Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)(N)c1ccc(Br)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(C)(C)c3ccc(Br)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the 2-(4-bromophenyl)propan-2-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 595/597 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:7]=1[CH2:8][NH:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([C@H:19]3[C@@H:23]4[O:24][C:25]([CH3:28])([CH3:27])[O:26][C@@H:22]4[C@@H:21]([CH2:29][N:30]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:31]4[CH2:34][CH:33]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:32]4)[CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1.O1CCCC1.CO.Cl>>[CH3:4][O:5][C:6]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:7]=1[CH2:8][NH:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([C@H:19]3[C@@H:23]4[O:24][C:25]([CH3:27])([CH3:28])[O:26][C@@H:22]4[C@@H:21]([CH2:29][N:30]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:31]4[CH2:32][CH:33]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:34]4)[CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)CCC1CC(N(CC(C)C)C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Lithium hydroxide, monohydrate (1.11 g, 26.4 mmol) was added to a solution ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)cyclobutyl)propanoate (1.75 g, 2.64 mmol) in Tetrahydrofuran (13 ml, 160 mmol) and Methanol (3 ml, 70 mmol). The reaction was stirred for 24 hours at RT, acidified with 1 N HCl to pH=6, the volatiles removed in vacuo and remaining water removed by azeotropic distillation with ethanol followed by 18 hours on lyophilizer. The resulting off white solid was used without further purification.
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:42](=[O:43])[N:12]2[C:13]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:14]([CH2:18][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C@@H:15]([CH3:17])[S:16][C@H:11]12)=O.P(Cl)(Cl)(Cl)(Cl)Cl.OP([O-])([O-])=O.[K+].[K+].OP(O)(O)=O>C(Cl)Cl.CO.N1C=CC=CC=1>[NH2:9][CH:10]1[C:42](=[O:43])[N:12]2[C:13]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])=[C:14]([CH2:18][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C@@H:15]([CH3:17])[S:16][C@H:11]12
Reactant: C[C@H]1S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1CSc1nnnn1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1S[C@@H]2C(N)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1CSc1nnnn1C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A 3.7 ml portion of pyridine was added to a solution of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate in 100 ml of CH2Cl2, followed by adding 2.4 g of PCl5 at -12° C., further followed by stirring at the same temperature for 45 minutes. MeOH was added in once, and the mixture was further stirred at -10° C. for 30 minutes and at room temperature for 1 hour. 100 ml of 0.5M K2HPO4 solution was added to the reaction solution, followed by adding further 25% H3PO4 to adjust to pH 1.5. After stirring for 45 minutes, the CH2Cl2 layer was separated out, then washed with saturated aqueous NaCl solution, and dried over MgSO4 to distill off the CH2Cl2 under reduced pressure. Et2O was added to the residue, thus yielding 1.73 g (72%) of crystals of 7-amino-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[CH2:1]([NH:4][C:15](=[O:16])[O:17][CH2:18][CH3:19])[C:2]#[CH:3]
Reactant: CCOC(=O)Cl
Reactant: C#CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCNC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
115 g (2. 1 mol) of propargylamine is introduced into 1 1 of toluene, 91 g of sodium hydroxide dissolved in 400 ml of water are added, and 239 g (2.2 mol) of ethyl chloroformate are added dropwise at 10° C. The mixture is stirred for three hours at room temperature, the organic phase is separated off, the aqueous phase is extracted using toluene, the organic solutions are dried over magnesium sulphate and concentrated, and the concentrate is distilled.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH3:30][S:31](Cl)(=[O:33])=[O:32].CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])[CH2:5][CH2:6][N:7]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1

Procedure:
The title compound is prepared by treatment of morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride with methanesulfonyl chloride and a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[NH:31][CH:32]=[CH:33][N:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1ncc[nH]1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1ncc[nH]1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(1H-imidazol-2-ylmethyl)-amine
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:62]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:63]([C:71]([NH:73][C@H:74]([C:81](O)=[O:82])[CH2:75][C:76]1[N:80]=[CH:79][NH:78][CH:77]=1)=[O:72])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C(#N)C.C(OCC)(=O)C>[CH:4]1([CH2:3][C@H:2]([NH:1][C:81]([CH:74]([NH:73][C:71]([C@@H:63]([NH:62][C:84](=[O:85])[O:86][C:87]([CH3:89])([CH3:88])[CH3:90])[CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:72])[CH2:75][C:76]2[N:80]=[CH:79][NH:78][CH:77]=2)=[O:82])[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH:22]([CH3:23])[CH3:24])[CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)[C@@H](CCOc1ccccc1)C[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
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: CC#N
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](CCOc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.8 %

Procedure:
174 mg (0.5 mmol) of (2S,3S,5S)-2-amino-1-cyclohexyl-5-isopropyl-7-phenoxy-3-heptanol are dissolved in 8 ml of acetonitrile, the solution is treated with 0.102 ml (0.5 mmol) of Hunig base, 220 mg (0.5 mmol) of BOP and 204 mg (0.5 mmol) of Boc-Phe-His-OH and the reaction mixture is stirred at room temperature for 3.5 hours. Thereafter, the mixture is taken up in ethyl acetate and the organic phase is washed once each time with 1N hydrochloric acid and 2N sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel with a 15:1 mixture of methylene chloride and methanol as the eluting agent yields 226 mg (60%) of t-butyl [(S)-α-[[1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-6-phenoxyhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as a resin, MS: 732 (M+ H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:26])[F:25])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.CCOCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:25])[F:26])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: O=Cc1cc(Br)ccc1OC(F)F
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (3.60 g, 0.025 mol) in anhydrous 1,2-dimethoxyethane (8 ml) is added sodium methoxide (1.51 g, 0.028 mol) in one portion. After stirring at this temperature for 5 minutes a solution of 5-bromo-2-difluoromethoxy-benzaldehyde (5.66 g, 0.023 mol) in 1,2-dimethoxyethane (8 ml) is added dropwise over 10 mins, followed by stirring at 0° C. for a further 1 hour. After warming to room temperature the reaction mixture is diluted with ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulfate and evaporated in vacuo to afford 4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (8.89 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:17][C:18]([O:20]CC)=O)[C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].C(N(CC)CC)C>CO>[O:3]=[C:2]1[NH:1][C:18](=[O:20])[CH2:17][N:4]1[C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution containing the product from Example 36B (6.8 g, 20.9 mmol) in methanol (30 mL) was treated with triethylamine (5.6 mL, 40.2 mmol), stirred at 50° C. for 2 hours, and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (2.53 g, 47% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.N1C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC1CCc2c(ccc(F)c2-n2ccnc2)N1

Procedure:
A solution of 10.2 g (44.9 mmole) of 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline, 16.7 g (180 mmole) of pyridine:diborane complex (that commercially available from Aldrich) and 200 ml of glacial acetic acid was stirred for about 22 hours at about 20° C. The solution was evaporated to reduce its volume, then 100 ml of 10% hydrochloric acid was added in small portions. The solution was heated on a steam bath for another one hour, then cooled with an ice bath and basified (pH 9 to 10) with 10% aqueous sodium hydroxide. The solid was separated by filtration, washed with water, and dissolved in ethyl acetate and dried. Recrystallization from aqueous ethanol provided 6-fluoro-5-(imidazol-1-yl)-1,2,3,4-tetrahydro-2-methylquinoline, m.p. 162°-164° C. Analysis: Calculated for C13H14FN3 : %C, 67.5; %H, 6.1; %N, 18.2; Found: %C, 67.5; %H, 6.1; %N, 18.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[C:15]1([CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[S:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C)C=O>O>[C:15]1([CH2:21][CH2:22][NH:23][C:24]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)[N:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: NC(=S)NCCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2csc(NCCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]-ethanone (5.34 g), N-(2-phenylethyl)thiourea (3.60 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (5.20 g, yield 74%) as colorless crystals.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:15])[N:14]=1.[CH3:16][C:17]1[N:18]=[C:19]([N:22]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[C:23]2=[O:37])[S:20][CH:21]=1>>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:27][N:24]3[CH2:25][CH2:26][N:22]([C:19]4[S:20][CH:21]=[C:17]([CH3:16])[N:18]=4)[C:23]3=[O:37])=[CH:29][CH:30]=2)[S:11][CH:12]=1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Reactant: Cc1csc(N)n1
Solvent: NCc1ccccc1
Product: Cc1csc(NC(=O)c2ccc(CN3CCN(c4nc(C)cs4)C3=O)cc2)n1
Yield: 41 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-amino-4-methylthiazole to react with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 41% yield: mp 197-198° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 11.54 (br s, 1H), 7.87 (d, J=6.0 Hz, 2H), 7.37 (d, J=6.0 Hz, 2H), 6.52 (s, 1H), 6.43 (s, 1H), 4.53 (s, 2H), 4.11-4.06 (m, 2H), 3.46-3.41 (m, 2H), 2.30 (s, 3H), 1.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 158.9, 158.7, 156.0, 147.3, 146.9, 141.2, 132.1, 128.5, 128.3, 108.6, 106.9, 47.7, 42.3, 42.0, 17.3, 16.6; MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:46][CH2:45][C:40]3([O:44][CH2:43][CH2:42][O:41]3)[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[O:41]1[C:40]2([CH2:39][CH2:38][N:37]([C:34]3[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([CH:33]=3)[C:11]([NH:13][C:14]3[CH:26]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:24]=[CH:23][C:15]=3[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:12])[CH2:46][CH2:45]2)[O:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC3(CC2)OCCO3)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC3(CC2)OCCO3)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)benzamido)-4-phenylbenzoate (0.18 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.091 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.12 g of tert-butyl 2-(5-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)-2-hydroxybenzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][N:8]([C:11]2[N:12]=[C:13]([CH2:38][CH2:39][CH3:40])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:15]=2[C:16]([O:18]C)=[O:17])[CH:7]=1)([OH:3])=[O:2].[OH-].[Li+]>C(O)C.O>[C:1]([CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][N:8]([C:11]2[N:12]=[C:13]([CH2:38][CH2:39][CH3:40])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1)([OH:3])=[O:2]
Reactant: CCCc1nc(-n2ccc(CCC(=O)O)c2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nc(-n2ccc(CCC(=O)O)c2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.5 %

Procedure:
A solution of methyl 4-(3-carboxyethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol 5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (Example 73, 0.2 g) in ethanol (2.5 mL) and water (1.25 mL) was treated with lithium hydroxide (0.17 g) ant the reaction mixture stirred a room temperature for 3 days. The reaction mixture was diluted with water, extracted with ether, and the aqueous layer acidified to pH 2 with 1N HCl. The cloudy solution was extracted with ether and the combined organic layers dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue taken-up in ethyl acetate. Petroleum ether was added dropwise to precipitate the product which was collected by filtration to yield 0.11 g of the title compound 4-(3-carboxyethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid. MS (CI, CH4 +NH4) 410 (M-CO2H, --CO2Et).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:32])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[N:28]=[CH:29][N:30]([CH3:31])[C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH3:42][O:43][CH2:44][CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH3:42][O:43][CH2:44][CH2:45][N:46]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:16](=[O:32])[N:17]2[C:22]=1[C:21]1[N:28]=[CH:29][N:30]([CH3:31])[C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: COCCNc1ccccc1
Reactant: Cn1cnc2c1ccn1c(=O)c(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3c(ncn3C)c12)c1ccccc1

Procedure:
From 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene and treatment with triethylamine and (2-methoxy-ethyl)-phenyl-amine in dichloromethane.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C=O)[CH:12]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl.[NH2:24][OH:25]>C(O)C>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:11]2[CH2:12][C:13](=[N:24][OH:25])[CH:14]=[CH:15][CH:16]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: NO
Reactant: C#CCn1c(-c2cccc(C=O)c2)nc(CC)c(CC)c1=O
Agent: Cl
Solvent: CCO
Product: C#CCn1c(C2=CC=CC(=NO)C2)nc(CC)c(CC)c1=O
Yield: 60.9 %

Procedure:
To a 100 mL RBF were charged 1.1 g (3.7 mmol) of 5,6-diethyl-2-(3-formyl-phenyl)-3-propargyl-4(3H)-pyrimidinone, 0.52 g (7.5 mmol) of hydroxylamine hydrochloride and 50 mL of ethanol. The reaction mixture was refluxed for 17 hours. The ethanol was removed in vacuo and ether and ethyl acetate were added to the residue. The organics were washed 3 times with water. The organic layer was gravity filtered to remove 0.22 g of 5,6-diethyl-2-(3-hydroxyiminophenyl)-3-propargyl-4(3H)-pyrimidinone (compound 139). The organic layer was dried over MgSO4 and concentrated to yield a further 0.67 g of 5,6-diethyl-2-(3-hydroxyiminophenyl)-3-propargyl-4(3H)-pyrimidinone (compound 139) as a white solid. A combined yield of 77.6% was obtained. 1H-NMR (CDCl3) 1.25(6H,m); 2.35(1H,t); 2.65(4H,m); 4.6(2H,d); 7.49-8.15(4H,m); 8.7 (1H,s)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14]Cl.[NH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19]>>[CH2:18]([CH:17]([N:16]1[C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([CH3:12])[C:3]=2[CH2:13][CH2:14]1)[CH2:20][CH3:21])[CH3:19]
Reactant: Cc1cc2nc(C)c(CCCl)c(Cl)n2n1
Reactant: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3cc(C)nn3c21

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (4.0 g, 16 mmol), 3-aminopentane (40 mL) in acetonitryl (120 mL) was heated under reflux for nine hours. After evaporating, the residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (3.7 g) as white crystals.
Reaction SMILES: N[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O.O>[OH:14][C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
Following the procedure of Johnson, 1980, D-phenylalanine (16.5 g, 100 mmol) was dissolved in 1N H2SO4 (150 ml) and cooled to 0° C. A solution of NaNO2 (10.5 g, 150 mmol) in water (50 ml) was added dropwise. The mixture was stirred for 2 h at 0° C. and for 3 h at 25° C. The product was extracted into ether (5×100 ml) and the combined ether extracts were dried over Na2SO4 and concentrated in vacuo to about 100 ml. Hexane (300 ml) was added and the product which crystallized out was collected by vacuum filtration to afford the title compound as a colorless solid (9 g, 54%); mp=124°-125° C.