Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:7][N:6]1C(OC(C)(C)C)=O)=[N+:2]=[N-:3].Cl>ClCCl.O1CCOCC1>[N:1]([CH2:4][C@H:5]1[NH:6][CH2:7][C@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:9]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 174C (440 mg, 1.221 mmol) dissolved in dichloromethane (2 mL) was added 4 M HCl in 1,4-dioxane (4 mL). The resulting mixture was stirred at ambient temperature for 30 minutes and was then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH2:5]([O:12][C@:13]1([CH3:36])[C@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:15][C@@H:14]1O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO>C(N(CC)CC)C>[CH2:28]([O:27][CH2:26][C@@H:16]([OH:15])[C@@H:17]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH:36]=[N:4][O:3][CH3:2])[CH3:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1O
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C[C@](C)(OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
0.69 g of O-methylhydroxylamine hydrochloride was added to a mixture of 2.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol and 10 mL of methanol, and thereafter, 0.56 g of triethylamine was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 6 hours. Thereafter, the solvent was distilled away under reduced pressure, and 20 mL of ethyl acetate and 20 mL of water were then added to the obtained residue. The organic layer was fractionated, and was then washed with water twice. The solvent was distilled away under reduced pressure, so as to obtain 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=4[F:33])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:37]=[C:38]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.C(Cl)Cl>[CH3:46][N:45]([CH3:47])[CH2:44][CH2:43][O:42][C:38]1[CH:37]=[C:36]([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=5[F:33])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Cl)n3)c2)c1F
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluoro-3-methylbenzamide (100 mg, 0.21 mmol) (prepared in a manner similar to that described in Example 186) and {2-[(3-aminophenyl)oxy]ethyl}dimethylamine (47 mg, 0.26 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The reaction was stirred at 80° C. overnight. After 16 h, the mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and adsorbed onto silica. The crude product was purified by column chromatography to generate the title compound in 86% yield (112 mg, 0.18 mmol). 1H NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1H), 9.55 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.45-7.52 (m, 4H), 7.36 (d, J=7.3 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.12-7.16 (m, 3H), 6.53 (d, J=5.1 Hz, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.58 (t, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(#N)C>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.230 mmol) in 5 mL of dichloromethane. Added 0.5 mL of acetic anhydride. After 10 min, reaction is complete and trituration with acetonitrile gave 2-[5-(4-acetyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 91%). MS(ESI) m/z 477.3 (M+H)+
Reaction SMILES: N1C2C(=CC=CC=2)C=[CH:2]1.C[C@]12C3C=C(OC(NC)=O)C=CC=3N(C)[C@H]1N(C)CC2.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][C:46]=1[CH:47]([CH3:49])[CH3:48])[NH:43][CH:42]=[CH:41]2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([Mg]Br)C.CI>C1COCC1>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][C:46]=1[CH:47]([CH3:49])[CH3:48])[NH:43][CH:42]=[C:41]2[CH3:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)c1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c[nH]c2cc(C(C)C)c(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The methylation carried out in this step follows the procedure for indole alkylation reported by Marino et al. in “The Enantioselective Synthesis of (−) Physostigmine Via Chiral Sulfoxides”, J. Am. Chem. Soc. (1992), 114, 5566-5572. 5-Benzyloxy-6-isopropyl-1H-indole (0.855 g, 3.22 mmol) was dissolved in 20 mL of dry THF, and the resulting solution was cooled in an ice bath. Ethyl magnesium bromide (4.9 ml, 4.9 mmol in ether) was added dropwise to the solution, and the solution was then stirred for 4 hours at room temperature. Methyl iodide (1.42 g, 10 mmol) was then added, and stirring was continued for an additional 18 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified with flash chromatography (ethyl acetate/hexanes=1/9) to yield 325 mg of 5-benzyloxy-6-isopropyl-3-methyl-1H-indole Mass Spec (M+H): 280.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C[N:18](C=O)C.[OH-].[NH4+]>S(Cl)(Cl)=O.CC(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
2,4-Dinitro-5-chlorobenzoic acid (7.00 g, 28.4 mmol) was suspended in 40 mL thionyl chloride containing 3 drops of DMF. The suspension was warmed to reflux for four hours. After cooling to room temperature, solvent was removed by rotary evaporation leaving a golden yellow liquid. This was diluted with 30 mL acetone and added dropwise over 20 minutes to a 0° C. solution of 20 mL concentrated ammonium hydroxide. The reaction was stirred at 0° C. for 30 minutes, then poured into 250 g of ice. The yellow orange precipitate was collected by filtration and washed well with water. The solid was dried first by water aspirator then under high vacuum to furnish 5.9 g (24 mmol, 84% yield) of product. NMR (400 MHz; acetone-d6): δ 8.75, s 1H, 8.25, s 1H; mp 201-203° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](C3C=CC(SC)=CC=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.[C:29](O)(=O)[CH3:30]>O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([S:7]([C:1]3[CH:6]=[CH:5][C:29]([CH3:30])=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylsulfonyl-3-(4-methylthiophenyl)indole (8.89 g, 23.4 mmol) in glacial acetic acid (15 mL) was added 30% H2O2 solution (2.45 g, 72 mmol) and the resulting 2-phase mixture was heated at reflux for 30 min during which time it became a solid mass. The reaction mixture was cooled to ambient temperature and diluted with H2O and ethyl acetate and the solid was filtered off. The filtrate layers were separated and the organic phase was washed with saturated aqueous NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/ether and the resulting solid was combined with the solid obtained above and recrystallized from ethyl acetate to give 8.15 g of 1-phenylsulfonyl-3-(4-methylphenylsulfonyl)indole. mp 188.9°-189.7° C.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[N:36]=[C:37](SC)SC>CN(C=O)C>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]1[O:11][C@:3]2([CH2:2][N:1]=1)[CH:8]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]1)[CH2:4]2
Reactant: CSC(=Nc1nc2ccccc2o1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2oc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 10 ml-vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (69.5 mg, 0.361 mmol), DMF (2 ml), DIEA (0.063 mL, 0.361 mmol) and Cs2CO3 (235 mg, 0.722 mmol) at room temperature, followed by dimethyl benzo[d]oxazol-2-ylcarbonimidodithioate (86 mg, 0.361 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS then indicated consumption of starting material. The mixture was diluted with MeOH and purified by preparative HPLC to afford the expected product, (R)—N-(benzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (101.5 mg, 0.323 mmol, 90% yield), as a tan gum. 1H NMR (400 MHz, Acetone-d6) δ ppm 2.07-2.14 (m, 2H) 2.20 (ddd, J=8.78, 5.27, 3.26 Hz, 2H) 2.33-2.45 (m, 1H) 2.62 (d, J=2.26 Hz, 1H) 3.34-3.47 (m, 3H) 3.48-3.58 (m, 1H) 3.75-3.88 (m, 2H) 4.15 (d, J=10.54 Hz, 1H) 4.32 (d, J=10.54 Hz, 1H) 7.13-7.26 (m, 2H) 7.41 (td, J=3.70, 1.63 Hz, 1H) 9.24 (br, s, 1H). MS (LC/MS) R.T.=0.792, [M+H]+=299.17.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([O:23]C)=[C:18]([O:21]C)[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH2:2][CH3:3].B(Br)(Br)Br.CO>ClCCl>[CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([OH:21])[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCN1Cc2cccc3c2C(C1)c1ccc(O)c(O)c1O3
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The N-propyl amine 12a (0.90 g; 2.8 mmol) was dissolved in 200 ml of dichloromethane and cooled to −78° C. In a separate 250 ml round bottom flask, 125 ml of dry dichloromethane was cooled to −78° C., and 1.4 ml (14.8 mmol) of BBr3 was added via syringe. The BBr3 solution was transferred using a cannula to the flask containing the starting material. The solution was stirred overnight, while the reaction slowly warmed to room temperature. After recooling the solution to −78° C., 50 ml of methanol was slowly added to quench the reaction. The reaction was then concentrated to dryness. Methanol was added and the solution was concentrated. This process was repeated three times. The resulting tan solid was suspended in hot isopropyl alcohol. Slowly cooling to room temperature resulted in a fine yellow precipitate. The solid was collected by filtration (0.660 g; 63%): mp 259-264° C. dec; 1H NMR: (300 MHz, CDCl3): 7.16 (t, 1H, J=9 Hz); 6.97 (d, 1H, J=12 Hz); 6.83 (d, 1H, J=9 Hz); 6.55 (d, 1H, J=9 Hz); 6.46 (d, 1H, J=9 Hz); 4.45 (d, 1H, J=15 Hz); 4.10 (m, 3H); 3.17 (q, 2H, J=6 Hz); 3.04 (t, 1H, J=9 Hz); 1.73 (q, 2H, J=9 Hz); 0.90 (t, 3H, J=6 Hz). Anal. Calc'd. for C18H20BrNO3: C, 57.16; H, 5.33; N, 3.70. Found: C, 56.78; H, 5.26; N, 3.65.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH2:24]([OH:27])[CH2:25][OH:26]>>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[O:26][CH2:25][CH2:24][OH:27]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: O=C1Nc2ccc(F)c3c(OCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (396 mg, 1.0 mmol) in ethylene glycol (Fisher Scientific, 60 mL) was added NaH (Aldrich, 95%, 2.0 g, 79.2 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 2 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were successively washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes) to give 6-fluoro-5-(2-hydroxy-ethoxy)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 127.0 mg, 40.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[C:15]([O:21]C(C)(C)C)[CH:14]=[C:13]3[Br:26])O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[C:15]([OH:21])[CH:14]=[C:13]3[Br:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol (500 mg, 0.82 mmol, 1.00 equip), dichloromethane (50 mL), triethylsilane (1 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with saturated sodium bicarbonate (3×100 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol as a yellow solid. LCMS (ES, m/z) 538 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:19][CH2:18][NH:17][CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:17]2[CH2:18][CH2:19][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]4[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8][C:7]=4[C:6]=3[CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccc(Cl)cc1)N1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Yield: 104.4 %

Procedure:
The 7-nitroquinoxalinedione from Example 31 (100 mg, 0.38 mmol) was treated with the CDI adduct of 4-chlorobenzoic acid (0.57 mmol) by a procedure similar to that in Example 32 to give a yellow solid (159 mg, 99% yield). mp=280-283° C. (dec.). MS(CI) M+1 401; CHN calc'd for C18H13ClN4O5 within ±0.4.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[N:22]1([CH2:31][C:32](O)=[O:33])[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:22]3[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc(F)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 95.9 %

Procedure:
The title compound (900 mg, 96%) was synthesized by reaction of 1-(4-fluoro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (680 mg, 2.0 mmol) with (thymin-1-yl)-acetic acid (369 mg, 2.0 mmol) as per the procedure of example 64.
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(C#Cc2ccc(CC(=O)OC)cc2)cc1C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 mmols) in triethylamine (8 mL) was treated with copper(I)iodide (67.0 mg, 0.35 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 0.35 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-7% EtOAc-hexanes) afforded 270.0 mg (53%) of the title compound as a pale-yellow oil.
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:41]=[CH:42][CH:43]=2)[CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]3[CH2:27][C@@H:26]([C:28]4[CH:39]=[CH:38][C:31]5[O:32][C:33]([CH3:37])([CH3:36])[O:34][CH2:35][C:30]=5[CH:29]=4)[O:25][C:24]3=[O:40])=[CH:17][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:45].[Na+]>CCO.O>[CH:1]1([S:6]([C:7]2[CH:8]=[C:9]([CH:41]=[CH:42][CH:43]=2)[CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]3[CH2:27][C@@H:26]([C:28]4[CH:39]=[CH:38][C:31]5[O:32][C:33]([CH3:37])([CH3:36])[O:34][CH2:35][C:30]=5[CH:29]=4)[O:25][C:24]3=[O:40])=[CH:17][CH:16]=2)=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(SC6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)C6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A solution of (5R)-3-{2-[4-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (276 mg) in EtOH (15 ml) and water (5 ml) was treated with sodium periodate (391 mg) and stirred at room temperature under nitrogen for 3 h. The solution was concentrated in vacuo before pouring into water and extracting with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and concentrated in vacuo to give the title compound (278 mg). LCMS RT=3.42 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:7]=2[NH:6][C:5]1=[O:38].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:7]4[N:6]([CH2:46][C:47]#[N:48])[C:5](=[O:38])[CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]=4[N:10]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)C(=O)C(CCO)O4)cc2)CCC1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (51 mg, 0.099 mmol) in DMF(2 ml) was added potassium carbonate (41 mg) and 2-bromoacetonitrile (35.5 mg, 0.297 mmol). The reaction mixture was stirred at 50 degree for 3 h.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].O>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[CH2:14][CH2:13][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: FC(F)(F)CCBr
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
27.6 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide, 27.6 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, a mixture of 17.7 g of 1-bromo-3,3,3-trifluoropropane and 20 ml of N,N-dimethylformamide was added thereto and the mixture was further stirred for 1 hour. Thereafter, the reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 11.3 g of 2-(3,3,3-trifluoropropyl)malononitrile.