Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:26]4[CH2:27][CH2:28][CH2:29][N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:25]4=[N:24][C:18]=3[CH:19]=[N+:20]2[O-])=[CH:15][CH:14]=1.[OH-].[NH4+:39]>ClCCl.O>[NH2:39][C:19]1[C:18]2[N:24]=[C:25]3[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:17]=2[C:16]2[C:21](=[CH:22][C:13]([Br:12])=[CH:14][CH:15]=2)[N:20]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCn2c1nc1c[n+]([O-])c3cc(Br)ccc3c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCn2c1nc1c(N)nc3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (441 mg, 2.3 mmol) was added to a mixture of tert-butyl 3-bromo-5-oxido-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate (0.97 g, 2.3 mmol), dichloromethane (30 mL), and concentrated ammonium hydroxide (3 mL), and the reaction was stirred overnight at room temperature. Water and dichloromethane were added. The aqueous layer was separated and extracted four times with dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide/methanol in dichloromethane), and the resulting product was recrystallized from 1,2-dichloroethane and hexanes to provide 0.16 g of tert-butyl 6-amino-3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CSc1cccc(C=O)c1
Product: CSc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 74A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]1(=O)[NH:23][C:22](=[O:24])[CH:21]=[CH:20]1>FC(F)(F)C(O)=O>[CH:6]1[C:5]2[O:1][C:2]3[C:10]4[NH:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[C:20]4=[CH:21][C:22](=[O:24])[N:23]=[C:19]4[C:3]=3[C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2[nH]c(-c3cc4ccccc4o3)cc2c1
Reactant: O=C1C=CC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=c2c(c3c4ccccc4oc3c3[nH]c4ccccc4c23)=N1
Temperature: 125 °C
Yield: 48.3 %

Procedure:
A mixture of 2-(2-benzofuryl)indole 2 (250 mg; 1.0 mmol) and maleimide (110 mg; 1.2 mmol) in trifluoroacetic acid (2 mL) was heated in a sealed reaction vial at 125° C. for 18 h. The solid precipitated was collected, washed with TFA and dried to give 150 mg (48%) of product. Recrystallization (THF) gave a tan solid; mp>300° C., MS (ES+) 312 (M+), 1H NMR (DMSO--d6) δ 4.00 (s, 2H), 4.13 (s, 2H), 7.12 (t, 1H), 7.37 (t, 2H), 7.45 (t, 2H), 7.71 (d, 1H), 7.95 (d, 1H), 8.54 (d, 1H), 10.12 (s, 1H), 11.79 (s, 1H). Anal. calcd for C20 H12N2O2 0.4 H2O; C, 75.18; H, 4.04; N, 8.77. Found: C, 75.29, H, 3.86, N, 8.60.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([C:18]#[N:19])(C)C.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[N:1]1([C:7]2[C:8]([C:18]#[N:19])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(N2CCCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1N1CCCCC1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl 1′-oxide (1.30 g, 7.30 mmol), trimethylsilyl cyanide (1.45 g, 14.6 mmol) and triethyl amine (1.47 g, 14.6 mmol) in dry CH3CN (25 mL) was heated at reflux for 16 h, yielding a red solution. The reaction mixture was then cooled to room temperature, and saturated aqueous NaHCO3 (20 mL) was added. After concentrated under reduced pressure the mixture was extracted with CH2Cl2 (4×30 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2) to afford 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile as a pale yellow solid (1.26 g, 92%). 1H NMR (CDCl3) δ 1.58-1.66 (m, 2H), 1.75-1.83 (m, 4H), 3.21 (t, 4H, J=5.7 Hz), 7.34-7.38 (m, 2H), 8.19-8.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl[Sn](Cl)(Cl)Cl>C1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]2=[O:14]
Reactant: COc1ccc(SC(C)(C)CC(=O)O)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=O)CC(C)(C)S2
Yield: 78.3 %

Procedure:
To a solution of 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (20.0 g, 83.2 mmol) in 250 mL of benzene at room temperature was added a solution of oxalyl chloride (15.84 g, 124.8 mmol) in 10 mL of benzene over 30 minutes. After 4 hours the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure), followed by ice cold H2O, and finally saturated aqueous NaCl. The solution was dried (Na2SO4) and concentrated under reduced pressure to give a clear yellow oil. This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ: 7.45 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 3.84 (3H, s), 3.12 (2H, s), 1.41 (6H, s). Step 3: To a solution of the acyl chloride product of Step 2 (21.5 g, 83.2 mmol) in 250 mL of CH2Cl2 at 0° C. was added dropwise a solution of SnCl4 (21.7 g, 83.2 mmol) in 30 mL of CH2Cl2. After 2 hours the reaction was quenched by slow addition of 150 mL H2O. The organic layer was washed with 1M aqueous HCl, 5% aqueous NaOH, H2O, and finally saturated aqueous NaCl before being dried over MgSO4. Concentration under reduced pressure and vacuum distillation of the residual oil (Bulb-to-bulb, 125-135° C., 5 mm/Hg) afforded 14.48 g (78%) of 6-methoxy-2,2-dimethyl-thiochroman4-one as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.62 (1H, d, J=2.9 Hz), 7.14 (1H, d, J=8.6 Hz), 7.03 (1H, dd, J=2.8 Hz), 3.83 (3H, s), 2.87 (2H, s), 1.46 (6H, s).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:17]1([CH2:23][CH2:24][C:25]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
To a solution of 2-phenylbenzo[d]oxazol-5-amine (50 mg, 0.24 mmol) in dichloromethane (2 mL) at room temperature was added 3-phenylpropanoyl chloride (44.1 mg, 0.26 mmol) followed immediately by diisopropylethylamine (82 μL, 0.48 mmol). The resulting mixture was stirred at room temperature for 16 h. Dichloromethane was added and the organic layer was washed with saturated aqueous Na2CO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was dissolved in methanol, passed through an acidic scavenger column (silica-based quaternary amine SPE-AX from Biotage®) and then evaporated to afford 61.1 mg (75%) of the title compound (LCMS RT=6.45 min, MH+ 343.2)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[C:13]4[CH2:18][CH2:17][NH:16][CH2:15][C:14]=4[C:19](=[O:21])[O:20][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:22].[Cl:23][CH2:24][CH2:25][N:26]1[CH2:32][CH:31]2[CH2:33][CH2:34][CH:28]([CH2:29][CH2:30]2)[CH2:27]1>>[ClH:23].[ClH:22].[CH:31]12[CH2:33][CH2:34][CH:28]([CH2:29][CH2:30]1)[CH2:27][N:26]([CH2:25][CH2:24][N:16]1[CH2:17][CH2:18][C:13]3[C:10]4[CH:11]=[CH:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][C:9]=4[O:20][C:19](=[O:21])[C:14]=3[CH2:15]1)[CH2:32]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: O=c1oc2cc(-c3ccccc3)ccc2c2c1CNCC2
Agent: Cl
Product: O=c1oc2cc(-c3ccccc3)ccc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2
Yield: 9.2 %

Procedure:
Prepared by the method described for Example 1 from 8-phenyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.54 g, 0.02 moles) and 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (4.48 g, 0.02 moles). Recrystallization from methanol gave the product (920 mg), mp 260°-265° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:29]1[CH2:30][CH2:31][N:26]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH2:27][CH:28]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C(c1ccccc1)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.77 mL, 9.250 mmol), 1-benzoyl-4-piperidone (1.0 g, 4.933 mmol) at room temperature and resulting solution was refluxed for 3 days. The reaction cooled to room temperature and the solid was filtered off. The product was washed with cold ethanol (2×10 mL) and dried under vacuum to obtain compound 68 (1.05 g, 98%) as a solid. mp 280-282° C.; 1H NMR (DMSO-d6) δ 2.55-2.61 (m, 2H), 3.54-3.58 (m, 1H), 3.86-3.90 (m, 1H), 4.15-4.34 (m, 2H), 6.14-6.30 (m, 1H), 7.39-7.55 (m, 5H), 7.67 (d, 1H, J=9.6 Hz), 7.72 (s, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70-8.78 (m, 1H), 11.94 (s, 1H); ESI-MS m/z (%): 348 (M+, 100), 276 (83), 244 (40).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:58]2[CH:59]=[CH:60][C:61]([C:63]3[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=3)=[CH:62][C:57]=2[O:56][CH2:55][CH2:54]1>CN(C=O)C>[O:53]1[C:58]2[CH:59]=[CH:60][C:61]([C:63]3[CH:64]=[C:65]([NH:69][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=3)=[CH:62][C:57]=2[O:56][CH2:55][CH2:54]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 67% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:29])[CH:16]([NH2:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH3:31]C(C)([O-])C.[Na+].O>C1COCC1>[CH2:11]([O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]2[C:3](=[O:2])[NH:28][CH:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:15](=[O:29])[NH:14][C:5]=2[CH:6]=1)=[O:9])[CH3:31]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(N)CCCNC(=O)OC(C)(C)C)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C(CCCNC(=O)OC(C)(C)C)NC2=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
The compound (303.8 mg) obtained in Example 14-2 and sodium t-butoxide (manufactured by Wako Pure Chemical Industries, Ltd.) (138.4 mg) were dissolved in anhydrous THF (6.0 ml) and the whole was stirred at 60° C. for 15 hours. After completion of the reaction, water was added thereto and the whole was subjected to extraction with chloroform.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.C([O:14][C:15](=O)[C:16](=[N:20]O)[C:17](=O)[CH3:18])(C)(C)C.O>C(O)(=O)C.[Zn]>[CH:15]([C:16]1[NH:20][C:6]([CH3:7])=[C:5]([C:4]([OH:3])=[O:9])[C:17]=1[CH3:18])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 60 °C

Procedure:
Ethyl-3-oxobutyrate (130 g, 1 mol) was dissolved in 400 mL of acetic acid in a 2 L 3-neck round bottom flask equipped with a thermometer, an addition funnel, mechanical stirring and placed in an oil bath. Zinc dust (50 g, 0.76 mol) was added and the mixture heated to 60° C. with stirring. The crude t-butyl-2-hydroximino-3-oxobutyrate solution prepared above was cautiously added keeping the temperature at about 65° C. by slowing the addition and cooling the flask. More zinc dust (4×50 g, 3.06 mol) was added in portions during the addition with the last portion added after all the t-butyl ester had been added. The temperature of the mixture reached a maximum of 80° C. At the end of the additions the temperature was 64° C. The temperature was increased by heating to 70-75° C. for one hour and then poured into 5 L of water. The gray floating precipitate was collected by vacuum filtration and washed with 2 L of water to give 354 g of wet crude product. The crude product was dissolved in 1 L of hot methanol and hot filtered to remove zinc. The filtrate was cooled to give a precipitate that was collected by vacuum filtration to give 118 g of product. The filtrate was put in the refrigerator overnight to give a total of 173.2 g of
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@H:17]([C:22]([N:24]([C@@H:26]([CH:33]([CH3:35])[CH3:34])/[CH:27]=[C:28](/[C:30](O)=[O:31])\[CH3:29])[CH3:25])=[O:23])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[C:4]([CH3:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C(#N)C>[CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@H:17]([C:22]([N:24]([C@@H:26]([CH:33]([CH3:35])[CH3:34])/[CH:27]=[C:28](\[CH3:29])/[C:30]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:31])[CH3:25])=[O:23])[C:18]([CH3:20])([CH3:21])[CH3:19])=[O:15])[C:4]([CH3:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1
Reactant: C1COCCN1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1cccc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N1CCOCC1)C(C)C)C(C)(C)C)C(C)(C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
By using an analogous procedure to that described in General Procedure I Method A, N,β,β,3-tetramethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropyl-2-butenyl]-N1,3-dimethyl-L-valinamide (100 mg, 0.205 mmol) is treated with hydroxybenzotriazole (36 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) in anhydrous acetonitrile (3 ml) at room temperature for 15 hours, followed by addition of morpholine (0.036 ml, 0.41 mmol). After stirring at room temperature for 15 hours, the product is purified using the aqueous work-up method, to provide the title compound (89 mg, 78%) as a orange amorphous solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][C:8]([CH3:12])([OH:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:12][C:8]1([OH:11])[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[C:3]=2[CH2:10][CH2:9]1
Reactant: CC1(O)CCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC1(O)CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 85 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-13) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 85% yield. MS: 294.1 (M+H+)
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11]([CH2:15][CH3:16])C(O)=O>C(#N)C>[C:7]([C:3]1[NH:1][C:11]([CH2:15][CH3:16])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: CCC(N)C(=O)O
Solvent: CC#N
Product: CCc1nc(C)c(C(C)=O)[nH]1

Procedure:
To 4.78 g (0.037 moles) of 3-oximino-2,4-pentanedione dissolved in 40 ml of acetonitrile was added 3.82 g (0.037 moles) of 2-aminobutyric acid. The mixture was brought to reflux, while stirring rapidly under nitrogen, with an oil bath. After 22.5 h the reaction mixture was cooled, suction filtered, and the residue washed with acetonitrile (50 ml). The combined filtrates were concentrated in vacuo, and the resulting oil dissolved in 1 M hydrochloric acid (30 ml). The acid solution was washed with methylene chloride (4×20 ml), then neutralized with solid potassium carbonate. Extraction with methylene chloride, followed by drying over anhydrous potassium carbonate and concentration in vacuo furnished 0.021 moles (67.8%) yield based on recovered d,l-norvaline) of 5-acetyl-2-ethyl-4-methylimidazole.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:4]=1.[CH2:17](Cl)Cl>CO.CCCCCC>[F:16][C:2]([F:15])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH3:17])=[O:12])[CH:4]=1
Reactant: CC(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Reactant: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C(C)Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-trifluoromethyl-2-pyridyloxy)propionic acid (Step A, 15 g, 55 mol) in 100 mL CH2Cl2 and 100 mL MeOH at 0° C. was added trimethylsilydiazomethane (2 M solution in hexane) until a yellow color persisted. After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluted with 0 to 10% EtOAc in hexane to give methyl 2-(4-trifluoromethyl-2-pyridyloxy)propionate (10 g), which was used immediately for methylation following the procedure described in Reference Example 39, Step B substituting ethyl iodide with methyl iodide. 1H NMR (500 MHz, CD3OD): δ 8.25 (d, 1H), 7.18 (d, 1H), 7.15 (s, 1H), 3.65 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[N:25]([CH3:33])[C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:23])=[O:22])=[C:16]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38].C(OCC)(=O)C>CCOCC>[ClH:38].[CH3:37][S:34]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[NH:20][S:21]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:23])(=[O:36])=[O:35]
Reactant: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCNCC3)cc2S(C)(=O)=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[3-methanesulfonyl-4-(1-methyl-1H-indole-2-sulfonylamino)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.038 g) was treated with 2.5 N HCl/ethyl acetate (2.5 ml). The reaction mixture was stirred at rt for 2 h, then ether (20 ml) was added. The precipitate was collected, washed with ether and dried under high vacuum over P2O5 to produce the title compound (0.032 g) as an off-white powder. MS (ISN): 446.4 (M−H)−
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:12](=[O:40])[NH:13][CH:14]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[N:23]=[N:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=1)=[O:16])[CH2:10][CH3:11])C)(C)(C)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH2:27]([N:25]1[N:24]=[N:23][C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:15](=[O:16])[CH:14]([NH:13][C:12](=[O:40])[C@@H:9]([NH:7][CH3:6])[CH2:10][CH3:11])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:26]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC[C@@H](C(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](NC)C(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound G in DCM (2 mL) is added TFA (2 mL) at 0° C. The solution is stirred at room temperature for 1 hr and dried under vacuum. The crude oil is purified by HPLC to provide the title compound. M+H+=467.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([SH:6])[CH3:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=O)C>ClCCl>[CH2:4]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])[CH3:5]
Reactant: CC(=O)OC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCSC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of 572 mg sodium hydroxide in 50 ml. water was added 1.32 ml. of ethanthiol. After 10 minutes a solution of 5.02 g. 4-acetoxy-3-(p-nitrobenzyloxycarbonyloxyethyl)-2-oxo-azetidine in 100 ml. dichloromethane was added and the mixture was stirred vigorously at 0° C. for 30 minutes then at 25° C. for 3 hours. The dichloromethane layer was separated and the aqueous phase was extracted with two 70 ml. portions of dichloromethane. The combined dichloromethane extracts were washed with 70 ml. water, then with 70 ml. saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The crude product was purified by column chromatography silica gel, eluting with 5:1 chloroform ethyl acetate, to obtain 4.15 g. of the title compound.