Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1B(O)O>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.O>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(=O)OCC)c(-c2cc(C)ccc2C)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Diethyl bromoterephthalate (46.2 g, 150 mmol), K2CO3 (41.5 g, 300 mmol), 140 ml of toluene and 140 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 2,5-dimethylbenzeneboronic acid (24.8 9, 165 mmol) (cf. B3) and Pd(PPh3)4 (0.7 g, 0.6 mmol) were subsequently added under protective gas. The brownish mixture, which was turbid due to phase separation, was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. The reaction was complete after 24 hours (according to TLC). After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The product was obtained as a yellow oil in sufficient purity (greater than 97%). Yield: 48.7 g (99%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3nc(S(N)(=O)=O)sc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (25 ml) was added p-toluenesulfonyl chloride (1.9 g, 0.01 mole). The reaction mixture was stirred at 25° C. for 21/2 hours, treated with p-toluenesulfonyl chloride (0.3 g.), stirred 1 hour then poured into ice water plus excess hydrochloric acid. The product was extracted into ether, washed with water, dried over magnesium sulfate, concentrated to dryness and chromatographed on silica (150 g., 70-230 mesh) eluting with ethyl acetate-hexane (1:1) to obtain 1.4 g. of (2-sulfamoyl-6-benzothiazolyl) 4-methylphenyl sulfonate which melts at 142° C. after recrystallization from toluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC(C)(C)C)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65][O:66][C:67]([NH:69][C:70]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)([CH3:74])[C:71]([OH:73])=O)=[O:68]>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:71](=[O:73])[C:70]([NH:69][C:67]([O:66][CH3:65])=[O:68])([C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH3:74])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 20 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using 2-Methoxycarbonylamino-2-phenyl-propionic acid (0.068 g, 0.308 mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.035 g, 20%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.92 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Reactant: OC1CCNCC1
Solvent: CCO
Product: OC1CCN(c2ncc(-c3ccccc3Cl)nn2)CC1

Procedure:
7.4 g of 3-chloro-6-(2-chlorophenyl)-1,2,4-triazine, prepared according to J. Het. Chem. 16, 1402 (1979), and 9 g of 4-hydroxypiperidine are heated under reflux in 150 ml of ethanol for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-bromobenzenesulfonyl chloride according to METHOD A, using a Quest 210 apparatus and at 30° C., giving 1.16 g (27%) of an off-white solid: mp 155° C.; MS (Ionspray, [M+H]+) m/z 405; Anal. Calcd (found) for C13H13BrN2O4S2: C, 38.5 (38.4)%, H, 3.2 (3.0)%, N, 6.9 (6.6)%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([O:11][CH3:12])=[CH:4][N:3]=1.[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][C:25]([O:24][C:22]([N:13]([C:6]1[C:5]([O:11][CH3:12])=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: COc1cnc(Br)cc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: COc1cnc(Br)cc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 11.8 %

Procedure:
A mixture of 2-bromo-5-methoxypyridine-4-boronic acid (10 g, 43.1 mmol), di-tert-butyl azodicarboxylate (9.93 g, 43.1 mmol), and copper(II) acetate (7.48 mg, 0.041 mmol) in MeOH (150 mL) was stirred 20 h at 50° C., filtered, concentrated, diluted with brine (100 mL), and extracted with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→3:1) to provide 2.13 g of the title compound. tR: 1.21 min (LC-MS 4); ESI-MS: 418.2 [M+H]+ (LC-MS 4); Rf=0.67 (hexane/EtOAc, 1:1).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])S[C:7]=1[NH2:13])=[O:5])C.CO[C:16]1[NH:17][CH2:18][CH2:19][CH:20]=1.P(Cl)(Cl)(Cl)=O>[Ni]>[CH3:11][CH:10]([C:6]1[C:4](=[O:5])[N:17]2[CH2:18][CH2:19][CH2:20][C:16]2=[N:13][CH:7]=1)[CH2:9][CH3:12]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: COC1=CCCN1
Agent: [Ni]
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)c1cnc2n(c1=O)CCC2
Yield: 36.5 %

Procedure:
According to Khim. Geterosikl. Soedin, 6, 765, 1975, ethyl-2-amino-4,5-dimethyl-thiophene-3-carboxylate is reacted with 2-methoxy-pyrroline in the presence of phosphoryl chloride and the obtained 2,3-dimethyl-4-oxo-5,6-tetramethylene-4H-thieno[2,3-d]pyrimidine is desulphurated in an alcoholic solution with Raney-nickel and thus 3-(1-methyl-propyl)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine is obtained. In the complicated two-step synthesis the pyrrolo-pyrimidine derivative is obtained with a yield of 36.5%.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH2:23])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH:23][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)C2CCC2)sc1C(=O)NCc1ccccc1
Yield: 46 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclobutanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 46% yield; 1H NMR (DMSO-ds, 300 MHz) δ 7.38-7.25 (m, 4H), 5.96 (s, br, 1H), 4.58-4.50 (m, 2H), 3.25-3.14 (m, 1H), 2.53 (s, 3H), 2.42-1.90 (m, 6H); MS (ES+) m/z 330.0 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[NH2:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2cc(C)cc(NC(=O)OC(C)(C)C)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(Cc2cc(C)cc(N)c2)CC1

Procedure:
To a solution of tert-butyl 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylphenylcarbamate (306 mg, 0.88 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL) at room temperature. After 2 hours the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylaniline as a white solid. 1H-NMR (300 MHz, CDCl3) δ 6.52 (s, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 3.62 (m, 4H), 3.45 (m, 2H), 3.39 (s, 2H), 2.40 (m, 4H), 2.25 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH:25][CH2:26]CN1CCNCC1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:26][OH:25])[CH2:19][CH2:20]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: CN1CCN(C2Cc3ccccc3Sc3cc(F)c(F)cc32)CC1
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(C2Cc3ccccc3Sc3cc(F)c(F)cc32)CC1

Procedure:
A mixture of 7,8-difluoro-10-chloro-10,11-dihydrodibenzo(b,f)thiepine (see Example 15) (6.35 g), 1-(2-hydroxyethyl)-piperazine (6.1 g) and chloroform (10 ml) was refluxed for 7.5 hours under stirring. The chloroform was evaporated under diminished pressure, the residue dissolved in benzene (200 ml) and the solution thoroughly washed with water and shaken with 3 N-HCl (150 ml). The precipitated hydrochloride was filtered, added to the aqueous layer of the filtrate and the resultant suspension made alkaline by addition of ammonium hydroxide. The liberated base was taken up in benzene and the extract yielded 7.1 g (84%) of the desired oily base. This was crystallized from aqueous acetone in the form of the hemihydrate, which in the pure state melts at 101°-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]1[CH2:24][CH2:23][CH2:22][C:21]21[O:28][CH2:27][CH2:26][O:25]2
Reactant: OCCO
Reactant: O=C1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(OC2CCCC23OCCO3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 g. of N-[4-bromo-3-(cyclopentanon-2-yloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 0.68 g. of ethyleneglycol, 0.2 g. of p-toluenesulfonic acid and 30 ml. of benzene was refluxed with stirring under removing water for 8 hours and the reaction mixture was cooled to room temperature and then, 20 ml. of ethyl acetate was added to the reaction mixture to extract the product. The extract was washed with water and dehydrated over sodium sulfate and the solvent was distilled off and the product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:4) to obtain 1.35 g. of Compound No. 9 shown in Table 1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]1([S:18]([O-:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>CN(C)C(=O)C>[C:12]1([S:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2.6 g) (available from Aldrich) and sodium benzenesulfinate (3.0 g) (available from Aldrich) were heated in N,N-dimethylacetamide (40 ml) at 50° C. for 16 h. After cooling the mixture was filtered, the filtrate collected and the solvent removed in vacuo. The residue was triturated with cyclohexane and the resultant precipitate collected by filtration to give the title compound as a white solid (3.5 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=1.Cl[CH2:17][CH:18]1[O:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]([CH:29]([CH3:31])[CH3:30])[CH2:19]1.C[O-].[Na+]>>[OH:1][C:2]1[C:7]([O:8][CH2:17][CH:18]2[O:22][CH:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH:29]([CH3:31])[CH3:30])[CH2:19]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=1
Reactant: CC(C)N1CC(CCl)OC1c1ccccc1
Reactant: O=C1CCC(c2cccc(O)c2O)=NN1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)N1CC(COc2cccc(C3=NNC(=O)CC3)c2O)OC1c1ccccc1

Procedure:
6-(2,3-Dihydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone was reacted with 5-chloromethyl-3-isopropyl-2-phenyloxazolidine in the presence of sodium methoxide to give 6-[2-hydroxy-3-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [N:1]1([C:7](=[O:22])[CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:23][CH:24]([CH2:38][CH3:39])[C@@H:25]([C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)[OH:26]>>[C:32]1([C:30]2[O:29][N:28]=[C:27]([C:25]([C@@H:24]([NH:23][C:10](=[O:12])[CH:9]([CH2:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:38][CH3:39])=[O:26])[N:31]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Product: CC[C@H](NC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
Similarly prepared according to the procedure for Example 43 but using 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and (S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol; MS: 541 (M+Na), LCMS retention time 4.44 and 4.53 min; 1H NMR (CDCl3) 8.18 (d, J=7 Hz, 2H), 7.69–7.51 (m, 3H), 7.27–7.10 (m, 5H), 6.99–6.7 (d, J=7 Hz, 1H), 5.38 (m, 1H), 3.70–3.36 (m, 8H), 2.99–2.56 (m, 4H), 2.27 (m, 1H), 2.11 (m, 1H), 1.87–1.60 (m, 4H), 1.44 (m, 1H), 1.02–0.97 (dt, J=7 Hz, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][N:23]([CH:30]1[CH2:33][NH:32][CH:31]1[CH3:34])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][C@@H:30]([N:23]([CH3:22])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C@@H:31]4[CH3:34])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1NCC1N(C)C(=O)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](N(C)C(=O)C(F)(F)F)CN1c1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Yield: 53.2 %

Procedure:
A mixture of 2.6 g (9.2 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.57 g (11 mmol) of 3-[N-(methyl)trifluoroacetamido]-2-methylazetidine hydrochloride and 3 g (30 mmol) of triethylamine in 30 ml of pyridine is heated to reflux for 2 hours. The mixture is evaporated under vacuum, the residue is diluted with ice-cold water, the resulting mixture is filtered and the product is washed with water. 2.5 g are obtained. The product is recrystallized from acetonitrile. 2.25 g of 1-cyclopropyl-6,8-difluoro-7-{trans-3-[N-(methyl)trifluoroacetamido]-2-methyl-1-azetidinyl}-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 246°-9° C., are obtained. 1H NMR, δ,J=Hz[DMSO]; 14.1, (s, 1H); 8.6 (s, 1H); 7.75 (d, 1H, J=13 Hz); 4.5 (m, 5H); 3.2 (s, 3H). IR(KBr).-1730, 1704, 1627, 1466 cm-1.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([OH:25])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To a precooled −78° C. solution of 2-methylbut-3-yn-2-ol (4.71 g, 0.05 mol) in THF (250 mL), n-BuLi (51.2 mL, 0.08 mol) was added under an inert atmosphere, and the mixture stirred for 30 min. Then, 4-(benzyloxy)benzaldehyde (8.0 g, 0.037 mol) in THF was added and the mixture was stirred for an additional 3 h at RT, quenched with a saturated NH4Cl solution and concentrated in vacuo. The residue was acidified with HCl (1 N) and extracted with DCM (3×200 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-(4-(benzyloxy)phenyl)-4-methylpent-2-yne-1,4-diol (6 g, 54%) as a solid.
Reaction SMILES: CS(O[CH2:6]/[CH:7]=[CH:8]\[CH2:9]OS(C)(=O)=O)(=O)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:15][C:16]1[CH:17]=[C:18]([N:19]2[CH2:9][CH:8]=[CH:7][CH2:6]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Br)c1
Reactant: CS(=O)(=O)OC/C=C\COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(N2CC=CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
Then, a mixture of 15 g of the cis-1,4-bis(methanesulfonyloxy)-2-butene, 10 g of 3-bromoaniline, 24 g of anhydrous potassium carbonate and 70 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 5% ethyl acetate/hexane, to give 6.6 g of the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[S:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.Br.C(OCC)C>C(O)(=O)C>[C:24]([C@@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[S:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
In 1.5 ml of acetic acid is dissolved 0.3 g of tertbutyl 3(R)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 1 ml of 30% hydrogen-bromide acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 0.5 hour. Ethyl ether (80 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 10 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized with 2 ml of acetic acid, and purified by XAD-2 column chromatography (water:methanol=1:1). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.1 g of 3(R)-[1(S)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27](OCC)=[O:28])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:26]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCc1cccnc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(Cc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 3-(pyridin-3-yl)propionate (1.2 eq., prepared in Synthetic Example 5) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-(pyridin-3-ylmethyl)-1,8-naphthyridin-2(1H)-one, mp 226 to 227° C./DMF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([NH2:16])[C:14]#[CH:15].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:16][CH2:13][C:14]#[CH:15]
Reactant: C#CCN
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C#CCNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,4-dimethoxybenzaldehyde (2.51 g, 15.13 mmol) in methanol (100 ml) was added prop-2-yn-1-amine (1.0 g, 18.16 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, and cooled to 0° C. NaBH4 (1.0 g, 27.2 mmol) was added in portions over 15 minutes. The mixture was warmed up to room temperature and stirred for additional 2 hours. The reaction mixture was quenched with brine (200 mL), and partitioned between brine and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated to afford the title compound. MS (DCI/NH3) m/z 206 (M+H)+.