Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C@H:18]1[O:22][C:21]([CH3:24])([CH3:23])[N:20]([C:25](=[O:27])[CH3:26])[C@H:19]1[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[NH4+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12]/[C:11](=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])/[CH2:10][C@@H:9]1[C@H:18]1[O:22][C:21]([CH3:24])([CH3:23])[N:20]([C:25](=[O:27])[CH3:26])[C@H:19]1[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C=C1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: COC(=O)/C=C1/C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1

Procedure:
Subject mixture of Z and E isomers of (R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-[1-methoxycarbonyl-methylidene]-pyrrolidine-1-carboxylic acid tert-butyl ester to reverse phase HPLC under basic conditions with aqueous ammonium bicarbonate (10 mM) at pH 8, Isocratic mode: 67% CH3CN. Retention time 3.7 (isomer E) and 4.1 min (isomer Z).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:17][C:18]([C@H:20]1[NH:23][C:22](=[O:24])[CH2:21]1)=[O:19])C1C=CC=CC=1>CO.[C].[Pd]>[NH:23]1[C@H:20]([C:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)=[O:19])[CH2:21][C:22]1=[O:24]
Reactant: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)O)N1
Yield: 99.7 %

Procedure:
In 150 ml of methanol was dissolved 782 mg of Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-L-proline benzyl ester (12) and the compound (12) was hydrogenated for 2 hours at room temperature using 156 mg of 10% palladium-carbon as a catalyst. When the catalyst was filtered off and the filtrate was concentrated, 620 mg of Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-L-proline (13) was obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[C@H:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].C([O-])(=O)C.[Na+].[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>C(Cl)Cl>[C:19]([O:8][C@@H:3]([C:2]([Cl:10])([Cl:9])[Cl:1])[CH:4]=[C:5]([CH3:7])[CH3:6])(=[O:20])[CH2:18][C:17]([CH3:16])=[O:21]
Reactant: CC(C)=C[C@@H](O)C(Cl)(Cl)Cl
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Yield: 85.2 %

Procedure:
A mixture of (2R)-1,1,1-trichloro-4-methyl-3-penten-2-ol (1.50 g., 7.35 mmole) from Example IA.1.(a) and a trace of sodium acetate was treated under nitrogen at 100° with freshly distilled diketene (0.70 g, 8.36 mmole) added dropwise over 1 hr. After stirring and heating an additional hour at 80°-83°, the cooled reaction mixture was diluted with 3 ml of CH2Cl2 and chromatographed on 8 (20×20 cm) preparative tlc plates, developed in CH2Cl2. Isolation and extraction afforded (1R)-3-methyl-1-trichloromethyl-2-butenyl acetoacetate (1.80 g, 85% isolated yield) as a pale yellow oil; [α]D31 =+21.1° (hexane).
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:1][C@:2]([CH3:19])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OC)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)[C@](C)(O)Cc1ccc(OC)c(OC)c1
Reaction time: 23 h
Yield: 12.1 %

Procedure:
To a suspension of ethyl (±)-2-hydroxy-2-methyl-3-(3,4-dimethoxyphenyl)propionate (301.1 mg, 1.12 mmol) in 50 mL of 50 mM sodium phosphate buffer pH 7.5 is added carboxypeptidase Y from Bakers Yeast (7.6 mg of protein). After 23 h, 90.6% conversion is observed by HPLC (C18 column, 254 nm detection, acid tR =5.8 min and ester tR =11.6 min). The reaction is extracted with 2×25 mL ethyl acetate. The combined extracts are treated with brine, dried with magnesium sulfate, then concentrated in vacuo to yield ethyl (R)-2-hydroxy-2-methyl-3-(3,4-dimethoxyphenyl)propionate (36.2 mg, 0.135 mmol, 12.1%). The enantiomeric excess of the unreacted ester is determined by HPLC analysis (Chiracel OD column from J. T. Baker, 280 nm, (S)-enantiomer tR =6.6 min and (R)-enantiomer tR =8.3 min) to be 31.2% (R -enantiomer.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23]>CN(C=O)C>[N+:1]([C:4]1[N:5]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCn1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
A mixture of 5 g (44 mmol) of 2-nitroimidazole and 6.1 g of K2CO3 in 50 ml of DMF was heated at 60° C. for 0.5 hours: then 6.61 g (44 mmol) of 3-(2-chloroethyl)-2-oxazolidinone was added and stirring continued for 18 hours; at 60° C. The mixture was then cooled and concentrated. The residue was partitioned between CHCl3 and water, the organic layer was dried and concentrated to a solid. The solid was crystallized from ethanol to give 3.5 g (35%) of the desired product, 3-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-2-oxazolidinone; mp 103°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cccc(Br)c1

Procedure:
In close analogy to the procedure described above, 2-(3-bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23.[Cl-].[CH3:28][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:2]1[CH:3]=[C:4]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23
Reactant: C[Zn+]
Reactant: Cn1nccc1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccnn2C)c2c3c1[nH]c(=O)n3C(c1ccccc1)CO2

Procedure:
A reaction mixture of 9-bromo-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (17 mg, 0.04 mmol), a solution of 2.0 M methylzinc chloride in THF (0.10 mL) and tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) in THF (0.5 mL) under nitrogen was heated in a microwave at 130° C. for 5 min. The title compound was purified by preparative LCMS using a pH10 buffer. LCMS calc. for C20H19N4O2 (M+H)+: m/z=347.1. found: 347.2.
Reaction SMILES: CON=[C:4]([CH2:10][C:11](=O)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25]>C(O)(=O)C.C(OCC)(=O)C>[CH3:12][C:11]1[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:24]([C:17]2[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=2[Cl:23])[N:25]=1
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 105 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
A mixture of ethyl 2-(methoxyimino)-4-oxopentanoate (2.00 g, 10.7 mmol) and 2,4,6-trichlorophenylhydrazine hydrochloride (3.39 g, 16.0 mmol) in acetic acid (40 ml) and 2-methoxuethanol (20 ml) was stirred for 20 h at 105° C. The solvent was under vacuum and the residue was dissolved in ethyl acetate. The organic solution was washed with 0.2N HCl and water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate/n-hexane to give the title compound (1.50 g, 42%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH2:34])[CH3:31])([CH3:27])([CH3:26])[CH3:25].O>CN1CCCC1=O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:34][CH2:33][CH2:32][N:30]([CH3:31])[C:29](=[O:35])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])[S:3][C:4]=3[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(NC(=O)c2ccc3nc(Br)sc3c2)cc1OC
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(NC(=O)c2ccc3nc(NCCN(C)C(=O)OC(C)(C)C)sc3c2)cc1OC
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide (392.4 mg, 0.998 mmol), N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (193.4 mg, 1.11 mmol) and N—N-diisopropylethylamine (148.6 mg, 1.15 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred in a preheated oil bath at 120° C. for 4 h, then allowed to cool to room temperature, poured into water and extracted into ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by gradient flash column chromatography, eluting with 70% to 80% ethyl acetate in heptane to yield tert-butyl 2-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-ylamino)ethyl(methyl)carbamate as a beige powder.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH:9]([OH:13])[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([NH:41][C:10](=[O:12])[CH:9]([OH:13])[CH:8]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCc1ccccc1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 4-phenyl-2-hydroxy-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with benzylamine; ESI-MS [M+H]+: 532.2
Reaction SMILES: COC1C=CC(CO)=CC=1.CC1(C)C2(C)C(O)CC1CC2.C(O)C1C=CC=CC=1.[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32][OH:33].N[C@H]1C(=O)N(CC2C=CC(OC)=CC=2OC)[C@H]1C(OC)=O.[CH3:57][O:58][C:59]1[CH:87]=[C:86]([O:88][CH3:89])[CH:85]=[CH:84][C:60]=1[CH2:61][N:62]1[C:65](=[O:66])[C@H:64]([NH:67][C:68](OCC2C=CC(OC)=CC=2)=[O:69])[C@@H:63]1[C:80]([O:82][CH3:83])=[O:81].C(OC(N[C@H]1C(=O)N(CC2C=CC(OC)=CC=2OC)[C@H]1C(OC)=O)=O)C1C=CC=CC=1>C(O)(C)(C)C>[CH3:57][O:58][C:59]1[CH:87]=[C:86]([O:88][CH3:89])[CH:85]=[CH:84][C:60]=1[CH2:61][N:62]1[C:65](=[O:66])[C@H:64]([NH:67][C:68]([O:33][CH2:32][C:31]([Cl:35])([Cl:34])[Cl:30])=[O:69])[C@@H:63]1[C:80]([O:82][CH3:83])=[O:81]
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccc(OC)cc2)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: OCC(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(C)C(O)C2
Agent: COC(=O)[C@H]1[C@@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Agent: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: CC(C)(C)O
Solvent: OCc1ccccc1
Product: COC(=O)[C@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
When p-methoxybenzyl alcohol, isoborneol, benzyl alcohol or 2,2,2-trichloroethanol is substituted for t-butanol in Preparation 5 in the reaction with methyl cis-3-amino-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl cis-1-(2,4-dimethoxybenzyl)-3-(p-methoxybenzyloxycarbonylamino)-4-oxoazetidine-2-carboxylate, methyl cis-1-(2,4-dimethoxybenzyl)-3-isobornyloxycarbonylamino-4-oxoazetidine-2-carboxylate, methyl cis-3-benzyloxycarbonylamino-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate or methyl cis-1-(2,4-dimethoxybenzyl)-4-oxo-3-(2,2,2-trichloroethoxycarbonylamino)-azetidine-2-carboxylate is obtained, respectively.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:4]([C:16](OCC)=[O:17])=[N:3]1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C1CCCCC1>[OH:17][CH2:16][C:4]1[C:5]([C:12]([F:13])([F:14])[F:15])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1nn(C)c(C(=O)OCC)c1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)c(CO)nn1C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A solution of 6.00 g (20.4 mmol) of diethyl 1-methyl-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate in 80 ml of tetrahydrofuran is admixed under argon at −78° C. with 38.9 ml (42.8 mmol) of a 1.1M solution of diisobutylaluminium hydride in cyclohexane and stirred overnight at this temperature. The reaction mixture is admixed with water and extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate, filtered over silica gel and concentrated by evaporation in vacuo. Chromatographic purification on silica gel gives 4.10 g of ethyl 3-(hydroxymethyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (80%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:19]=1
Reactant: Nc1cccnc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(Nc3cccnc3)ccc12
Yield: 48.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 3-aminopyridine (61 mg, 0.65 mmol) to provide 232 (31 mg, 54% yield) as a white solid. LC-MS (M+H=289, obsd.=289). 1H NMR (400 MHz, d6-DMSO): δ 11.74 (s, 1H), 9.10 (s, 1H), 8.54 (m, 2H), 8.47 (dd 1H), 8.23 (dd, 1H), 8.19 (d, 1H), 7.91 (d, 1H), 7.75 (m, 1H), 7.39 (m, 1H), 7.30 (m, 2H).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH2:26][C:25]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH2:26][C:25]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH2:35][C:36](=[O:37])[O:38][C:39]([CH3:42])([CH3:40])[CH3:41])[O:24][N:23]=3)[CH:17]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(OC(=O)c3ccc(NC(=N)N)cc3)c2)=NO1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (317 mg) was added to a mixture of di-tert-butyl 2,2′-(3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (265 mg), pyridine (0.3 mL), and NMP (0.3 mL) at 50 C, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, subsequently acetonitrile/acetic acid) and then further fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (94 mg).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:21])[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O>>[C:1]([O:12][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][N:14]([CH3:21])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CC(C)(C)CO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCC(C)(C)CN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 3-dimethylamino-2,2-dimethyl-1-propanol as starting materials to give the aimed compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cccc3C)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (8.5 g) in MeOH (80 mL) was added 1N NaOH (80 mL) and the solution was heated at 100° C. for 18 h. The mixture was washed with Et2O and the aqueous layer was carefully acidified to pH=2-3 with 1N HCl and the resulting precipitate was filtered, washed with water and dried under reduced pressure to give 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid as a red solid; MS (ESI)m/z 267 (M+H).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:13]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[CH:29]=[CH:28][CH:27]=1.[ClH:37].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[ClH:37].[ClH:37].[N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:13]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:14]=2[C:15]([NH:36][C:33]2[CH:34]=[C:35]3[C:30]([CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:31][CH:32]=2)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(C(F)(F)F)cc1N[C@@H]1CCCC[C@@H]1N1CCCC1

Procedure:
2-{[(1R,2S)-2-Pyrrolidin-1-ylcyclohexyl]amino}-4-(trifluoromethyl)benzoic acid (150 mg), quinolin-7-amine (67 mg), hydrochloride of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (121 mg) and 1-hydroxybenzotriazole (57 mg) were stirred at 110° C. for 15 minutes in N-methylpyrrolidone under microwave irradiation. A potassium carbonate aqueous solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane:ethyl acetate, 7:3 to 1:1). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate, 2-{[(1R,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}-N-quinolin-7-yl-4-(trifluoromethyl)benzamide dihydrochloride (66 mg) was obtained as an amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](O)=[O:31])[CH3:25]>>[CH2:24]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:31])[CH3:25]
Reactant: CCNC(=O)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCNC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N-ethyl-succinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-(ethylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=441; RT=1.13 min; UPLC Method I
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(Br)cc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (720 mg, 5 mmol) and 4-bromobenzoic acid (1.51 g, 7.5 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91 (dd, 1H), 8.18 (d, 1H), 8.14 (dd, 1H), 8.06, (m, 2H), 7.85 (d, 1H), 7.81 (d, 2H), 7.67 (d, 2H), 7.37 (dd, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]([CH3:16])=[C:10]([CH2:13][CH2:14]O)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CN(C)C=O>[OH:1][C:2]1[C:7]2=[N:8][C:9]([CH3:16])=[C:10]([CH2:13][CH2:14][Cl:19])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc2c(O)cccn2c(=O)c1CCCl

Procedure:
According to the U.S. Pat. No. 5,688,799 (hereinafter referred to as the '799 patent), the compound of formula I is prepared by the reaction of 2-amino-3-hydroxypyridine with 2-acetylbutyrolactone in the presence of p-toluenesulfonic acid in xylene solvent at reflux temperature for overnight using a water separator to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is converted into its hydrochloride salt, followed by reaction with thionyl chloride in dimethylformamide to produce 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28]CC1C=CC=CC=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[CH3:2]
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCO
Reaction time: 4 h
Yield: 78.9 %

Procedure:
Substantially monodispersed benzyl ether 3 (1.03 g, 2.0 mmol) was dissolved in 25 ml ethanol. To this solution was added 270 mg 10% Pd/C, and the mixture was placed under a hydrogen atmosphere and stirred for four hours, at which time TLC showed the complete disappearance of the starting material. The reaction mixture was filtered through Celite 545 to remove the catalyst, and the filtrate was concentrated in vacuo to yield the monodispersed compound 4 as a clear oil (0.67 g, 79%). FAB MS: m/e 425 (M+H), 447 (M+Na).