Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.P([O-])(O)(O)=[O:10].[Na+].OO.Cl([O-])=O.[Na+]>O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[O:8])[S:5][CH:6]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cc(Br)cs1
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Reaction time: 1 h
Yield: 334.9 %

Procedure:
To a flask equipped with a mechanical stirrer was added 25 g (130 mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company), acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate dissolved in 35 mL of water. After cooling this mixture on an ice-salt bath, 15 mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium chlorite were added, and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid was suspended in a mixture of water (175 mL) and 1 N hydrochloric acid (4 mL) and stirred for 10 min at rt. The solid was collected on a Büchner funnel and washed with water (2×150 mL) to afford 26 g (97%) of 4-bromothiophene-2-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:19]=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)[CH3:10].[I-:20].[Na+]>C(OCC)(=O)C.O>[CH2:9]([C:11]1[C:19]([I:20])=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)[CH3:10]
Reactant: CCc1cc2ccccn2n1
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
N-Chlorosuccinimide (411 g, 3.08 mol) was gradually added to a mixture of 2-ethylpyrazolo[1,5-a]pyridine (360 g, 2.46 mol), ethyl acetate (3600 mL), water (1800 mL) and sodium iodide (480 g, 3.20 mol, 1.3 equivalents) over a period of 30 minutes while cooling with ice, and then the reaction mixture was stirred for 2 hours and 20 minutes at room temperature. After the reaction, water and ethyl acetate were added to the reaction mixture and extraction was performed with ethyl acetate. The organic extract was washed twice with 10% aqueous sodium thiosulfate, and then concentrated. Hexane was added to the residue, the mixture was heated to dissolution and the resulting solution was filtered to remove insoluble residue. After then washing the hexane solution with water, the hexane layer was concentrated, the residue was dissolved in ethyl acetate and the solvent was evaporated to afford 663 g of the title compound (98.9% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10](C(O)=O)([CH2:11]3)[CH2:9]2.OS(O)(=O)=O.[N-:26]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]12[CH2:16][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:10]([NH2:26])([CH2:11]3)[CH2:9]2
Reactant: O=C(O)C12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Yield: 73.4 %

Procedure:
To a stirred solution of the acid obtained in step III (0.39 g, 1.31 mmol) in CHCl3 (7 mL) was added conc. H2SO4 (1.4 mL, 26 mmol). Solid NaN3 (0.26 g, 3.93 mmol) was added slowly in portions by keeping the reaction temperature below 40° C. The reaction mixture was stirred at r.t for 2, h then it was cooled to ice bath temperature, diluted with water, and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain 1-[(1,1-dioxidoisothiazolidin-2-yl) methyl]tricyclo[3.3.1.03,7]nonan-3-amine (0.26 g) as viscous liquid in 74% yield. m/z (M+1) 271; 1H NMR (CDCl3) 300 MHz δ 3.32 (t, J=6.8 Hz, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.92 (s, 2H), 2.40-2.28 (m, 3H), 2.01-1.83 (m, 3H), 1.75-1.52 (m, 6H), 1.50-1.43 (m, 1H), 1.39-1.32 (m, 1H).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29](OCC)=O)[CH2:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCCN1CCC(c2cccc3ccccc23)CC1
Reactant: ON=C1CCCCCC1
Product: c1ccc2c(C3CCN(CCCc4onc5c4CCCCC5)CC3)cccc2c1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(1-naphthyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(1-naphthyl)piperidin-1-yl)propyl-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH:21]=[O:22])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:23]>C1COCC1>[OH:22][CH:21]([C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7](=[O:23])[N:6]([CH3:5])[C:10]=2[CH:11]=1)[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Solvent: C1CCOC1
Product: CCC(O)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Reaction time: 3 h
Yield: 7.2 %

Procedure:
Ethylmagnesium bromide (3 M in THF, 0295 mL, 0.885 mmol) was added dropwise to a solution of 3-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-4-carbaldehyde (75 mg, 0.295 mmol) in THF (2 mL) at −36° C. The resulting mixture was stirred at this temperature for 3 h, and the reaction was quenched by the addition of saturated NH4Cl solution. The mixture was diluted with ethyl acetate and water. The organic layer was separated and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by reverse phase chromatography (10%-100%, v/v, ACN-water), 6 mg of desired product was obtained. ESI-MS m/z: 285.1 [M+1]+, Retention time 1.00 min; 1HNMR (CDCl3, 400.342 MHz) δ ppm 0.74 (t, J=7.3 Hz, 3H), 1.47-1.53 (m, 2H), 3.40 (s, 3H), 4.93 (t, J=5.5 Hz, 1H), 7.03 (dd, J=8.1, 1.2 Hz, 1H), 7.16 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 8.03 (d, J=5 Hz, 1H), 8.36 (s, 1H), 8.52 (d, J=5 Hz, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[N:19]=[C:18]([CH:31]([CH3:33])[CH3:32])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:31]([CH3:33])[CH3:32])=[N:19][N:20]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ccc3ccccc3n2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
N-bromosuccinimide (21.03 g, 118 mmoles) was added in one portion to a solution of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (39.16 g, 118 mmoles) in 400 mL DMF at 0° C. under an inert atmosphere. The mixture was warmed to room temperature and stirred for 16 hours, then poured into 500 mL H2O and the resulting precipitate was collected. The precipitate was air dried on a vacuum filter for 16 hours to give 47.20 g (97%) of the title compound as a white solid, mp 110°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCCOCc1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(OCCCCOCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
4-Fluorophenol (500 mg) and benzyl 4-bromobutyl ether (1.1 g) were dissolved in DMF (20 mL), and potassium carbonate (1.0 g) was added thereto at room temperature, followed by stirring at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 1-[4-(benzyloxy)butoxy]-4-fluorobenzene (851 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH3:25])[C:11]3=2)[NH:6][CH:5]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][NH:14][CH:13]([CH3:25])[C:11]3=2)[N:6]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:5]=1
Reactant: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.010 g, 0.42 mmol) was added to tert-butyl 10-chloro-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 43, 18 mg, 0.050 mmol) and benzenesulfonyl chloride (0.030 mL, 0.23 mmol) in DMF (2 mL). The mixture was was stirred at room temperature for 30 minutes. TFA (0.50 mL) was added to the reaction mixture and the solvent was evaporated. The residue was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (16.8 mg) in the form of the trifluoroacetate salt. MS m/z 377 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].[C:20](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:3][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
To a solution containing N-[(1,1-dimethylethoxy)carbonyl]phenylalanine (10 g, 37.7 mmole) in dimethylformamide (40 ml) is added solid sodium bicarbonate (4.75 g, 56.6 mmole) and iodometbane (16 g, 113 mmole). The mixture is heated at 40° under argon for 12 hours, the cooled and the reaction mixture partitioned between water (150 ml) and ether (250 ml). The organic layer is rinsed with 2% aqueous sodium bicarbonate (2×100 ml), 2% aqueous sodium bisulfite (100 ml), water (2×100 ml), and brine, dried over magnesium sulfate, and concentrated in vacuo to give 10.5 g of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)CCCC.[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:22])/[CH:17]=[CH:18]\[C:19]([O-])=[O:20]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH:17]([C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:18][C:19](=[O:20])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Cl
Reactant: CCCCCOC(=O)/C=C\C(=O)[O-]
Solvent: CC(=O)O
Solvent: CCCCCO
Product: CCCCCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 75 °C
Yield: 23.8 %

Procedure:
0.75 g of sodium hydroxide was added to a mixed solution comprising 15 ml of 1-pentanol and 30 ml of toluene, followed by dehydration using an azeotropic dehydrator under reflux with heating, and then toluene was distilled off. Further, 20 ml of toluene was added to the reaction system and then toluene was distilled off with heating again, to obtain a 1-pentanol solution of sodium pentaoxide. 2.5 g of 3-chloro-2-hydrazinylpyridine was added to the reaction liquid at from 70 to 80° C. little by little over a period of 5 minutes, and then 5 ml of 1-pentanol was added, followed by heating at from 70 to 80° C. for 25 minutes. Then, a mixed solution comprising 5.1 g of pentyl maleate and 5 ml of 1-pentanol was dropwise added over a period of 15 minutes, followed by reaction at from 70 to 80° C. further for 2 hours. After the reaction liquid was stood to cool, acetic acid was added to the reaction liquid for neutralization, followed by concentration under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate, and the organic layer was washed with diluted hydrochloric acid and a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/4 to 0/1) to obtain 1.29 g of the desired product (melting point: 66 to 68° C.) in the form of brown crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:14]Br)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19])[OH:17]>CC(C)=O>[O:17]1[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][CH2:14][CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(Br)CBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2ccccc2O1
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, add 18.2 g (131 mmol) of dry potassium carbonate and 13 g (50 mmol) of ethyl 2,3-dibromopropionate in succession to a solution of 20 g (181 mmol) of catechol dissolved in 120 cm3 of anhydrous acetone. The operation is repeated four times in succession at intervals of 15 minutes. The reaction mixture is heated at reflux for 18 hours, and then cooled and filtered through Celite. The filtrate is concentrated to a residual volume of 60 cm3, then hydrolysed with 80 cm3 of water and extracted with diethyl ether. After drying over magnesium sulfate, the ethereal phase is concentrated under reduced pressure and the crude product is purified by distillation under reduced pressure (b.p.=155° C. under 15 mm Hg). Ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 80%. nD25 =1.5214 ##STR27##
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:14]=[C:13]([Cl:15])[S:12][C:11]=2[CH:16]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:11]2[S:12][C:13]([Cl:15])=[CH:14][C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2sc(Cl)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 42b using 3-benzenesulfonyl-5-chlorothiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[CH:37]12[N:43]([C:44](=O)[CH2:45]Br)[CH:40]([CH2:41][CH2:42]1)[CH2:39][CH2:38]2>>[CH:37]12[N:43]([CH2:44][CH2:45][O:1][C:2]3[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=4[CH:18]4[CH2:27][CH2:26][C:25]5[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=5[CH2:19]4)=[CH:4][CH:3]=3)[CH:40]([CH2:41][CH2:42]1)[CH2:39][CH2:38]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 57.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][C:3]=1[F:19].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:14]([CH3:17])([CH3:18])[CH2:15][O:16][C:21]3=[O:23])[S:11][CH:12]=2)=[CH:4][C:3]=1[F:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Cl)c(F)c2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Cl)c(F)c2)cs1

Procedure:
In the same manner as described in step 7 of Example 78, using 2-[4-(4-chloro-3-fluoro-phenyl)-thiazol-2-ylamino]-2-methyl-propan-1-ol (810 mg, 2.66 mmol), prepared in the previous step, triphosgene (946 mg, 3.19 mmol) and diisopropylethyl amine (1.1 mL) in 20 mL of methylene chloride, the title compound was isolated (125 mg, 14%) after purification on silica gel using 6:1 hexane:ethyl acetate as the eluent. mp 140-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH2:14][NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(C2=NNCC2)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NN(C(=O)Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A scintillation vial equipped with a stir bar was charged with 3-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-pyrazole (412 mg, 2 mmol), Hunigs base (1 mL, 6 mmol) and dry CH2Cl2 (10 mL). To this mixture was added phenyl-acetyl chloride, (0.27 mL, 2 mmol) and the reaction was stirred at RT for 3 h. LC-MS indicated consumption of SM. The mixture was diluted with CH2Cl2 (50 mL) and added to water (50 mL). The phases were separated and the CH2Cl2 phase was washed with saturated Na2CO3, (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified using a 40 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 100% EtOAc. Amount obtained: 123 mg, 0.37 mmol, 19% yield. LC-MS (ESI) m/e 325 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.21 (t, J=10.03 Hz, 2H) 3.94 (s, 3H) 3.98 (s, 3H) 4.04 (t, J=10.03 Hz, 2H) 4.11 (s, 2H) 6.90 (d, J=8.35 Hz, 1H) 7.16 (dd, J=8.27, 1.88 Hz, 1H) 7.21-7.26 (m, 1H) 7.31 (t, J=7.42 Hz, 2H) 7.40-7.44 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:5]=[N:4][CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cncc(-c3ccc(CC(N)C(=O)O)cc3)n2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 7.9 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50 mg, 0.15 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 5.5 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08(m, 2H), 3.65(s, 3H), 4.0(m, 1H), 4.45(d, 2H), 4.65(m, 1H), 6.90(s, 2H), 6.95(s, 1H), 7.32(d, 2H), 7.60(t, 1H), 7.90(s, 1H), 7.95(d, 2H), 8.25(s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 1.00 g (3.36 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.63 g (3.38 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 1.00 g (9.91 mmol) of triethylamine, and 35 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered and washed with acetonitrile and ether. The crude product was suspended in 20 ml of 6M hydrochloric acid and 20 ml of glacial acetic acid and was heated at 60° C. for two hours. The solution was concentrated to an oil which was triturated with isopropanol. The solid was filtered and washed with ether to give 1.04 g of the title compound as the hydrochloride salt, mp >300° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH2:16])[NH:10][N:9]=2)=[CH:3][CH:2]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CCO.N1CCCCC1>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([N:16]=[CH:28][C:27]3[CH:30]=[CH:31][C:24]([OH:23])=[CH:25][CH:26]=3)[NH:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(-c3ccccc3)cc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2ccc(-c3ccccc3)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
3-([1,1′-biphenyl]-4-ylamino)-5-amino-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-([1,1′-biphenyl]-4-ylamino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.