Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[C:4]([F:19])[C:3]=1[C:20]([F:23])([F:22])[F:21].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:24](=[O:26])[CH3:25])[C:13](=[O:18])[CH2:12]3)[CH:5]=[C:4]([F:19])[C:3]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2N1
Product: CC(=O)N1C(=O)Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-2-indolinone (6.8 g, 18.9 mmol) in acetic anhydride is heated at reflux temperature with stirring for 30 minutes, cooled to room temperature and concentrated in vacuo to give a brown wet residue. The residue is re-evaporated twice using xylenes and chromatographed using 10% ethyl acetate in hexane to give the title product as a white solid, 5.1 g (67%), mp 119°-121° C., identified by 1HNMR.
Reaction SMILES: [BrH:1].[CH:2]1([NH:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:18])[C:13]=3[OH:17])[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3]1>[Pd].O>[BrH:1].[CH:2]1([NH:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:18])[C:13]=3[OH:17])[CH:8]2[OH:19])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccc(O)c(O)c2CCC1NC1CCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NC1CCC1)C2O

Procedure:
In the presence of 1.53 parts of 5% palladium-on-carbon, 1.5 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 200 volume parts of water is subjected to catalytic reduction at ordinary temperature and pressure. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst and filtrate is freeze-dried. The residue is recrystallized from a mixture of water, ethanol and ethyl ether, whereby 2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained as colorless crystals. Yield 0.65 part; melting point: 190°-200° C (decomposition).
Reaction SMILES: COC1C=C(N)C=C[C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16]O[CH2:14][CH2:13]1.[CH2:19]([OH:21])[CH3:20]>[Pd]>[CH3:8][O:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:20]([CH:19]=[O:21])[CH2:16][CH2:17]1
Reactant: CCO
Reactant: COc1cc(N)ccc1OCCN1CCOCC1
Agent: [Pd]
Product: COCCN1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-morpholine To a solution of (1-(2-hydroxyethyl)-morpholine) (1.94 ml, 16 mmol) in dimethylformamide was added sodium hydride [60% dispersion in oil] (544 mg, 16 mmol). After stirring at room temperature for 10 min, a solution of (1-chloro-2-methoxy-4-nitro-benzene) (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hours, concentrated, then the residue dissolved in ethyl acetate and washed with water. The organic phase was dried with magnesium sulphate, concentrated and the residue purified by column chromatography on silica gel to afford the title compound; MS(ES+) m/e 283 [M+H]+. Step 2. 3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine To a solution of the product of Step 1 (2.3 g, 8.6 mmol) in ethanol (100 ml) was added 10% palladium on charcoal (50 mg). The mixture was then stirred at room temperature under an atmosphere of hydrogen for 16 hours, filtered through celite and concentrated to give the title compound; MS(ES+) m/e 252 [M+H]+.
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:23].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:23].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15]1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 10.12 g of (3S,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-isopropyldihydrofuran-2-one obtained in Example (1e) (33.5 mmol), 16.7 ml of a solution of 4 N hydrochloric acid in dioxane (66.8 mmol) and 3.57 g of 10% palladium-carbon (50% wet) in ethanol (170 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 170 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain 8.50 g of crude (3S,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2-one hydrochloride.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[F:17][C:15]([F:16])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc(Oc2ccccc2C(F)(F)F)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=c1cc(Oc2ccccc2C(F)(F)F)cn[nH]1
Reaction time: 96 h
Yield: 70.1 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (3.66 g, 12.59 mmol), water (70 mL), and a 2N aqueous sodium hydroxide solution (7 mL, 14 mmol) was treated with 10% palladium on carbon (0.37 mg, 10% weight of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 4 d. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The aqueous residue was acidified with a 2N aqueous hydrochloric acid solution and was then extracted with a 90/10 methylene chloride/methanol solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ISCO, 120 g, 50%-70% ethyl acetate/hexanes) afforded 5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (2.26 g, 70%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.79 (d, J=2.7 Hz, 1H), 7.52-7.60 (m, 2H), 7.82 (t, J=8.5 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 13.04 (br. s., 1H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([O:18][CH3:19])[C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:21][C:22]([F:34])([F:33])[CH2:23][CH2:24][S:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:17][C:14]([F:15])([F:16])[CH:13]([O:18][CH3:19])[CH2:12][CH2:11][CH:28]([S:25]([CH2:24][CH2:23][C:22]([F:33])([F:34])[F:21])(=[O:27])=[O:26])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: COC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(OC)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.7 %

Procedure:
To a solution of 1.0 g of 4,4,4-trifluoro-3-methoxy-butyl p-toluenesulfonate and 0.8 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 0.4 g of potassium carbonate at room temperature, and the stirred at room temperature for 4 days. The reaction mixture was heated to 60° C., stirred at the same temperature for 20 hours, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.62 g of methyl 6,6,6-trifluoro-5-methoxy-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (24)).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:42])[C@H:13]([CH2:31][CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:14]([C:16](=[O:30])[C@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:18]C(OC(C)(C)C)=O)[CH3:15].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:42])[C@H:13]([CH2:31][CH2:32][CH2:33][NH2:34])[N:14]([C:16](=[O:30])[C@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:18])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)N(C)[C@@H](CCCN)C(=O)Nc1ccc2ccccc2c1

Procedure:
N-Boc-leucyl-Nδ-Boc-Nα-methylornithine 2-naphthylamide was treated with TFA at 25° C. for 30 min. The solution was concentrated in vacuo and the residue purified by reverse phase HPLC (Amberchrome—CH3CN/0.1% TFA—H2O). The desired fraction was lyophilized to give titled product: 1H NMR (400 MHz, D2O) δ1.0-1.1 (m, 6H), 1.7-1.9 (m, 5H), 2.0-2.2 (m, 2H), 3.1-3.3 (m, 5H), 4.6-4.7 (m, 1H), 5.1-5.2 (m, 1H), 7.5-7.7 (m, 3H), and 7.9-8.1 (m, 4H); mass spectrum, m/e 384 (M+), 271, 241, 194, and 129.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17]Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(C(OCCCl)c2ccccc2)cc1
Product: Cc1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 65 %

Procedure:
Following a procedure similar to that described in Preparation 5(c), but using 2-[α-(4-methylphenyl)-benzyloxy]ethyl chloride and anhydrous piperazine, the title compound was obtained in a yield of 65%.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=2[C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with pyridine-3-boronic acid as in Example 38 to afford 0.067 g (63%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C28H21NO4F3Cl 528.1190, found 528.1186.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[C:13]1([S:19]([C:3]2[CH:2]=[C:1]([OH:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[OH:11])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1cc(O)c2ccccc2c1O
Reaction time: 5 h

Procedure:
1,4-naphthoquinone (15.8 g) was dissolved in 100 ml of a mixture of ethyl acetate and acetic acid (9:1) and sodium benzenesulfinate (24.6 g) was added. The resulting mixture was stirred for 5 hours and the obtained crystals were filtered and washed with a small amount of acetone. (Yield: 22.5 g)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (2.01 g, 9.9 mmol) in tetrahydrofuran (20 mL) was dropped methylmagnesium bromide (10 mmol, 1N in tetrahydrofuran) and the mixture was stirred at room temperature for 30 minutes. TLC showed all starting material was consumed, then mixture was quenched with aqueous ammonium chloride (1N, 5 mL). To the mixture, water (50 mL) was added and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give the product 1-(4-bromo-2-fluorophenyl)ethanol as colorless oil (2.0 g, 92%). 1H NMR (300 MHz, CDCl3): δ 7.40-7.19 (m, 3H), 5.16 (q, J=6.3 Hz, 1H), 1.76 (s, 1H), 1.49 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([CH3:15])=[CH:14][C:5]2=1.[O:16]([CH2:23][CH:24]1[CH2:26][O:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:26][CH:24]([OH:25])[CH2:23][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]1[CH:11]=[N:12][C:13]([CH3:15])=[CH:14][C:5]2=1
Reactant: Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Reactant: c1ccc(OCC2CO2)cc1
Product: Cc1cc2c3cc(Br)ccc3n(CC(O)COc3ccccc3)c2cn1
Yield: 78 %

Procedure:
Following Representative Procedure 1, the title compound 1-(6-bromo-3-methyl-9H-pyrido[3,4-b]indol-9-yl)-3-phenoxypropan-2-ol was prepared from 6-bromo-3-methyl-9H-pyrido[3,4-b]indole and phenoxymethyloxirane in 78% yield after a precipitation from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:19][CH:20]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ncc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 5-Bromo-pyrimidin-2-ylamine to produce N-(5-Bromo-pyrimidin-2-yl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:30])[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25](OCC)=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:30])[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:25](=[O:26])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(C)(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1(C)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 10 h
Yield: 36 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, 0.30 mmol) in methanol (4 mL) was added hydrazine monohydrate (0.7 mL) at room temperature, the mixture was stirred under 30° C. for 10 hr. The solvent was evaporated to obtain crude solid, which was washed by 14 mL of mixture of ethyl acetate and methanol (13:1) to obtain the title compound as a green solid (40 mg, yield 36%). LC-MS (ESI) m/z: 376 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.39 (s, 3H), 3.71 (s, 3H), 4.74 (s, 1H), 6.72 (s, 1H), 7.03 (s, 1H), 7.06-7.11 (m, 2H), 7.16-7.19 (d, J=8 Hz, 1H), 7.25-7.28 (d, J=8 Hz, 1H), 7.49 (s, 1H), 7.54-7.58 (m, 3H), 12.05 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH:23]=[C:3]12.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2](=[O:1])[C:3]3=[CH:23][S:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:4]3=[N:5]2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (55 mg, 0.17 mmol) was suspended in anhydrous dimethyl acetamide (1 ml). Diisopropyl-ethyl amine (46.5 mg, 0.36 mmol, 62 μl) was added followed by 3-dimethylaminopropylamine (17.5 mg, 0.17 mmol) and [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 h and was purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 407 [M+H]+ Activity **
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].[BH4-].[Na+]>CO.C(O)C>[OH:32][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:3]=1[O:2][CH3:1])[C:7]([NH:9][C:10]1([C:19]([OH:21])=[O:20])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:8]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(=O)c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)c1ccccc1C
Yield: 18.5 %

Procedure:
The compound of example 240 (70 mg, 0.163 mmol) was dissolved in a mixture of methanol (1.5 ml) and ethanol (1.5 ml) and cooled in an ice bath. Sodium borohydride (18.9 mg, 0.49 mmol) was added in two batches and the mixture reacted with ice cooling until completion (3 h). The volatiles were evaporated and the residue was partitioned between diethyl ether and 1 N hydrochloric acid. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried and evaporated. The residue was purified by RP HPLC (water/ACN gradient) to yield 13 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([OH:23])=O)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[CH:35]=[CH:34][O:33][CH:32]=1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[O:30])=[O:23])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: CC(C)NNC(=O)c1ccoc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)N(NC(=O)c1ccoc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 55.9 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (180 mg, 0.54 mmol) and furan-3-carboxylic acid N′-isopropyl-hydrazide (110 mg, 0.65 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.237 ml, 1.36 mmol) and PyBroP (381 mg, 0.82 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with aqueous saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate in hexanes gradient to afford the product as a solid (145 mg, 56%). MS m/e 481.35 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]([CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[C:27]1[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:30]1[CH:31]=[CH:32][C:27]([N:26]([C:21]2[N:20]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:28][CH:29]=1
Reactant: O=S(=O)(Oc1ccc(N(c2ncccn2)C2CCOCC2)cc1)C(F)(F)F
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(c2ncccn2)C2CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 59.2 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (164.0 mg) was reacted with trifluoromethanesulfonic acid 4-[pyrimidin-2-yl-(tetrahydropyran-4-yl)amino]phenyl ester (220.0 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yl-(tetrahydro-pyran-4-yl)-amino)phenyl]pent-4-enoic acid methyl ester (178.5 mg). Column chromatography (silica gel, eluent: chloroform/cyclohexane=1/2→chloroform) and thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=1/1) were used for purification.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I-:27].[Na+]>C(#N)C>[I:27][CH2:2][O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCI

Procedure:
4-(N-CBz-L-valyloxy) butyric acid chloromethyl ester (1.54 g, 4 mmole) was dissolved in acetonitrile (15 ml). Sodium iodide (840 mg, 5.6 mmole) was added to the solution. After reaction at 55° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. Yield 1.9 g.
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][N:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([N:27]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccncc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccncc2)nc1-c1ccnn1-c1ccccc1
Yield: 16 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-pyridin-4-ylpyridazin-4(1H)-one (crude 158 mg, 0.58 mmol) in 20 mL of methanol was added phenylhydrazine (253 mg, 2.34 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-4-ylpyridazin-4(1H)-one (30 mg, 16% for two steps) as a yellow solid.