Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C1CNCCN1
Product: N#Cc1ccnc(N2CCNCC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-Chloro-isonicotinonitrile (80 g, 0.58 mol) and piperazine (199 g, 2.32 mol, 5 equiv) were combined and heated at 70° C. for 2.5 hours. The resulting suspension was cooled to room temperature and partitioned between a solution of 50% ethyl acetate/dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were concentrated in vacuo to about half the initial volume and ether was added. The suspension was stirred overnight, then filtered. The solid was dried under vacuum to give the desired product (31 g). The mother liquors were concentrated in vacuo and the residue was triturated with ether and filtered. The solid collected in this second batch was dried under vacuum and combined with the first batch to give the total amount of desired product (46 g, 42%). MS m/z 189 (M++1).
Reaction SMILES: [OH:1][CH:2]1[C:19]([CH3:21])([CH3:20])[O:18][C:17]2[C:4](=[C:5]3[C:14](=[C:15]([O:22][CH3:23])[CH:16]=2)[C:13](=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]4[CH:28]=[CH:27][CH:26]=[CH:25][C:11]4=2)[N:6]3[CH3:29])[C:3]1=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:1][CH:2]1[C:19]([CH3:20])([CH3:21])[O:18][C:17]2[C:4](=[C:5]3[C:14](=[C:15]([O:22][CH3:23])[CH:16]=2)[C:13](=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]4[CH:28]=[CH:27][CH:26]=[CH:25][C:11]4=2)[N:6]3[CH3:29])[C:3]1=[O:30])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(=O)C(O)C(C)(C)O2
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(=O)C(OC(C)=O)C(C)(C)O2

Procedure:
The compound is obtained according to the procedure of Example 14, starting from the compound of Example 16, using acetic anhydride instead of the butyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([Cl:23])[CH:12]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.[CH3:27][NH2:28]>O1CCCC1>[Cl:23][C:13]1[CH:12]=[C:11]([C:9]([NH:10][C:5]2[C:6]([C:7]([NH:28][CH3:27])=[O:24])=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:26])=[O:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:14]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 3, Step E) (6.32 g, 15.47 mmol) in tetrahydrofuran (50 mL) was added methylamine (2.0 M solution in THF, 38 mL, 77.38 mmol), and the reaction mixture was heated to 60° C., stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (4.57 g) melting at 225-226° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1O
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of titanium (IV) chloride (11.1 g) in THF (50 mL) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.26 g) and 3-hydroxy-4-methoxybenzaldehyde (3.00 g) in THF (50 mL) at 0° C., and then a solution of pyridine (4.00 g) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 1 hr, and water was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.50 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.[Rh+2].[Rh+2].FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:1][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10]2
Reactant: CCOC(=O)C(=Cc1cccc([Si](C)(C)C)c1)N=[N+]=[N-]
Agent: [Rh+2]
Agent: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc([Si](C)(C)C)ccc2[nH]1
Temperature: 40 °C
Reaction time: 7 h
Yield: 56.4 %

Procedure:
To a solution of 1.7 g (5.90 mmol) of ethyl 2-azido-3-(3-trimethylsilylphenyl)propenoate prepared according to the procedure described in the preceding step, in 25 mL of dry toluene, maintained under an inert atmosphere, is added 0.62 g (0.59 mmol) of dirhodium (II) heptafluorobutyrate dimer complex. The reaction mixture is stirred for 7 hours at 40° C. A second portion of 0.62 g (0.59 mmol) of dirhodium (II) heptafluorobutyrate dimer complex is added to the reaction mixture while maintaining the stirring and heating at 40° C. for a further 1 hour. After cooling to room temperature, the reaction mixture is filtered through silica gel, eluting with toluene. The filtrate is then concentrated under reduced pressure. The greenish solid obtained is triturated several times in a minimum amount of heptane, until a white powder is obtained. This powder is dried under reduced pressure to give 0.87 g of the expected ethyl 5-trimethylsilyl-1H-indole-2-carboxylate in the form of a white powder.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)[CH:30]=3)(=[O:28])=[O:27])=[O:12])=[CH:10][CH:9]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)cc3)c2)C1
Yield: 58.7 %

Procedure:
Compound 216 was prepared following the procedure outlined in Example 215 using terephthalic acid (10.7 mg, 0.0646 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 100 mg, 0.129 mmol). Purification by preparative HPLC gave the title compound (46.3 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (m, 6H), 7.73 (s, 2H), 7.59 (t, 2H), 7.52-7.49 (m, 4H) m, 6.80 (s, 2H), 4.77-4.69 (m, 4H), 4.49 (d, 2H), 3.587 (qs, 2H), 3.67-3.54 (m, 27H), 3.45 (t, 5H), 3.40 (t, 5H), 3.13 (s, 7H), 2.99 (t, 4H). MS (m/z): 1224.34 [M+H]+.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][C:12]=3[O:20][CH:21]([CH3:23])[CH3:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:24](O)=O>>[C:1]12([C:11]3[CH:16]=[C:15]4[C:14]([CH2:17][CH2:18][NH:19][CH2:24]4)=[CH:13][C:12]=3[O:20][CH:21]([CH3:23])[CH3:22])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=CO
Reactant: CC(C)Oc1cc(CCN)ccc1C12CC3CC(CC(C3)C1)C2
Product: CC(C)Oc1cc2c(cc1C13CC4CC(CC(C4)C1)C3)CNCC2
Temperature: 60 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of the product of Step E (0.4 g, 0.78 mmol) in HCOOH (3 ml) (CH2O)n (0.026 g, 0.87 mmol) was added and the mixture was stirred for 18 h at 60° C. This was evaporated to dryness and the residue was purified by FCC (SiO2) to give the desired product (0.17 g, 41%), as light yellow paste. 1H-NMR (CDCl3) 1.36 (d, 6H, J=6 Hz); 1.74 (s, 6H); 2.03 (s, 3H); 2.08 (s, 6H); 2.7 (tr, 2H, J=5.91 Hz); 3.10 (tr, 2H, J=5.99 Hz); 3.91 (5, 2H); 4.55-4.64 (m, 1H); 6.53 (s, 1H); 6.82 (s, 1H).
Reaction SMILES: [CH3:1][Al](C)C.[CH2:5]1[O:7][C@@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]1([C@@H:6]([CH3:1])[CH2:5][OH:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: C[Al](C)C
Solvent: Cc1ccccc1
Product: C[C@@H](CO)c1ccccc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
An oven dried 500.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with 2.0 M solution of trimethylaluminum (65.6 mL, 131.2 mmol) and toluene (75.0 mL). Reaction solution was then chilled to −60° C. with dry ice/acetone bath. To this solution was then added R-styrene oxide dissolved in 100.0 mL of toluene over a period of 50.0 minutes (reaction is quite exothermic and can be controlled by the rate of addition of substrate). After stirring at this temperature for 60.0 minutes, reaction was brought to room temperature and stirred for 4.0 hours. Reverse quenched reaction at room temperature into a slurry of THF (100.0 mL) and sodium sulfate decahydrate (46.0 g) very cautiously over a period of 90.0 minutes (quenching was quite exothermic with evolution of gas). Filtered the precipitate formed over hyflo, then concentrated filtrate to provide the intermediate title compound, (2R)2-phenylpropan-1-ol, (11.03 g, 92.6%) as an oil; 1H nmr (CDCl3, 300 MHz) δ 1.28-1.29 (d, 3H, J=6.9 Hz), 1.5 (b, 1H), 2.9-3.0 (m, 1H), 3.69-3.70 (d, 2H, J=6.64 Hz), 7.24-7.35 (aromatic); 13C nmr (CDCl3, 300 MHz) δ 18.31, 43.15, 69.40, 127.38, 128.20, 129.26, 144.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:39])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:39])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110 mg (0.28 mmol) of the compound from Example 100 were introduced into 20 ml of dichloromethane at 0° C., 68 mg (0.28 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 93 mg (81% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([C:25](=[O:28])[NH:26][CH3:27])=[CH:24][C:19]3=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[CH3:43])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:27][NH:26][C:25]([C:23]1[CH:22]=[N:21][N:20]2[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[C:17]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=3[CH3:43])[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:19]2[CH:24]=1)=[O:28]
Reactant: CNC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1cnn2c(C(=O)N3CCNCC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
To a solution of the compound of step 12 (0.150 g, 0.260 mmol) in 2.6 ml of DCM was added a 4 N solution of hydrogen chloride in dioxane (0.64 ml, 2.56 mmol). The mixture was stirred at room temperature for 5 h and then evaporated to dryness. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 50° C. to give 0.118 g of the title compound in the form of 6-(3-fluoro-2-methyl-benzyl)-5-phenyl-7-(piperazine-1-carbonyl)-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methylamide hydrochloride as a pale orange solid with the following characteristics:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:22]=[O:23])(=O)=O>CN(C)C=O>[C:29]1([CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=2[CH2:18][N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(CN2CCN(c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of N-phenylpiperazine (200 mg) and diiosopropylethylamine (130 mg) in dimethylformamide (1 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (320 mg). After stirring at room temperature for 3 hours the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash chromatography column using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give a gum which was crystallized from diethyl ether to give 4-phenylmethoxy-3-[[(4-phenyl)-1-piperazinyl]methyl]benzaldehyde (320 mg) as white crystals. 1H NMR (CDCl3) δ9.95 (s, 1H, CHO); 5.23 (s, 2H); 3.80 (s, 2H); 3.30 (m, 4H); 2.78 (m, 4H). TLC (silica gel): Rf=0.7 (petroleum ether:diethyl ether, 1:4).
Reaction SMILES: [C:1](=[O:4])([O-])N.[CH3:5][O:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=2[N:13]=1>>[CH3:5][O:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]2[C:17]([N:13]3[CH2:9][CH2:1][O:4][CH2:11][CH2:12]3)=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=2[N:13]=1
Reactant: NC(=O)[O-]
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Product: COC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1
Yield: 58 %

Procedure:
Carbamate formation using the same procedure as for (4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester yields the product as off-white solid in 58% yield. MS: m/e=324 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[BH4-].[Na+].CN([CH:36]=[O:37])C>CCO.O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:36][OH:37])=[C:9]2[CH3:23])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrole, 5, (in FIG. 6) (prepared as described in J. Med. Chem., 1997, 40, 1619) (1 mmol) in dry DMF (10 mL) at 0° C. is added phosphorus oxychloride (1 mmol). The reaction is monitored by tlc and when it is complete, the mixture is poured onto ice and made basic with aqueous sodium hydroxide. The product is isolated by extraction with CH2Cl2. The extract is dried and evaporated to afford a residue. To the residue, dissolved in EtOH (10 mL) is added sodium borohydride (100 mg). After one hour, the solution is added to water and extracted with ethyl acetate. The extract is washed with dilute HCl, dried and evaporated. The title compound 6 is purified and isolated by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:29]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.[H-].[Na+].[O:38]=O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:29]=[C:14]3[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])([OH:38])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reactant: O=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(/C=C/c2nc3n(n2)CCCC3(O)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-Trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (50 mg) was dissolved in DMF (3 mL). Sodium hydride (containing 40% of mineral oil, 8.3 mg) was added and the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was internally replaced with oxygen. The reaction solution was bubbled with oxygen and stirred for two hours. A sodium thiosulfate solution was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution and the organic layer was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) to obtain the title compound (10 mg). The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:20]3[O:21][C:22]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][C:24](=[O:26])[CH:25]=3)[CH2:9][C:8]=2[CH:7]=1.[OH-].[Na+:35]>C1COCC1>[Na+:35].[N:27]1([C:22]2[O:21][C:20]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:15]=3[S:16][C:17]3[CH:18]=[CH:19][C:6]([O:5][CH2:4][C:3]([O-:33])=[O:2])=[CH:7][C:8]=3[CH2:9]4)=[CH:25][C:24](=[O:26])[CH:23]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COC(=O)COc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])COc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of [5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yloxy]-acetic acid methyl ester (1.02 g, 2.18 mmol) in THF (25 ml) was added aqueous NaOH (2.4 ml, 2.4 mmol, 1M solution). The mixture was stirred at 40° C. for 2 hours whereupon it was cooled to room temperature and concentrated in vacuo to give a brown oil. The residue was azeotroped with toluene (3×10 ml) to give the title compound as a fine, dark brown powder that was used without further purification (1.03 g, 100%), m/z (LC-MS, ESP), RT=3.72 min, (M++1)-Na+=452
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:7]([O:9][CH3:10])=[O:8].[H][H]>C(O)C.[Pd]>[NH2:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N)c(OC(F)F)c1
Yield: 75.9 %

Procedure:
Methyl 3-(difluoromethoxy)-4-nitrobenzoate (0.9 g) was placed in a 250 mL round bottom flask and dissolved in 30 mL of ethanol. Pd/C (0.15 g, 10% Pd) was carefully added and a balloon of hydrogen was attached to the flask. The reaction was vigorously stirred over night. After checking by TLC, the reaction was filtered through a pad of celite and concentrated to give 0.6 g of methyl 4-amino-3-(difluoromethoxy)benzoate which was used without further purification.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:24])[NH:11][C:12]2[CH:13]=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)([OH:27])=[O:26]>>[C:1]1([C@H:7]([O:9][C:10]([NH:11][C:12]2[CH:13]=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:34]3[CH:35]=[CH:36][C:31]([C:28]4([C:25]([OH:27])=[O:26])[CH2:30][CH2:29]4)=[CH:32][CH:33]=3)=[CH:19][CH:18]=2)=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](OC(=O)Nc1cnoc1-c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Product: C[C@@H](OC(=O)Nc1cnoc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 4-(1-carboxycyclopropyl)phenylboronic acid.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6]OS(O)(=O)=O.C([O:14][C:15]([C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][C:22]([Br:29])=[C:23]([F:28])[CH:24]=2)[N:19]([CH:30]2[CH2:32][CH2:31]2)[C:18]=1[SH:33])=O)C.Cl>C1COCC1>[Br:29][C:22]1[CH:21]=[C:20]2[C:25]([C:26](=[O:27])[C:17]3[C:15](=[O:14])[NH:6][S:33][C:18]=3[N:19]2[CH:30]2[CH2:32][CH2:31]2)=[CH:24][C:23]=1[F:28]
Reactant: NOS(=O)(=O)O
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]sc2c1c(=O)c1cc(F)c(Br)cc1n2C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of NaHCO3 solution (51 mg, 0.9 ml water) and hydroxylamine-O-sulfonic acid (27 mg, 0.24 mmole, 4.2 equiv.) is added to a stirred solution of 7-Bromo-1-cyclopropyl-6-fluoro-2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (6, 22 mg, 0.057 mmole) in THF (0.7 ml). The reaction mixture is stirred at room temperature for approximately 3 hours until the reaction is complete. The reaction mixture is acidified by the addition of 0.5N HCl and filtered. The resulting solid is washed with water (3×) and dried yielding 7 as a white solid. 1H NMR (DMSO-d6) δ: 8.39 (d, 1H), 8.06 (d, 1H), 3.63 (m, 1H), 1.41 (m, 2H), 1.26 (m, 2H). 19F NMR (DMSO-d6) δ: 114.9 (s, 1H).