Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7]C(=O)CC.[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C)([O-])=O>[OH:7][C:2]1[CH:3]=[CH:4][C:5]([C:2](=[O:7])[CH2:1][CH3:6])=[CH:6][C:1]=1[CH3:12]
Reactant: CCC(=O)Oc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCC(=O)c1ccc(O)c(C)c1
Temperature: 50 °C
Yield: 125.7 %

Procedure:
At 0° C., to a mixture of nitromethane 150 ml and propionic acid o-tolyl ester (described in Reference Preparation example 113) 14 g was added aluminum trichloride 30 g. The resulting mixture was heated to 50° C. and was stirred for twelve hours. To the reaction mixture was added ice water 200 ml and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-hydroxy-3-methyl-phenyl)-propane-1-one 8.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17].CC(N(C)C)=O.[H-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: OCC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N)cc1OCC1CCCO1
Temperature: 70 °C

Procedure:
6-amino-4-chloronicotinonitrile (intermediate 16, 70 mg, 0.456 mmol) and (tetrahydrofuran-2-yl)methanol (233 mg, 2.28 mmol) were charged into a vial. DMA (1 ml) was added to the mixture at room temperature followed by NaH (60% in mineral oil dispersion, 109 mg, 2.73 mmol). The mixture was then heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted in EtOAc and washed with aq. pH7 buffer (2×) and brine. The organic layer was dried over
Reaction SMILES: O[C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5](O)[CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH:15](O)[CH:16]([CH3:18])[CH3:17])[CH2:3]1.P(Cl)(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:33][CH:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
To the solution of 3α,6α,24-trihydroxy-5β-cholestan (1.5 g) in pyridine (20 ml) was added phosphorus oxychloride (3 ml). After completion of the reaction, the reaction mixture was poured into ice-water and extracted with diethyl ether. The ether layer was washed with an aqueous solution of hydrochloric acid and then with water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel to give 0.6 g of 3-chlorocholest-5,24-diene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:5](N1C2C=CC=CC=2N=N1)=[O:6].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:5]([C:4]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:2]([Cl:1])[C:3]=2[OH:20])=[O:6])[CH2:23][CH2:22]1
Reactant: Br[Mg]C1CC1
Reactant: O=C(c1cc(Cl)cc(Cl)c1O)n1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)cc(Cl)c1O)C1CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
N-(3,5-Dichloro-2-hydroxybenzoyl)benzotriazole (prepared according to Katritizky et al., Synthesis 2007, 20, 3141-3146, which is expressly incorporated by reference herein; 2.0 g, 6.5 mmol) was stirred in dry THF (25 mL), cooled to −30° C., treated in portions with cyclopropylmagnesium bromide (0.5 M in THF; 28 mL, 14 mmol) and stirred at −30° C. for 30 min. The cooling bath was removed and the mixture was allowed to warm to 25° C. and stir for 3 h. The reaction was quenched by addition of 10 mL satd NH4Cl, and shaken with EtOAc (50 mL) plus 20% citric acid solution (30 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (450 mg): 1H NMR (400 MHz, CDCl3) δ 13.03 (s, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 2.70-2.54 (m, 1H), 1.41-1.32 (m, 2H), 1.24-1.15 (m, 2H); EIMS m/z 230.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][C:12]1[C:13]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:14][NH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][C:12]1[C:13]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:14][N:15]([CH2:38][CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:16]=1[C:17]([F:18])([F:20])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](Oc2nn(CCOCc3ccccc3)c(C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (300 mg) in N,N-dimethylformamide (3 mL) were added (2-bromoethoxymethyl)benzene (379 mg) and cesium carbonate (957 mg), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (154 mg).
Reaction SMILES: C(=[N:8][N:9]=[C:10]1[N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[O:21])[CH2:12][N:11]1[CH2:22][C:23]([O:25]C)=O)C1C=CC=CC=1>Cl>[CH2:19]([O:18][C:16]([CH2:15][N:14]1[C:13](=[O:21])[CH2:12][N:11]2[C:10]1=[N:9][NH:8][C:23](=[O:25])[CH2:22]2)=[O:17])[CH3:20]
Reactant: CCOC(=O)CN1C(=O)CN(CC(=O)OC)C1=NN=Cc1ccccc1
Agent: Cl
Product: CCOC(=O)CN1C(=O)CN2CC(=O)NN=C21
Yield: 39.1 %

Procedure:
To 230 mg of 2-benzylidenehydrazono-3-ethoxycarbonylmethyl-1-methoxycarbonylmethylimidazolidin-4-one obtained in step (1) of Example 7 was added 10 ml of 0.5N hydrochloric acid, the mixture was subjected to a steam distillation for 40 minutes. The reaction mixture obtained was concentrated under reduced pressure, and the residue formed was charged on silica gel column chromatography and eluted with a mixture of chloroform and ethyl acetate at 1:2 by volume to obtain 60 mg of 7-ethoxycarbonylmethyl-1,4,5,7-tetraazabicyclo[4,3,0]-nonan-5-ene-3,8-dione.
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.O>O1CCOCC1>[I:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc(I)cc1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
(Acheson, R. M.; Lee. G. C. M. J. Chem. Soc. Perkin Trans. I 1987, 2321-2332.) To a stirred suspension of sodium borohydride (5.68 g, 150 mmol, 2.0 equiv) in 50 mL dioxane at 0° C. was added dropwise a solution of 4-iodobenzoyl chloride (19.99 g, 75 mmol, 1.0 equiv) in 50 mL dioxane over 25 min. The resulting mixture was heated to 100° C. for 90 min under a reflux condenser then cooled to 0° C. 50 mL H2O was added cautiously under a flowing stream of nitrogen. [CAUTION: Evolves gas!] The mixture was extracted 3×125 mL CH2Cl2 and the combined organic extracts were washed with 2×H2O, 2×0.1N HCl, 2×1N NaOH, H2O, and brine, dried (MgSO4), filtered, and evaporated to yield 16.9 g of crude 4-iodobenzyl alcohol as a white solid, determined by NMR to contain 78% desired product with the remainder residual starting material and 4-iodobenzoic acid. The crude product was used without further purification. mp: 61.0-66.5° C. TLC Rf: 0.27 (3:1 hexanes/EtOAc). IR (film): 3306, 1005, 791. 1H-NMR (400 MHz, CDCl3): δ 7.69 (d, 2H, J=8.3, C4-H, C6-H), 7.12 (d, 2H, J=8.5, C3-H, C7-H), 4.66 (br d, 2H, J=:4.1, C1-H2), 1.67 (br t, 1H, C1-OH). 13C-NMR (125 MHz, CDCl3): δ 140.4, 137.6, 128.8, 93.0, 64.6. EI-MS m/z (rel int): 234 (M+, 100).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][OH:35])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:35][CH2:34][CH2:33][N:6]1[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:8]=2[N:32]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCO)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCOS(C)(=O)=O)CCCC3
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl-1-(2-hydroxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.55 g, 1.13 mmol) and anhydrous dichloromethane (11 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to −10° C. in a methanol/ice bath. To the cooled solution was added triethylamine (0.23 g, 2.26 mmol) and methanesulfonyl chloride (0.19 g, 1.70 mmol). The reaction was judged to be complete after stirring at −10° C. for 15 minutes and was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-{4-[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol) as a gummy yellow solid. The material was used without further purification. MS (CI) for C27H42N4O7S m/z 567 (MH+), 467, 367, 271.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:8]3[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:13][C:14]=2[F:30])=[CH:23][CH:22]=1)=[N+:32]=[N-:33]
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
A solution of 52 (9.27 g, 21.26 mmol) in anhydrous N,N-dimethylformamide (DMF, 50 mL) was treated with sodium azide (NaN3, 5.53 g, 85.04 mmol, 4.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 70-80° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with H2O (150 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2×50 mL), and dried in vacuo. The crude desired N-[3-(4′-azidomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 53 (7.16 g, 88% yield) was obtained as off-white solids. The material was found to be essentially pure by TLC and HPLC and was directly used in the subsequent reaction without further purification. LCMS (ESI) m/e 384 (M+H)+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Cl)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Cl)n2)sc2ccccc12
Yield: 36.4 %

Procedure:
A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), 2-cyano-6-chloropyridine (0.54 g, 3.9 mmol), triethylamine (1.00 ml, 7.2 mmol) and toluene (2.0 ml) was refluxed for 6.5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.39 g, 37%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Title compound in example 659. A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1-((1R,5S)-8-{2-[4-(1,3-benzodioxol-5-yl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (0.18 g, 82%). 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 1H), 7.29 (m, 3H), 6.83 (m, 2H), 6.75 (m, 1H), 6.21 (m, 1H), 6.00 (s, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.38 (m, 2H), 2.98 (m, 2H), 2.86 (s, 3H), 2.56 (m, 2H), 2.31 (m, 4H), 2.07-2.21 (m, 4H), 1.82 (m, 4H), 1.26 (s, 9H). HRMS C34H44N4O3 m/z 557.3492 (M+H)Cal., 557.3495 (M+H)Obs..
Reaction SMILES: Cl.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([O:29]CC)=[O:28])[C:12]2=[O:32]>O>[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
To 3 ml of a mixed solution (1:1, v/v) of 4 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 510 mg of ethyl 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylamino-pyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 2.5 hours. After adding 2 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 454 mg of the title compound as a gray powder.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]O)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: OCCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Product: Brc1cnc(Nc2ccc(CCN3CCCC3)cc2)nc1Nc1ccccc1

Procedure:
Using an analogous method to that described in Example 32, but starting from 4-anilino-5-bromo-2-[4-(2-hydroxyethyl)anilino]pyrimidine (Method 11) and pyrrolidine, the product was obtained. MS (MH+): 438.1, 440.1; HPLC (RT): 5.64.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[CH:34]=[C:33]([F:35])[N:32]=[CH:31][C:30]=5[CH:36](O)[CH3:37])=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[C:17]([F:39])=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1.C(N(CC)CC)C.[CH:47]1([NH2:50])[CH2:49][CH2:48]1>C(Cl)Cl>[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[C:30]([CH:36]([NH:50][CH:47]6[CH2:49][CH2:48]6)[CH3:37])=[CH:31][N:32]=[C:33]([F:35])[CH:34]=5)=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[C:17]([F:39])=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1
Reactant: NC1CC1
Reactant: CC(O)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC1CC1)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
Slowly add methanesulfonyl chloride (0.04 mL, 0.55 mmol) to a solution of newly synthesized 1-(4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-fluoropyridin-3-yl)ethanol (240 mg, 0.50 mmol) and triethylamine (0.14 mL, 1.0 mmol) in methylene chloride (5 mL) at −78° C. After stirring the mixture at the same temperature for another 60 min, add cyclopropylamine (0.040 mL, 0.55 mmol) and leave it overnight at RT. Heat it to 45° C. for 5 h, cool to RT, and remove the solvent. Purify by column chromatography (10% methanol in DCM) to afford the title compound (42 mg 17%). MS (ES) m/z 519 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1

Procedure:
4-Bromo-1-fluoro-2-nitro-benzene (5 gms.), 3.85 gms. 3-methoxyphenylboronic acid and 22 mL of a 2M aqueous solution of sodium carbonate are suspended in 100 mL of a 1:1 (v:v) mix of toluene and ethanol. The resulting suspension is then treated with 0.8 gms. tetrakis(triphenylphosphine)palladium (0) at room temperature. The reaction mixture is then heated at reflux for 12 h. The reaction mixture is subsequently concentrated in vacuo, and the resulting residue is taken up in ethyl acetate (200 mL). The ethyl acetate solution is then washed successively with water (2×200 mL), and brine (2×200 mL). The organic layer is then dried by filtering through phase separator paper and concentrated in vacuo to yield 7.19 gms. of crude product. The crude product is then recrystallized from hot ethanol yielding 4-fluoro-3′-methoxy-3-nitro-biphenyl as a yellow-white solid in the amount of 4.767 gms.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][C:13]=1[C:28](OCC)=[O:29]>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([NH:3][C:28]([C:13]2[N:14]=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[C:21]([C:12]=2[OH:11])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:29])=[N:5][CH:6]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)c1nc(-c2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
A stirred slurry of 2.3 g of sodium hydride in 100 ml of dry tetrahydrofuran was treated with 6.1 g of 2-amino-5-chloropyridine and immersed in an ultrasonic bath for 30 minutes. The stirred slurry was then treated with a solution of 7.0 g of 4-hydroxy-1-phenyl-3-isoquinolinecarboxylic acid, ethyl ester in 70 ml of tetrahydrofuran and refluxed for 16 hours. Thereafter, the solution was cooled to room temperature and quenched with 20 ml of water. The resulting precipitate was solubilized in 500 ml of aqueous methanol and treated with carbon dioxide gas. Recrystallization of the precipitate from 500 ml of warm dimethylformamide afforded 7.5 g (84%) of N-(5-chloro-2-pyridyl)-4-hydroxy-1-phenyl-3-isoquinolinecarboxamide, m.p. 249°-251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:23]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:24]1[O:26][CH2:25]1>>[CH2:28]([O:27][CH2:23][C@H:24]([OH:26])[CH2:25][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@@H](O)COCc3ccccc3)cc12

Procedure:
Using the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step C of Example 1-1 and (R)— benzyl glycidyl ether as raw materials, the captioned compound was synthesized by a reaction similar to step A of Example 2-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.Br[C:14]1C=CC(OC)=C2[C:15]=1C=CN2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:6]([O:8][CH3:9])[CH:7]=1)[NH:10][CH:15]=[CH:14]2
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Reactant: COc1ccc(Br)c2cc[nH]c12
Product: COc1cc(Br)cc2cc[nH]c12

Procedure:
5-Bromo-7-methoxyindole CV was prepared from 5-bromo-2-nitroanisole using the procedure described above for preparation of 4-bromo-7-methoxyindole LII (Example 13).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[O:31]1[CH2:34][CH:33]([NH2:35])[CH2:32]1>C(O)C>[N:25]1([C:23]([N:9]2[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:12][CH:7]([C:5]3[O:4][N:3]=[C:2]([NH:35][CH:33]4[CH2:34][O:31][CH2:32]4)[N:6]=3)[CH2:8]2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NC1COC1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(NC3COC3)no2)C1
Reaction time: 72 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 335 mg (4.50 mmol) of oxetan-3-amine, and then the reaction mixture was stirred at 80 for 3 days. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 59.7 mg (55% of theory)