Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:22])[CH2:10][N:11]2[CH2:14][CH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].Cl.[NH2:29][OH:30]>CC(O)C.C(OCC)(=O)C>[OH:22][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1](=[N:29][OH:30])[NH2:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:12][CH:13]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:14]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C#N)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C(N)=NO)cc2)C1
Temperature: 85 °C
Yield: 99.1 %

Procedure:
To a mixture of tert-butyl 1-(2-(4-cyanophenyl)-2-hydroxyethyl)azetidine-3-carboxylate (100 mg, 0.331 mmol) and sodium bicarbonate (111 mg, 1.323 mmol) in 2-propanol was added hydroxylamine hydrochloride (22.98 mg, 0.331 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to yield 110 mg of tert-butyl 1-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethyl)azetidine-3-carboxylate. MS (m+1)=336. HPLC Peak RT=0.91 minutes (Analytical Method B).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>[Pd].CO>[CH2:32]([C:13]1[CH:14]=[C:15]([C:16]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:11][CH:12]=1)[CH3:33]
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
N-(6-Methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (62.0 mg, 0.140 mmol) and palladium on activated carbon (Aldrich, St. Louis, Mo. 10% Pd, 19.1 mg) were added to MeOH (2.0 mL) and TFA (0.30 mL). The reaction flask was evacuated and back-filled with hydrogen, and the reaction was stirred at room temperature for one hour. Then, the hydrogen balloon was removed, and stirring was continued at room temperature, without the balloon of hydrogen, for 90 minutes. Then, the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (45° C.-50° C.), and stirring was continued under nitrogen overnight. The reaction was cooled to room temperature and filtered through a pad of Celite® (diatomaceous earth), which was washed with DCM and MeOH and a couple of drops of TFA. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (50° C.). Then, the material was washed with Et2O, MeOH, and Et2O, collected, and dried under high vacuum overnight to give 5-ethyl-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (17.8 mg, 35% yield). MS (ESI pos. ion) m/z 362 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.53 (s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=2.54 Hz, 1H), 8.22-8.13 (m, 2H), 6.84 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 2.85 (s, 3H), 2.65 (q, J=7.37 Hz, 2H), 1.26 (t, J=7.53 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6].[CH3:23][NH2:24]>>[CH3:23][NH:24][C:3](=[O:2])[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6]
Reactant: CN
Reactant: COC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CNC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
A 500-mL flask was charged with 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-3-oxo-propanoic acid methyl ester (24.3 g, 79.3 mmol) and a 40% methylamine solution (55 g). The solution was stirred for 2 h. The conversion of the starting material (Rf 0.91) to the title compound (Rf 0.4) was monitored by TLC using 1:1 ethyl acetate-hexane as solvent and UV detection of the substances. The solution was diluted with 2-propanol (100 mL) and evaporated. The solid residue was taken up in boiling 2-propanol (ca. 100 mL) and evaporated again. The residue was again taken up in boiling toluene (ca. 75 mL) and the hot solution was concentrated to afford a crystalline suspension. This suspension was re-dissolved by heating and the hot solution was diluted with cyclohexane (80 mL) to cause immediate crystallization. The suspension was homogenized by reheating, allowed to cool to room temperature, then refrigerated overnight and filtered. The filter cake washed with cyclohexane and hexane, dried to constant weight at 65° C. and 20 torr to afford 22.77 g of the title compound. This material was recrystallized by dissolving in boiling toluene (ca. 120 mL) followed by the addition of cyclohexane (100 mL). The suspension was allowed to cool to room temperature, then refrigerated and filtered. The filter cake was washed with cyclohexane then hexane and dried to constant weight at 65° C. and 20 torr to afford 22.03 g of the title compound (91%). TLC (1:1 ethyl acetate-hexane) Rf 0.48; 1H-NMR (300 MHz, DMSO-d6) δ 1.37 (9H, s), 2.57 (3H, d, J=4.6 Hz), 3.73 (2H s), 7.73 (2H, s), 7.85 (1H, s), 8.08 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1F
Yield: 68.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 2-fluoro-4-methylphenylboronic acid (0.077 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.067 g (67%) of the title compound.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.CC(=O)OCC>[C:14]([O:17][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1coc(CCl)n1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1coc(COC(C)=O)n1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(chloromethyl)oxazole-4-carboxylate (Organic Process Research & Development 2001, 5, 37-44) (20.00 g, 113.91 mmol) in acetic acid (80 mL) was treated with acetic anhydride (8.0 mL) followed by sodium acetate (39.72 g, 484.14 mmol). The reaction mixture was stirred at 120° C. for 3 h. EA (400 mL) was added at rt and the suspension was neutralized with sat. aq. sodium carbonate. The layers were separated and the aq. layer was extracted with EA (2×400 mL). The combined org. layers were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 06: tR=0.48 min, [M+H]+=200.41.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2>C(#N)C.O>[Br:1][C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[CH2:14][CH2:15][CH2:16]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
N-bromosuccinimide (1.26 g, 7.1 mmol) was added to a solution of 5-methoxyindan 124 (1.0 g, 6.7 mmol) in acetonitrile (34 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-10% ethyl acetate in hexane) provided 125 (1.53 g, 100%) as a liquid.
Reaction SMILES: [OH-].[K+].[C:3]([O-:9])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH3:10][C:11](O)([CH:13](Cl)[CH2:14][C:15](Cl)([Cl:17])[Cl:16])[CH3:12]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:5]([CH:4]1[CH:13]([CH:14]=[C:15]([Cl:17])[Cl:16])[C:11]([CH3:12])([CH3:10])[O:9][C:3]1=[O:8])(=[O:6])[CH3:7]
Reactant: CC(C)(O)C(Cl)CC(Cl)(Cl)Cl
Reactant: CC(=O)CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)C1C(=O)OC(C)(C)C1C=C(Cl)Cl
Temperature: 80 °C

Procedure:
112 g of 50% strength KOH were added dropwise at room temperature to 162 g (0.5 mol) of the acetoacetate of 2-methyl-3,5,5,5-tetrachloropentan-2-ol in 200 ml of toluene and 5 g of tetrabutylammonium bromide. The mixture was then heated to 80° C. for a further 1-2 hours. After cooling the mixture, the aqueous phase was rendered strongly acid and the salts which had precipitated were dissolved with water. The organic phase was then separated off and dried with sodium sulphate and the solvent was stripped off under reduced pressure. 105 g of 2-acetyl-3-(2',2'-dichlorovinyl)-4-methyl-γ-valerolactone were obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[C@H:64]([C:66](O)=[O:67])[CH3:65].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:63]([C:69]([O:71][C:72]([CH3:73])([CH3:75])[CH3:74])=[O:70])[C@H:64]([C:66]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:67])[CH3:65]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
At 0° C. the solution of 1490 mg (1.63 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 25 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 320 mg (169 mmol) of Boc-Ala-OH, 220 mg (1.63 mmol) of 1-hydroxybenzotriazole and 350 mg (1.70 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 16 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 100 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 50 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated. The residue was purified on sinica gel chromatography (CHCl3/CH3OH, 30/1) to provide 1620 mg (94%) of the title compound as a glassy mass . Mp 96–98° C., FAB-MS (m/e) 1076.7[M+Na]+, 1093.4[M+K]+, 954.9[M-Boc]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].CO>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:19][C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[Cl:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Cl)CC1

Procedure:
To a solution of 9.199 g (46.168 mM) of 1-(tert-butoxycarbonyl)-4-piperidone and 19.5 g (46.2 mM) of 2-chlorobenzyltriphenylphosphonium chloride in 50 ml of methanol was added 8.91 g (46.2 mM) of 28% sodium methoxide-methanol at room temperature and the mixture was refluxed for 36 hours. This reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The pooled organic layer was dried over Na2SO4 and the solvent was distilled off under reduced pressure. To the residue was added diethyl ether and the resulting precipitate (triphenylphosphine oxide) was filtered off and washed with diethyl ether. The filtrate and washes were combined and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 6/1) and crystallized from cold hexane to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([F:9])[CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:9][CH:6]1[CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:23])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH:3]([CH2:2][NH:1][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:8][CH2:7]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CC(F)CCC2CN)c(-c2ccccc2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CC(F)CCC2CNc2ccc(C(F)(F)F)cn2)c(-c2ccccc2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-5-fluoropiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone (0.18 mmol, 0.06 g), 2-chloro-5-(trifluoromethyl)pyridine (0.38 mmol, 0.07 g) and Cs2CO3 in DMF (1.5 mL) was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The desired (5-fluoro-2-((5-(trifluoromethyl)pyridin-2-ylamino)methyl)piperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone was isolated by preparative HPLC. MS (ESI) 479 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: CC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CC(=CC(=O)Nc1ccc([N+](=O)[O-])cc1)N1CCCC1
Yield: 93.6 %

Procedure:
A mixture of 11.10 g (50 mmol) of N-(4-nitrophenyl)-3-oxobutanamide and 4.26 g (60 mmol) of pyrrolidine in 125 ml of benzene was refluxed for one hour using a Dean-Stark trap to separate water. The reaction was cooled to give 12.89 g (94% yield) of N-(4-nitrophenyl)-3-pyrrolidyl-2-butenamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCOC(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 3a using 3-oxopentanoic acid ethyl ester and 1-bromomethyl-4-trifluoromethoxybenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2ncc(Cl)c(Cl)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2ncc(Cl)c(N3CCCC3)c2c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
A mixture of methyl 3,4-dichloroquinoline-6-carboxylate (100 mg), pyrrolidine (33 mg), and NMP (2 mL) was heated under stirring at 180° C. for 10 minutes under microwave irradiation. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 3-chloro-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (40 mg).
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@@H:16]([CH2:21][OH:22])[C:17]([O:19]C)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@@H:16]([CH2:21][OH:22])[C:17]([OH:19])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cccc2c1NC1CCCC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CO)C(=O)O)c1cccc2c1NC1CCCC21
Yield: 16.9 %

Procedure:
Following the procedure of method 7D, methyl (2S)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]-3-hydroxypropanoate (8.9 mmol, 2.7 g) was hydrolyzed to the acid using 1 M aqueous lithium hydroxide (40 mL) in THF (40 mL) to yield a red oil (1.5 mmol, 430 mg, 17%).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CN(C)C=O>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC(F)(F)F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (74%).
Reaction SMILES: [CH2:1]([C@@:4]1(C)[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]([CH:44]2[CH2:46][CH2:45]2)[CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]1=[O:47])C=C.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC[O:70][C:71]([CH3:73])=[O:72]>O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(#N)C>[Si:27]([O:26][CH2:25][C@@H:24]([N:6]1[C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:9][C@@:4]([CH2:73][C:71]([OH:70])=[O:72])([CH3:1])[C:5]1=[O:47])[CH:44]1[CH2:45][CH2:46]1)([C:40]([CH3:42])([CH3:43])[CH3:41])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To a rapidly stirring solution of (3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (1450 mg, 2.08 mmol; Example 251, Step D) in a mixture of water (11 mL), acetonitrile (7.2 mL), and CCl4 (7.2 mL) was added sodium periodate (1780 mg, 8.32 mmol), followed by ruthenium (III) chloride hydrate (47 mg, 0.21 mmol). After being stirred vigorously for 16 h, additional water (5.4 mL), acetonitrile (3.6 mL), and CCl4 (3.6 mL) were added and to the resulting clear dark solution as was added additional sodium periodate (890 mg, 4.16 mmol) and ruthenium (III) chloride hydrate (24 mg, 0.10 mmol). After being stirred vigorously for additional 4 h, the reaction was acidified (10% citric acid) and diluted (EtOAc). The reaction mixture was filtered through pad of Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth) and the filtrate was extracted (2×EtOAc). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (80 g SiO2, 30%, 40%, and 50% EtOAc/Hex) provided the title compound as a pale yellow foam.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:3])[NH2:2].C(OCC)(=O)C.Cl>C(O)C>[ClH:19].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][CH:6]2[CH2:5][NH:4][C:1]([NH2:2])=[O:3])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNC(N)=O)C1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)NCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-[(carbamoylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (160 mg) in ethanol (0.5 mL) was added 4 N hydrogen chloride-ethyl acetate solution (3.0 mL), and the mixture was stirred at room temperature for 2 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-water to give the title compound (102 mg).