Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19][C:20](=[O:22])[CH3:21])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19][C:20](=[O:22])[CH3:21])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1C
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1C)OCC(c1ccc(O)cc1)C2=O
Reaction time: 62 h

Procedure:
Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-4H-chromen-7-yl ester (26.32 g), 10% Pd/Al2O3 (12.93 g, 50%) and ethyl acetate (EtOAc) (1.5 L) were added to a hydrogenation round bottom flask (2 L). The flask was placed on the hydrogenator, evacuated, purged with nitrogen gas (×5) and hydrogen gas (×5). The reaction was monitored by HPLC. 10% Pd/Al2O3 (9 g, 35%) was added to the round bottom flask at 40 hours, indicated there was no product peak present, only starting material was present. HPLC at 62 hours indicated that the major peak was product peak with starting material peak being half height of product peak. 10% Pd/Al2O3 (5.69 g, 20%) was added to the round bottom flask to speed up reaction rate. Reaction was completed at 64 hours. The reaction mixture was filtered through celite to remove the Pd/Al2O3 catalyst, the celite was rinsed with EtOAc (1 L) to ensure majority of product was collected. The EtOAc was evaporated off on a rotary evaporator to give a yellow solid. The solid was re-crystallised in 95% EtOH (650 ml) and left in the freezer overnight. Off-white crystals were collected by suction filtration. 1HNMR in d-CDCl3 indicated the off-white crystals were 8 Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester with >95% purity. The crystals were stored in a desiccator for 24 hours, and weighed (18.37 g, 69%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:22][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:13]=1)=O)C.[NH3:23]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@@H:10]3[CH2:22][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([NH2:23])=[O:3])=[N:13]1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: N
Product: NC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 100 °C
Yield: 67.5 %

Procedure:
(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (200 mg, 0.657 mmol) was partially dissolved in a 7 M methanolic solution of ammonia (2 mL, 14.00 mmol). The mixture was heated under microwave irradiation in a sealed, thick-walled glass tube for 1 h at 100° C., then 2 h at 120° C. and 12 h at 125° C. The methanol was removed under reduced pressure. The remaining residue was triturated with ether and the precipitate was collected by filtration to give the title compound (122 mg) as a tan solid. LCMS m/z=276.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.40 (td, J=4.4, 3.4 Hz, 1H), 1.15 (td, J=7.8, 4.7 Hz, 1H), 2.15-2.20 (m, 1H), 2.23-2.30 (m, 1H), 2.77 (d, J=16.7 Hz, 1H), 2.89 (dd, J=16.4, 6.4 Hz, 1H), 7.22 (bs, 1H), 7.28-7.33 (m, 1H), 7.35 (bs, 1H), 7.56-7.62 (m, 1H), 7.77 (td, J=8.9, 6.0 Hz, 1H).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:21][CH:20]([N:22](CC3C=CC=CC=3)[CH2:23][C@H:24]([OH:41])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33]CC4C=CC=CC=4)=[CH:29][CH:28]=3)[CH2:19]2)=[CH:14][CH:13]=1)[C:9](=[O:11])[CH3:10])(=[O:7])[CH3:6]>CO.[Pd]>[C:5]([N:8]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH:20]([NH:22][CH2:23][C@H:24]([OH:41])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH2:21]2)=[CH:16][CH:17]=1)[C:9](=[O:11])[CH3:10])(=[O:7])[CH3:6]
Reactant: CC(=O)N(C(C)=O)c1ccc(N2CC(N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)N(C(C)=O)c1ccc(N2CC(NC[C@H](O)COc3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Ammonium formate (0.57 g, 9.1 mmol) was added to a solution of N-acetyl-N-[4-(3-{benzyl-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl]-acetamide (which was obtained in Example 402) (0.25 g, 0.45 mmol) and 10% Pd/C (0.05 g) in dry methanol (7 mL). The reaction was stirred at room temperature overnight. The solution was passed through a pad of celite and then was concentrated. The crude solid was treated with saturated aqueous NaHCO3 (30 mL) followed by extraction with ethyl acetate (3×20 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and evaporated to afford 0.18 g of the desired product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.05 (s, 6H), 2.61 (s, 1H), 2.75 (m, 2H), 3.49 (m, 2H), 3.75 (m, 1H), 3.85 (d, 2H, J=7.13 Hz), 4.02 (t, 2H, J=5.3 Hz), 4.12 (q, 1H), 6.32 (d, 2H, J=11.12 Hz), 6.90 (d, 2H, J=11.32 Hz), 6.55 (q, 4H, J=4.6 Hz), 7.53 (d, 2H, J=7.02 Hz), 7.61 (brs, 1H); MS (ES) m/z: 414.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:22]/[CH:23]=[CH:24]\[CH2:25]Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:25][CH:24]=[CH:23][CH2:22]2)[CH:7]=1
Reactant: COC(=O)Cc1cc(F)cc(OC)c1
Reactant: ClC/C=C\CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cc(F)cc(OC)c2)CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a stirred solution of methyl 5-fluoro-3-methoxyphenylacetate (708 mg, 3.6 mmol) in THF (10 ml) was added a 1.0 M solution of potassium t-butoxide in THF (4.0 ml, 4.0 mmol) at -30° C. over 0.25 hr. After stirring for 1 h at the same temperature, a solution of cis-1,4-dichlorobut-2-ene (526 mg, 4.0 mmol) in THF (2 ml) was added dropwise and the reaction mixture was warmed to room temperature over 2 hr period. The reaction mixture was cooled to -30° C., and 1.0 M solution of potassium t-butoxide in THF (4.0 ml, 4.0 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 150 g; hexane/ethyl acetate (20/1)) afforded 495 mg (55%) of methyl 1-(5-fluoro-3-methoxyphenyl)cyclopent-3-ene-1-carboxylate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:25])[CH2:10][C:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)(O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:25])[CH:10]=[C:11]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:12]([F:14])([F:15])[F:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 6.00 g of 1-(3-bromo-4-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutane-1-one and 4.70 g of thionyl chloride in 30 mL of toluene, 3.12 g of pyridine was added while heating and stirring the solution at 80° C. and the resultant reaction mixture was continued to be stirred at the same temperature further for 2 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and was diluted with 30 mL of toluene, and the diluted reaction mixture was washed with water (30 mL×1). Subsequently, the washed reaction mixture was dehydrated and dried over a saturated brine and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure to obtain 6.04 g of the objective substance as a yellow oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:11]([CH3:13])[CH3:12])[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:6]=1)=O.[NH3:30]>CO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[N:7]1[C:8]([CH2:10][N:11]([CH3:12])[CH3:13])=[N:9][C:5]([C:3]([NH2:30])=[O:2])=[N:6]1)=[O:29]
Reactant: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: N
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8.66 g (0.020 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester is covered over with 400 ml of methanol and 80 ml of concentrated aqueous ammonia solution. The reaction solution is stirred for 16 hours at room temperature, and thereupon concentrated in vacuo to dryness. Water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice-cold 1 N sodium hydroxide solution and is then extracted twice with 2 N hydrochloric acid solution. To the aqueous acidified solutions there are added ice and sufficient 5 N sodium hydroxide solution to bring the pH-value to 10. The precipitated base is taken up in methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated by evaporation to dryness. The amorphous residue is triturated with ether, whereupon the reaction product precipitates in crystalline form. It is filtered off with suction and washed with ether. After drying, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide, m.p. 177°-180°.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:24](=[O:26])[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:27])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC1(C)c2cc(OCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), piperazine-1-carboxylic acid tert-butyl ester (31 mg, 2 eq.), and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (20 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH:39]1[C:44](O)=[CH:43][CH:42]=[C:41]([Br:46])[CH:40]=1>>[Br:46][C:41]1[CH:42]=[CH:43][C:44]([O:1][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25](=[O:38])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:39][CH:40]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: Oc1ccc(Br)cc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(Br)cc3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-bromophenol, to afford 420 mg of the title compound as a powder.
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[H-].[Na+].I[CH2:26][CH3:27]>C1COCC1.O>[CH2:26]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[CH2:8]1)[CH3:27]
Reactant: CCI
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
The product of Example 1E (22 mg, 0.076 mmole) was dissolved in 2.5 ml anhydrous THF under nitrogen. Sodium hydride (95%, 4 mg, 0.167 mmole) was added and the mixture was stirred at room temperature for 1 hour. Iodoethane (18 μl, 0.225 mmole) was added and the mixture was stirred at room temperature over night. The mixture was diluted with water and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with a mixture of 0.2% ammonium hydroxide and 2% methanol in dichloromethane) to provide the title compound (11 mg, 46%). 1H NMR (CDCl3) δ ppm 7.64 (d, J=1.36 Hz, 4H) 7.50 (d, J=8.82 Hz, 2H) 6.65 (d, J=8.82 Hz, 2H) 4.14-4.23 (m, 1H) 3.47-3.60 (m, 1H) 3.27-3.39 (m, 1H) 2.92-3.04 (m, 1H) 2.70-2.81 (m, 1H) 2.38-2.67 (m, 5H) 2.11-2.25 (m, 1H) 1.89-2.03 (m, 1H) 1.08 (t, J=7.12 Hz, 3H); MS (M+H)+=318.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[Na].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: CC(c1cccnc1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1cccnc1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (4.30 g) with 1H-1,2,4-triazole, sodium salt (3.0 g) in N,N-dimethylformamide (50 ml) according to the method of Example 1(ii), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (1.13 g), m.p. 113°-114° (from ether).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([C:5]1[CH:6]=[C:7]([O:22]CC2C=CC=CC=2)[C:8]2[N:12]=[C:11]([CH3:13])[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=2[CH:21]=1)=[O:4]>[OH-].[Pd+2].[OH-]>[CH3:30][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[N:12]=[C:11]([CH3:13])[N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:9]=2[CH:21]=1)=[O:4]
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Yield: 92 %

Procedure:
The title compound was prepared as a white solid in 92% yield (4.10 g) from 1,1-dimethylethyl 6-[(dimethylamino)carbonyl]-2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-1-carboxylate (5.68 g, 13.9 mmol, STEP 1) and 20% palladium hydroxide (2.4 g) by the same manner in STEP 3 of Example 4.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphopsphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)O1.C(N(CC)CC)C.[C:28]1(=[O:33])[CH2:32][CH2:31][CH:30]=[CH:29]1>O1CCOCC1.O.[Cl-].[Na+].O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:30]2[CH2:31][CH2:32][C:28](=[O:33])[CH2:29]2)=[CH:10][C:11]=1[C:16]([F:17])([F:18])[F:19]
Reactant: CC1(C)OB(c2ccc(O)c(C(F)(F)F)c2)OC1(C)C
Reactant: O=C1C=CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CC[C@H](c2ccc(O)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
[Rh(S-BINAP)(nbd)]BF4 (0.03 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenol (preparation 9) (1.5 mmol) were added to a 25 mL-flask containing a magnetic stir bar and a septum inlet. The flask was flushed with argon. Triethylamine (1.5 mmol) and 2-cyclopenten-1-one (1.0 mmol) dissolved in 1,4-dioxane —H2O (6:1, 3 mL) were then added. The mixture was stirred for 6 h at 25° C. Brine was added, the mixture was extracted with ethyl acetate, and the solvents were removed in vacuo to afford the title compound. 1H NMR (300 MHz, DMSO) δ 10.37 (bs, 1H), 7.45-7.36 (m, 2H), 6.97 (d, 1H), 3.43-3.23 (m, 1H), 2.57-2.44 (m, 1H), 2.37-2.17 (m, 4H), 1.96-1.77 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of methyl 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.31 mmol) in MeOH (10 mL) was added sodium hydroxide (49 mg, 1.2 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 6 with HCl (1 N). The solids were collected by filtration to afford 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (99 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [OH-:1].[Na+].[O:3]=[C:4]1[NH:9][C:8]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C:7]=2[N:6]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:5]12>O1CCOCC1>[O:3]=[C:4]1[NH:9][C:8]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16](=[O:1])[C:7]=2[N:6]2[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:5]12
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3=O

Procedure:
5 ml of 1N sodium hydroxide are added to a suspension of 0.2 g of ethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in 15 ml of dioxane, and the reaction mixture is stirred vigorously while compressed air is bubbled for 15 hours. After addition of 10 ml of distilled water the mixture is acidified with concentrated hydrochloric acid. The precipitate form is filtered off, washed with water and dried to produce 0.13 g of 4,5-dihydro-4,10-dioxoimidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid in the form of a brown powder whose melting point is higher than 260° C. (1H spectrum in DMSO, T=300K, δ in ppm (200 MHz): between 7.35 and 7.65 (3H, m, CH arom. ), 7.75 (1H, d, J=7 Hz, CH arom.), 8.38 (1H, s, CH arom.), 12.5 (1H, s, NH)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:22]([O:23][CH3:24])=[CH:21][C:19]([NH2:20])=[C:18]([O:25][CH3:26])[CH:17]=1>>[Cl:15][C:16]1[C:22]([O:23][CH3:24])=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[C:18]([O:25][CH3:26])[CH:17]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1cc(NC(=O)c2cc(C(N)=O)ccc2OC)c(OC)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-chloro-2,5-dimethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.