Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[CH:60]=[C:59]([CH3:61])[C:57](=[O:58])[NH:56][C:54]1=[O:55])[O:30]2)[CH2:32][O:33][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[CH:60]=[C:59]([CH3:61])[C:57](=[O:58])[NH:56][C:54]1=[O:55])[O:30]2)[CH2:32][OH:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cn([C@@H]2O[C@@]3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.9 %

Procedure:
In a stream of nitrogen, tetrabutylammonium fluoride (1.0 M in THF, 379 μl, 0.379 μmol) was added to a tetrahydrofuran solution (1 ml) of Compound 37 (188.7 mg, 0.316 mmol), and the mixture was stirred for 2.5 hours at room temperature. The reaction mixture was distilled under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (AcOEt-hexane, 1:1→1:0) to obtain a white powder, Compound 38 (94.6 mg, 0.262 mmol, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15](I)=[CH:16][C:9]=23)[CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15]([C:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of Example 87B (1.600 g, 3.15 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.071 g, 3.46 mmol), tetrakistriphenylphosphine palladium (0.182 g, 0.157 mmol), and aqueous sodium bicarbonate solution (15 mL) in N,N-dimethylformamide (60 mL) was degassed with nitrogen and heated at 80° C. for 3 hours. After cooling, the mixture was quenched with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion flash system eluting with heptane/ethyl acetate (65:35 to 5:5) to afford the title compound. MS (ESI+) m/z 564.1 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:27])[N:30]([O:31][CH3:32])[CH3:29])[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Add 1,1′-carbonyldiimidazole (414.33 g, 2.56 mol) portion wise to a stirred solution of (S)-N-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (500 g, 2.32 mol) in dichloromethane (5.81 L) and stir at room temperature under nitrogen for 1 hour. Add N,O-di-methylhydroxylamine hydrochloride (253.04 g, 2.56 mol) and stir at room temperature for 48 hours. Quench the reaction with 1N HCl, and extract with ethyl acetate (2×). Wash the combined organics with saturated NaHCO3 and brine. Dry (MgSO4), filter and concentrate under reduced pressure to provide 535 g (89%) of the title compound. MS (m/z)=203 (M−55).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[CH:36][CH:35]=2)=[N:4]1)[CH3:2].NC1C=CC=CC=1.NO.[OH-].[Na+]>CO.[OH-].[OH-].[Pd+2]>[NH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][C:15]([C:17]5[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=5)=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:39][CH:38]=1
Reactant: CCn1cc(-c2ccnc3c2cc(-c2cccc(CO)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd+2]
Agent: NO
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CO
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CO)c4)cc23)c(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To {3-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanol (26.90 g, 46.4 mMol) in MeOH (400 mL) was added 20% Pd(OH)2/C (Pearlman's catalyst) (˜3.0 g). Two balloons of H2 were attached and the reaction stirred overnight at RT. (LCMS of the reaction mixture showed 31% of the desired aniline (M+H)+=550.3, 50% of the hydroxylamine intermediate (M+H)+=566.2 and 20% of the starting material and nitroso intermediate (M+H)+=580.4 and 564.1.) Another 3.0 g of the Pearlman's catalyst was added and the reaction stirred under H2 for an additional 24 h. (LCMS showed that the reaction had gone to >90% complete. The same reaction was later shown to go to completion, under 50 psi H2, in the Parr reactor overnight at RT.) The reaction was filtered through a pad of Celite®, rinsed with MeOH and concentrated under vacuum. The remaining residue was taken up in MeOH (300 mL) and treated with aq. 6 N NaOH (25 mL, 150 mMol). The reaction was stirred and heated at 70° C. for 8 h, cooled to RT and concentrated to near dryness under vacuum. The slurry was triturated with cold water, filtered, washed with cold water, and dried under vacuum. Purification by flash chromatography on silica gel (5 to 15% MeOH/CHCl3) (product slow to dissolve on the column) gave the title compound (16.19 g, 85%) as a yellow solid: MS (ES) m/e 410.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.11 (d, J=1.8 Hz, 1H), 8.21 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 6.81 (d, J=2.3 Hz, 1H), 6.80 (d, J=5.1 Hz, 1H), 6.49 (d, J=8.6 Hz, 2H), 5.27 (t, J=5.8 Hz, 1H), 5.14 (s, 2H), 4.56 (d, J=5.8 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([O:13][CH3:14])[C:10](Cl)=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:27](=[O:28])[CH2:26][NH:25][C:24]2=[O:29])[CH:19]=[C:20]([Cl:22])[CH:21]=1>O1CCCC1>[CH3:14][O:13][N:9]([CH3:8])[C:10]([N:25]1[CH2:26][C:27](=[O:28])[N:23]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[C:20]([Cl:22])[CH:19]=2)[C:24]1=[O:29])=[O:11]
Reactant: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: CON(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 20 °C

Procedure:
At about 20° C, 10.5 parts of triethylamine and subsequently 12.4 parts of methylmethoxycarbamoyl chloride are added to a suspension of 24.5 parts of 3-(3,5-dichlorophenyl)-hydantoin in 250 parts of dry tetrahydrofuran. After all has been added, the mixture is refluxed for 3 hours. After the mixture has been cooled to 20° C, the precipitated triethylamine hydrochloride is removed by suction filtration. The filtrate is concentrated. The residue is dissolved in a 1:1 mixture of n-pentane and ether, suction filtered, dried and recrystallized from toluene.
Reaction SMILES: [C:1]([Si:5]([CH3:45])([CH3:44])[O:6][C:7]1[CH:8]=[C:9]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:10]2[CH2:21][S:20][CH2:19][C@@H:18]([CH2:22]O)[NH:17][C:16](=[O:24])[C@@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][O:13][C:12](=[O:33])[C:11]=2[C:34]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:47][CH2:22][C@@H:18]1[NH:17][C:16](=[O:24])[C@@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:14][O:13][C:12](=[O:33])[C:11]2[C:34]([CH3:35])=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:45])[CH3:44])[CH:8]=[C:9]([O:36][Si:37]([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39])[C:10]=2[CH2:21][S:20][CH2:19]1
Reactant: Cc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)CSC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CBr)CSC2
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 103 mg of tert-butyl (4R, 7S)-12, 14-bis (tertbutyldimethylsilyloxy)-1,3,4,5,6,7,8, 10-octahydro-4-hydroxymethyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate in 2 ml of methylene chloride was treated with 99 mg of carbontetrabromide and 79 mg of triphenylphosphine, and then stirred at 20° C. for 15 minutes. The solution was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield tert-butyl (4R, 7S)-4-bromomethyl-12,14-bis-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzooxathiaazacyclododecine-7-carbamate. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/hexane, tert-butyl (4R, 7S)-4-bromomethyl- 1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.C(N(CC)[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O1CCCC1.C1CCCCC1>[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[O:34]2)=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCN(CC)C(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)c1ccc(C2OC(=O)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of 1.28 g of N,N,N',N'-tetramethylethylene-diamine in 25 ml of tetrahydrofuran was added 10.5 ml of 1.05 M cyclohexane solution of sec-butyl lithium under a nitrogen gas atmosphere, and a solution of 1.77 g of N,N-diethylbenzamide in 15 ml of tetrahydrofuran was added to the solution at -78° C. After stirring for 10 minutes at -78° C., a solution of 2.24 g of 4-dimethylaminobenzaldehyde in 10 ml of tetrahydrofuran was added to the mixture. After stirring at -78° C. for 1.5 hours, the temperature was gradually elevated to 5° C. and the reaction mixture was concentrated under reduced pressure. To the residue were added 50 ml of water and 50 ml of ethyl ether, and pH of the mixture was adjusted to 0.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 50 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The crude product obtained was subjested to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=50:50:5). A fraction eluted secondly was concentrated under reduced pressure and the concentrate was tritylated with methyl alcohol to give 0.54 g of 3-(4-dimethylaminophenyl)-1,3-dihydro-isobenzofuran-1-one (Compound A).
Reaction SMILES: CC1[N:3]=[C:4]2[C:9]([CH3:10])=[C:8]([C:11]3[O:12][C:13]([N+]([O-])=O)=[CH:14][CH:15]=3)[N:7]=[C:6]([NH2:19])[N:5]2N=1.C([NH:24]C1NC(=O)C(C)=C(C2OC=CC=2)N=1)(=O)C.O.NN>>[NH2:19][C:6]1[N:7]=[C:8]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:9]([CH3:10])=[C:4]([NH:3][NH2:24])[N:5]=1
Reactant: CC(=O)Nc1nc(-c2ccco2)c(C)c(=O)[nH]1
Reactant: Cc1nc2c(C)c(-c3ccc([N+](=O)[O-])o3)nc(N)n2n1
Agent: NN
Solvent: O
Product: Cc1c(NN)nc(N)nc1-c1ccco1

Procedure:
1-methyl-2-[2,8-dimethyl-7-(5-nitro-2-furyl)-s-triazolo[2,3-c]pyrimidinyl-5-]-imino-pyrrolidine (m.p. 244° - 246°C.) from the N-methyl-pyrrolidone-(2)-phosphorus oxychloride adduct and 2,8-dimethyl-5-amino-7-(5-nitro-2-furyl)-s-triazolo[2,3-c]pyrimidine; the latter compound (m.p. 290° - 295°C.) used as starting material was obtained by chlorinating 2-acetamido-4-(2-furyl)-5-methyl-6(1H)-pyrimidinone and the intermediate obtained (m.p. 155° - 160°C.) reacted with hydrazine hydrate to give 2-amino-4-(2-furyl)-6-hydrazino-5-methyl-pyrimidine (m.p. 220° - 222°C.) which was cyclised with orthoacetic acid triethyl ester, the intermediate obtained then nitrated to give 5-amino3,8-dimethyl-7-(5-nitro-2-furyl)-s-triazolo[4,3-c]pyrimidine (m.p. 290°C.; decomp.) which was heated in ethanol saturated with hydrogen chloride;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
A mixture of 10 g (35 mmol) of 4-chloro-2-(4-chlorophenyl)-6-methylquinoline, 8.9 g (70 mmol) of isonipecotamide, and 20 g of phenol was stirred and heated in an oil bath at 165°-170° for 3.5 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 11.9 g of crude product. Recrystallization from pyridine gave the named compound as off-white prisms, mp 261°-265° dec.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.[O-:13]CC.[Na+]>C1(C)C=CC=CC=1>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:13])[N:3]=1)[CH3:10]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Reactant: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml, three necked, flask equipped with an agitator and a condensor were added 3.0 g (0.014 mol) of 2-hydroxy-2-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 50 ml of toluene and 0.95 g (0.014 mol) of sodium ethoxide. The resulting solution was stirred at room temperature for 30 minutes. A 1 ml sample of the reaction mixture was then removed from the flask and diluted according to the procedure described in Example 4. The HPLC assay set forth in Example 3 indicated that 6.6% of the thiazoline substrate had converted to the desired titled compound.
Reaction SMILES: N1C=CC=CC=1C([O-])=O.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[N:20][C:21]([C:24]([O:26][CH2:27]C)=[O:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH3:11]>OS(O)(=O)=O.CO>[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:20][C:19]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:16][CH:17]=1)[CH3:11]
Reactant: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccccn2)n1
Agent: O=C([O-])c1ccccn1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1ccc(-c2ccc(C(=O)OC)nc2-c2ccccn2)cc1

Procedure:
Following General Procedure E, ethyl 5-(4-ethylphenyl)-6-(pyridine-2-yl)phenyl)pyridine-2-carboxylate (Compound 50, 16 mg, 0.05 mmol) and conc. H2SO4 (10 drops) in methanol were reacted to produce the title compound as a light yellow solid.
Reaction SMILES: C(OP([O:9][CH2:10][CH3:11])(OCC)=O)C.[CH:12]1[CH2:19][CH2:18]C=[CH:16][CH2:15][CH2:14][CH:13]=1>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2].C1C=CC=CC=1>[OH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:19][CH2:18]1
Reactant: C1=CCCC=CCC1
Reactant: CCOP(=O)(OCC)OCC
Agent: [Co+2]
Agent: CCCCC(CC)C(=O)[O-]
Solvent: c1ccccc1
Product: OCC1CCCCCCC1
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 8 millimols of cobalt 2-ethylhexoate and 20 millimols of triethylphosphate in 200 ml. of benzene was treated in an autoclave with 1:1 H2 :CO mixture for one hour at 170° C. and 3,700-114 3,750 psig. The autoclave was cooled and vented, and 250 g. of 1,5-cyclooctadiene was added. This mixture was treated with 1:1 H2 :CO at 145°-185° C. and 1,800-3,000 psig. for 3 hours. Distillation of the reactor effluent gave 203 g. of hydroformylation products boiling at 36°-75° C. at 5 mm. Hg pressure and 79 g. of residue. Reduction of a portion of the distilled oxygenated products over a nickel-based catalyst with hydrogen at elevated temperatures and pressures gave a 90% yield of hydroxymethylcyclooctane.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:35])[C:21](=[O:34])[N:22]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.O1C2C=CC(O)=CC=2OC1.[O:46]1[C:50]2[CH:51]=[C:52]([OH:55])[CH:53]=[CH:54][C:49]=2[CH2:48][CH2:47]1>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([OH:35])([C:53]1[C:52]([OH:55])=[CH:51][C:50]3[O:46][CH2:47][CH2:48][C:49]=3[CH:54]=1)[C:21](=[O:34])[N:22]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(Cc2ccccn2)c2cccc(Br)c21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 4-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (91%) as a colorless solid: mp >225° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.54 (d, 1H), 7.70 (dt, 1H), 7.61 (br, 1H), 7.32-7.26 (m, 2H), 7.07 (d, 1H), 7.00 (d, 1H), 6.72 (d, 1H), 6.60 (br, 1H), 6.02 (s, 1H), 4.91 (ABq, 2H), 4.47 (t, 2H), 3.06 (d, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 160.4, 156.3, 153.8, 149.6, 146.1, 137.5, 130.9, 130.8, 126.5, 125.8, 123.1, 121.5, 118.8, 117.3, 116.4, 108.3, 96.7, 76.6, 71.9, 45.7, 29.1; MS (ES+) m/z 455.4 (M+1), 437.4 (M−17).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:21][C:22]1[C:23]([F:40])=[CH:24][C:25]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:26]=2[CH:27]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:21][C:22]1[C:23]([F:40])=[CH:24][C:25]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=4)[C:29]3=[O:37])[C:26]=2[CH:27]=1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: Br
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, 5,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (29%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=4.1 Hz, 1H), 7.71 (ddd, J=9.4, 7.7, 1.7 Hz, 1H), 7.31-7.22 (m, 3H), 7.15 (dd, J=7.4, 0.9 Hz, 1H), 7.05 (ddd, J=8.4, 7.5, 0.9 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.79 (dd, J=10.3, 6.3 Hz, 1H), 6.66 (dd, J=9.2, 7.9 Hz, 1H), 5.23 (d, J=15.9 Hz, 1H), 5.06-4.96 (m, 2H), 4.77 (d, J=9.1 Hz, 1H); MS (ES+) m/z 365.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[C:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccccc1CCN
Product: Cc1ccccc1CCNC(=O)C(C)(C)C

Procedure:
1-Amino-2-(2-methylphenyl)ethane and pivaloyl chloride were reacted in the same way as in step (a) of Example 1 to afford 1-pivaloylamino-2-(2-methylphenyl)-ethane. The product was successively reacted in the same way as in steps (b), (c), (d) and (e) of Example 1 to afford 1-tert-butylsioquinoline-5-acetonitrile.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH2:32]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:32]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[CH2:16][CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCN(C4CCOCC4)CC3)n(C)c2n1
Temperature: 120 °C
Yield: 71.5 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-{2-[4-(tetrahydropyran-4-yl)piperazin-1-yl]ethyl}-9H-purine (37 mg, 0.08 mmol), 2-ethylbenzimidazole (13 mg, 0.09 mmol), Pd2(dba)3 (1.9 mg, 2.5 mol %), Xphos (3.9 mg, 10 mol %) and Cs2CO3 (37 mg, 0.11 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 557 (32 mg, 70%) as a pale beige solid. LCMS: (Method I): RT 2.42 min; [M+H]+ 560.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.97 (m, 1 H), 7.77-7.72 (m, 1 H), 7.29-7.22 (m, 2 H), 4.56-4.21 (m, 4 H), 4.04 (dd, J=11.4, 4.2 Hz, 2 H), 3.86 (t, J=4.7 Hz, 4 H), 3.77 (s, 3 H), 3.38-3.34 (m, 2 H), 3.34 (q, J=7.5 Hz, 2 H), 3.13-3.00 (m, 2 H), 3.00-2.87 (m, 2 H), 2.82-2.58 (m, 6 H), 2.57-2.42 (m, 1 H), 1.88-1.75 (m, 2 H), 1.71-1.55 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H)