 was obtained after lyophilization (28 mg, 12.5%). High-Res MS: calculated 328.1656 (M+H)+. found 328.1642 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[NH:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccc2)oc2c(N)cccc2c1=O
Reactant: O=C=NCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(NC(=O)NCCCl)cccc2c1=O
Reaction time: 5 h

Procedure:
4 ml of 2-chloroethylisocyanate were added, under stirring at ambient temperature, to a solution of 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 52 ml of anhydrous dimethylformamide. Stirring was continued at 70° C. for 5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was evaporated to dryness in vacuo. The residue was suspended in diethyl ether under stirring. The title product was then filtered off and recrystallized from methanol. Yield 3.74 g, m.p. 213°-214° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O)([O-])=O>C(O)C>[C:1]([N:5]1[CH:11]=[C:10]2[C:9]([CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)n1cc2ccc([N+](=O)[O-])cc2n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Tert-butylamine (2 mL) was added to a solution of 2,4-dinitrobenzaldehyde (1.96 g) in ethanol (10 mL), and the reaction solution was stirred at 40° C. for 30 minutes. The solvent was evaporated under vacuum, then tert-butylamine (1 mL) was added to the resultant residue, and the reaction solution was heated at 50° C. for 30 minutes. The solvent was evaporated under vacuum, then trimethyl phosphite (6 mL) was added, and the reaction solution was stirred at 110° C. for 1 hour. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate). Thereafter, isopropyl ether was added to the resultant residue, and the precipitate was filtrated to obtain 2-(tert-butyl)-6-nitro-2H-indazole as a white solid.
Reaction SMILES: O=[C:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Ni].C(O)C.O>[CH2:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1Cn2c(cc3ccccc32)C1=O
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1Cc2cc3ccccc3n2C1
Reaction time: 5.5 h
Yield: 13.3 %

Procedure:
6 spoon spatula measures of Raney nickel were added to a solution of 5.08 g of ethyl 2,3-dihydro-1-oxo-1H-pyrrolo[1,2-a]indole-2-carboxylate in 180 ml of ethanol and 90 ml of water. The mixture was heated to reflux for 10 hours. Then, an additional 3 spoon spatula measures of Raney nickel were added. Heating was continued for 5.5 hours, whereupon the mixture was cooled and filtered. The filter residue was washed with ethyl acetate and dichloromethane. The combined filtrate and washings were evaporated and the residue was purified by chromatography on silica gel with diethyl ether/petroleum ether (1:2). Crystallization from methanol gave 635 mg of ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate of melting point 55°-57° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[Cu]I>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C
Reaction time: 40 h

Procedure:
Under N2, the mixture of 3-hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol), 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), CuI (Strem Chemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol) in toluene (anhydrous, Aldrich, 50 mL) was stirred at 110° C. for 40 h. After the reaction went to completion, the reaction mixture was diluted with chloroform (100 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCl/NH3) m/z 330 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[CH:12]=[C:13]([F:14])[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:14][C:13]1[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:12]=1
Reactant: Cc1ccccc1-c1cc(F)c2c(c1)CC(CN=[N+]=[N-])O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccccc1-c1cc(F)c2c(c1)CC(CN)O2
Yield: 22 %

Procedure:
Treatment of 4-bromo-2-fluorophenol (25.0 g, 130.9 mmol) with potassium carbonate (72.35 g, 523.53 mmol) and allyl bromide (19.00 g, 157.06 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-4-bromo-6-fluorophenol. Treatment of 2-allyl-4-bromo-6-fluorophenol (25.6 g, 110.8 mmol) with 3-chloroperoxybenzoic acid (57.36 g, 332.38 mmol, 77%) followed by potassium carbonate (38.28 g, 277.0 mmol) generally according to the procedure described for Intermediate 9 afforded 19.1 g (70%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (18.61 g, 75.3 mmol) with p-toluenesulfonyl chloride (17.22 g, 90.34 mmol) generally according to the procedure described for Intermediate 10 gave 22.6 g (75%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.25 mmol) and 2-methylphenylboronic acid (0.254 g, 1.87 mmol) generally according to the procedure described for Intermediate 35 afforded 0.282 g, (55%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (99%) of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.30 g, 3.0 mmol) according to the procedure described in Example 154 afforded 0.038 g (22%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]amine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[CH:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1>[Pd].CN(C=O)C>[NH:12]1[CH2:11][CH2:10][CH:9]([N:3]2[CH2:4][CH2:5][C:6](=[O:8])[NH:7][C:2]2=[O:1])[CH2:14][CH2:13]1
Reactant: O=C1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1CCN(C2CCNCC2)C(=O)N1
Yield: 102.7 %

Procedure:
A solution of benzyl 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)piperidin-1-carboxylate (0.18 g) obtained in Example 45d) and 20% palladium on carbon (containing 60% water, 36 mg) in DMF (10 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.11 g, quantitative) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=4)[N:13]=[C:12]([OH:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1>Br>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=4)[N:13]=[C:12]([OH:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1OC
Agent: Br
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)c(O)c3)c(=O)c12
Yield: 67.8 %

Procedure:
7-Chloro-4-hydroxy-2-(3,4-dimethoxyphenyl)-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (1.00 g, 2.50 ml) was refluxed in 48% HBr (40 mL) for 6 hours to give an orange suspension. Heat was removed and the suspension was filtered while still warm. The collected solids were washed with water and then ether to give the crude product (0.94 g) as a yellow powder. This material was recrystallized from refluxing methanol (600 mL) to give the title compound (0.63 g, 68%) as a yellow powder, mp=269-272 C; MS(CI): 372 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([O:20]C)=[O:19])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2ccc(C)nc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2cc(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of methyl N-((7-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetyl)-N-(2-tert-butyloxycarbonylaminoethyl)glycinate (0.775 g, 1.79 mmol) in THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was added LiOH (2M, aqueous) (2.0 mL). The resulting solution was stirred at rt for 30 min, additional water was added, and the THF removed in vacuo. The pH of the aqueous solution was adjusted to pH 3.0 and the precipitate collected, and washed (2×10 mL) by filtration, to yield the desired product (424 mg, 56%) as a colorless precipitate (mp 94-95° C.). 1H NMR (DMSO-d6; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.05 (s br, 1H), 7.90 (7.96) (d, 7.9 Hz, 1H), 7.78 (7.71) (s, 1H), 7.11 (d, 7.9 Hz, 1H), 6.90 (6,73) (m, 1H), 3.97 (4.23) (s, 2H), 3.59 (s, 2H), 3.44 (s, 3H), 3.04 (3.15) (m, 2H), 1.37 (1.36) (s, 9H). 13C NMR (DMSO-d6): δ 170.94 (171.22), 170.00 (170.16), 162.6, 159.1, 155.7, 148.8, 136.30 (136.57), 135.90 (136.09), 128.28 (128.62), 118.12, 111.96 (112.00), 77.9, 48.08 (48.29), 47.5, 38.39 (38.05), 33.44 (33.66), 28.3, 24.2. FAB+ HRMS (m/z): 417.1794, calc. C20H25N4O6 417.1774.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][Mg]Br>C1COCC1.C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]([OH:26])[CH3:31])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of 399 g (899 mmol) of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 151, Step B) in THF (9 L) was added 1.93 L (2.70 mol) of a 1.4 M solution of methylmagnesium bromide 75:25 in toluene/tetrahydrofuran slowly over a 30 min period so as to maintain an internal reaction temperature below 6° C. The yellow solution was warmed to room temperature and stirred for 1.5 h. At this time the reaction was cooled to 0° C. and quenched by cautious, slow addition of saturated aqueous ammonium chloride (4.6 L) so as to maintain an internal reaction temperature below 15° C. The mixture was warmed to room temperature, ethyl acetate was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (1×) and then saturated aqueous sodium chloride (1×), dried over Na2SO4, filtered and the filtrate was concentrated to afford a yellow oil. Purification of the residue by chromatography on silica (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5% acetone/5% EtOAc/90% hexanes grading to 5% acetone/29% EtOAc/66% hexanes) provided the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12].C1OC(C2C=CSC=2)OC1.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C(=O)(O)[O-].[Na+]>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][S:11]([C:7]1[S:8][CH:9]=[CH:10][C:6]=1[CH:2]1[O:3][CH2:4][CH2:5][O:1]1)(=[O:13])=[O:12])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CNS(=O)(=O)c1sccc1C1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride, prepared from thiophene-3-carboxaldehyde ethylene acetal (13.27 g, 85.1 mmol) as described in Example 6, Step A, was combined with glycine ethyl ester hydrochloride (33.99 g, 221 mmol) and a saturated aqueous solution of sodium bicarbonate (250 mL). After stirring for 18 hr at ambient temperature, the organic layer was separated, dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate/hexane) to give an oil (16.55 g, 61%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[C:10]3[C:15]([N:16]=[C:17]4[C:22]=2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+]>C1COCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:10]3[C:15]([N:16]=[C:17]4[C:22]=2[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:24][CH:25]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccc(C(F)(F)F)cc3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccc(C(F)(F)F)cc3)c21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
In 100 ml of dry THF dissolved 2.49 g of 3,4-dihydro-9-(4-trifluoromethylbenzylamino)acridin-1(2H)-one. The mechanically stirred solution was cooled under nitrogen to 10° C. and 3.4 ml of 1M LiAlH4 in THF was added dropwise over 10 minutes. After 1/2 hour of stirring, the reaction was complete. It was neutralized with 1 ml of saturated ammonium chloride solution and the resulting salts were filtered. The filtrate was evaporated to a solid which was recrystallized from 1:1 dichloromethane/pentane to yield 1.91 g of solid, mp 174°-176° C.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]([F:51])([F:50])[F:49])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]([F:50])([F:49])[F:51])[CH:42]=2)[CH:29]=1
Reactant: FC(F)(F)Oc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCO
Product: O=c1[nH]nc(CCc2cccc(OC(F)(F)F)c2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((3(trifluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 39) except that the solvent used for the hydrogenation was ethanol and the final compound was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[CH3:15][C:16]([S@@:19](/[N:21]=[C:22]1\[CH2:23][CH2:24][O:25][C:26]2[C:27]\1=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:20])([CH3:18])[CH3:17]>CC1OCCC1>[CH3:18][C:16]([S@@:19]([NH:21][C@@:22]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[O:25][CH2:24][CH2:23]1)=[O:20])([CH3:15])[CH3:17]
Reactant: CC(C)(C)[S@](=O)/N=C1\CCOc2cccnc21
Reactant: Brc1ccc2ccccc2c1
Agent: II
Agent: [Mg]
Solvent: CC1CCCO1
Product: CC(C)(C)[S@](=O)N[C@]1(c2ccc3ccccc3c2)CCOc2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of magnesium turnings (0.083 mL, 5.80 mmol) and iodine (10 mg) in 2-MeTHF (6 mL) under N2 at room temperature was slowly added a solution of 2-bromonaphthalene (1.0 g, 4.83 mmol) in 2-MeTHF (4 mL). After addition, the mixture was stirred at room temperature for 18 h. The mixture was cooled to −78° C., and a solution of (S,E)-2-methyl-N-(2H-pyrano[3,2-b]pyridin-4(3H)-ylidene)propane-2-sulfinamide (0.490 g, 1.942 mmol) in 2-MeTHF (3 mL) was added dropwise. The mixture was then stirred at −78° C. for 1 h and at room temperature for 5 h. The mixture was quenched with saturated NH4Cl (1.5 mL). The mixture was then extracted with EtOAc (2×5 mL). The combined organic extracts were dried over MgSO4, concentrated, and purified by silica gel column chromatography using ISCO (30-60% EtOAc/hexanes) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 381.0 (M+H)
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[Cl:16][CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=O>>[Cl:16][CH2:17][CH2:18][N:20]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CCl
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: NS(=O)(=O)c1ccc2c(c1)CCN2CCCl
Yield: 78.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-(2-chloroacetyl)indoline-5-sulfonamide (Intermediate 75A, 400 mg, 1.46 mmol) was converted to the title compound (300 mg, 79%). 1H NMR (DMSO-d6) δ 7.45 (dd, J=8.3, 1.9 Hz, 1H), 7.41 (br s, 1H), 6.91 (s, 2H), 6.56 (d, J=8.4 Hz, 1H), 3.83-3.80 (m, 2H), 3.60-3.51 (m, 4H), 2.99 (t, J=8.7 Hz, 2H); MS(ESI+) m/z 261.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]([C@@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:10][CH3:11])=[N:8][C:4]=2[CH:3]=1.[Br-].[CH2:23]([Zn+])[C:24]([CH3:27])([CH3:26])[CH3:25].O1CCCC1.FC(F)(F)C(O)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]([C@@H:9]([NH2:12])[CH2:10][CH3:11])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)C[Zn+]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2cc(CC(C)(C)C)ccc2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
Argon was bubbled through a mixture of (S)-tert-butyl (1-(5-bromo-1H-benzo[d]imidazol-2-yl)propyl)carbamate (Preparation 18, 150 mg, 0.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48.2 mg, 0.0659 mmol), and neopentylzinc bromide in tetrahydrofuran (0.5 M, 2.5 mL, 1.3 mmol) for 5 minutes. The mixture was then heated under microwave irradiation for 10 minutes at 140° C. After cooling, the reaction was concentrated in vacuo, redissolved in dichloromethane (9 mL) and treated with trifluoroacetic acid (1 mL, 13 mmol). After stirring for 2.5 hours, the reaction was concentrated in vacuo and redissolved in a saturated solution of hydrogen chloride in methanol and stirred for 18 hours. The fully deprotected product was concentrated in vacuo and purified by preparative HPLC followed by silica gel column chromatography eluting with 0-50% CMA80/methylene chloride to afford the title compound (10 mg, 15%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccc(O)cc1C
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(OCCCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,4-Dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. 75 ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol) was added to the solution. The mixture was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered off. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 h, monitored with HPLC. It was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. It was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after being kept in water at room temperature over night.