Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1([CH2:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=3)[C:10]2=[O:20])CCCCC1.[C-:21]#[N:22].[K+]>O.Cl>[C:21]([CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=2)[C:10]1=[O:20])#[N:22]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)CC(CN1CCCCC1)C2=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CC(CC#N)C2=O

Procedure:
The starting material is prepared as follows: To the solution of 47.5 g of 2-piperidinomethyl-5-methoxy-1-indanone hydrochloride (m.p. 177°-180°) in 290 ml of water, 13.5 ml of concentrated hydrochloric acid are added, followed by the slow addition of the solution of 21 g of potassium cyanide in 160 ml of water, which is introduced below the surface of the liquid. The mixture is refluxed for 21/2 hours, cooled, the resulting precipitate filtered off and dried, to yield the 2-cyanomethyl-5-methoxy-1-indanone, melting at 117°-120°.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:18])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (1.75 g, 9.30 mmol) produced in Example C6(ii) in tetrahydrofuran (20 mL) were added oxalyl chloride (0.943 mL, 11.0 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: COCCNCCOC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: COCCN(CCOC)S(=O)(=O)c1ccc(Br)cc1
Yield: 99 %

Procedure:
Starting materials: bis(2-methoxyethyl)amine and 4-bromobenzenesulfonyl chloride. Yield: 99% as a yellow oil: 1H NMR (CDCl3) δ 7.69 (d, J=9 Hz, 2H), δ 7.62 (d, J=9 Hz, 2H), 3.49 (m, 4H), 3.39 (m, 4H), 3.27 (s, 6H); MS (ESP) m/z 352, 354 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH2:16][O:17][CH3:18])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (1.15 mmol) is dissolved in DMF (2 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added and the suspension is stirred 45 min at room temperature. 1-Bromo-2-methoxy-ethane (1 eq.) is added and the reaction suspension is heated to 100° C. for 24 hours. The reaction solution is pored into water and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-Chloro-3-(2-methoxy-1-ethoxy)-2-nitro-pyridine is obtained after column chromatography as beige solid in a yield of 60%; mp. 71.5-72.5°; HPLC (method C): 1.63 min; LC-MS (method A): 1.36 min, 232.95 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.O=[C:23]([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:24]([OH:26])=[O:25])[CH2:27][CH2:28][CH3:29])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: CCCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 9, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with α-oxopentanoic acid at room temperature to give 7-chloro-2-[(1-carboxybutylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: ClCCl.[F:4][CH:5]([F:35])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:22](COCC[Si](C)(C)C)[C:16]3[CH:17]=[N:18][NH:19][C:20](=[O:21])[C:15]=3[CH:14]=2)=[CH:9][C:8]=1[O:31][CH:32]([CH3:34])[CH3:33].N>CO>[F:35][CH:5]([F:4])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:22][C:16]3[CH:17]=[N:18][NH:19][C:20](=[O:21])[C:15]=3[CH:14]=2)=[CH:9][C:8]=1[O:31][CH:32]([CH3:33])[CH3:34]
Reactant: CC(C)Oc1cc(-c2cc3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)ccc1OC(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1cc(-c2cc3c(=O)[nH]ncc3[nH]2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
To 2 ml of dichloromethane solution containing 99 mg (0.21 mmol) of 2-(4-difluoromethoxy-3-isopropoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 39-(a) was added 0.1 ml of boron trifluoride diethyl ether complex under ice-cooling, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, methanol and 28% aqueous ammonia were added to the solid obtained by filtrating the reaction suspension, and the mixture was stirred at room temperature for 12 hours. Then, the solution was concentrated under reduced pressure, and the obtained solid was washed with chloroform and dried under reduced pressure to obtain 29 mg of the title compound as a white solid. (Yield: 42%)
Reaction SMILES: [ClH:1].[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.O=[C:12]([CH3:28])[CH2:13][S:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.Cl>C(O)(C)C>[ClH:1].[CH3:28][C:12]1[NH:8][C:5]2[C:6]([C:13]=1[S:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20]1)=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2
Reactant: CC(=O)CSC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(C)c(SC3CCN(Cc4ccccc4)CC3)c2c1
Reaction time: 0.5 h

Procedure:
Paratolylhydrazine hydrochloride (20 g) is added to a solution of 4-[(2-oxopropyl)thio]-1-(phenylmethyl)piperidine (33.2 g, prepared in Example 9) in isopropanol (150 ml) under nitrogen. After 30 minutes, the solution is cooled to 0° C. and saturated with gaseous hydrogen chloride. After 4 hours at room temperature, the precipitate formed is filtered off, washed with water and then taken up in hot ethanol. After cooling, the white crystals of 2,5-dimethyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole hydrochloride (28.3 g) are filtered off.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOC(C)=O.Cl>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:9][N:8]=[C:7]([CH3:18])[C:6]=2[CH2:5][CH2:4][OH:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid ethyl ester (1.37 mmol) in THF (3 mL) at 0° C. was added lithium aluminum hydride (0.060 g, 1.47 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and 1 N aqueous HCl, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCN(CC)C(=O)Cl
Reactant: O=S(=O)(CC1CCCC1)c1nc[nH]n1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Diethylcarbamoyl chloride (0.65 ml; 5.08 mmol) was added to cyclopentylmethyl 1,2,4-triazol-3-yl sulfone (1.00 g; 4.65 mmol) in dry pyridine (5 ml) under dry nitrogen, and the solution stirred at room temperature overnight. The resulting mixture was poured into 2M hydrochloric acid (20 ml) at 3° C. and the mixture extracted into ethyl acetate (3×30 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated, to afford 3-(cyclopentylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (1.44 g; 99%) as white crystals, m.p. 77°-79° C., (Found, C: 49.82; H: 6.75; N: 17.96; S: 10.44. C13H22N4O3S requires C: 49.66; H: 7.05; N: 17.82; S: 10.20%) NMR - d(CDCl3 ; 60 MHz) 1.0-2.6 (15H, m), 3.3-3.8 (6H, m) and 9.0 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C)C=O>[CH2:21]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH:20]=[CH2:19]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
(3,4-Difluorophenyl)acetic acid (52 g; 0.3 mol) was dissolved in N,N-dimethylformamid (200 mL). Potassium carbonate (61 g, 0.45 mol) was added and the mixture was stirred at room temperature (rt) for 15 min. Allyl bromide (47 g, 0.39 mol) was added and the suspension was stirred at room temperature for 20 h. The mixture was thrown into water (250 mL) and extracted with diethylether (2×300 mL). The combined organic phases were washed with water (4×100 mL), dried (Magnesium sulphate) and evaporated in vacuo to give 64 g (3,4-Difluoro-phenyl)acetic acid allyl ester as a clear oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[ClH:21]>C(O)(C)C>[ClH:21].[ClH:21].[F:1][C:2]([F:12])([F:11])[C:3]1[C:4]2[NH:9][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: FC(F)(F)c1cccc2c3c([nH]c12)CCNC3
Temperature: 95 °C
Yield: 63 %

Procedure:
To a solution of (2-trifluoromethyl-phenyl)-hydrazine (12.0 g, 68.13 mmol) and 4-piperidone monohydrate (10.46 g, 68.09 mmol), in iso-propyl alcohol was bubbled HCl (g) for 15 minutes at rt. The reaction was sealed in a pressure vessel and heated to 95° C. for 5 h, then cooled to rt. The reaction mixture was filtered and washed with iso-propyl alcohol and dried in vacuo to yield 6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole bis-hydrochloride as a white solid (13.3 g, 63% yield). 1H NMR (CD3OD, 300 MHz) δ 3.203 (t, 2H, 12.4 Hz), 3.642 (t, 2H, 12.0 Hz), 4.472 (t, 2H, 2.6 Hz), 7.189 (t, 1H, 15.7 Hz), 7.435 (d, 1H, 7.7 Hz), 7.709 (d, 1H, 8.0 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]=2)[CH:8]=[CH:7][CH:6]=1.P(Cl)(Cl)([Cl:27])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:15]1[CH:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]=[C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[Cl:1])[N:10]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc(O)nc(-c2cccc(Oc3ccccc3Cl)n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1cc(Cl)nc(-c2cccc(Oc3ccccc3Cl)n2)n1
Yield: 87.3 %

Procedure:
To solution of 2-(6-o-chlorophenoxy-2-pyridinyl)-4-hydroxy-6-n-propylprimidine (5 g) in toluene (100 ml), was added phosphoryl chloride (5 g). The mixture was heated under refluxing for one hour and left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chlono-2-(6-o-chlorophenoxy-2-pyridinyl)-6-n-propylpyrimidine (4.6 g, yield 87%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]2[C:19]2[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccncn2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Pd/C (40 mg) is added to a solution of (2S,4R)-1-(2-chloro-pyrimidin-4-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (100 mg, 0.273 mmol) in ethanol (2 mL). The reaction is stirred under hydrogen atmosphere overnight at room temperature. The reaction is filtered through Celite® and the filtrate is concentrated. Purification by pre-HPLC eluting with 4-45% acetonitrile/water provides the title compound. ESI m/z 332 [M+H+].
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4](C(OC(C)(C)C)=O)[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)[C:7]=1[C:8](=[O:10])[NH2:9]>O1CCOCC1.CO>[ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)[C:7]=1[C:8](=[O:10])[NH2:9]
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c(C(N)=O)c1N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c[nH]c1N
Temperature: 50 °C
Reaction time: 15 h

Procedure:
0.575 cm3 of a 4M hydrochloric acid solution in dioxane is added at a temperature in the region of 20° C., under an argon atmosphere, to 0.06 g (0.115 mmol) of tert-butyl 2-amino-3-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}pyrrole-1-carboxylate in solution in a mixture of 1.2 cm3 of dioxane and 1.2 cm3 of methanol. After stirring for 15 hours at a temperature in the region of 50° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 2-amino-3-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole hydrochloride which is taken up in 2.5 cm3 of ethyl acetate. 0.01 cm3 of triethylamine and 0.013 cm3 of acetic anhydride are added at a temperature in the region of 20° C., under an argon atmosphere. After stirring for 1 hour at a temperature in the region of 20° C., a catalytic quantity of DMAP is added and then the stirring is maintained for 30 minutes. The reaction mixture is diluted with 5 cm3 of ethyl acetate. The organic phase is washed with twice 5 cm3 of water. All the aqueous phases are combined and extracted with 5 cm3 of ethyl acetate. All the organic phases are combined, washed with 5 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.054 g of a residue which is purified by flash chromatography [eluent: dichloromethane/methanol (98/2 by volume)]. After concentrating the fractions under reduced pressure, 0.010 g of 1-acetyl-2-amino-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained, in the form of a yellow solid; 1H NMR (300 MHz, (CD3)2SO, —δ in ppm): 2.14 (s: 3H); from 5.20 to 6.10 (broad m: 1H); 6.40 (d, J=2.0 Hz: 1H); from 6.70 to 7.60 (broad m: 1H); 7.30 (broad d, J=8.5 Hz: 2H); 7.38 (mt: 1H); from 7.45 to 7.54 (m: 3H); 8.62 (dd, J=7.5 and 2.5 Hz: 1H); 8.92 (broad s: 1H); 9.25 (broad s: 1H); 10.7 (broad s: 1H); 11.4 (broad s: 1H); ES+: m/z=464 (MH+).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20](C(O)=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (0.102 mol) is added to a solution of 4-(4-hydroxyphenyl)benzoic acid (0.102 mol) and 2.5N sodium hydroxide (0.102 mol) and the mixture stirred at 70° C. for a period of 18 hours. The reaction mixture is allowed to cool and then acidified to pH 3 and partitioned between ethyl acetate and water. The organic phase is washed with water and brine and the solvent then removed to obtain the 4'-n-octyloxy 1,1'-biphenyl!-4-ylcarboxylic acid, C21H23O3, M.W. 326.4.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10](=[O:49])[C@H:11]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:12][C:13](=[O:41])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:40])[CH2:20][NH:21][C:22](=[O:39])[C@H:23]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=CC=1)([O-])=O.O.NN>>[C:28]([O:27][C:25]([NH:24][C@H:23]([C:22]([NH:21][CH2:20][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([NH:12][C@H:11]([C:10]([OH:49])=[O:9])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:41])=[O:40])=[O:39])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
the product of stage (g) is treated with hydrazine hydrate to obtain hydrazide of tert-butoxycarbonylphenylalanylglycylprolylphenylalanine;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=4)[CH:17]=3)[CH:11]([C:32]([O:34]C)=[O:33])[CH2:10]2)=[N:7][CH:8]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[N:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[O:24][N:23]=4)[CH:17]=3)[CH:11]([C:32]([OH:34])=[O:33])[CH2:10]2)=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)C(C(=O)O)C2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
Methyl 4-(5-cyanopyridin-2-yl)-1-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl)piperazine-2-carboxylate (130 mg, 0.3 mmol) was dissolved in MeOH (4 mL) and cooled to 0° C. 1N NaOH solution (0.3 mL) was added and the reaction mixture was slowly warmed to room temperature and stirred at 50° C. for 1 h. The MeOH was removed under reduced pressure and the aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 2-3 using 1.5N HCl, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated over reduced pressure. The crude product was purified by preparative TLC (eluent petroleum ether/EtOAc/AcOH 4:6:0.1 v/v) to get 4-(5-cyanopyridin-2-yl)-1-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl)piperazine-2-carboxylic acid (30 mg, yield 24%). 1H NMR (400 MHz, DMSO-d6) δ 8.49-8.47 (m, 1H), 8.20-8.12 (m, 1H), 8.07 (br s, 1H), 7.89-7.83 (m, 1H), 7.75-7.71 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 5.00-4.89 (m, 1H), 4.72-4.54 (m, 1H), 4.33-4.23 (m, 1H), 3.62-3.47 (m, 2H), 3.17-3.12 (m, 2H). MS (ESI) m/z: Calculated for C21H15F3N6O4: 472.11. found: 473.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:9])[NH:8][C:3]=1[CH:2]([F:1])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(F)F)[nH]c1=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(C(F)F)[nH]c1=O
Reaction time: 2 h

Procedure:
4.1 g (20 mmol) of methyl 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 20 ml of N,N-dimethylformamide, and 5.35 g (30 mmol) of N-bromosuccinimide were added at room temperature. After 2 hours of stirring, the reaction mixture was added to water and extracted with tert-butyl methyl ether. The extract was subsequently washed repeatedly with water. Drying and concentration finally gave 3.7 g (65% of theory) of the product.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27]N.Cl>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH3:29])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1ccccc1-n1nccc1-c1nn(-c2ccccc2)ccc1=O
Yield: 55 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and o-tolylhydrazine×HCl according to the method described for Example 1 in 55% yield. MS: M=329.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[S:7](=[O:10])(=[O:9])[NH:8][C:11](=[O:13])[C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(S(N)(=O)=O)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)S(=O)(=O)NC2=O
Yield: 89.3 %

Procedure:
A mixture of 0.5 gm (2.26 millimols) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid, 0.5 gm (2.2 millimols) of phosphorus pentachloride and 30 ml of anhydrous toluene was refluxed for 9 hours. The mixture was worked up in analogy to Example 1 and yielded 0.41 gm (89% of theory) of 5-methyl-thieno[3,2-d]isothiazole-3-(2H)-one-1,1-dioxide. M.p. 231° C. (from methanol).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[O:11][N:10]=1)=O.[C:21]([S@@:25]([NH2:27])=[O:26])([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:21]([S@@:25](/[N:27]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[O:11][N:10]=1)=[O:26])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: NC(=O)c1ccc2c(-c3ccccc3C=O)noc2c1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1ccccc1-c1noc2cc(C(N)=O)ccc12
Temperature: 0 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(2-formylphenyl)benzo[d]isoxazole-6-carboxamide (Compound 7) (4.12 g) in tetrahydrofuran (50 mL) was added (S)-(−)-t-butylsulfinamide (1.97 g) followed by titanium (IV) ethoxide (4.8 mL). The mixture was stirred for three days then poured onto stirred ice-water (200 mL) and ethyl acetate (200 mL) added and filtered through dicalite and the plug of solid was washed with hot ethyl acetate (200 mL), the organic layer was dried over anhydrous magnesium sulfate and evaporated to give the title compound (5.7 g) as a partially solidified gum.