Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:22][C:19]3[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(-c2cccnc2F)ccn1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1

Procedure:
To a 25 mL round bottomed flask was added 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (0.7204 g, 3.828 mmol), 4-aminophenol (0.4254 g, 3.832 mmol), and cesium carbonate (1.6144 g, 4.593 mmol) in dimethyl sulfoxide at 90° C. Upon completion, the reaction was filtered through Celite™ and the filtrate was condensed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The organic extract was washed with water (3×15 mL), brine (3×15 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH2:6][C:5](=O)[C:4]=1[CH3:9])[CH3:2].C[Li].C([O:14][CH2:15][CH3:16])C.BrCBr.C([Mg]Cl)(C)(C)C>O>[CH2:7]([C@:3]12[CH2:9][C@@:4]1([CH3:5])[C:15]([CH3:16])([OH:14])[CH2:2][CH2:1]2)[CH3:6]
Reactant: CCOCC
Reactant: CCC1=C(C)C(=O)CC1
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]C
Solvent: BrCBr
Solvent: O
Product: CC[C@@]12CCC(C)(O)[C@]1(C)C2
Reaction time: 18 h

Procedure:
Prepared as described in Example 20 (System B) from 3-ethyl-2-methylcyclopent-2-enone (4 g, 32 mmol) (G. Berube, A. G. Fallix, Can. J. Chem. 69, 77-78, 1991), addition of methyl-lithium 1.6 M in diethyl ether (28 ml, 45 mmol) at −20° C., dibromomethane (2×8.4 g, 97 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (2×24 ml, 97 mmol). Work-up after 18 h at 25° C. (as described in example 1) and bulb-to-bulb distillation gives 3 g (60%) of a waxy yellowish solid. 1H NMR (CDCl3): δ-0.1 (d, 1H), 0.75 (d, 1H), 0.95 (t, 3H), 1.1 (s, 3H), 1.25 (s, 1H), 1.2-1.3 (1H), 1.3-1.4 (2H), 1.5-1.6 (2H), 1.7 (1H) ppm. 13C-NMR (CDCl3): δ 11.4 (q), 12.7 (q), 18.4 (t), 24.9 (q), 25.8 (t), 28.5 (t), 32.35 (s), 34.6 (s), 36.5 (t), 81.3 (s). Cis-configuration determined by NMR-analysis in water-free DMSO. MS (EI): m/z (%) 154 (M+, 1), 139 ([M-15]+, 38), 136 ([M-18]+, 67), 125 (37), 121 (27), 107 (86), 96 (59), 81 (100), 67 (30), 57 (42), 55 (36), 43 (86), 41 (40). IR (film): 3297 (br, OH), 2959 (s), 2859 (m), 1452 (s), 1365 (s), 1300 (m), 1199 (s), 1167 (m), 1115 (vs), 1062 (m), 970 (s), 938 (s), 926 (s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]([CH3:28])=[N:26][C:25]([NH2:29])=[N:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]([CH3:28])=[N:26][C:25]([NH:29][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:24]2)=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1nc(N)nn1-c1ccc(F)cc1
Product: Cc1cn(-c2ccc(Nc3nc(C)n(-c4ccc(F)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-fluoro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamine (prepared in analogy to Gazzetta Chimica Italiana 29, 105 (1899)). The title compound was obtained as a slightly brownish solid (Yield=24%). MS ISP (m/e): 374.1 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1.ClC1C=CC(CCl)=CN=1.[C:19]1(=[O:29])N[C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[OH-].[K+]>C(O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])=[CH:4][N:3]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: ClCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1

Procedure:
It is known that 2-chloro-5-aminomethyl-pyridine, an intermediate for the preparation of insecticides, is obtained when, in a first step, 2-chloro-5-chloromethyl-pyridine is reacted with phthalimide in the presence of potassium hydroxide, dimethylformamide and ethanol to give N-(2-chloro-pyridin-5-yl-methyl)-phthalimide and, in a second step, the desired 2-chloro-5-aminomethyl-pyridine is liberated from this using hydrazine hydrate in ethanol (cf. EP-A 302,389, p. 23).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:14][C:15]1[C:21](F)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[C:21]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: OCCCCN1CCCCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
382 mg of sodium hydride (60% in suspension in oil) are added in small portions, over two hours, to a solution of 4-piperidin-1-ylbutan-1-ol in 10 mL of DMF, cooled to 0° C. with an ice bath. A solution of 4,5-difluoro-2-nitroaniline in 5 mL of N,N-dimethylformamide is then added dropwise. The medium is stirred at ambient temperature for 24 hours. 60 mL of distilled water are added and the reaction medium is extracted with 3×30 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus with an Analogix RS-12 silica cartridge, with a 100% to 85/15 dichloromethane/-methanol elution gradient. 700 mg of 4-fluoro-2-nitro-5-(4-piperidin-1-ylbutoxy)phenylamine are isolated in the form of a red oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): from 1.29 to 1.62 (m, 8H); 1.75 (m, 2H); 2.28 (m, 6H); 4.07 (t, J=6.5 Hz, 2H); 6.62 (d, J=7.5 Hz, 1H); 7.48 (broad s, 2H); 7.74 (d, J=12.0 Hz, 1H).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][NH:32][CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+].C=O>O1CCCC1>[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][N:32]([CH3:39])[CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 2 h
Yield: 15.8 %

Procedure:
To a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 190 mg, 0.30 mmol, 1.00 equiv, 75%) in tetrahydrofuran (10 mL) were added NaBH(OAc)3 (252 mg, 1.13 mmol, 3.00 equiv, 95%) and HCHO (37%) (2.2 mL, 2.00 equiv). The resulting mixture was stiffed for 2 h at 40° C. in an oil bath and then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with aqueous saturated sodium bicarbonate and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product (˜80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (36% CH3CN up to 48% in 8 min, up to 100% in 1 min, down to 36% in 1.5 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 23.4 mg (16%) of the title compound as a white solid. m/z (ES+) 494 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 7.37-7.31 (m, 1H), 7.26 & 7.15 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak), 4.02-3.90 (m, 1H), 3.73-3.57 (m, 1H), 3.57 (s, 2H), 3.34-3.21 (m, 1H), 3.06-2.94 (m, 2H), 2.90-2.77 (m, 4H), 2.54 (s, 3H), 2.45 & 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.11-1.86 (m, 6H), 1.86-1.54 (m, 4H).
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])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O>C(Cl)Cl>[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]=[O:26])[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](CC)CO)C1=O
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O

Procedure:
To a solution of 218 mg (0.49 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in a mixture of water (13.20 μL, 0.733 mmol) and DCM (4883 μL) was added 1,1,1,-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)one (“Dess Martin periodinane”) (311 mg, 0.733 mmol) at ambient temperature. The reaction was monitored by LCMS, and several small portions of additional periodinane were added until the reaction was complete. The reaction was quenched (2 mL, 1 M Na2S2O3), extracted (2×DCM), and the combined organic layers were washed with sat. NaHCO3 solution (2×), sat NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes, gradient elution) provided the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C(C2C=CC(C3C=CC(F)=CC=3)=CC=2)=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[C:30]([O:34][C:35](=[O:38])[NH:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>C(O)C.C(OCC)(=O)C>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:37][NH:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=1)(=[O:9])=[O:10]
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of Example 1D (212 mg, 0.49 mmol) and tert-butylcarbazate (976 mg, 2.3 mmol) in ethanol (5 mL) was heated to reflux, stirred for 16 hours, diluted with ethyl acetate (50 mL), washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:0.5:98.5/methanol:acetic acid:dichloromethane, then 2:0.5:97.5/methanol:acetic acid:dichloromethane to provide the desired product. MS (ESI(−)) m/e 331 (M−H)−.
Reaction SMILES: O.NN.[S:4]1[CH:8]=[CH:7][C:6]2[C:9](=O)[C:10]3[C:22]([C:5]1=2)=[CH:21][C:13]1[C:14](=O)[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]=1[CH:11]=3.[OH-].[K+].N.O>C(O)COCCO>[S:4]1[CH:8]=[CH:7][C:6]2[CH2:9][C:10]3[C:22]([C:5]1=2)=[CH:21][C:13]1[CH2:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]=1[CH:11]=3
Reactant: O=c1c2cc3c(cc2c2sccc12)c(=O)c1ccsc13
Agent: N
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: c1cc2c(s1)-c1cc3c(cc1C2)-c1sccc1C3
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Hydrazine hydrate (11.9 cm3, 245 mmol) is added to a suspension of 4,9-dihydro-s-indaceno[1,2-b:5,6-b′]dithiophene-4,9-dione (9.6 g, 32.6 mmol) and KOH (5.5 g, 97.8 mmol) in diethylene glycol (100 cm3). The mixture is heated to 180° C. for 6 hours, and then allowed to cool to 23° C. overnight. NH3/H2O (1:1, 200 cm3) is added and the mixture is stirred for 30 minutes. The solid is collected by filtration, washed with H2O (2×300 cm3) and IMS (2×300 cm3), and dried under vacuum to yield the product as a brown solid (6.89 g, 79%). 1H NMR (300 MHz, d6-DMSO): δ(ppm) 7.71 (s, 2H, Ar—H), 7.55 (d, J=4.9 Hz, 2H), 7.21 (d, J=4.9 Hz, 2H, Ar—H), 3.77 (s, 4H, CH2).
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:13][CH2:14][C@@H:15]1[C@H:33]([OH:34])[C@H:32]([CH3:35])[CH:31]=[C:30]([CH3:36])[CH:29]=[C:28]([O:37][CH3:38])[C:26](=[O:27])[O:25][C@H:24]([C@H:39]([C@@H:41]([OH:67])[C@@H:42]([C@@H:44]2[O:49][C@H:48](/[CH:50]=[CH:51]/[CH3:52])[C@@H:47]([CH3:53])[C@H:46]([O:54][C@@H]3O[C@H](C)[C@@H](OC(N)=O)[C@H](O)C3)[CH2:45]2)[CH3:43])[CH3:40])[C@@H:23]([O:68][CH3:69])[CH:22]=[CH:21][CH:20]=[C:19]([CH3:70])[CH2:18][C@@H:17]([CH3:71])[C@@H:16]1[OH:72].C([O-])(O)=O.[Na+]>CC#N.O>[CH3:13][CH2:14][C@@H:15]1[C@H:33]([OH:34])[C@H:32]([CH3:35])[CH:31]=[C:30]([CH3:36])[CH:29]=[C:28]([O:37][CH3:38])[C:26](=[O:27])[O:25][C@H:24]([C@H:39]([C@@H:41]([OH:67])[C@@H:42]([C@@H:44]2[O:49][C@H:48](/[CH:50]=[CH:51]/[CH3:52])[C@@H:47]([CH3:53])[C@H:46]([OH:54])[CH2:45]2)[CH3:43])[CH3:40])[C@@H:23]([O:68][CH3:69])[CH:22]=[CH:21][CH:20]=[C:19]([CH3:70])[CH2:18][C@@H:17]([CH3:71])[C@@H:16]1[OH:72]
Reactant: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: C/C=C/[C@H]1O[C@@H]([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O)[C@@H]1C
Temperature: 38 °C
Reaction time: 12 h

Procedure:
350 mg (1.83 mmol, 3 equiv.) of toluenesulfonic acid monohydrate (recrystallised from CHCl3) are added to a solution of 467 mg of 21-deoxyconcanamycin A (0.55 mmol) in 55 ml of CH3CN/H2O (5:1) and the reaction mixture is stirred at 38° C. for 12 hours. For working-up, the reaction mixture is cooled to 0° C. and 50 ml of saturated NaHCO3 solution are added; the organic solvent is removed in vacuo and the aqueous phase is extracted with CHCl3. TLC monitoring on silica gel (eluant: EtOAc/hexane 1:1) revealed two new zones in addition to the starting material at the starting spot. Column chromatography on silica gel (gradient EtOAc/hexane, 1:1 EtOAc) yields 63 mg (22% of the conversion) of 16-demethyl-21-deoxyconcanolide A, 122 mg of 21-deoxyconcanolide A (42% of the conversion) and 105 mg of starting material.
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:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:34]([O:36][CH2:37][CH2:38][NH2:39])[CH3:35]>>[CH2:34]([O:36][CH2:37][CH2:38][NH:39][C:28]([C:14]1[C:15](=[O:27])[N:16]([CH2:19][C:20](=[O:26])[N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]2[C:12]([C:13]=1[OH:33])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:29])[CH3:35]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-l -[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.18 (1H, br m), 8.53 (1H, d, J=1 Hz), 7.15 (2H, dd, J=8.6, 5.5 Hz), 7.08 (1H, s), 7.02 (2H, m), 4.87 (2H, s), 4.11 (2H, s), 3.61 (4H, m), 3.59-3.44 (6H, m), 2.04 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz), 1.22 (3H, t, J=7 Hz); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2190.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16]O)[CH:5]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][C:25]=1[CH3:31])[CH3:19].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C.O>[CH2:18]([O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:16][C:4]2[CH:5]=[C:6]([O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:26][C:25]=1[CH3:31])[CH3:19]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(Br)cc(O[Si](C)(C)C(C)(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol (6.4 g; 20.17 mmol) and (4-mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (5.02 g; 22.19 mmol) were dissolved in THF (200 mL). Tributylphosphine (8.15 g; 40.34 mmol) and 1,1′-(azodicarbonyl)dipiperidine (10.17 g; 40.34 mmol) were added, and the reaction mixture was stirred for 14 h at room temperature. Water and ethyl acetate were added to the reaction mixture. The phases were separated. The organic phase was washed with water, dried, and evaporated. The crude product was purified by flash chromatography (heptane:dichloromethane (1:1)). Yield: 8 g; 80%. HPLC-MS: m/z: 527.0 (M+1); Rt: 3.10 min.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=O)=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>ClCCl.CN(C=O)C>[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([Cl:4])(=[O:21])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCCc2cc(S(=O)(=O)O)ccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCCc2cc(S(=O)(=O)Cl)ccc21
Reaction time: 2 h
Yield: 20.3 %

Procedure:
Oxalyl chloride (20 g, 157.60 mmol) was added dropwise at room temperature to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (5 g, 22.00 mmol) in dichloromethane (100 mL) and DMF (10 mL). The resulting solution was stirred for 2 hours, then quenched by adding 200 mL of iced water. The resulting solution was extracted using dichloromethane (2×100 mL), and the combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:4 ethyl acetate/petroleum ether solvent system to afford 1.1 g (20.1%) of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.69 (d, 1H), 7.51 (s, 1H), 6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m, 2H).
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=C)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=[O:33])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C=O)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 2-(4-methyl-N-phenyl-2-vinylnicotinamido)acetate (8) (767 mg, 1.88 mmol) in 1,4-dioxane-H2O (3:1, 20 mL) at RT, osmium tetraoxide (2.5% wt in H2O, 0.5 mL, 0.05 mmol) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, sodium periodate (1.21 g, 5.53 mmol) was added and the resulting mixture was stirred at RT for 30 h. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-8-carbaldehyde (15) (730 mg, 95% yield) as a yellowish solid. ESI-MS m/z: 411.2 [M+H]+.
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3[O:20]N=C4C5C(CCC=34)=CC(C=O)=CC=5)C=N2)C=CC=CC=1.[CH:31]1([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[O:47][N:46]=[C:45]4[C:48]5[C:53]([CH2:54][CH2:55][C:44]=34)=[CH:52][C:51]([CH:56]=C)=[CH:50][CH:49]=5)=[CH:39][C:38]=2[C:58]([F:61])([F:60])[F:59])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[O:47][N:46]=[C:45]4[C:48]5[C:53]([CH2:54][CH2:55][C:44]=34)=[CH:52][C:51]([CH:56]=[O:20])=[CH:50][CH:49]=5)=[CH:39][C:38]=2[C:58]([F:59])([F:60])[F:61])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(C2CCCCC2)c(C(F)(F)F)c1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89B employing 3-(4-cyclohexyl-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (118D) as a starting material. The compound had an HPLC retention time=4.43 min. (condition C); LC/MS M+1=426.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2[CH:31]=[CH:32][CH:33]=[N:34]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:34][CH:33]3[CH2:31][CH2:32]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), cyclopropylamine (15 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C14H18ClN5O2, 324.12; found 324.2.