Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccc(Cn3cc([N+](=O)[O-])cn3)o2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-4-nitro-1H-pyrazole (427 mg, 1.53 mmol), iron powder (258 mg, 4.59 mmol) and NH4Cl (413 mg, 7.65 mmol) in a mixture of EtOH (8.0 mL) and water (4.0 mL) was stirred at 75° C. for 2.5 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (30 mL) was added followed by 1M NaOH (30 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. LC-MS-conditions 02: tR=0.58 min; [M+H]+=250.4.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])=[CH:8][C:7]=2[S:32][CH3:33])[CH2:3][CH2:2]1.CO.O.O[Li].O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[CH:8][C:7]=2[S:32][CH3:33])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(SC)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(C(CC(C)C)C(=O)O)cc(-c2ccc(C(F)(F)F)cc2)c1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (80 mg, 0.166 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (20 mg, 0.832 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The crude material was purified by column chromatography to afford 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (38 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.75 (d, 2H), 7.65 (d, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 3.65 (t, 1H), 3.60 (d, 2H), 2.82 (s, 3H), 1.98 (m, 1H), 1.65 (m, 1H), 1.5 (m, 1H), 1.22 (m, 1H), 0.9 (d, 6H), 0.38 (d, 2H), 0.01 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22](CO)[S:23][CH:24]=1)=[CH:16][CH:15]=3.[H-].[Na+].C1(Br)CC1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[CH:22][S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Agent: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cscn4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.3 mmol) of compound 3-(2,4-dichlorophenyl)-6-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from Example 9 above are dissolved in 10 ml of DMF. 50 mg of 60% NaH (0.96 mmol) are added and the mixture is stirred at ambient temperature for 30 min. 0.05 ml (0.6 mmol) of cyclopropyl bromide are added and the mixture is then stirred at ambient temperature for 3 hours. Water is added and the mixture is extracted with EtOAc. The product is washed with a saturated NaCl solution followed by adsorption onto silica. Purification is carried out by chromatography on a silica column, elution being carried out with EtOAc.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2](=[CH2:6])[C:3]([O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: C=C(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(Br)C(=O)OCc1ccccc1
Yield: 54.8 %

Procedure:
A suspension of 2-bromoacrylic acid (25.0 g, 166.66 mmol), benzyl bromide (21.8.0 mL, 183.32 mmol) and K2CO3 (46 g, 333.32 mmol) in acetonitrile (250 mL) was stirred at 80° C. for 3 h until complete consumption of 2-bromoacrylic acid, as evidenced by TLC analysis. The reaction mixture was filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford benzyl 2-bromoacrylate (22 g, 53%) as a yellow liquid (TLC solvent system: 5% EtOAc in PE; Rf: 0.7).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.F[B-](F)(F)F.[CH3:16][O+](C)C>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH3:16])[CH:4]=2
Reactant: Brc1cccc2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2c(Br)cccc2n1
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of 4-bromo-1H-indazole (2.24 g, 11.4 mmol) in ethyl acetate (110 mL) was added trimethyloxonium tetrafluoroborate (2.19 g, 14.8 mmol) at room temperature, and the mixture was stirred for 3 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (2.29 g, yield 95%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])[C:2]1C=CC=CC=1.[CH:40](N)(C)C>>[CH2:34]([CH:26]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[C:25]([NH:24][CH:15]1[CH:14]2[C:13](=[O:39])[CH2:12][CH:11]([C:9](=[O:10])[NH:8][CH:1]([CH3:40])[CH3:2])[CH2:23][N:21]3[C:22]2=[C:18]([CH:19]=[CH:20]3)[CH2:17][CH2:16]1)=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Reactant: CC(C)N
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NC(C)C)C3
Yield: 60 %

Procedure:
The compound of Example 3g was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using isopropylamine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.55 mmol/g) and purification by RP-HPLC provided 15.5 mg (60%) of the title compound as a white powder. MS (M+H)+=485.5.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH2:10]([N:12]1[C:16]([OH:17])=[C:15]([C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21](F)[C:20]=2[Cl:30])[CH:14]=[N:13]1)[CH3:11]>CN(C)C=O>[CH2:10]([N:12]1[C:16]([OH:17])=[C:15]([C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([N:3]3[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]3)[C:20]=2[Cl:30])[CH:14]=[N:13]1)[CH3:11]
Reactant: Cc1cc(C)[nH]n1
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(F)c2Cl)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(-n3nc(C)cc3C)c2Cl)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,5-Dimethylpyrazole (215 mg, 2.23 mmol) was added to a suspension of 150 mg (3.75 mmol) of 60 percent oil dispersed sodium hydride in 6 mL of dry dimethylformamide. After gas evolution had subsided, 500 mg (1.45 mmol) of 1-ethyl-4-(2-chloro-3-fluoro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole was added and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated by evaporation under reduced pressure and partitioned between dichloromethane and 1N aqueous hydrochloric acid. The aqueous phase was extracted with additional dichloromethane. The organic layers were combined and extracted with dilute aqueous sodium bicarbonate. The aqueous extract was acidified with 1N aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The solvent was removed from the organic extract by evaporation under reduced pressure and the crystalline residue obtained was purified by rinsing with diethyl ether to obtain 360 mg (59 percent of theory) of the title compound as a white powder melting at 217-218° C.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH:20]1([CH2:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[CH:20]1([CH2:29][NH:30][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1CCc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A mixture of 3.0 g of 6-chloropurine riboside, 2.0 g of 1-indanylmethylamine as prepared in Example A hereinafter and 3.18 g of triethylamine are refluxed in 75 ml of absolute ethanol under nitrogen for 24 hours. The reaction is cooled to room temperature, precipitated nucleoside is filtered, washed with ethanol and dried affording 2.78 g (67%) of N6 -[2,3-dihydro-1H-inden-1-yl]methyl-adenosine having a melting point of 137°-139° C. Anals. calcd. for C20H23N5O4 ; Found: C=60.44; H=5.83; N=17.62 C=60.81; H=5.70; N=17.35.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12]([Cl:21])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCC2(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCC2(C)C

Procedure:
20.0 g (0.075 mol) of 4,4,8-trimethyl-1,1-dioxothiochroman-7-carboxylic acid were dissolved in 200 ml of toluene and three drops of dimethylformamide and 10.7 g (0.09 mol) of thionyl chloride were added. After three hours of heating under reflux, the solvent was removed and the colorless oil that remained (yield 21.3 g) was directly used further.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]([NH:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1)=[O:11].[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40](ON3C(=O)CCC3=O)=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]([NH:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH:19][C:40]([O:39][CH2:38][CH:36]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:37]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:41])=[CH:15][CH:14]=1)=[O:11]
Reactant: N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine hydrochloride salt (30 mmol, 10.59 g), N-(9-fluorenylmethoxycarbonyloxy)succinimide (30 mmol, 10.12 g) and sodium carbonate (300 mmol, 31.8 g) were added dioxane (75 mL) and water (25 mL) at room temperature. The suspension was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. The inorganic solids were filtered through celite and washed with ethyl acetate. While washing with ethyl acetate some organic compound was precipitated out from filtrate which was collected and air dried. The filtrate was concentrated under vacuum and the residue was combined with the above organic solid compound and the product was taken up in hot THF and precipatated with ether to obtain 14.1 g (81%), as a white solid, mp 230-234° C. LR MS (C31H24Cl2N2O5): Obs mass, 597. Calcd mass, 597, (M+Na).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH2:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]1
Reactant: COC(=O)C1(C)CCC(NCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(C)CCC(N)CC1
Reaction time: 20 h
Yield: 68.9 %

Procedure:
0.2 g of 10% palladium-carbon was added to a solution of 3.1 g of methyl 4-(N-benzylamino)-1-methyl-1-cyclohexanecarboxylate (Example 15) in 200 ml of methanol. The solution was reacted at room temperature under normal-pressure hydrogen gas. The reaction was stopped after 20 hours, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. As a result, 1.4 g of methyl 4-amino-1-methyl-1-cyclohexanecarboxylate was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:55]([O:57][C:58](=[O:61])[CH2:59][NH2:60])[CH3:56]>CN(C=O)C.O>[CH2:55]([O:57][C:58](=[O:61])[CH2:59][NH:60][C:20]([C:17]1[CH:16]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:19][N:18]=1)=[O:22])[CH3:56]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid (0.7 g, 0.00237 mol) in DMF (4 mL) was added DIPEA (1.226 g, 0.00948 mol), HOBt (0.4 g, 0.0029 mol) and EDCI.HCl (0.57 g, 0.0029 mol) at ambient temperature. After 5 minutes glycine ethyl ester hydrochloride (0.347 g, 0.0024 8 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (65% ethyl acetate in hexane) afforded 0.66 g (73%) of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester. To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester (0.65 g, 0.00171 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.215 g, 0.00512 mol) at ambient temperature. The resulting mixture was stirred overnight. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 0.56 g of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid. LCMS: 353.11 (M+1)+, 60.4%.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][Si](C)(C)C)=[N:9][CH:10]=1)([CH3:4])[CH3:3].C(NC(C1C(=O)C2C(=NC=CC=2)N(C2C=CC=C(C#C[Si](C)(C)C)C=2)C=1)=O)(C)C>>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:10][N:9]=1)#[CH:12]
Reactant: CC(C)(O)c1ccc(C#C[Si](C)(C)C)nc1
Agent: CC(C)NC(=O)c1cn(-c2cccc(C#C[Si](C)(C)C)c2)c2ncccc2c1=O
Product: C#Cc1ccc(C(C)(C)O)cn1

Procedure:
Following the procedure of Step 2 of EXAMPLE 5, but substituting the product 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine from present Step 2 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine compound was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([NH2:14])[CH2:13][CH2:12]1>C(O)C>[CH:11]1([NH:14][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CC1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1NC1CC1
Temperature: 80 °C
Yield: 96.2 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (0.50 g, 3.5 mmol) in ethanol was added cyclopropyl amine (0.60 g, 10.5 mmol). The solution was heated to 80° C. overnight and concentrated. The residue was purified by biotage column chromatography to give N-cyclopropyl-2-nitroaniline (0.60 g)
Reaction SMILES: [CH:1]12[N:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH3:18][C@:19]1([NH2:34])[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20]1.FC(F)(F)S([N-]S(C(F)(F)F)(=O)=O)(=O)=O.[Li+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:18][C@:19]1([NH:34][C@@H:1]2[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]2[NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20]1
Reactant: C[C@]1(N)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(OCc1ccccc1)N1C2CCCCC21
Agent: O=C([O-])O
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Product: C[C@]1(N[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 45 °C
Reaction time: 72 h
Yield: 16.2 %

Procedure:
A solution of benzyl 7-azabicyclo[4.1.0]heptane-7-carboxylate (170 mg, 0.733 mmol) in CH2Cl2 (1 mL) was added to a 25 mL flask containing (S)-3-methyl-1-(4-nitrophenyl)piperidin-3-amine (115 mg, 0.489 mmol). Then lithium bis(trifluoromethylsulfonyl)amide (28.1 mg, 0.098 mmol) was added in one portion. The resulting greenish orange mixture was stirred at 45° C. under argon for 3 days. The reaction was cooled to rt and diluted with CH2Cl2. Then saturated aqueous NaHCO3 solution (4 mL) was added to the reaction and the reaction was stirred at rt for 30 min. The separated aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified using ISCO column eluting with a gradient of 50-100% EtOAc/Hex. Two diastereomers were separated. The slower eluting fraction which had shorter Rf was the desired product. The fractions containing the desired product were concentrated to give title compound, benzyl (1R,2R)-2-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate (37 mg, 0.079 mmol, 16.2% yield) as a yellow oil. Anal. Calcd. for C26H34N4O4 m/z 466.5, found: 467.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08-7.96 (m, 2 H), 7.39-7.29 (m, 5 H), 6.75 (d, J=9.34 Hz, 2 H), 5.13-5.01 (m, 2 H), 3.38-3.28 (m, 1 H), 3.24 (d, J=12.64 Hz, 1 H), 3.19-3.07 (m, 2 H), 2.98 (d, J=12.64 Hz, 1 H), 2.43-2.29 (m, 1 H), 2.21-2.09 (m, 1 H), 2.02-1.91 (m, 1 H), 1.88-1.77 (m, 1 H), 1.67-1.57 (m, 4 H), 1.55-1.44 (m, 3 H), 1.35-1.15 (m, 4 H), 1.07 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][O:43]C)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.BrCC([N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)=O.BrCCOC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][C:42](=[O:43])[N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:8][CH:7]=2)=[CH:45][CH:46]=1
Reactant: O=C(CBr)N1CCCC1
Reactant: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COCCBr
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OCC(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized as described for Compound 475, except 2-bromo-1-pyrrolidin-1-yl-ethanone was used for alkylation instead of 1-bromo-2-methoxy ethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([F:25])[C:17](F)=[C:18]([F:23])[CH:19]=3)[N:14]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:34][OH:35].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([F:25])[C:17]([O:35][CH3:34])=[C:18]([F:23])[CH:19]=3)[N:14]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CO
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(F)c(F)c(F)c21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(COCC[Si](C)(C)C)c2c1F
Temperature: 140 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-oxo-6,7,8-trifluoro-1-(2-(trimethylsilyl)ethoxy) methyl-3-quinolinecarboxamide (1.00 g) from Preparation No. 13 and methanol (163 μL) are dissolved in DMF (20 mL). Sodium hydride (60% dispersion, 80 mg) is added and the mixture is heated to 140° C. for 1 h. The mixture is allowed to cool to rt, is poured into sat. aq. ammonium chloride (100 mL), and is extracted with ethyl acetate (3×50 mL). The organic layer is washed with brine (10 mL), dried (MgSO4), and concentrated. The crude product is purified by column chromatography (heptane/ethyl acetate, 4/1; 3/1) to afford N-((4-chlorophenyl)methyl)-6,8-difluoro-7-methoxy-4-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-3-quinolinecarboxamide. The resulting crude amide is suspended in ethanol (15 mL), heated to 85° C., and to the mixture is added 50% aq. hydrochloric acid (5 mL). The mixture is heated an additional 1.5 h and allowed to cool to rt. The reaction mixture is neutralized with solid sodium bicarbonate and filtered. The solids are washed with ethanol (10 mL) followed by ethyl acetate (20 mL), and the combined filtrates are concentrated to afford a tan solid. The crude product is purified by recrystallization from acetic acid/water followed by column chromatography (heptane/2-propanol, 95/5) to afford 27 mg of the title compound.