Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([F:16])=[CH:9][C:8]=2[Br:17])=[O:4].[C:18]([O-])([O-])=O.[K+].[K+].CI.O>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:18])[C:12]2[C:7](=[C:8]([Br:17])[CH:9]=[C:10]([F:16])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(=O)c2cc(F)cc(Br)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c2cc(F)cc(Br)c2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Alternatively, into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 350 mg (1.17 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid methyl ester and 242 mg (1.75 mmol, 1.5 equiv.) of K2CO3. This material is suspended in 20 mL of DMSO then heated to 70° C. for 1 hr. The anion formation of the anion is apparent when the mixture becomes cloudy. The mixture is allowed to cool to 35° C. then 331 mg, 145 μL (2.33 mmol, 2.0 equiv.) of methyl iodide are added and stirring is continued for 2 hr. At the end of this time it is determined if the reaction is complete by LC/MS. Upon completion the mixture is poured into 200 mL of water and the solids which form are collected by filtration and washed with water to give 340 mg (93%) of the O-methylated product after drying.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>ClCCl>[Br:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12]
Reactant: Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a 500 mL flask, N-Boc-D-Proline (300 mg, 1.39 mmol) was dissolved in dichloromethane (35 mL) and cooled to 0° C. under nitrogen. N-Methylmorpholine (153 μL, 1.39 mmol) was added followed by dropwise addition of iso-butyl chloroformate (180 μL, 1.39 mmol) and the reaction mixture stirred at 0° C. for 1 h. 2-Bromoaniline (1.31 mL, 1.39 mmol) was dissolved in dichloromethane (5 mL) then added quickly to the activated acid at 0° C. The mixture was stirred overnight from 0° C. to room temperature. The reaction mixture was diluted with dichloromethane, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc, 50/50 to 0/100 then EtOAc/MeOH 80/20) to give the product (394 mg, 77%) as a yellow oil. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH:8]2[O:10][C:7]2([CH3:11])[CH2:6][CH2:5]1)=[CH2:3].[Cl-].[Li+].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(O)C>[C:2]([CH:4]1[CH2:5][CH2:6][C:7]([CH3:11])([OH:10])[CH:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)([CH3:1])=[CH2:3]
Reactant: C1COCCN1
Reactant: C=C(C)C1CCC2(C)OC2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: C=C(C)C1CCC(C)(O)C(N2CCOCC2)C1
Yield: 49.5 %

Procedure:
(+)-Limonene oxide (13.2 g, 0.087 moles) was dissolved in ethanol (40 ml) and lithium chloride (5.9 g, 0.14 moles) was added with stirring. Morpholine (11.4 g, 0.13 moles) was added and the reaction mixture was heated at 60° for 48 hours. The solvent was evaporated under reduced pressure and the residue taken up in dichloromethane. Washed with water. Extracted into 2M hydrochloric acid and washed with dichloromethane. Basified to pH 10 by addition of 2M sodium hydroxide. Extracted with diethyl ether and washed with water. Dried over anhydrous magnesium sulphate and evaporated the solvent under reduced pressure to give the product as a yellow oil (10.3 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([C:29](OC)=[O:30])[CH:22]=[C:23]([C:25](OC)=[O:26])[CH:24]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[OH:26][CH2:25][C:23]1[CH:24]=[C:19]([NH:18][C:16]([C:13]2[N:12]=[N:11][N:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH3:15])=[O:17])[CH:20]=[C:21]([CH2:29][OH:30])[CH:22]=1
Reactant: COC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2cc(CO)cc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dimethyl 5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzenedicarboxylate (Intermediate 14) (0.65 g, 1.3 mmol) in THF (40 mL), was added a 1M solution of DIBAL-H in toluene (10 mL, 7 eq) and the reaction was stirred to room temperature for 2 hours. Solid NH4Cl was added and the reaction mixture was stirred at RT for 30 min. The aqueous phase was extracted with ether and AcOEt, dried over sodium sulphate and evaporated. After recrystallisation from acetonitrile, the title compound was obtained as a white solid (240 mg, 44%). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0833, Rt: 2.51 min. MP: 194.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccccn2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(4-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The solid obtained from flash chromatography was further purified by reverse phase HPLC on a Polar reverse phase column using a gradient of 5-45% acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid as a buffer) as the eluant. The product-containing fractions were evaporated. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as a pale solid, m/z 342 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:37](CS([O-])(=O)=O)([CH3:39])[CH3:38]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:37]([CH3:39])[CH3:38])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)CS(=O)(=O)[O-]
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2n1C(C)C
Temperature: 95 °C
Yield: 99.9 %

Procedure:
To a solution of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid ethyl ester (1.55 g, 3.5 mmol) in acetonitrile (25 ml) under an argon atmosphere were added caesium carbonate (2 eq., 2.44 g) and isopropylmethanesulfonate (2 eq., 1.03 g). The mixture was heated at 95° C. (oil-bath temperature) overnight. The mixture was cooled to room temperature and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (3:1 heptane/ethyl acetate eluant) to afford the product as a light-brown oil (1.6 g, 93%). MS (m/z): 458.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](F)([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH3:34])=[O:32])=[C:5]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:4]=1)#[N:2].[C:39](C1C=CC(C2C3C(=O)CCCC=3N(C3C=CC=C(C(F)F)C=3)C(=O)N2C(OC2C=CC([N+]([O-])=O)=CC=2)=O)=C(S(C)(=O)=O)C=1)#N.C(N)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH2:34][CH3:39])=[O:32])=[C:5]([S:35]([CH3:38])(=[O:36])=[O:37])[CH:4]=1)#[N:2]
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCN
Product: CCNC(=O)N1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-(methylsulfonyl)phenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (example 47), using 4-nitrophenyl 4-(4-cyano-2-(methylsulfonyl)-phenyl)-1-(3-(difluoromethyl)-phenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 39, 34 mg, 53 μmol) as starting material and replacing methylamine with ethylamine Yield: 10 mg, ESI mass spectrum [M+H]+=543; Retention time HPLC: 1.02 min (Z018_S04).
Reaction SMILES: Cl.Cl.C[NH:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1C.[CH:13]1C(N)=CC=C(N)C=1.C([O-])(=O)C.[NH4+].[OH-].[NH4+].OO>C(O)C>[C:5]1([NH2:4])([CH3:13])[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[CH2:10]1
Reactant: Nc1ccc(N)cc1
Reactant: CNc1cc(N)ccc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: OO
Solvent: CCO
Product: CC1(N)C=CC=C(N)C1
Reaction time: 0.5 h

Procedure:
0.104 g. (0.0005 M) 2-methylamino-4-aminotoluene dihydrochloride (meta component) and 0.054 g. (0.0005 M) p-phenylenediamine (para component) was added to 3 ml. of ethanol and 20 g. of an aqueous solution composed of 1% Carbopol 934 (thickening agent) 0.1% Dupanol C (surfactant) and 3.8% ammonium acetate. The mixture was stirred with 3 ml. ammonium hydroxide (28%) and 20 ml. 6% hydrogen peroxide. A sample of human hair was dyed with this composition for 30 minutes at 30° C. A blue color was obtained which was perspiration, light and washfast, and superior in these characteristics to a similar dyeing obtained in which m-toluenediamine was used as the meta component.
Reaction SMILES: [Br:1][C:2]1[C:45]([N+:46]([O-])=O)=[CH:44][CH:43]=[CH:42][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:7]1.[CH:49]([Mg]Br)=[CH:50][CH3:51].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH:6]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:14][CH:13]=3)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:7]2)=[CH:42][CH:43]=[C:44]2[C:45]=1[NH:46][CH:49]=[C:50]2[CH3:51]
Reactant: CC=C[Mg]Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)c[nH]c3c2Br)cc1
Reaction time: 0.25 h

Procedure:
The solution of 0.500 g of benzyl 3-(2-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxy-benzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 6.5 ml of tetrahydrofuran is cooled to −45° C. under argon and admixed slowly with 4.0 ml of 1-propenylmagnesium bromide (0.5M in tetrahydrofuran). The reaction mixture is stirred over 15 minutes, subsequently poured onto saturated aqueous ammonium chloride solution (10 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with water (25 ml) and brine (25 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane); Rt=6.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.[NH2:14][C@@H:15]([CH2:23][OH:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:15]([NH:14][C:11](=[O:13])[CH:10]=[CH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:23][OH:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: COc1ccc(C=CC(=O)O)cc1
Product: COc1ccc(C=CC(=O)NC(CO)Cc2ccccc2)cc1

Procedure:
Prepared in a similar manner as described in example 4 from 3-(4-methoxy-phenyl)-acrylic acid and D-phenylalaninol. MS (M+H, 312.3).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:4]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7](=[O:8])[C:2]([CH3:1])=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccccc2)n(-c2ccccc2[N+](=O)[O-])c(-c2ccccc2)cc1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(-c2ccccc2)n(-c2ccccc2N)c(-c2ccccc2)cc1=O
Yield: 51.1 %

Procedure:
To 50 ml of a suspension of 1.8 g (0.0050 mole) of 3-methyl-1-(2-nitrophenyl)-2,6-diphenyl-4(1H)-pyridinone and 0.2 g of 10% Pd-C in methanol, 1.5 g (0.023 mole) of ammonium formate (as a reducing agent) was added. After heating the resultant mixture under reflux for 3 hours under a nitrogen gas stream, solid matter was filtered off from the reaction mixture and the solvent was distilled off. The residue was then extracted with chloroform and the organic layer (the extract) was washed with 50 ml of a 10% aqueous solution of sodium hydroxide. After washing the organic layer with water, it was dried with anhydrous sodium sulfate and the solvent was then distilled off. The crystals thus-obtained were washed with acetone to give 0.9 g of 1-(2-aminophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of not lower than 300° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccs1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccs3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 87.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.96 g) and 2-(chloromethyl)thiophene (0.25 g) as a starting material, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.95 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained. melting point: 125-129° C.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[CH:18]=[CH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[C:10]([CH3:31])([CH3:30])[CH2:9][C:8]1=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:33](N1C2C(=CC(C(=O)C)=CC=2)C(C)(C)CC1=O)CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[CH:18]=[CH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[C:10]([CH3:31])([CH3:30])[CH2:9][C:8]1=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:33]
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Yield: 51 %

Procedure:
Following a procedure similar to that used for the preparation of Compound 8a but using N-heptyl-6-acetyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 6b) as the starting material afforded the title compound as a light yellow solid (51% yield).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[CH3:19][C:20]1[C:21]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:33]2[CH2:34][CH2:35][N:30]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:23][N:22]=3)[CH2:31][CH2:32]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C(C)C)cc2)CC1
Yield: 30.7 %

Procedure:
By reaction and treatment in the same manner as in Example 29 and using (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (490 mg) described in Preparation Example 51, the title compound (292 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:37]([OH:39])=[O:38])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([CH2:35][CH3:36])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:37]([OH:39])=[O:38])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH2:35][CH3:36])[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O

Procedure:
810 mg (1.38 mmol) (R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 25 mL MeOH were combined with 80 mg of 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:16]([O:25][CH3:26])=[N:17][C:18]([O:23][CH3:24])=[N:19][C:20]=2[O:21][CH3:22])[CH2:12][C:11](=[O:27])[C:10]=1[C:28](=O)[CH2:29][CH3:30]>C(O)C.O>[CH2:2]([O:4][N:5]=[C:28]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[C:16]([O:25][CH3:26])=[N:17][C:18]([O:23][CH3:24])=[N:19][C:20]=2[O:21][CH3:22])[CH2:12][C:11]=1[OH:27])[CH2:29][CH3:30])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(OC)nc(OC)nc2OC)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(OC)nc(OC)nc2OC)CC1=O
Yield: 88.6 %

Procedure:
Ethoxyamine hydrochloride (0.30 g) and then aqueous sodium hydroxide (0.15 g in 2 ml of water) were added to a solution of 3-hydroxy-5-(2,4,6-trimethoxy-5-pyrimidyl)-2-propionylcyclohex-2-en-1-one (0.90 g) in absolute ethanol (30 ml) at 20° C. with stirring. After 20 hours at 20° C. the mixture was diluted with water (150 ml) and extracted with chloroform (2×75 ml). The chloroform layer was dried over anhydrous magnesium sulphate and the solvent was removed by evaporation under reduced pressure to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethoxy-5-pyrimidyl)cyclohex-2-en-1-one (900 mg) as a pale yellow oil. The product was characterized by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccccc1

Procedure:
The title compound, light yellow solid (65 mg, 60%), MS (ISP) m/z=431.5 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and benzoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:24][CH3:25])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:24][CH3:25])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1SC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CSc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
3-(3-cyano-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (142 mg) was dissolved in N,N-dimethylformamide (1 mL), and lithium chloride (64 mg) was added to the solution, and then the mixture was stirred at 100° C. for 1.5 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (95 mg) as a yellow crystal.