Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[NH:10][CH2:11][C:12](=[O:39])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][O:27]C(=O)C)=[O:23])=[CH:17][C:16]=1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=[O:46])C>CO>[CH2:1]([O:8][C:9](=[O:40])[NH:10][CH2:11][C:12](=[O:39])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])=[CH:17][C:16]=1[C:31](=[O:46])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc(CNC(=O)CNC(=O)OCc2ccccc2)c(Cc2ccccc2F)c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NCc1ccc(NC(=O)NCCO)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of benzyl{[[2-(o-fluorobenzyl)-4-[3-(2-acetoxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate dissolved in 10 ml of absolute methanol are treated with 50 mg of sodium methylate, stirred at room temperature for 1 hour and buffered with a small amount of acetic acid. The mixture is poured on to ice/10% sodium bicarbonate and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. After crystallisation from ether/ethanol, there is obtained benzyl{[[2-(o-fluorobenzoyl)-4-[3-(2-hydroxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate which melts at 117°-120° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:21])([OH:20])[C@H:9]([OH:22])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].ClCCl.[CH3:38][O:39][CH2:40][CH2:41]O>>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:21])([OH:20])[C@@H:9]([O:22][CH2:41][CH2:40][O:39][CH3:38])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24]
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@@](C)(O)[C@@H](c1ccccc1)N3
Reactant: COCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@]1(C)O
Temperature: 60 °C
Reaction time: 40 h

Procedure:
A mixture of 0.5 g of (7R,8S,9R)-2,3,8-trimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine and 0.2 ml of conc. sulfuric acid in 10 ml of 2-methoxyethanol is heated at an oil bath temperature of 60° C. for 24 h and then stirred at room temperature for 40 h. The reaction solution is poured into a mixture of 50 ml of saturated aqueous sodium hydrogencarbonate solution and 50 ml of dichloromethane and vigorously stirred. After separating off the organic phase, the aqueous phase is extracted a further three times with 50 ml of dichloromethane each time, the organic phases are combined, the solvent is stripped off in vacuo and the residue obtained is chromatographed on silica gel (eluent: diethyl ether/diethylamine 1/1). 0.3 g of the title compound is obtained as colorless crystals of melting point 1734° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](SC)=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]#[N:16])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][CH:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:29][CH:24]([CH3:23])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]#[N:16])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cc(F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Product: CC(NC(Nc1cc(F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 49 %

Procedure:
3-(3-Fluoro-5-trifluoromethylphenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.176 g, 0.5 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 98 mg (49%) of the title compound. Mp 183-1850° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 1.03 (d, 3H), 3.05 (m, 1H), 3.13 (s, 3H) 7.02 (br d, 1H), 7.15 (m, 2H); EI SP/MS: 407 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:11])([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3]([Cl:15])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The product of Step A, 2,2-dimethyl-3-acetyloxypropionic acid (11.76 g, 80 mmol) was dissolved in benzene (100 mL), and the reaction solution was cooled to 0° C., and then oxalyl chloride (15.0 g, 120 mmol) was slowly added dropwise. After 3 hours, the solvent was removed in vacuo, and the reaction mixture was distilled in vacuo to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:55][CH2:56][N:57]([C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:9])[CH2:58][CH2:59]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g (45.8 mmol) of pyridine-4-carboxylic acid were suspended with stirring in 150 ml of DMF. With further stirring, 6.93 g (68.5 mmol) of N-methylmorpholine and then a solution of 35.6 g (68.5 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 10.18 g (45.8 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 60 ml of DMF were added to this mixture. The mixture was stirred at room temperature for 24 hours, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:17]O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.N12CCCN=C1CCCCC2.C1(P([N:52]=[N+:53]=[N-:54])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:52]([CH2:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:4]=2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1sc(-c2cc(CO)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1sc(-c2cc(CN=[N+]=[N-])cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution (7 mL) of the compound (1.3 g, 3.4 mmol) obtained in Example 95c in tetrahydrofuran were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol) and diphenylphosphoryl azide (1.1 g, 4.1 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=85/15) to give the title compound (1.1 g, 80%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]([C:8]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:7].[ClH:34]>C(OCC)(=O)C.C(O)(C)C>[ClH:34].[CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]([C:8]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC(=O)C(C)(C)C)(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester (250 mg 0.54 mmol) in ethyl acetate (3 mL) is added a solution of hydrogen chloride in isopropanol (3 mL 5-6N). The mixture is stirred at room temperature for 3 h, then concentrated under reduced pressure. The solid is triturated in diisopropyl oxide to give piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester, hydrochloride melting at 1500.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([O-])(=[O:17])=[O:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].S(Cl)([Cl:24])=O>>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([Cl:24])(=[O:17])=[O:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(NCCS(=O)(=O)[O-])OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (20 mL) was added to sodium 2-(4-nitrobenzyloxycarbonylamino)-ethanesulfonate (A, 1.25 g). After stirring at room temperature for 10 min, the mixture was refluxed for 3 hr and concentrated in vacuo. The residue was suspended in benzene and the mixture was filtered over diatomaceous earth. The filtrate was concentrated in vacuo to afford the title compound (0.1 g) as a white powder: 1H NMR (400 MHz, CDCl3) δ 3.82-3.97 (m, 4H), 5.23 (s, 2H), 5.43 (br s, 1H), 7.51 (d, J=8.8 Hz, 2H), and 8.23 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[C:3]=1[Cl:11].C1(N[C:23](=[O:25])[CH3:24])C2CCCCC=2C=CC=1>>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:23](=[O:25])[CH3:24])=[C:4]([CH3:10])[C:3]=1[Cl:11]
Reactant: Cc1cc(N)c(C)c(Cl)c1Br
Reactant: CC(=O)Nc1cccc2c1CCCC2
Product: CC(=O)Nc1cc(C)c(Br)c(Cl)c1C

Procedure:
The title compound (0.82 g) was prepared from 21C (0.74 g, 3.17 mmol) in a manner similar to that described in Experiment 2A.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-(4-fluorobenzoyl)benzoic acid (5 g; 20.47 mmol) is suspended in ethanol (100 ml). Hydrazine (3 M in ethanol; 60 mmol) is added, and the mixture is stirred at room temperature for 4 days. A white solid precipitates, is filtered off and is washed with ethanol (20 ml). Yield: 3.20 g of 4-fluorophenylphthalazine-1-one.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:19])[O:17][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:19]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH3:18])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from methyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained methyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 136°-137.5° C.;
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)c1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (500 mg, 1.61 mmol) was placed in DMF (20 mL) and Cs2CO3 (627 mg, 1.93 mmol) was added. The reaction was stirred for 5 min and 2-chloro-4-(chloromethyl)pyridine (312 mg, 1.93 mmol) was added. The reaction was stirred at 45° C. overnight and was then partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with H2O (2×50 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 10%-100% EtOAc) to afford 5-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow solid (420 mg, 60%). MS (ES+) C18H12ClF3N6O2 requires: 436. found 437 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.42 (d, J=5.1 Hz, 1H), 8.28 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 7.05 (d, J=5.1 Hz, 1H), 5.46 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].CC(C)([O-])C.[K+].Br[CH2:20][C:21]([N:23]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])=[O:22]>CN(C=O)C>[C:1]([N:3]([CH2:20][C:21](=[O:22])[N:23]([CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)#[N:2]
Reactant: N#CNC(=O)Cc1ccccc1
Reactant: CC(C)CN(CC(=O)N1CCOCC1)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN(CC(=O)N1CCOCC1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
N-Cyano-2-phenylacetamide (160 mg, 1.00 mmol) was dissolved in 5 mL of dry DMF. Potassium t-butoxide (112 mg, 1.00 mmol) was added. This mixture was stirred at room temperature for 30 min. The 2-bromo-N-isobutyl-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide (321 mg, 1.00 mmol) from above was dissolved in 5 mL of dry DMF and added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h and then heated at 70° C. for 6 h. Solvent was removed in vacuo and residue was purified by HPLC to give the title compound (87 mg, 22%) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:22][C:20]1[CH:19]=[C:18]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]2)[CH:21]=1)[CH3:35]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CCOC(=O)CCCCCOc1cc(Oc2ccc(C#N)cc2)cc(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c1
Yield: 86 %

Procedure:
Using 0.84 g (1.86 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexaanoic acid ethyl ester (0.41 g, 1.86 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (DMSO-d6): δ 1.15 (3H, t), 1.25 (2H, m), 1.4 (9H, s), 1.45 (3H, m), 1.6 (2H, m) 1.7 (2H, m), 1.8 (4H, m), 2.3 (2H, t), 3.2 (1H, m), 3.7 (1H, m), 4.05 (4H, m), 6.72 (1H, d), 6.88 (1H, s), 7.12 (3H, m), 7.3 (1H, s), 7.84 (2H, d), 8.24 (1H, d).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[CH2:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCc2ccccc2Cc2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above ester (0.8 g, 2.1 mmol) was dissolved in ethanol (10 ml) and 2N sodium hydroxide (3.1 ml) was added. The mixture was stirred at ambient temperature overnight. Excess concentrated hydrochloric acid was added followed by dichloromethane. The mixture was concentrated in vacuo and water and dichloromethane was added. The phases were separated and the organic phase was dried (MgSO4). The solvent was evaporated in vacuo to give a foamy residue which was re-evaporated with dichloromethane to give 0.65 g of the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14](N)(=O)[C:15]1C=CC=C[CH:16]=1.C(Cl)(=O)C>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:14]([CH2:15][CH3:16])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Solvent: CC(=O)Cl
Product: CCc1nc(O)c2ccc(OC)c(C)c2n1
Yield: 100 %

Procedure:
The general procedure described in Example 10 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and acetic acid chloride as acid chloride [B], which gave the title compound (2.2 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[N:22][CH:23]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[N:22][CH:23]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionate (651 mg, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>C(O)C>[OH:1][C@H:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)NCCN
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Solvent: CCO
Product: CC(C)C(=O)NCCNC[C@H](O)COc1ccccc1

Procedure:
A mixture of (S)-1,2-epoxy-3-phenoxypropane (0.495 g.) and N-(2-aminoethyl)isobutyramide (0.429 g) in ethanol (25 ml) was heated under reflux for 48 hours. The reaction mixture was cooled and solvent removed by rotary evaporation in vacuo. The residual solid was purified by column chromatography on silica (Merck, Art. 7736) using 5% v/v methanol in dichloromethane as eluant. The solid thereby obtained was purified by recrystallisation from ethyl acetate to give (S)-N-(2-[2-hydroxy-3-phenoxypropyl]aminoethyl)isobutyramide (0.425), m.p. 88°-89° C., 24 [α]D -5.8° [c, 1.04; methanol], mixed m.p. with material from Preparation 1, 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:27]([CH3:30])([CH3:29])[CH3:28])(=O)=O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[CH:6][C:7]=1[Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Clc1cc(Br)ccc1I
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(Br)cc1Cl
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
3-chloro-4-iodobromobenzene (3.1 g) was dissolved in diethyl ether (100 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.59 M, 6.1 ml) at −78° C. The mixture was then stirred at the same temperature for 30 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethane sulfonate (3.77 ml; 17.4 mmol). The mixture was then stirred for 1 hour. After the quenching of the reaction by gradually adding water over an ice bath, the product was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The crude product thus obtained was then purified twice through silica gel column chromatography (silica gel produced by Merck Ltd., Japan; hexane) to obtain 3-chloro-4-trimethylsilyl-bromobenzene (2.3 g) (yield: 90%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2].C([N-]C(C)C)(C)C.[Li+].[F:26]N1C(C)(C)C2C=CC=CC=2S1(=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([F:26])([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCCC2c1ccns1
Reactant: CC1(C)c2ccccc2S(=O)(=O)N1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CCCC2(F)c1ccns1
Temperature: 25 °C

Procedure:
6-Cyano-1-(5-isothiazolyl)-1,2,3,4-tetrahydronaphthalene (Example 26) is converted into the carbanion by treatment with lithium diisopropylamide in THF at -78° and then reacted with N-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzothiazole-1,1-dioxide. The reaction mixture is allowed to warm to room temperature and is worked up in aqueous medium, yielding the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[CH3:27])[CH3:2].Cl.[CH3:30][NH:31][OH:32].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:31]([CH3:30])[O:32][C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:12]=2)=[CH:7][C:6]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Reactant: CNO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C

Procedure:
0.62 g of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid ethyl ester (XVIIa) was mixed with 0.21 g of N-methylhydroxylamine hydrochloride and 0.42 ml of triethylamine in 10 ml of dry ethanol. The mixture was refluxed for 20 hours, evaporated to dryness and purified on silica gel giving 0.275 g (42%) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) as a colorless oil 1H-NMR (CDCl3, δ in ppm): 7.93 (d, 1H), 7.30-7.45 (m, 5H), 5.43 (s, 1H), 4.37 (q, 2H), 2.99 (s, 3H), 2.61 (s, 3H), 1.40 (t, 3H).