Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:14]1[CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:9][CH:8]=2)[CH2:11][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1CNCC(c2ccc(CCO)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(CCO)cc2)CN(C(C)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5.58 g (9.33 mmol, purity 44%) of the compound from Example 56A in dichloromethane (80 ml) was admixed with 2.60 ml (1.89 g, 18.7 mmol) of triethylamine and then cooled to 0° C. At this temperature, 0.33 ml (0.37 g, 4.67 mmol) of acetyl chloride was added dropwise and the mixture was stirred for 2 h. A further 0.13 ml (0.15 g, 1.86 mmol) of acetyl chloride was added and the mixture was stirred for 1 h. Subsequently, the reaction solution was washed with aqueous 1 N hydrochloric acid, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 30:1), and the crude product obtained was purified once more by means of preparative HPLC. Yield: 1.17 g (41% of theory)
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:10][C:9]=2[CH:18]=1.[OH-].[Na+].Cl>CO.O>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:18][C:9]=2[N:10]=1
Reactant: COC(=O)Cc1ccc2oc(CC(C)(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)Cc1nc2cc(CC(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Methyl[(2,2-dimethylpropyl)benzoxazol-5-yl]acetate [from step 6] (5.00 g, 0.0185 mole) was dissolved in methanol (5 ml) and then a solution of sodium hydroxide (0.81 g, 0.0204 mole) in water (5 ml) was added slowly over 20 minutes, maintaining the temperature below 25° C. by external cooling. Once the addition was complete, the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was poured slowly into water (50 ml) and concentrated hydrochloride acid was added until the pH of the mixture was below pH6. The mixture was stirred for 1 hour then filtered and the solid was washed thoroughly with water and dried. Trituration with hexane gave [(2,2-dimethylpropyl)benzoxazol-5yl]acetic acid (4.51 g) as a white solid, m.p. 108-109° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[N:25]=[C:24]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:16]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].ClCCl>O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[N:25]=[C:24]([C:26]3[CH2:27][CH2:28][N:29]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:30][CH:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:34])([F:36])[F:35])=[N:16]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
1-(2-Chloro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-6-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate (20.0 mg, 0.04 mmol) prepared in Step 1, triethylamine (15.0 uL, 0.11 mmol) and methanesulfonyl chloride (4.1 uL, 0.05 mmol) were added at 0° C. to dichloromethane (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with dichloromethane two times. The combined extract was washed with 1N hydrochloride, a saturated solution of sodium carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 3.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13](C(C)C)=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=3[C:10]([N+:21]([O-:23])=[O:22])=[C:9]2/[CH:24]=C/N(C)C)=[CH:4][CH:3]=1.S(C1C=CC=CC=1[C:35](OC(=O)C1C=CC=CC=1S(O)(=O)=O)=[O:36])(O)(=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1.[OH-].[Na+].CO>[CH3:24][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:36][CH3:35])=[CH:3][CH:4]=2)[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Reactant: Cc1ccc(-n2c(/C=C/N(C)C)c([N+](=O)[O-])c3ccc(O)c(C(C)C)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C)c([N+](=O)[O-])c3ccc(O)cc32)cc1
Yield: 54 %

Procedure:
23.6 g of ID-1 were refluxed together with 20.2 g of sulphobenzoic anhydride and 9 ml of pyridine in 200 ml of toluene. The oil formed was taken up in 300 ml of NaOH 1N and again heated to reflux with 200 ml of toluene. After elimination of the solvents by evaporation the precipitate formed was taken up in 500 ml of methanol. The precipitate, a lightly yellow powder, dissolved but recrystallized immediately. The yield was 54%.
Reaction SMILES: C([Li])CCC.C1C[O:9][CH2:8]C1.CC1CCCN(C)C1(C)C.[F:21][C:22]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C=O)C>C1COCC1.O.C(O)(=O)C>[F:21][C:22]1[C:34]([CH:8]=[O:9])=[C:33]([F:35])[CH:32]=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1F
Reactant: C1CCOC1
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(F)c(C=O)c1F
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
At −78° C., 17.62 ml of 1.59 M n-butyl lithium-THF solution was added dropwise to 100 ml of THF solution containing 4.73 ml of tetramethylpiperidine. This was stirred at −10° C. for 10 minutes, cooled to −78° C., mixed with 5.00 g of tert-butyl 2,4-difluorobenzoate dissolved in 20 ml of THF and then stirred for 1 hour. Subsequently, 7.23 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour, mixed with 5.34 ml of acetic acid and then risen to room temperature. This was mixed with an appropriate amount of purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 5.65 g (100%) of tert-butyl 2,4-difluoro-3-formylbenzoate (Reference Example 4-1) from a hexane-ethyl acetate (20:1-10:1) eluate.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[C:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:41])([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:4]([OH:42])=[O:3])=[CH:8][CH:9]=3)[N:17]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionic acid ethyl ester (3.6 mmol) in MeOH (7 mL) was treated with 2N NaOH (7 mL) and warmed to 55° C. After 18 h, the mixture was concentrated under reduced pressure and then acidified with 5N HCl to pH=1. The solution was extracted with EtOAc and then the organic phases dried (Na2SO4), filtered and concentrated to a white solid (7%). MS [EI+] 534 (M+H)+, 566 (M+Na)+, [EI−] 532 (M−H)+; HPLC: T=3.29 min, purity 99%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[C:3]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=2)=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1nccnc1C(=O)Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2nccnc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a mixture of the above 3-amino-N-(5-chloropyridin-2-yl)pyrazine-2-carboxamide (255 mg, 1 mmol) in pyridine (20 mL) was added 4-tert-butylbenzoyl chloride (402 mg, 86 mmol). The mixture was stirred for 36 hours at 55° C. It was cooled to room temperature then concentrated to dryness in vacuo. The residue was mixed with CH2Cl2 and purified by radial chromatography from which was recovered 85 mg (21%) of product.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([S:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: SCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 124.8 %

Procedure:
Z-Arg-OH.HCl (6 g, 8.7 mmoles) and benzyl mercaptan (4.2 ml, 17.4 mmoles) are dissolved in dimethylformamide (DMF) and cooled to 0° C. DCC (3.6 g, 8.7 mmoles), dissolved in DMF, is then added to the above reaction mixture, stirred at 0° C. for 30 minutes, then stirred overnight at room temperature. The precipitate formed is removed by filtration and the filtrate is concentrated under vacuum to yield an oil. This oily residue is dissolved in ethyl acetate and washed, successively, with 0.1 N HCl, 5% NaHCO3, and saturated aqueous NaCl. The organic layer is dried over anhydrous Na2SO4 and the solvent removed by evaporation. The crude product is purified by silica gel column, using a CHCl3 /methanol system, yielding 4.5 g of the product.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[C:9]([CH3:22])=[C:8]1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[NH:14][C:15](=[O:17])[C:16]2[N:7]([CH3:6])[C:8]([CH3:23])=[C:9]([CH3:22])[C:10]1=2)=[O:4]
Reactant: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CCl
Reaction time: 2 h

Procedure:
A solution of 21 of chloroacetyl chloride in 10 ml of toluene is added dropwise to 31 g of 1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5-]benzodiazepin-10-one, 6 g of anhydrous potassium carbonate, 40 ml of dioxane and 20 ml of toluene in the course of 30 minutes at 70° to 80° C., and the thus-prepared mixture is stirred at this temperature for a further 2 hours. The mixture is concentrated to dryness, the residue is boiled 3 times with 25 ml of chloroform each time, and the filtrate is concentrated to dryness. 3.6 g of the title compound are thus obtained.
Reaction SMILES: [NH2:1]C1C(C(N)=O)=NC=C(C2C(C)=CC=CN=2)C=1.[N:18]1([CH2:23][C:24]2[N:33]=[C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[C:31]3[C:26](=[CH:27][C:28]([C:45]4[C:50]([C:51](F)(F)F)=[CH:49][CH:48]=[CH:47][N:46]=4)=[CH:29]C=3)[N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:51][C:50]1[C:45]([C:28]2[CH:29]=[N:1][C:31]3[C:32]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:39][CH:40]=4)=[N:33][C:24]([CH2:23][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:25][C:26]=3[CH:27]=2)=[N:46][CH:47]=[CH:48][CH:49]=1
Reactant: Cc1cccnc1-c1cnc(C(N)=O)c(N)c1
Reactant: FC(F)(F)c1ccc(Nc2nc(CN3CCCC3)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Product: Cc1cccnc1-c1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(CN3CCCC3)nc2c1

Procedure:
The title compound is prepared from 3-amino-5-(3-methyl(2-pyridyl))pyridine-2-carboxamide in a manner analogous to that used for the preparation of [2-pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 2.A, steps 6 to 9).
Reaction SMILES: C1COCC1.C([O:9][CH:10]([CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:42])[C:23](=[C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[NH:34]2)[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:25])[CH:17]=1)[OH:15])[CH:11]([OH:13])[CH3:12])(=O)C.[OH-].[Na+].[Cl-].[NH4+]>CO>[NH:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[NH:37][C:33]1=[C:23]([C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:14]([OH:15])[CH:10]([OH:9])[CH:11]([OH:13])[CH3:12])[CH:17]=1)=[O:42])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[O:25]
Reactant: CC(=O)OC(C(C)O)C(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)C(O)C(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
A 10 ml portion of THF solution containing 104 mg of 1-[{3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]phenyl}(hydroxy)methyl]-2-hydroxypropyl acetate and 2 ml of methanol solution were mixed with 0.62 ml of 1.0 M sodium hydroxide and stirred for 30 minutes. This was mixed with appropriate amounts of saturated ammonium chloride aqueous solution and purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 35 mg (37%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(1,2,3-trihydroxybutyl)phenyl]propane-1,3-dione (Example 9-1) from a hexane-ethyl acetate (1:1-1:3) eluate.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:11](=[O:12])[C:10]([N:13]3C(=O)C4=CC=CC=C4C3=O)=[C:9]([N:24]3C(=O)C4=CC=CC=C4C3=O)[C:8](=[O:35])[C:7]=2[N:36]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12>O.NN>[NH2:36][C:7]1[C:8](=[O:35])[C:9]([NH2:24])=[C:10]([NH2:13])[C:11](=[O:12])[C:6]=1[NH2:5]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)=C(N2C(=O)c3ccccc3C2=O)C(=O)C(N2C(=O)c3ccccc3C2=O)=C1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: NC1=C(N)C(=O)C(N)=C(N)C1=O
Temperature: 60 °C

Procedure:
Tetraphthalimido-1,4-benzoquinone (30.00 g, 0.044 mole) is added to 200 ml of 80% hydrazine hydrate. The mixture is heated to 60° C. for two hours. After cooling to room temperature, the mixture is filtered yielding dark purple crystals melting at 260°-262° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:22]=1.[N+:23]([O-])([OH:25])=[O:24]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N+:23]([O-:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(Br)cc12
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (50 g, 137.6 mmol) in CHCl3 (500 mL), fuming HNO3 (50 mL) was added dropwise at −15° C. and the mixture was stirred for 0.5 hour. The reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer was washed with a.q. sat. NaHCO3 and brine, after removed the most of solvent, the resulting residue was crystallized with petroleum ether/dichloromethane=20/1 to provide product of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (35 g, yield: 66%). 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.02˜8.04 (m, 3H), 7.13˜7.18 (m, 2H), 4.36˜4.41 (m, 2H), 1.37 (t, J=4.0 Hz, 3H). MS (M+H)+: 408/410.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH2:26][C:27]([O:29]CC)=[O:28])=[CH:4][CH:3]=1.[Li+].[OH-].Cl.C(OCC)(=O)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH2:26][C:27]([OH:29])=[O:28])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1ccc2c(c1)c(Sc1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
To 100 mg of the ethyl ester from Step 1 in 1.0 mL tetrahydrofuran and 0.5 mL methanol was added 0.5 mL of 2.0 N LiOH at room temperature. After 45 min 1 N HCl and ethyl acetate were added. The organic layer was separated, washed with brine and dried over MgSO4. Filtration and concentration gave the title compound as a white solid which was triturated with hexane and filtered, mp 151°-153°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.C(N)CCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([NH:34][CH2:32][CH2:31][CH2:30][CH3:29])=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (10 mg, 0.25 mmol) in THF (4 mL) is added HOBt (68 mg, 0.5 mmol). After 10 min EDCl (96 mg, 0.5 mmol) and triethylamine (0.104 mL, 0.75 mmol) are added and the solution is stirred for 30 min then a solution of n-butylamine in 2 mL THF is added and the mixture is stirred at RT for 6 h. The solvent is removed under reduced pressure to afford the title compound: (M−1)−=442.
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]#[N:8])[C:3]([OH:5])=O.[CH:9]1([NH:16][C:17]([NH2:19])=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:16][C:17]2[S:18][CH:2]([CH2:6][C:7]#[N:8])[C:3](=[O:5])[N:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CC[C@H](N)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: N#CCC1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from (2S)-2-amino-3-cyanopropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](C(N)=O)[CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:27])[N:3]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:51]>CCOC(C)=O.O>[NH2:51][C:20]1[CH:19]=[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:27])[N:3]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[N:16][CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of 4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)picolinamide (111 mg, 0.25 mmol) in EtOAc (2 mL), CH3CN (2 mL) and H2O (1 mL) was added PhI(OAc)2 (97 mg, 0.3 mmol). The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and further stirred for 12 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light beige solid (85 mg, 81.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].P(Cl)(Cl)([Cl:12])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Product: Cc1cc(Cl)nc(Cl)c1
Yield: 43 %

Procedure:
A mixture of 2-chloro-4-methyl-pyridine 1-oxide (1.0 g, 7.0 mmol) and phosphorus oxychloride (10 mL) was heated at reflux for 4 h. The volatiles were evaporated and the residue dissolved in ethyl acetate. The solution was washed with ice-water followed by sodium bicarbonate solution. The organic phase was again washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by column chromatography over silica gel (60-120 mesh) using petroleum ether as eluent to afford 2,6-dichloro-4-methyl-pyridine (491 mg, 43%) as a white solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([N+:25]([O-])=O)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[NH2:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(N)cc1OCCCCCCCC
Yield: 97 %

Procedure:
3,4-Dioctyloxynitrobenzene (25.25 g, 0.067 mol) was dissolved in ethyl acetate (250 mL) in a Parr bottle. 10% Pd on charcoal (3.5 g) was added and the mixture was hydrogenated (5–6 hr) at 50 psi until the hydrogen uptake ceased. The reaction mixture was filtered and evaporated. The aniline was obtained as a dark syrup. (22.5 g, 0.064 mol, 97% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: C=Cc1ccccc1Br
Product: C=Cc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 76.9 %

Procedure:
With 10.0 g of 1-bromo-2-vinyl benzene and 4.72 g of 5-chloroisatin as starting materials, 5.71 g of the title compound (light brown solid) was obtained by a similar method to Step 21-1.