Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1>FC(F)(F)C(O)=O.ClCCl>[C:21]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=4)[CH:11]=[N:10][CH:9]=3)[CH2:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc2cncc(N3CCC(O)(c4ccccc4)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2cncc(N3CC=C(c4ccccc4)CC3)c2c1
Yield: 84.9 %

Procedure:
4-(4-Hydroxy-4-phenylpiperidin-1-yl)isoquinoline-6-carboxamide (134 mg, 0.386 mmol) produced in Example 23 was dissolved in trifluoroacetic acid (1 mL)/dichloromethane (1.5 mL), and the resulting mixture was heated to reflux overnight. Upon completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 50:50-0:100, V/V) to give the desired title compound (108 mg, yield 85%).
Reaction SMILES: [C:1]([C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[CH2:10][C:9]([OH:15])([CH3:14])[C:8](C)=[C:7]([CH3:17])[C:6]=2[O:5]1)([OH:3])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=C[CH:27]=1>>[C:19]([O:15][C:9]1([CH3:14])[CH:8]=[C:7]([CH3:17])[C:6]2[O:5][C:4]([C:1]([OH:3])=[O:2])([CH3:18])[CH2:13][CH2:12][C:11]=2[CH:10]1[CH3:27])(=[O:21])[CH3:20]
Reactant: CC1=C(C)C(C)(O)CC2=C1OC(C)(C(=O)O)CC2
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Product: CC(=O)OC1(C)C=C(C)C2=C(CCC(C)(C(=O)O)O2)C1C
Reaction time: 16 h

Procedure:
To a partial solution of 5.0 g. (20 mmol) of (±)-2-carboxy-6-hydroxy- 2,6,7,8-tetramethylchroman in 8.0 ml. of pyridine was added, dropwise over 10 minutes, 12.0 ml. of acetic anhydride. The solution was allowed to stand for 16 hours and was then worked up and dried by the procedure of Example 2 utilizing dichloromethane as a solvent to give a white solid. Crystallization from a mixture of ether-petroleum ether (b.p. 30°-60° centigrade) gave (±)-6-acetoxy-2carboxy-2,5,6,8-tetramethylchroman.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:11][CH:12]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=2)[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-chloro-1-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (278 mg) in a mixture of acetic anhydride (5 ml) and acetic acid (5 ml), nitric acid (sp. gr. 1.42) (0.5 ml) was added at 0° C. After 30 minutes, the resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crystals. The resulting crystals were washed with ethyl acetate to give 3-chloro-1-(4-methoxy-3-nitro-phenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (297 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([S:27][C:28]([CH3:36])([CH3:35])[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[S:25][CH:26]=2)[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:31]([C:29](=[O:30])[C:28]([S:27][C:24]1[S:25][CH:26]=[C:22]([CH2:21][CH2:20][N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=2)[C:12]2[N:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][N:17]=2)[N:23]=1)([CH3:35])[CH3:36])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)C(C)(C)C)n2)Cc2ccc(C(=O)OC)cc2)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)C(C)(C)C)n2)Cc2ccc(C(=O)O)cc2)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
4-{[(2-{2-[(2-tert-Butyl-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethyl)(5-ethylpyrimidin-2-yl)amino]methyl}benzoic acid methyl ester (2.2 g) synthesized in Example 437-1 was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL), 1N aqueous sodium hydroxide solution (16 ml) was added, and the mixture was stirred at 60° C. for 4 hr. Aqueous 10% citric acid solution was added, and the mixture was extracted with chloroform. The insoluble material was filtered off, and the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.0 g) as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:9][C@H:8]1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=3[S:20][CH:21]=2)[CH2:13][CH2:12]1)=[O:6]>O1CCOCC1.CO>[F:28][C:26]([F:27])([F:29])[C:23]1[CH:24]=[CH:25][C:18]2[C:17]([N:14]3[CH2:15][CH2:16][N:11]([CH2:10][C@@H:8]4[CH2:9][C@H:7]4[C:5]([OH:6])=[O:4])[CH2:12][CH2:13]3)=[CH:21][S:20][C:19]=2[CH:22]=1
Reactant: COC(=O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Yield: 81 %

Procedure:
Add 5N NaOH solution (425 mL, 226 mmol) to a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester, Example 6a, (18.0 g, 45.1 mmol) in dioxane/methanol (400 mL, 3:1) and heat the reaction at 60° C. for 6 h. Selectively remove most of the methanol and acidify the remaining dioxane solution to pH 5-6 with 2N acetic acid. Collect the desired compound, which precipitates from solution, to obtain 14.08 g (81%) of colorless crystals, m/z=385 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]=[C:33]([C@@H:36]5[CH2:40][C@H:39]([CH3:41])[CH2:38][N:37]5C(OC(C)(C)C)=O)[NH:34][CH:35]=4)=[CH:27][CH:26]=3)=[CH:22][C:16]=2[N:15]=1)=O)(C)(C)C.[ClH:49].O1CCOCC1>CO>[ClH:49].[CH3:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[C:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]5[N:32]=[C:33]([C@@H:36]6[CH2:40][C@H:39]([CH3:41])[CH2:38][NH:37]6)[NH:34][CH:35]=5)=[CH:29][CH:30]=4)=[CH:22][C:16]=3[N:15]=2)[CH2:10]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)nc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6)nc5c4)cc3)c[nH]2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (56 mg, 0.086 mmol) in methanol (2 mL) is added 4M HCl/dioxane (430 uL, 1.72 mmol). The mixture is stirred at rt for 3 hours. Removal of the solvent under vacuum gives 2-[(2S,4S)-4-methylpyrrolidin-2-yl]-5-[2-[4-[2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-imidazol-4-yl]phenyl]ethynyl]-1H-benzimidazole HCl salt. The crude is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([NH:12][C:13]1C=CC=CC=1O)=[O:11].[C:30](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.F[B-](F)(F)F.CNC>ClCCl.O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([N:12]([CH3:13])[CH3:30])=[O:11]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Agent: CNC
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of methyl N-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (203 mg) and 1,1′-thiocarbonyldiimidazole (100 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (10 l) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate (1-), 3-oxide (TBTU, 321 mg) and a solution of dimethylamine in tetrahydrofuran (0.5 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (8:1 to 1:2 cyclohexane:ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=[C:11]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Product: COc1cc(CNC(=O)c2ncc(OCC(F)(F)F)c(-c3ccc(Cl)c(Cl)c3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example AA) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials, 477.0 (M+H)+.
Reaction SMILES: CO.[C:3](Cl)(=O)C.[OH:7][C@H:8]1[CH2:12][NH:11][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:9]1>CCOCC>[C:13]([C@H:10]1[CH2:9][C@@H:8]([OH:7])[CH2:12][NH:11]1)([O:15][CH3:3])=[O:14]
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and a reflex condenser were placed dry methanol (40 ml) and cooled in ice bath under argon atmosphere. To this stirred solution was added acetyl chloride (4.32 g, 55 mmol) followed by cis-4-hydroxy-D-proline 34 (5.00 g, 38.17 mmol). The resulting solution was heated at reflex for 7-8 h and cooled to room temperature. The solution was diluted with ether, and the resulting white solid was collected by suction, was with ether and dried under vacuum over solid NaOH. Yield; 6.9 g (100%) . 1HNMR (CDCl3): 2.09 (2 dd, 1H), 2.34 (m, 1H), 3.49-3.73 (m, 3H), 3.79 (s, 3H, CH3), 4.34 (m, 2H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:22]([O:23][CH3:24])=[CH:21][C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2].[N+](C1C=CC=CC=1CBr)([O-])=O.Br[CH2:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>>[CH2:1]([O:3][C:4]1[C:22]([O:23][CH3:24])=[CH:21][C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9][CH:10]([CH2:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[C:40]#[N:41])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2C
Reactant: N#Cc1ccccc1CBr
Agent: O=[N+]([O-])c1ccccc1CBr
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1C#N)C(=O)N2C
Yield: 58 %

Procedure:
By replacing 1-ethyl-7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbd) in example IIbh by 8-ethoxy-7-methoxy-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIda), and 2-nitrobenzyl bromide by 2-bromomethyl-benzonitrile, and proceeding in the same manner, the abovenamed product is obtained. Yield: 58%. M: 238–240° C. 1H-NMR (CDCl3, 200 MHz): d 1.53 (s, 3H, CH3), 3.40 (s, 3H, NCH3), 3.71 (s, 3H, OCH3), 3.78–3.90 (m, 3H, —CH2Ph+CH), 4.17 (q, 2H, CH2), 6.64 (s, 1H Ar), 6.76 (s, 1H Ar), 7.31–7.78 (m, 9H Ar).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-:12].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.C(OCC)(=O)C>[C:15]1([CH2:14][O:21][C:22]([NH:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
In a four necked flask equipped with mechanic stirrer, thermometer, pH-meter and dripping funnel, 91.3 g (0.50 moles) of L-lysine hydrochloride are dissolved under stirring in 800 ml of water and then a 30% (w/v) aqueous solution of sodium hydroxide is added until the pH value is brought to 11.5. 185.3 Grams (1.05 moles) of 97% benzylchloroformate are added under stirring during one hour and half while keeping the temperature at 20° C.-25° C. and the pH value between 11.0 and 11.5 by addition of a 30% (w/v) aqueous solution of sodium hydroxide. The reaction is kept another hour and half under stirring while keeping the same values of pH and temperature, subsequently the pH value is brought between 7 and 8 by addition of a 30% (w/v) aqueous solution of hydrochloric acid, 500 ml of ethyl acetate are added and the pH value is brought between 1.0 and 1.5 always by addition of a 30% (w/v) aqueous solution of hydrochloric acid. The stirring is discontinued after 15 minutes and the layers are separated 20 minutes later. The aqueous layer is eliminated off while the organic layer is first washed with 150 ml of a 10% (w/v) aqueous solution of sodium chloride and then is evaporated to dryness obtaining 223.5 g of product in the form of an oily residue having a pureness equal to 87.2% with a yield equal to 94%.
Reaction SMILES: [CH:1]([NH:4][S:5]([CH2:8][C:9](=O)[CH3:10])(=[O:7])=[O:6])([CH3:3])[CH3:2].[N+:12]([C:15]1[CH:16]=C([CH:20]=[CH:21][CH:22]=1)C=O)([O-:14])=[O:13].N1CCCCC1.[C:29](O)(=[O:31])[CH3:30]>C1C=CC=CC=1>[C:29]([C:9]([C:10]1[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)=[CH:8][S:5]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:7])=[O:6])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC(=O)CS(=O)(=O)NC(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=CS(=O)(=O)NC(C)C)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 7.5 g (about 0.04 mol) of N-isopropyl-2- -oxopropanesulfonamide and 6.0 g (0.04 mol) of 3-nitrobenzaldehyde in 40 ml of benzene is treated with 0.16 ml of piperidine and 0.48 ml of glacial acetic acid in an analogous manner to that described in Example 1. The oily crude product is triturated with ether, whereby crystallization occurs. There are obtained 2.5 g of α-acetyl-N- -isopropyl-3-nitrostyrenesulfonamide in the form of colorless crystals, m.p. 153°-157°.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13](O)=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:36]([NH:39][NH2:40])(=[O:38])[CH3:37]>C1COCC1.CN(C=O)C.O>[C:36]([NH:39][NH:40][C:13](=[O:14])[CH2:12][N:11]1[C:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:10]1)(=[O:38])[CH3:37]
Reactant: CC(=O)NN
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (300 mg, 0.96 mmol) in THF (5 mL) and DMF (2 mL) was added CDI (345 mg, 2.12 mmol) and the suspension sonicated for 5 minutes to give a solution that was stirred for 2 hours at room temperature. To this was added acetic hydrazide (210 mg, 2.89 mmol) and the resulting suspension stirred for 18 hours at room temperature. The resulting suspension was diluted with water (50 mL) and the solid filtered off and washed with water (30 mL) and EtOAc (50 mL) to yield pure N′-acetyl-2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetohydrazide. This was suspended in THF (5 mL) then Burgess' reagent (279 mg, 1.17 mmol) was added and the mixture heated to reflux for 2 hours. The reaction was cooled to ambient temperature, the volatiles removed in vacuo, and the residue was taken into EtOAc (50 mL) and washed with water (2×50 mL), brine (50 mL), dried over MgSO4, filtered and stripped. The residue was purified by Biotage flash chromatography, eluting with 1-4% MeOH/DCM to afford the title compound as a white solid, 200 mg, 73%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.50-8.68 (2 H, m), 7.52-7.70 (2 H, m), 7.16 (2 H, dd, J=8.59, 5.31 Hz), 6.93-7.08 (2 H, m), 6.44 (1 H, s), 5.40 (2 H, s), 4.08 (2 H, s), 2.47 (3 H, s); m/z (APCI+) for C19H16N5FO 350.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([O:13][CH2:14][CH3:15])=[CH:7][C:6]=1[CH3:16])=[O:4].C(O)C[OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]2([O:19][CH2:15][CH2:14][O:13]2)[CH2:7][C:6]=1[CH3:16])=[O:4]
Reactant: CCOC1=CC(C)=C(C(=O)OC)C(C)(C)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)CC2(CC1(C)C)OCCO2

Procedure:
670 g. of crude 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-carboxylic acid methyl ester and 185 g. of ethylene glycol were heated in 3 l. of benzene in the presence of 3 g. of p-toluene sulfonic acid. The reaction was stopped after 1.5 l. of benzene had distilled over. The cold solution was washed with sodium bicarbonate solution and water, dried, and evaporated. The remaining oil was identified as 7,9,9-trimethyl-1,4-dioxaspiro [4,5] dec-7-en-8-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16](F)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][S:36](C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([S:36][CH3:35])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reactant: CS(C)=O
Solvent: O
Product: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C

Procedure:
In a solution of 0.92 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-fluoro-N-(2-pyridylmethyl) benzoic acid amide (Compound of the present invention No. 5-041) synthesized similarly to Synthetic Example 4 in 12 ml of dimethylsulfoxide, 0.12 g of sodium methane thiolate was added with stirring at room temperature, and stirred at 100° C. for 90 minutes. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with chloroform, and 0.89 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: C1(C[CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:35](O)=[O:36])[CH:32]=3)[CH2:27]2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[CH2:12][CH3:13].C1C2C(=CC=CC=2)CN1C(NC1C=C[C:53]([C:54](O)=[O:55])=CC=1)=O>>[N:10]1([C:35]([C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[CH2:27][N:26]([C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15](=[O:16])[NH:14][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=2)=[O:25])[CH2:34]3)=[O:36])[CH2:9][CH2:8][O:55][CH2:54][CH2:53]1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)N4CCOCC4)cc3C2)cc1

Procedure:
The title compound was prepared as described in Example 1C, substituting morpholine for 3-phenylpropan-1-amine and 2-{[4-(propylcarbamoyl)phenyl]carbamoyl}isoindoline-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.80-7.73 (m, 2H), 7.69-7.62 (m, 2H), 7.47-7.41 (m, 2H), 7.35 (dd, J=7.7, 1.6 Hz, 1H), 4.82 (bs, 4H), 3.73-3.43 (m, 6H), 3.28-3.12 (m, 4H), 1.60-1.44 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 437 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[CH:13]([C:11]4[O:12][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:9][N:10]=4)[OH:14])=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].CN(C=O)C.[N-:18]=[N+:19]=[N-:20].[Na+]>CCOC(C)=O>[N:18]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution consisting of 2-bromo-1-(4-methylsulfanyl-phenyl)-ethanone (2.00 g, 8.16 mmol) and DMF (7 mL) was cooled to 15° C. and treated portion-wise with sodium azide (583 mg, 8.98 mmol). Once addition was complete, the reaction mixture was stirred for 3 h with gradual warming to rt. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (25 mL×2), NaHCO3 (satd., 25 mL×2), and brine. The combined organic phases were dried (Na2SO4) and concentrated to dryness to yield the title compound (1.69 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)[N:10]=2)[CH:7]=1.CC(O)=O>[Fe].C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[C:13]([NH2:21])[CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Fe (0.447 g) is added to a mixture of 6-bromo-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridine (0.618 g), HOAc (0.733 mL), and EtOH—H2O (10 mL, 4:1). The mixture is stirred at 80° C. for 2 hours, then concentrated, taken into sat. aqueous NaHCO3 and extracted with EtOAc and CH2Cl2. Organics are dried and concentrated to give the title compound (463 mg), which is used without further purification. LCMS m/z=356.4 [M+H]+, tR=2.04 min.