Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=[C:25]([CH:31]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])O1.[F-].[Cs+]>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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[C:23]([CH:22]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[C:23]([CH:22]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Brc1ccc2ccc(Br)cc2c1
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)OCC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccc3ccc(-c4cc(C(=O)OCC)cc(C(=O)OCC)c4)cc3c2)c1
Yield: 76 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromonaphthalene (2.00 g, 6.99 mmol), diethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (6.09 g, 17.48 mmol), CsF (4.00 g) and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen. 160 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen for 2 days. The solvent was removed on a rotary evaporator. 120 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was washed with acetone and then hexane (3×20 mL for each) to give a pure product with a yield of 76% (3.02 g) based on 2,7-dibromonaphthalene. 1H NMR (300 MHz, DMSO-d6): δ 1.39 (t, 12H), 4.42 (q, 8H), 7.90 (d, 2H), 8.11 (d, 2H), 8.45 (s, 4H), 8.52 (s, 4H).
Reaction SMILES: CC([O:7][C:8]([C:10]1[N:15]2[C:16]([C@@H:18]([NH:19][C:20](/[C:22](/[C:26]3[O:30][CH:29]=[CH:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C@H:14]2[S:13][CH2:12][C:11]=1[CH2:31][O:32][C:33]([NH2:35])=[O:34])=[O:17])=[O:9])OC(C)=O.C[O-].[Na+].Cl>O1CCCC1.CO>[CH3:25][O:24]/[N:23]=[C:22](\[C:20]([NH:19][C@@H:18]1[C:16](=[O:17])[N:15]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[CH2:12][S:13][C@H:14]12)=[O:21])/[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Temperature: -60 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of cefuroxime axetil (20.4 gm, S-isomer >90%, R-isomer <10%) in a mixture of tetrahydrofuran (204 ml) and methanol (14 ml) maintained at −60° C. was added freshly prepared sodium methoxide (1.89 gm, sodium metal was reacted in 28 ml methanol). The reaction contents were stirred for 1 hour and 15% aqueous hydrochloric acid (17 ml) was added. The solvent was distilled at low temperature under vacuum and water was added to the remaining reaction mass. Ethyl acetate was added and the pH level was adjusted to 6.0 with aqueous potassium bicarbonate. The aqueous layer was separated and acidified to pH 1.0 with aqueous hydrochloric acid. The separated solid was filtered, washed with water and dried to yield cefuroxime (15.66 gm).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=4[CH:28]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-:29].[K+]>CCO.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]([OH:29])=[O:27])=[CH:23][C:22]=4[CH:28]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc4oc(C=O)cc4c3)no2)cc1OCC
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C(=O)O)cc4c3)no2)cc1OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a suspension of the product of Step E (0.009 g; 0.024 mmol) and AgNO3 (0.06 g; 0.14 mmol) in EtOH (0.2 ml) H2O (0.1 ml) was added at room temperature, followed by 10% KOH (0.1 ml). The resulting black suspension was stirred for 1 h at ˜50° C. and cooled to room temperature and filtered. The insoluble material was washed with H2O (2×0.2 ml). The combined filtrates were acidified to pH=1 with HCl and the product was taken up by extraction with EtOAc (2×5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was purified by FCC (SiO2, CH2Cl2/acetic acid (AcOH) 98/2) to give the title compound (0.00012 g; 12.8%), as a creamy solid. 1H-NMR (CDCl3+CD3OD) 8.48 (s, 1H); 8.22 (m, 1H); 7.77 (m, 1H); 7.64-7.66 (m, 2H); 7.58 (s, 1H); 6.96 (d, 1H, J=6 Hz); 4.19 (m, 4H); 1.4-1.54 (m, 6H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH:17]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 90.6 %

Procedure:
In toluene, dissolved were 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]ethanone (10 g, 39 mmol) and DMFDMA (N,N-dimethyl formamide dimethyl acetal) (13.9 g, 117 mmol), and the mixture was heated under reflux. The reaction mixture was extracted with EA, and the extract was washed twice with brine, dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The mixture was purified via column chromatography (MC/MeOH=10/1) to obtain 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-3-(dimethylamino)prop-2-en-1-one (11 g, 92%).
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]([CH3:25])[CH3:24])[C:8]=2[NH:7][C:6]1=[O:26])(=O)C.[I-].[Na+].[K].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>CN(C)C=O>[C:30]1(=[O:40])[N:34]([CH:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]([CH3:25])[CH3:24])[C:8]=3[NH:7][C:6]2=[O:26])[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)OC1N=C(c2ccccc2F)c2cccc(C(C)C)c2NC1=O
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc2c1NC(=O)C(N1C(=O)c3ccccc3C1=O)N=C2c1ccccc1F
Temperature: 90 °C
Reaction time: 1.3 h
Yield: 90.6 %

Procedure:
A mixture of (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (2.73 g), sodium iodide (11.5 g) and phthalimide potassium salt (2.14 g) in N,N-dimethylformamide (18 ml) was stirred at 90° C. for 1.3 hours. The hot reaction mixture was poured into an ice with stirring to afford precipitates, which were collected by filtration, washed with water and air dried at room temperature to afford (3RS)-3-phthalimido-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.08 g, 90.6%) as a crystalline powder.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](ON1C(=O)CCC1=O)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>O.CC(C)=O>[C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 94.1 %

Procedure:
The title compound was prepared similarly as shown in example 3 from L-lysine monohydrochloride (0.94 g, 5.1 mmol) and succinimidyl stearate (1.94 g, 5.1 mmol) in the presence of triethylamine (2.15 ml, 15.3 mmol) in 9.4 ml of water and 9.4 ml of acetone. The product was washed with cold water and ethanol and then dried yielding 1.98 g (92.7%) of the title compound. Infrared: 1580-1590 cm-1 (ionized carboxyl group), 1635 and 1520-1535 cm-1 (amide bands).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[BH4-].[Na+]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(C2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1

Procedure:
To a solution of 11.1 g (0.048 mol) of 4-(4-dimethylaminomethylphenyl)-cyclohexanone in 100 ml of absolute methanol, which has been cooled to -10° C., is added 1.82 g (0.048 mol) of sodium borohydride in batches with stirring. The reaction mixture is allowed to react for 1.5 hours at ambient temperature and then evaporated down in vacuo. The residue remaining is mixed with water, acidified with concentrated hydrochloric acid, stirred for 30 minutes at ambient temperature, made alkaline with 50% sodium hydroxide solution and extracted several times with chloroform. The combined extracts are dried with sodium sulphate and evaporated down in vacuo. The residue remaining, which consists of a mixture of trans/cis-4-(4-dimethylaminomethyl-phenyl)-cyclohexanol (cis fraction <10%) is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/methylethyl ketone=5:1). White crystals are obtained, melting point 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:51][CH:52]([F:54])[F:53])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:51][CH:52]([F:54])[F:53])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cn(CC(=O)N2CCC(C(=O)OCC3CCNCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reaction time: 0.17 h

Procedure:
A solution of [1-[(tert-butoxy)carbonyl]piperidin-4-yl]methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate (150 mg, 0.19 mmol) and saturated HCl dioxane solution (10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of methanol. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 33.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 82.3 mg (59%) of the formic acid salt of piperidin-4-ylmethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as a light yellow solid. LCMS (Method 20) [M+H]+=671.3, RT=1.58 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.33 (dd, 1H, J=1.2, 6.9 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.5, 7.2 Hz), 7.01 (t, 1H, J=73.5), 5.25-5.23 (m, 2H), 4.24-4.19 (m, 1H), 3.93-3.85 (m, 3H), 2.83-2.80 (m, 1H), 2.72-2.64 (m, 3H), 1.92-1.87 (m, 3H), 1.71-1.67 (m, 3H), 1.59-1.48 (m, 1H), 1.44-1.23 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>>[S:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:14][CH2:15]1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: C1CSCCN1
Product: O=c1[nH]nc(N2CCSCC2)c2ccccc12

Procedure:
4-chlorophthalazin-1(2H)-one and thiomorpholine were processed using a method similar to that described in Example 1A to afford the title compound. MS (APCI+) M/Z 248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[N:4][C:5]([F:13])=[C:6]([Cl:12])[C:7]=1[CH2:8]C(O)=O.[Br:15]Br>ClC1C=CC=CC=1.[Hg]=O>[Br:15][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([F:14])[N:4]=[C:5]([F:13])[C:6]=1[Cl:12]
Reactant: O=C(O)Cc1c(Cl)c(F)nc(F)c1Cl
Reactant: BrBr
Agent: O=[Hg]
Solvent: Clc1ccccc1
Product: Fc1nc(F)c(Cl)c(CBr)c1Cl
Temperature: 145 °C
Yield: 83.2 %

Procedure:
To a 1 L 3-neck flask equipped with addition funnel, was placed chlorobenzene (150 ml). 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetic acid (21 g, 86.77 mmol) and mercury oxide (20 g, 92.34 mmol) were added in this order. The mixture was heated up to 140-150° C. in an oil bath. Bromine (5.4 mL, 105 mmol) in chlorobenzene (90 ml) was then added dropwise through the addition funnel for 2˜2.5 hr. After the addition of bromine solution, the reaction mixture was refluxed for further 1 hr. and cooled to room temperature. The mixture was filtered through celite pad and the pad was washed with chlorobenzene. The combined filterate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:10)) to give 20 g (80%) of 4-(bromomethyl)-3,5-dichloro-2,6-difluoropyridine as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.66 (2H, s). m/z (EI) 277 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][CH:16]([F:26])[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=[C:17]2[CH:16]([F:15])[F:26])[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: FC(F)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of 2-difluoromethyl-benzimidazole and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86%) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine. (2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87%) of the titled compound as colorless crystals.
Reaction SMILES: C([O:8][C:9]([CH2:11][O:12][C:13]1[CH:49]=[CH:48][C:16]([C:17]([N:19]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=5)[CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH2:23][CH2:22][C:20]2=[O:21])=[O:18])=[CH:15][CH:14]=1)=[O:10])C1C=CC=CC=1>CN(C=O)C.C(O)C.[Pd]>[C:9]([CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=5)[CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH2:23][CH2:22][C:20]2=[O:21])=[O:18])=[CH:48][CH:49]=1)([OH:10])=[O:8]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc(OCC(=O)OCc4ccccc4)cc3)CC2)cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc(OCC(=O)O)cc3)CC2)cc1OC
Yield: 89.7 %

Procedure:
To a solution of 1-(4-benzyloxycarbonylmethoxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (4 g) in a mixture of DMF (30 ml) and ethanol (30 ml) was added 10% palladium on carbon (500 mg) and the mixture was hydrogenated at room temperature and atmospheric pressure. After completion of reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane. The solution was washed with water, dried and evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:2 to 1:1) to give 1-(4-carboxymethoxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (3.1 g).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH2:60])[CH3:59])=[N:57][C:53]=2[CH:52]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:60][C@H:58]([C:56]2[NH:55][C:54]3[CH:61]=[CH:62][C:51]([Cl:50])=[CH:52][C:53]=3[N:57]=2)[CH3:59])=[O:15])=[CH:11][C:10]=1[CH3:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)c1ccccc1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)c1ccccc1
Yield: 91 %

Procedure:
Prepared analogously to Example 1g from 4-benzoyl-3-methylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 91%; Rf value: 0.54 (silica gel: dichloromethane/ethanol=9:1); C24H20ClN3O2 (417.894); mass spectrum: (M+H)+=418/420 (chlorine isotope) and (M−H)−=416/418 (chlorine isotope).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]([O:21][CH3:22])=[O:20])([O-])=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[NH2:6][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc2c([N+](=O)[O-])cccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc2c(N)cccc12
Temperature: 70 °C
Yield: 116.2 %

Procedure:
1 cm3 of 97% sulphuric acid is added to a suspension of 4.7 g of 5-nitro-1-naphthoic acid in 50 cm3 of methanol and the reaction mixture is then brought to reflux for 12 hours. The solution is cooled to a temperature in the region of 20° C. and the precipitate formed is filtered off by centrifuge and washed twice with 5 cm3 of ice-cold methanol and then dried to constant weight. 4.56 g of methyl 5-nitro-1-naphthoate are obtained, melting at 105° C. 21.5 g of tin(II) chloride dihydrate are added to a solution of 4.45 g of methyl 5-nitro-1-naphthoate in a mixture of 150 cm3 of ethyl acetate and 35 cm3 of ethanol. The solution is heated to a temperature in the region of 70° C. for 30 minutes and then cooled to a temperature in the region of 20° C. The reaction mixture is poured onto 200 cm3 of ice and the pH of the solution is progressively brought to 7-8 by addition of a 5% (w/v) sodium hydrogen carbonate solution. The mixture obtained is filtered on a sintered glass covered with Celite, the organic phase is separated by settling and the aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 4.5 g of methyl 5-amino-1-naphthoate are obtained in the form of an oil which are used in the following stage without other purification. 14.75 g of S-triphenylmethyl-N-(tert-butoxycarbonyl)cysteinal, 0.14 cm3 of concentrated acetic acid, molecular sieves (3Å) and then 4.15 g of sodium cyanoborohydride are added to a solution of 4.5 g of methyl 5-amino-1-naphthoate in 30 cm3 of methanol. The reaction mixture is stirred for 2 days at a temperature in the region of 20° C. and then filtered on sintered glass covered with Celite. The sintered glass is washed with methanol. The filtrate is concentrated under reduced pressure, redissolved in 150 cm3 of ethyl acetate and washed with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution, with 100 cm3 of a 10% (w/v) aqueous citric acid solution, with 100 cm3 of distilled water, with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution and finally with 100 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The product is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (85/15 by volume)]. 3.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate are obtained in the form of a beige foam which are used in the following stage without other purification.