Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>C(O)C>[ClH:1].[ClH:1].[N:16]1[CH:17]=[CH:18][C:13]([NH:12][CH2:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:14][CH:15]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Nc1ccncc1
Solvent: CCO
Product: Cl
Product: c1ccc2[nH]c(CNc3ccncc3)nc2c1
Temperature: 0 °C
Yield: 113.1 %

Procedure:
A solution of 1.665 g (10 m mol) of 2- chloromethybenzimidazole and 1.88 g (20 m mol) of 4- aminopyridine in 20 ml of ethanol was refluxed under heating for three hours. The solution was evaporated in vacuo to a dark oil, dissolved in 20 ml of water and washed twice with 20 ml of ethylacetate The aqueous phase was evaporated in vacuo. The residual oil was dissolved in 3 ml of concentrated hydrochloric acid and chilled (0° C.) causing a crystalline precipitate to form. The crystals were filtered with the aid of ethanol. Recrystallization from methanol gave 1.68 g (53.3%) of the title compound (I).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9]Cl.[I-].[K+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CN(C)C(=O)C>[C:15]([C:14]1([C:13]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8]1)(=[O:16])[CH3:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A total of 165.6 g of potassium carbonate, 390.0 g of 1,2-dichloroethane, 234.0 g of N,N-dimethylacetamide, 5.0 g of potassium iodide, and 78.0 g of ethyl acetoacetate were mixed, followed by a reaction at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and was filtrated, the resulting filtrate was washed with two portions of 5% by weight hydrochloric acid, and the organic layer was washed with water. The organic layer was then concentrated under a reduced pressure to distill off 1,2-dichloroethane, was subjected to distillation under a reduced pressure and thereby yielded 31.7 g of ethyl 1-acetyl-1-cyclopropanecarboxylate as a colorless liquid as a fraction at 80° C./20 mmHg.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH3-]C#[N:29].[Na+].[BH4-].[Na+]>CO.O.C(O)=O>[NH2:29][CH2:1][C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc(-c2conn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: CO
Product: NCc1ccc(-c2conn2)s1
Reaction time: 16 h

Procedure:
To a solution of the 5-formyl-thiophen-2-yl-oxadiazol derivative (1 eq., usual scale 0.02-0.25 mmol) and the appropriate amine (2-40 eq.) in methanol (24 mL/mmol), sodium triacetoxy borohydride (NaBH(OAc)3) (10 eq.) is added. The mixture is stirred for 2 h before NaBH3CN (10 eq.) is added. Stirring of the suspension is continued for 16 h before NaBH4 (20 eq.) is added and stirring is continued for another 16 h at rt. The reaction mixture is diluted with water (4 mL/mmol) and formic acid (4 mL/mmol) and the resulting solution is separated by prep. HPLC (Waters Symmetry C18 19×50 mm, 5 μm, 10 to 95% acetonitrile in water containing 0.5% HCOOH) to give the desired 5-aminomethyl-thiophen-2-yl-oxadiazol derivative as a colourless to pale yellow resin.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[C:14]3[C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:13]=3[N:12]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[C:11]3[N:10]=1)[CH2:2]2.[NH:35]1[CH:39]=[N:38][C:37]([C:40](O)=[O:41])=[N:36]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[N:35]1[N:36]=[C:37]([C:40]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([C:9]2[C:14]4[C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:13]=4[N:12]4[N:20]=[CH:21][C:22]([C:23]5[CH:24]=[N:25][C:26]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:27][CH:28]=5)=[C:11]4[N:10]=2)[CH2:2]3)=[O:41])[NH:38][CH:39]=1
Reactant: O=C1CCNc2c1c(C1CC3CCC(C1)N3)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Reactant: O=C(O)c1nc[nH]n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCNc2c1c(C1CC3CCC(C1)N3C(=O)c1nnc[nH]1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(8-azabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one (86 mg, 0.19 mmoL), 1H-1,2,4-triazole-3-carboxylic acid (25.9 mg, 0.23 mmoL), EDC (73 mg, 0.38 mmoL), HOBt (51.6 mg, 0.38 mmoL) and DIEA (199 uL, 1.15 mmoL) in DMF (4 mL) was stirred at room temperature for 2 h. Purification with prep-LC provided 5-(8-(4H-1,2,4-triazole-3-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one: LCMS tR=2.33 Min (10 min run, UV254nm). Mass calculated for, M+ 545.2, observed LC/MS m/z 546.01 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:22]([NH:40][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCCCCCCCCCCCCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and stearylamine were used to obtain N-Stearyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 6 h
Yield: 45.3 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.9 g.), palladium-carbon (0.9 g.), methanol (20 ml.) and tetrahydrofuran (20 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature for 6 hours. After the insoluble substance was removed by filtration and washed with methanol, the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and a sodium bicarbonate aqueous solution, and filtered out. The ethyl acetate layer was separated and extracted with a sodium bicarbonate aqueous solution. The aqueous solution was washed with ethyl acetate and ethyl acetate was added thereto. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. The ethyl acetate layer was washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-chloro-3 -cephem-4-carboxylic acid (syn isomer, 0.7 g.).
Reaction SMILES: [CH2:1]([C:3]([C:5]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[O:7][N:6]=1)=O)[CH3:2].Cl.[OH:21][NH2:22]>CO>[OH:21][N:22]=[C:3]([C:5]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[O:7][N:6]=1)[CH2:1][CH3:2]
Reactant: CCC(=O)c1noc(COc2ccc(Cl)cc2Cl)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCC(=NO)c1noc(COc2ccc(Cl)cc2Cl)n1
Yield: 84.7 %

Procedure:
0.9 g of 3-ethylcarbonyl-5-[(2,4-dichlorophenoxy)methyl]-1,2,4-oxadiazole and 0.21 g of hydroxyamine hydrochloride were added to 10 ml of methanol. The mixture was heated to reflux for 4 hours. After evaporation of methanol, water was added to the residue. The aqueous solution was extracted with ethylacetate. After evaporation of ethylacetate, the residue was purified by column chromatography(benzene:ether=1.1) to provide 0.80 g of the desired product(yield: 85.0%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.O>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c(N2CCCCC2)nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
A solution of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (7.5 g), piperidine (2.4 g), and triethylamine (2.9 g) in ethanol (50 ml) was stirred at 20° C. for 2 hours. Water was added and the product was extracted into chloroform. Evaporation of the solvent and recrystallisation from ethanol gave the title compound mp 184°-185° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[CH:13]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C>C(O)C>[CH2:6]([O:5][C:1]([NH:2][N:3]=[CH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=CC1CCCCC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Benzyl carbazate (25 g, 150.44 mmoles) was dissolved in 200 mL ethanol under a nitrogen atmosphere in a round bottom flask equipped with magnetic stirring. Cyclohexanecarbaldehyde (17.7 g, 158 mmoles) and acetic acid (1 mL) were added to the solution and the mixture was stirred at room temperature for 8 h. The resultant solid precipitate was filtered, washed with hexanes, crystallized from ethyl acetate, and dried overnight on the open bench to provide 28.87 g (73.7% yield) white crystalline N′-cyclohexylmethylene-hydrazinecarboxylic acid benzyl ester. Rf=0.67 (1:3 hexanes:ethyl acetate), 1H NMR (400 MHz, CDCl3) δ 7.8 (1H, br s), 7.4 (5H, m), 7.1 (1H, br s), 5.3 (2H, s), 2.4 (1H, m), 1.7-1.9 (4H, m), 1.3 (6H, m); HRMS (ESI) m/z calcd for C15H21N2O2 [M+H]+ 261.1603, found 261.1592, calcd for C15H20NaN2O2 [M+Na]+ 283.1426, found 283.1417.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O>C1COCC1>[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=Cc1ccco1
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=Cc1ccco1
Yield: 60.5 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-furaldehyde (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.69 g, 61%) as a pale yellow oil (bp 136-139° C./0.05 torr). IR: 3500-2500, 1730, 710 cm-1 ; 1H-NMR: 1.40 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 11.40 (bs, 1H). Anal. Calcd. for C13H18O3 : C, 70.25, H, 8.16%; Found: C, 69.98, H, 8.26%. Z:E=79:21.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: BrCC1CC1
Reactant: N#Cc1nc(N)nc(Nc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1nc(N)nc(N(CC2CC2)c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-6-phenylamino-[1,3,5]triazine-2-carbonitrile (prepared in an analogous manner to Intermediate 5, 160 mg, 0.75 mmol) in DMF (6 mL) was added potassium carbonate (207 mg, 150 μmol) followed by bromomethyl-cyclopropane (111 mg, 830 μmol). The mixture was heated at 120 C for 3 h, allowed to cool to room temperature before extracting into ethyl acetate (10 mL) and washing with water (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound, which was used without further purification (300 mg, >100%). Method C HPLC-MS: MH+ requires m/z=267. Found: m/z=267, Rt=1.38 min (43%).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[CH2:3][CH:4]([C:11]#[N:12])[CH2:5][C:6]([O:8]CC)=[O:7].O.[OH-].[Li+].Cl>CO.COCCOC.O>[CH3:14][Si:2]([CH3:1])([CH3:13])[CH2:3][CH:4]([C:11]#[N:12])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C#N)C[Si](C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CC(C#N)CC(=O)O
Yield: 99.5 %

Procedure:
A solution of ethyl 4-(trimethylsilyl)-3-cyanobutanoate (341 mg, 1.60 mmol) in methanol/1,2-dimethoxyethane/water (3:2:1, 4.2 ml) was added with lithium hydroxide monohydrate (135 mg, 3.21 mmol), and the mixture was refluxed by heating for 1 hour with stirring. The reaction mixture was cooled on ice, and added with aqueous hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crystals were purified by recrystallization, and the mother solution was subjected to purification by silica gel chromatography (2% methanol/chloroform) to obtain 4-trimethylsilyl-3-cyanobutanoic acid (295 mg, quant.) mentioned in the title as colorless scaly crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[CH2:20]([C@@H:22]1[O:24][CH2:23]1)[Cl:21]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][C@@H:22]([OH:24])[CH2:20][Cl:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC[C@H]1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CCl)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (commercial; 1.40 g, 7.6 mmol) in dry MeOH (25 mL) was treated with MgSO4 (1.9 g). (R)-Epichlorohydrin (1.47 mL, 18.9 mmol) was added dropwise and the mixture was heated at 35° C. for 2 h and was then stirred at rt overnight. The mixture was filtered over Celite and concentrated under reduced pressure. The residue was taken up in DCM and washed with water. The org. phase was dried over MgSO4 and concentrated under reduced pressure to afford the crude 4-((R)-3-chloro-2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester. To a solution of the above intermediate chlorohydrin (2.10 g, 7.53 mmol) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (2.15 g, 1 eq, prepared according to WO2007107965) in DMF (30 mL) was added LiOtBu (10.3 mL, 2.2M in THF) at rt. The mixture was stirred at rt over night and subsequently at 50° C. for 5 h. The mixture was partitioned between EA and 0.5M HCl. The aq. phase was basified (NH4OH) and extracted with EA. The org. layer was dried over MgSO4 and concentrated under reduced pressure to afford the title compound as a colorless solid (1.15 g, 36%).
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21](=[O:39])[C@@H:22]([NH:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([O:9]CC1C=CC=CC=1)=[O:8])=[O:4].O.O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]([CH2:20][C:21](=[O:39])[C@@H:22]([NH:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A suspension of the phenylmethyl ester product from part (g) (0.8 g., 1.5 mmole) in methanol and palladium hydroxide (20% on carbon) is hydrogenated at room temperature and atmospheric pressure for 30 minutes. The mixture is filtered, the solids are rinsed with methanol, and the filtrate is concentrated to give 0.42 g. of yellow oil. The residue is chromatographed on LPS-1 silica gel using an elution gradient of 3→10% acetic acid in chloroform. Fractions containing the desired material are combined and concentrated. The residue is dissolved in methanol/water, filtered, concentrated (methanol removed) and lyophilized to give a white solid. The material is rechromatographed on CC-4 silica gel using ethyl acetate as the eluant. Fractions containing the desired produced are combined and lyophilized from water/dioxane to give 1-[[methyl[(S)-2-oxo-4-phenyl-3-[(1-piperidinylcarbonyl)amino]butyl]amino]carbonyl]-L-proline as a white solid; m.p. 69°-72°; [α]D25 =-37° (c=0.2, methanol). TLC (silica gel; toluene:acetic acid, 4:1) Rf =0.18.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(N(CC)CC)C>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCCCC(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 36 h

Procedure:
6-Aminocaproic acid (26 g, 0.2 mole) was dissolved in dichloromethane (200 mL) by the addition of triethylamine (100 mL). Trityl chloride (120 g, 0.45 mole) was added and the solution stirred for 36 hours. The resulting solution was extracted with 1N HCl and the organic layer evaporated to dryness. The residue was suspended in 2-propanol/1N NaOH (300 mL/100 mL) and refluxed for 3 hours. The solution was evaporated to a thick syrup and added to dichloromethane (500 mL). Water was added and acidified. The phases were separated, and the organic layer dried over sodium sulfate and evaporated to dryness. The residue was suspended in hot 2-propanol, cooled, and filtered to give 43.5 (58%) of 6-(tritylamino)caproic acid, useful as an intermediate compound.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Br:20][C:21]1[C:22]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: Nc1scc(Br)c1-n1nccn1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Br)c1-n1nccn1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.31 g, 1.14 mmol) and 4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g, 1.42 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=6.9, method [7], MS(ESI) 498.0 (M+H). 1H NMR (CDCl3) δ 10.56 (s, 1H), 7.90-7.89 (m, 2H), 7.86 (s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.9 Hz, 2H), 5.16 (s, 2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>OP(O)(O)=O>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:17][C:18](=[O:19])[O:5]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Product: O=c1cc(-c2ccccc2)c2ccc(O)cc2o1
Temperature: 85 °C

Procedure:
A mixture of resorcinol (20 g), ethyl benzoylacetate (23.8 mL) and O-phosphoric acid (130 mL) was heated at 85° C. (care!) for 1 hr. The solution was cooled, poured onto H2O, extracted 3×EtOAc/THF, washed twice with H2O, and then twice with brine. The organic phase was dried and evaporated. Trituration with Et2O followed by filtration afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([CH:28]3[CH2:31][C:30](=O)[CH2:29]3)[O:25][N:24]=2)=[CH:19][C:18]=1[NH:33][C:34]([C:36]1[N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]2=[N:38][CH:37]=1)=[O:35]>C1(C)C=CC=CC=1>[CH2:29]1[C:30]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:31][CH:28]1[C:26]1[O:25][N:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[C:18]([NH:33][C:34]([C:36]3[N:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]4=[N:38][CH:37]=3)=[O:35])[CH:19]=2)[N:27]=1
Reactant: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2noc(C3CC4(C3)OCCO4)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 100 °C

Procedure:
Ethylene glycol (10 mg), TsOH (5 mg) and N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10) (50 mg) were combined in toluene (3 mL) and heated at 100° C. for 5 hours. The reaction was filtered and purified by preparative reverse phase HPLC to afford N-(5-(5-(5,8-dioxaspiro[3.4]octan-2-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F8). 1H NMR (400 MHz, d4-MeOH) δ 9.53 (d, J=7.2 Hz, 1H), 8.50 (s, 1H), 8.13-8.12 (m, 1H), 7.90 (dd, J=8.2, 2.0 Hz, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.60-7.55 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.18 (ddd, J=7.2, 7.2, 1.2 Hz, 1H), 4.45-4.43 (m, 1H), 3.98-3.81 (m, 4H), 3.32-3.31 (m, 4H), 2.43 (s, 3H). MS m/z 432.1 (M+1)+.