Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:16][C:17]1[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O.NC1C=CC=CC=1C(C1C=CC(F)=CC=1)=O>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:18]3[C:17](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: COC(=O)CC(=O)C1CC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
47.9 g of methyl 3-cyclopropyl-3-oxopropionate and 100 g of 2-amino-4′-fluorobenzophenone methanesulfonate were added to 584 g of toluene, and the mixture was dehydrated and refluxed at an internal temperature of 79 to 81° C. under a reduced pressure of 40 kPa. The reaction mixture was analyzed with HPLC during the reaction, and methyl 3-cyclopropyl-3-oxopropionate was added thereto by dividing it into several parts until the residual amount of 2-amino-4′-fluorobenzophenone was less than 2%. An additional amount of methyl 3-cyclopropyl-3-oxopropionate was 13.8 g. After 40 hours of reaction time, the residual amount of 2-amino-4′-fluorobenzophenone was 1.7%. The reaction solution was washed with 320 g of 4% aqueous solution of sodium hydroxide and then 140 g of 2% aqueous solution of sodium hydroxide. The reaction solution was further washed with 100 g of 5% brine solution, and then dried over 10 g of anhydrous magnesium sulfate. Toluene was removed under a reduced pressure, and crystallization was carried out in 740 g of cyclohexane to obtain 88.4 g of methyl 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:7]=[CH:6]2.C(Cl)(Cl)Cl.Cl.C(COC)OC>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 50 °C
Reaction time: 23 h
Yield: 57.5 %

Procedure:
A mixture of 90 mg (0.37 mmol) of methyl (+)-α-(6-methoxy-2-naphthyl)propionate having a 100% optical purity [α]D20 +78.2° (CHCl3)], 1 ml of 12N aqueous hydrochloric acid and 1 ml of dimethoxyethane was stirred at 50° C. for 23 hours. After adding 10 ml of water, the mixture was extracted with diethyl ether (8 ml×3), and the extract was washed with water (3 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography [silica gel, hexane+ethyl acetate (1:2)] to obtain 49 mg of (+)-α-(6-methoxy-2-naphthyl)propionic acid as colorless crystals. Yield, 63%.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:18])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH:4]([C:19]([OH:21])=[O:20])[CH2:3]1.CO.[CH2:24](O)[CH3:25]>>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:18])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH:4]([C:19]([O:21][CH2:24][CH3:25])=[O:20])[CH2:3]1
Reactant: COc1ccc(C(=O)N2CC(O)CC2C(=O)O)cc1OC
Reactant: CCO
Solvent: CO
Product: CCOC(=O)C1CC(O)CN1C(=O)c1ccc(OC)c(OC)c1
Yield: 60 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)-pyrrolidine-2-carboxylic acid by 4-hydroxy-1-(3,4-dimethoxybenzoyl)pyrrolidine-2-carboxylic acid and methanol by ethanol, the title product is obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1.[OH:25][C:26]([CH3:41])([C:30]([NH:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[O:31])[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1>>[CH2:18]([O:17][CH2:16][CH2:15][N:5]1[CH2:4][C@H:3]([NH:2][C:27](=[O:28])[C:26]([OH:25])([CH3:41])[C:30]([NH:32][CH2:33][C:34]([F:39])([F:40])[C:35]([F:36])([F:38])[F:37])=[O:31])[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O

Procedure:
In an analogous manner to that described in Example 1e), the condensation of (S)-3-amino-5-(2-benzyloxy-ethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride and (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid with 1-hydroxy-benzotriazole and N-(3-dimethylaminpropyl)-N′-ethyl-carbodiimide hydrochloride as the condensating agents yielded a 1:1-mixture of the epimeric title compounds as a light yellow solid; MS (m/e) 559 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:8])=[CH:4][CH2:3]1.ClCCl.C(N(CC)CC)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(OCC)(=O)C.O>[CH3:8][C:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH2:3][CH:4]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1=CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=CCC(NC(=O)Nc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The residue containing 1-amino-4-methylcyclohex-3-ene was taken up into dichloromethane (5 ml). To the mixture were added triethylamine (0.6 ml) and 4-fluorophenyl-isocyanate (97 μl) at 0° C. and the resultant mixture was allowed to stir for 30 minutes at 0° C. Evaporation under reduced pressure gave a residue, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed with brine, evaporated under reduced pressure, and triturated with n-hexane to give N-(4-methylcyclohex-3-en-1-yl)-N′-(4-fluorophenyl)urea (0.206 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:24]2[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]2=[O:32])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([F:15])[CH:17]=2)[C:25]1=[O:32])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1ccc(N2CCC(C(=O)O)C2=O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1F
Yield: 39.5 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.113 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 25% of ethyl acetate in dichloromethane) to give 0.072 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:34][CH:35]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(C2CCCCC2)cc1

Procedure:
The title compound, white solid (114 mg, 89%), MS (ISP) m/z=513.6 [(M+H)+], mp 230° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-cyclohexyl-benzoic acid.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([O:9]C(C1C=CC=CC=1)=O)=[O:8])=[O:4].[OH-].[K+]>O.C1COCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
The Boc-Gly-Pro-OBz (19.4 g, 0.054 mol.) was dissolved in a mixture of 100 ml H2O and 100 ml THF. After cooling the solution to 0° C., KOH (4.8 g, 0.085 mol.) in 50 ml H2O was added slowly. The solution was stirred for one hour. Then, the THF was removed under reduced pressure and the aqueous solution was extracted with ethyl acetate to remove the benzyl alcohol. The resulting aqueous phase was covered by 200 ml ethyl acetate and was acidified at 0° C. to about pH 2 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase with ethyl acetate 3×200 ml. The organic layers were combined and washed with brine 2×30 ml, and dried by Na2SO4. Removal of the ethyl acetate gave the product Boc-Gly-Pro-OH (white solid, 12.3 g, 85%) TLC Rf=0.25 (CMA, 85:15:3) FAB-MS, observed MH+=273. 1H-NMR (360 MHz, DMSO-d6, 20° C.) δ12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 4.50 (dd, 0.25H, Pro α-minor), 4.20 (dd, 0.71H, Pro-α-major), 3.81-3.62 (m, 1.7H, Gly-α-major) 3.47-3.33 (m, 2H, Pro-δ and Gly-α-minor), 2.25-2.00 (m, 1.2H, Pro-β), 1.96-1.60 (m, 2.7H, Pro-β and Pro-γ), 1.36 (s, 9H, Boc).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Yield: 92 %

Procedure:
Thionyl chloride (11.1 mL, 15.3 mmol) was added to 4-acetoxybenzoic acid (2.50 g, 13.9 mmol), and the reaction was warmed to reflux. The reaction was cooled after heating for 3.5 hours, and concentrated in vacuo to give a colorless oil. Toluene was added to the residue and the mixture was concentrated in vacuo to remove any residual thionyl chloride. This process was repeated twice more to give 510 (2.54 g, 92%) as a colorless oil. This material was used in the next step without additional purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:45]1([CH:50]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][N:61]3[C:66](=[O:67])[CH2:65][O:64][C:63]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[N:62]3)=[CH:56][CH:55]=2)[C:51](O)=[O:52])[CH2:49][CH2:48][CH2:47][CH2:46]1.[OH-].[Na+]>CS(C)=O>[CH:45]1([CH:50]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][N:61]3[C:66](=[O:67])[CH2:65][O:64][C:63]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[N:62]3)=[CH:56][CH:55]=2)[C:51]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[N:6]=2)=[O:52])[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: CCOC(=O)CCc1csc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(O)CCc1csc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 mg (0.1 mmol) of ethyl 3-(2-amino-1,3-thiazol-4-yl)propanoate [Beilstein Reg. No. 9762098], 41.7 mg (0.13 mmol) of TBTU and 25.8 mg of ethyldiisopropylamine were added to a solution of 39.2 mg (0.1 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (Example 51A) in 0.5 ml DMSO. The mixture was stirred at room temperature overnight. 0.3 ml of 2 M aqueous sodium hydroxide solution was then added, and the mixture was once more stirred overnight. The solvent was then evaporated, and the residue obtained was purified directly by preparative HPLC/MS. This gave 7.1 mg (0.013 mmol, 13% of theory) of the title compound.
Reaction SMILES: [Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+].O=C1C[CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31]C1.O>C1COCC1>[CH2:22]=[C:23]1[CH2:26][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:24]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Br-]
Agent: [K+]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of THF, and potassium tert-butoxide (16.8 g, 0.15 mol) was added at −20° C. Reacted for 0.5 h after the temperature was raised to 0° C. Subsequently, ethyl 4-oxo-cyclohexylcarboxylate (Compound 8-1) (17 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise to the flask under nitrogen, reacted at room temperature for 3 hours, then a small amount of water was added to dissolve the solid, and rotary evaporated to remove THF, extracted with anhydrous diethyl ether, dried, and concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 8-2 as a colorless liquid (16.1 g, 95.7% yield).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][C:26]([CH3:29])=[N:27][N:28]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:29][C:26]1[S:25][C:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13]/[CH:2]=[C:3]3\[C:4](=[O:12])[NH:5][C:6]4[C:11]\3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[N:28][N:27]=1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Product: Cc1nnc(NS(=O)(=O)c2ccc(N/C=C3\C(=O)Nc4ccccc43)cc2)s1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and 4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide. 1H NMR (DMSO) 13.90 (bs, 1H); 10.84 (d, 1H); 10.58 (s, 1H); 8.62 (d, 1H); 7.81 (d, 2H); 7.60 (d, 1H); 7.55 (d, 2H); 7.12 (m, 1H); 6.95 (m, 1H); 7.84 (d, 1H); 2.48 (s, 3H). Electrospray MS 414 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[NH:5][C:6]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC(OC)=CC=3)=[C:24]([O:38][CH3:39])[CH:23]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:13]=[C:8]2[N:7]=1)[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:1]([O:3][C:4](=[O:40])[NH:5][C:6]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:38][CH3:39])[CH:23]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:13]=[C:8]2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a stirred solution of ethyl(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (2.50 g, 4.61 mmol) in dichloromethane (100 mL) at 0° C. was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0° C. After 2 h, the mixture was treated with 2M potassium carbonate solution to adjust the pH to ˜9. The basic mixture was extracted with 1:1 methanol/dichloromethane solution (2×50 mL). The combined organic phases were washed with brine (2×50 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.80 g (93%) of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.
Reaction SMILES: [N:1]1([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:27]([NH2:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:27]([NH:29][C:24]([C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:12]2[N:11]=[C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[N:2]3)[C:15]([Cl:16])=[CH:14][N:13]=2)[CH2:19][CH2:20]1)=[O:26])[CH3:28]
Reactant: CCN
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1CC[C@H](Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of trans-4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexane-carboxylic acid (70 mg, 0.17 mmol), ethyl amine (21 μL, 0.26 mmol), BOP (114 mg, 0.26 mmol) and DIPEA (59 μL, 0.34 mmol) in THF (60 mL) was stirred at RT for 2 days. The white solid formed was removed by filtration and the filtrate was diluted with water (25 mL) and extracted 3 times with a mixture isopropanol/chloroform (1/1, 20 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give an off white residue that was purified via flash chromatography (DCM/MeOH, 98/2) to afford 68 mg (quantitative yield) of trans-4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexane-carboxylic acid ethylamide as a white solid. MS: 400.17 (M+1)+, 372.17 ((M+1)+−28). 1H NMR (250 MHz, CD3OD) δ ppm: 8.55 (1 H, s), 8.09-8.21 (2 H, m), 7.69 (1 H, dd, J=7.50 Hz), 7.55 (1 H, dd, J=7.50 Hz), 3.71-3.88 (1 H, m), 3.18 (2 H, q, J=7.29 Hz), 2.10-2.25 (3 H, m), 1.82-1.95 (2 H, m), 1.50-1.71 (2 H, m), 1.26-1.48 (2 H, m), 1.10 (3 H, t, J=7.29 Hz).
Reaction SMILES: [C:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1=CCCC1)C2=O
Reactant: Cc1cc(NN)ccc1C#N
Agent: Cl
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2=CCCC2)ccc1C#N

Procedure:
The title compound was injustices prepared from methyl 6-(cyclopent-1-en-1-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 24 and 4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 according to Method B and Method C. The title compound was largely present as (±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.85 (m, 4H), 1.88-2.12 (m, 2H), 2.18 (s, 2H), 2.38 (s, 3H), 2.99 (d, J=4.0 Hz, 2H), 3.55-3.75 (m, 1H), 5.39 (d, J=10.7 Hz, 1H), 5.62 (s, 1H), 6.86 (br. s., 1H), 7.13 (br. s., 1H), 7.52 (d, J=8.6 Hz, 1H), 7.69-7.89 (m, 2H), 8.03 (d, J=7.8 Hz, 1H), 12.99 (s, 1H); ES-MS m/z 398 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:5]2.[CH2:26]([O:28][CH:29](OCC)OCC)[CH3:27]>S(=O)(=O)(O)O.CCCCCC>[CH2:26]([O:28][CH:29]=[N:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)=[N:5]2)[CH3:27]
Reactant: CCOC(OCC)OCC
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CCOC=Nc1ccc2nc(N3CCN(C)CC3)c(N3CCN(C)CC3)nc2c1

Procedure:
A 17.05 g. portion of 6-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) is thoroughly mixed with 100 ml. of triethylorthoformate, then 5 drops of concentrated sulfuric acid is added with magnetic stirring and the mixture is heated at reflux in an oil bath (145°-150° C.). The solid is dissolved in about 30 minutes but shortly thereafter a yellow solid is precipitated out. Stirring is continued and the mixture allowed to reflux overnight at a distillate temperature of about 75°-80° C. After refluxing for 16 hours the reflux condenser is replaced with a takeoff condenser with a 10 cm. Vigreux column attached and 6.5 ml. of distillate with a boiling point of about 80° C. is collected over a 21/2 hour period. The maximum oil bath temperature over this period of time is 180° C. The reaction mixture is cooled and the liquid layer is decanted from a small amount of insoluble material. The decanted liquid is stripped of solvent by water pump evacuation and the residual oil is triturated with 50 ml. of hexane and heated to boiling on the steam bath to dissolve the oil. The solution is cooled in an ice bath to yield a solid yellow mass. Additional hexane is added and the precipitate is filtered, washed on the filter with hexane, and pressed dry with suction to give 18.5 g. of the product of the example as a yellow solid.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]2[NH:26][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccncc3)[nH]2)cc1
Yield: 33.2 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.0 g) and 4-methoxybenzylamine (1.7 g) were dissolved in toluene (80 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.4 g), melting point 211-212° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:22]([NH:24][C@H:25]([C:36]([NH:38][C@H:39]([C:44]([NH:46][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:45])[C@H:40]([CH2:42][CH3:43])[CH3:41])=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33])=[O:23])[CH2:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>CCOC(C)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:22]([NH:24][C@H:25]([C:36]([NH:38][C@H:39]([C:44]([NH:46][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:45])[C@H:40]([CH2:42][CH3:43])[CH3:41])=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33])=[O:23])[CH2:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N[C@H](C(=O)NCC(=O)OC)[C@@H](C)CC
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N[C@H](C(=O)NCC(=O)OC)[C@@H](C)CC

Procedure:
A sample of the pentapeptide (12) suspended in EtOAc is treated exactly as described for the preparation of tetrapeptide HCl salt (11) to give product (13).