Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]Cl.[SH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O.[OH-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: ClSc1ccccn1
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCSSc1ccccn1

Procedure:
2.4 g of 2-pyridine sulfenyl chloride are dissolved in 40 ml of methylene chloride, and a solution of 1.75 g of 3-mercaptopropionic acid in 10 ml of methylene chloride is added slowly, whilst stirring and cooling with an ice bath. When the addition is complete, the mixture is stirred at ambient temperature for 15 hours. 50 ml of water are added and the pH is brought to 4.5 by adding 1 N sodium hydroxide solution. The organic phase is separated off and dried over sodium sulphate and the solvent is evaporated off to dryness. An oily product remains and this crystallises (1.8 g). It is purified by dissolution in 16.8 ml of a 0.5 M aqueous solution of sodium bicarbonate. Activated charcoal is added, the solution is filtered and the expected product is then precipitated by adding concentrated acetic acid (0.5 ml) so as to bring the pH to between 3 and 3.5. The precipitate is filtered off and dried under high vacuum and a solid (1.3 g), melting point (capillary method): 62°-64° C., is obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[N:27][C:28](F)=[CH:29][C:30]=3[CH3:31])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[N:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:15][CH:16]=1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reactant: C[C@@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)OC[C@H]2C)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of (R)-4-methyloxazolidin-2-one (222 mg) described in Preparation Example 25 in DMF (4 mL) was added sodium hydride (84 mg) at 10° C., and the mixture was stirred for 30 min. Furthermore, [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (447 mg) described in Preparation Example 113 was added, and the mixture was stirred at 80° C. for 3 hr and at 100° C. for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-3-{5-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-4-methyloxazolidin-2-one (260 mg).
Reaction SMILES: Cl.[C:2]1([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH:2]1([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C1=C(c2c[nH]cn2)c2ccccc2C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CCC2c1c[nH]cn1

Procedure:
4-(3H-Inden-1-yl)-1H-imidazole hydrochloride (80 mg) is dissolved in ethanol (6 ml). The reaction solution is hydrogenated at 40-50° C. with 10% palladium on carbon as catalyst until no more hydrogen is consumed. Work-up of the reaction mixture gives the crude product which is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:28]=[CH:27][C:6]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([NH:19]C(=O)OC(C)(C)C)[CH:13]=[CH:12]3)=[O:8])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.ClCCl>[NH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:7]([C:6]1[CH:27]=[CH:28][C:3]([N:2]([CH3:29])[CH3:1])=[CH:4][CH:5]=1)=[O:8])[CH:18]=[CH:17]2
Reactant: CN(C)c1ccc(C(=O)c2ccc3cc(NC(=O)OC(C)(C)C)ccc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(C(=O)c2ccc3cc(N)ccc3c2)cc1
Yield: 95.7 %

Procedure:
The compound 9 (70 mg, 0.18 mmol) was stirred in 10% TFA in dichloromethane (10 mL) at room temperature for 1 hour and extracted with ethyl acetate with aqueous NaHCO3. The organic layer was dried over Na2SO4, and the filtrate was concentrated to give intermediate D (50 mg, 96%). 1H-NMR (CD3OD) 8.02 (s, 1H), 7.59-7.78 (m, 5H), 7.00-7.07 (m, 2H), 6.80 (m, 3H), 3.09 (s, 6H) ppm; ESI-MS m/z calcd for C19H18N2O: 290.3590. found 291.1821 [M+1].
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][OH:26])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:39]=[C:40]1[O:44][C:42](=[O:43])[CH2:41]1>ClCCl>[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][O:26][C:42](=[O:43])[CH2:41][C:40](=[O:44])[CH3:39])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In dichloromethane (50 ml) was dissolved 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.49 g) and, at room temperature, triethylamine (0.51 g) and diketene (1.26 g) were added. The reaction was conducted for 2 hours, after which time the solvent was distilled off under reduced pressure. The residue was diluted with water and adjusted to pH 6.0. This aqueous solution was extracted twice with ethyl acetate, brought down to pH 2.0 with 4 N-HCl and extracted three times with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, treated with magnesium sulfate and filtered. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate-ether. The above procedure provided 7β-phenylacetamido-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (4.16 g) (yield 96.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:20])=[C:6]([CH3:21])[C:5]=1[O:22][CH3:23].[CH:24]([O:27][P:28]([CH2:34]Br)(=[O:33])[O:29][CH:30]([CH3:32])[CH3:31])([CH3:26])[CH3:25].CC(C)([O-])C.[Li+]>CN(C=O)C>[CH:30]([O:29][P:28]([CH2:34][O:1][CH2:2][CH2:3][C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7](=[C:6]([CH3:21])[C:5]=1[O:22][CH3:23])[CH2:8][O:9][C:10]2=[O:20])(=[O:33])[O:27][CH:24]([CH3:26])[CH3:25])([CH3:32])[CH3:31]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCO)C(=O)OC2
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCOCP(=O)(OC(C)C)OC(C)C)C(=O)OC2

Procedure:
A mixture of 6-(2-hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (79 mg, 0.23 mmol) was heated with bromomethylphosphonic acid diisopropyl ester (120 mg, 0.46 mmol) in the presence of lithium t-butoxide (22 mg, 0.27 mmol) in DMF (2 mL) at 70° C. overnight. The reaction mixture was purified by RP HPLC (acetonitrile and 0.1% aqueous CF3COOH) to provide the desired product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.13-1.25 (m, 2H), 1.26 (t, 12H, J=6 Hz), 2.12 (s, 3H), 2.98 (t, 2H, J=7 Hz), 3.60-3.73 (m, 4H), 3.77 (s, 3H), 4.05-4.16 (m, 2H), 4.62-4.74 (m, 2H), 5.07 (s, 2H) ppm; MS (m/z) 539 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:9]([OH:10])[CH2:8]1.[OH-].[K+].C[O:40][C:41]([C:43]1[O:49][C:46]([CH2:47]Cl)=[CH:45][CH:44]=1)=[O:42]>O1CCOCC1>[C:41]([C:43]1[O:49][C:46]([CH2:47][O:10][C@@H:9]2[C@@H:11]([CH2:12][OH:13])[O:33][C@@H:7]([N:6]3[CH:34]=[C:2]([F:1])[C:3](=[O:36])[NH:4][C:5]3=[O:35])[CH2:8]2)=[CH:45][CH:44]=1)([OH:42])=[O:40]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)o1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
To a solution of 5.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 100 ml of dioxane were added 5.74 g of fine powder of potassium hydroxide and 2.67 g of 5-methoxycarbonylfurfuryl chloride, and the mixture was stirred at temperature of 80° C. for 2.5 hours. The reaction mixture was concentrated and the residue was dissolved in 100 ml of water. The reaction mixture was adjusted to a pH of 4 with one normal hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried and concentrated To the residue was added 100 ml of 80% acetic acid The mixture was left to stand at a temperature of 80° C. for one hour. The solvent was distilled off and the residue was washed with ethyl acetate and methanol, giving 2.53 g (67%) of 3'-O-(5carboxyfurfuryl)-2'-deoxy-5-fluorouridine.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CCN(CC)CC>C(O)C>[Cl:1][CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@@H](O)CCl
Yield: 75.8 %

Procedure:
In a 200 ml autoclave were charged 40.0 g (0.24 mol) of ethyl 4-chloro-3-oxobutyrate, 20 mg of Ru2Cl4((S)-Tol-BINAP)2.NEt3, and 40 ml of ethanol, and reaction was conducted at 100° C. under a hydrogen pressure of 300 KPa for 5 hours. After the solvent was removed, the reaction mixture was distilled (60° C./200 Pa.) to give 30.3 g of the title compound. Optical purity: 95%e.e.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([SH:9])=[N:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([S:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[N:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(C(F)(F)F)cn2)cc1
Temperature: 110 °C
Yield: 86.6 %

Procedure:
A mixture of 5-trifluoromethyl-pyridine-2-thiol (6.99 g, 39.0 mmol), 4-fluorobenzaldehyde (4.79 g, 38.6 mmol), anhydrous K2CO3 (8.16 g, 59.1 mmol) and DMF (70 mL) was heated at 110° C. for 18 h. The mixture was cooled to room temperature and partitioned between MTBE and water. The phases were separated. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to give a crude product which was purified by flash column chromatography (eluent: 5% MTBE in petroleum ether). Evaporation of the appropriate fractions gave the product (9.47 g, 87% yield). 1H NMR (CDCl3) δ 10.06 (s, 1H), 8.69-8.66 (m, 1H), 7.97-7.92 (m, 2H), 7.78-7.72 (m, 3H), 7.23-7.16 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C:13]([CH3:42])([CH3:41])[C:14]([N:16]([C:18]2[C:19]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][S:31][CH3:32])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:42])[C:14]([N:16]([C:18]2[C:19]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:30][S:31]([CH3:32])=[O:53])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CSCC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC(CS(C)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a solution of 0.25 g (0.39 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 10 ml dichloromethane were added 95 mg (70%, 0.39 mmol) 3-chloroperbenzoic acid at 0° C. After completed addition, the reaction mixture was allowed to warm to room temperature and stirred over night. An aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Basification with 1 N aqueous sodium hydroxide solution was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.23 g (89%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=1.Cl.[OH-].[Na+]>O>[Cl:18][C:19]1[N:20]=[C:21]([NH2:26])[N:22]=[C:23]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:9]3[CH:8]=[CH:7][N:6]=[C:5]4[NH:1][CH:2]=[CH:3][C:4]=34)=[CH:12][CH:13]=2)[CH:24]=1
Reactant: Nc1ccc(Nc2ccnc3[nH]ccc23)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Nc3ccnc4[nH]ccc34)cc2)n1
Temperature: 100 °C

Procedure:
125 mg (0.56 mmol) of N-1H-pyrrolo[2,3-b]pyridin-4-ylbenzene-1,4-diamine and 118 mg (0.72 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.72 ml of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7 M ammonia) 100:1 to 10:1).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]2[S:21][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(Nc1cnccc1O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nc3cnccc3s2)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A mixture of N-(4-hydroxypyridin-3-yl)-4-nitrobenzamide (5.18 g, 0.02 mol) and P2S5 (8.90 g, 0.04 mol) in pyridine (25 mL) and p-xylene (100 mL) was stirred at 140° C. for 18 h. The solvent was removed under vacuo while hot and the residue was purified by recrystallization from EtOH to afford 2-(4-nitrophenyl)thiazolo[4,5-c]pyridine as a yellow solid (3.00 g, yield: 59%). MS (ESI), calcd for C12H7N3O2S (m/z): 257, found: 258 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 84.8 %

Procedure:
A mixture of 0.42 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.39 g of anhydrous piperazine and 10 ml of pyridine was heated under reflux for 2.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was washed with ethanol and then dissolved in water and a 1N aqueous solution of sodium hydroxide. The solution was neutralized with a 10% aqueous solution of acetic acid. The crystals which precipitated were collected by filtration, washed with water, and dried to give 0.44 g of 5-amino-1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as pale yellow needles. m.p. 214°-216° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:24][C@@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][OH:27].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:24][C@@H:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][OH:27])[C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:15]=[C:16]([CH3:17])[C:10]=2[N:9]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3Cl)nc12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Temperature: 80 °C

Procedure:
To a solution of 2-(4,6-dichloro-pyrimidin-5-yl)-6-imidazol-1-yl-4-methyl-1H-benzimidazole (40 mg, 0.16 mmol) in isopropanol (5 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (35 mg, 0.23 mmol) and triethylamine (0.5 mL). The reaction mixture was heated to 80° C. for 4 h, cooled to room temperature and concentrated with high vacuum. The crude product was used for the next step without purification. LCMS (M+H)+ m/z 460 (t=2.13 min.).
Reaction SMILES: [CH:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH:14][C:15](=[O:27])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]1)([CH3:3])[CH3:2].[CH2:28]([O:30][CH2:31][CH2:32]Br)[CH3:29]>CN(C=O)C.[F-].[K+]>[CH:1]([C:4]1[C:9]([O:10][CH2:29][CH2:28][O:30][CH2:31][CH3:32])=[CH:8][CH:7]=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH:14][C:15](=[O:27])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Reactant: CCOCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c1C(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of N-(2,6-diisopropyl-3hydroxyphenyl)-2-[4-(3-hydroxypropyl) piperazin-1-yl]acetamide (180 mg, 0.61 mmol) in DMF (3 ml) were added 2-bromoethyl ethyl ether (2 ml) and potassium fluoride catalyst carried on alumina (40 wt %, 355 mg, 2.39 mmol) followed by stirring at 50° C. for 3 hours. After the catalyst was filtered off, the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=20:1) to provide 90 mg (yield 42%) of N-(2,6-diisopropyl-3-(2-ethoxyethyloxy)phenyl)-2-[4-(3-hydroxypropyl)piperazin-1-yl]acetamide as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([OH:19])=O)[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:19])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(CC(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
159 mg (499 μmol) of [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetic acid, 116 mg (599 μmol) of tert-butyl 4-aminobenzoate, 228 mg (599 μmol) of HATU and 261 μl (1.50 mmol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide were reacted according to General Method 5A. The solvent was removed and the residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 54.5 mg (22% of theory)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].I[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:22]([C:18]1[N:17]([CH2:16][CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:21]=[CH:20][CH:19]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1cccn1CCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of diethyl malonate (5.40 g, 33.8 mmol) in anhydrous N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60% in mineral oil, 1.35 g, 33.8 mmol). The reaction mixture was warmed and stirred at room temperature for 30 minutes. To this mixture was then added a solution of 1-(2-iodoethyl)-2-benzoylpyrrole (11.0 g, 33.8 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water (1000 mL) and extracted with ethyl acetate (3×300 mL). The ethyl acetate extracts were combined, washed with water (2×200 mL) and saturated aqueous sodium chloride (300 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to provide 9.85 g (82%) of 2-benzoyl-1-[3,3-di(ethoxycarbonyl)propyl]pyrrole.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCCCCCc1ccccc1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCCCCc2ccccc2)n1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of 6-bromopyridine-2-caboxaldehyde (30.0 g), 7-phenyl-1-heptyne (26.8 g), triethylamine (48.9 g), bis(triphenylphosphine)palladium(II)chloride (2.3 g, 2%), and copper(I)iodide (0.31 g, 1%) in dry tetrahydrofuran (100 ml) was heated under nitrogen at 55° C. for 70 hrs. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate was washed with ethyl acetate. The filtrate was evaporated. The residue was dissolved in ethyl acetate, the solution washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The residue was flash chromatographed on silica gel, eluting with 0.5% to 2%-ethyl acetate:hexane. The appropriate fractions were collected and concentrated to yield 29.5 g of the product.