Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[O:8][CH2:9][CH:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[O:12][CH2:11]2)C=CC=CC=1.[H][H]>CO.[Pd]>[O:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:19][C@@H:10]([CH2:9][OH:8])[CH2:11]1.[O:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:19][C@H:10]([CH2:9][OH:8])[CH2:11]1
Reactant: [H][H]
Reactant: c1ccc(COCC2COc3cccnc3O2)cc1
Agent: [Pd]
Solvent: CO
Product: OC[C@@H]1COc2cccnc2O1
Product: OC[C@H]1COc2cccnc2O1

Procedure:
A mixture of 2,3-dihydro-3-[(phenylmethoxy)methyl]-1,4-dioxino[2,3-b]pyridine (0.0638 mol) in CH3OH (250 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. This fraction was purified by HPLC (eluent ethanol/methanol 60/40; column: Chiralpak AD 20 μm). Two fractions were collected and the solvent was evaporated, yielding 4.06 g of (S)-2,3-dihydro-1,4-dioxino[2,3-b]-pyridine-3-methanol (intermediate 2-a) ([α]D20=−34.33°; c=25.34 mg/5 ml in methanol) and 3.81 g of (R)-2,3-dihydro-1,4-dioxino[2,3-b]-pyridine-3-methanol (intermediate 2-b) ([α]D20=+32.740; c=22.60 mg/5 ml in methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: C([Li])CCC.CCCCCC.CO[C:14]([C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)=[O:15].Cl.[C:26](#[N:28])[CH3:27]>C1(C)C=CC=CC=1>[O:15]=[C:14]([C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)[CH2:27][C:26]#[N:28]
Reactant: COC(=O)c1cnn2ccccc12
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: N#CCC(=O)c1cnn2ccccc12
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of dry acetonitrile in toluene (0.66 mL, 13 mmol, 5 eq) cooled down to −78° C. under nitrogen, a solution of n-butyllithium in n-hexane (5.2 mL, 13 mmol, 5 eq) was added dropwise. The mixture was left stirring at −78° C. for 20 minutes and then a solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.46 g, 2.6 mmol, 1 eq, prepared according to the reported procedure (Anderson et al. Journal of Heterocyclic Chemistry 1981, 18, 1149-1152) in toluene was added and the reaction allowed to reach room temperature. Upon reaction completion, after about 20 minutes, the mixture was cooled down to 0° C. and HCl 2N was added to pH 2. The organic phase was recovered, dried over Na2SO4 and concentrated under reduced pressure, affording the title product which was used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]5[N:34](C(OC(C)(C)C)=O)[C:35]6[C:40]([C:41]=5[CH3:42])=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:30]([CH2:50][CH2:51][OH:52])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]([CH2:50][CH2:51][OH:52])=[C:31]([C:33]5[NH:34][C:35]6[C:40]([C:41]=5[CH3:42])=[CH:39][CH:38]=[CH:37][CH:36]=6)[N:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4c(C)c5ccccc5n4C(=O)OC(C)(C)C)n3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4[nH]c5ccccc5c4C)n3)cc12

Procedure:
To a solution of tert-butyl 2-(6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-(2-hydroxyethyl)pyridin-2-yl)-3-methyl-1H-indole-1-carboxylate (50 mg, 0.069 mmol) in CH2Cl2 (1.5 mL) was added TFA (1.5 mL). The resultant mixture was stirred at ambient temperature for 1.5 h then was concentrated in vacuo, diluted with EtOAc and washed successively with saturated NaHCO3 (aq) solution (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. MS (M+H): 627.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:26][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: BrCC1CCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCC2)c1

Procedure:
Alkylation reaction of phenol 58 with cyclobutylmethyl bromide gave 2-(3-(3-(cyclobutylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.430 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.82-7.84 (m, 2H), 7.69-7.71 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.66 (dd, J=7.6, 2.4 Hz, 1H), 3.88 (d, J=6.4 Hz, 2H), 3.75 (t, J=7.2 Hz, 2H), 2.70-2.79 (m, 1H), 2.66 (t, J=8.0 Hz, 2H), 2.10-2.17 (m, 2H), 2.00-2.07 (m, 2H), 1.82-1.98 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC#N>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:19]=[C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)cc2n1
Solvent: CC#N
Product: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
18 mmol of 7-furan-2-yl-2-methanesulfonyl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (Maybridge plc, Trevillett, Tintagel, Cornwall, England) was suspended in 50 mL of CH3CN along with 5 eq. of piperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 7-furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1>CO>[CH3:1][O:2][C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccncc2)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2ccncc2)nn1

Procedure:
63 ml of a 32% sodium methoxide solution in methanol are added to a solution of 57 g 3-Chloro-6-pyridin-4-yl-pyridazine in methanol, and the reaction mixture is stirred under reflux for 1.5 h. The solvent is removed under reduced pressure, the residue suspended in 0.7 L water and the pH adjusted to 7. Extraction with dichloromethane yielded 57 g 3-Methoxy-6-pyridin-4-yl-pyridazine, which is used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Br:15])[C:8]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[C:8]2[C:16]1[CH2:20][C:19]([C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccc(Br)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccc(Br)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid methyl ester (Example 8.1) (400 mg) in tetrahydrofuran (3.5 ml) was added a solution of potassium hydroxide (1.9 g) in methanol (3.5 ml) and water (3.5 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then acidified by addition of aqueous hydrochloric acid (4N) and the mixture extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×10 ml) and brine, dried over sodium sulfate and concentrated to give 8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid (342 mg). LC-MS: RT=2.41 min, [M−H]−=532/534, Method A.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.075 g, 16%). MS (ISP) 460.1 [(M+H)+]; mp 323° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](I)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cu][C:14]#[N:15]>CN(C)C=O.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:14]#[N:15])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1I
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)cc([N+](=O)[O-])c1C#N
Yield: 104.5 %

Procedure:
A stirred mixture of 19.0 grams (0.068 mole) of 4-fluoro-2-nitro-6-methylphenyl iodide and 7.0 grams (0.078 mole) of copper(I) cyanide in 100 mL of N,N-dimethylformamide was heated at 150°-155° C. for 30 minutes. The reaction mixture was then diluted with 400 mL of water and 100 mL of ethyl acetate. The mixture was filtered, and the filtrate was placed in a separatory funnel. The organic layer was separated, and the aqueous layer was washed with 200 mL of ethyl acetate. The combined wash and organic layer was then washed with three 150 mL portions of aqueous 5% lithium chloride. The mixture was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 methylene chloride: petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 12.8 grams of 4-fluoro-2-nitro-6-methylbenzonitrile, mp 61°-63° C. The NMR spectrum was consistent with the proposed structure. Step E Synthesis of 2-amino-4-fluoro-6-methylbenzonitrile as an intermediate
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:33][S:34]([C:37]1[S:41][C:40]([NH2:42])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH2:31][OH:32])[CH3:30]>>[OH:32][CH2:31][C:29]([NH:33][S:34]([C:37]1[S:41][C:40]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH2:28][OH:27])[CH3:30]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(CO)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(CO)CO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 637.0 [(M−H)−]; mp 250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH2:27][CH2:28][CH2:29][OH:30]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[N:16]3[CH2:27][CH2:28][CH2:29][OH:30])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: OCCCI
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 94.1 %

Procedure:
In a similar manner to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.0584 mmol), lithium (bis-trimethylsilyl)amide (0.18 mL of a 1 M tetrahydrofuran solution, 0.18 mmol), and 3-iodo-1-propanol (0.03 mL, 0.350 mmol) was prepared ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (22 mg, 95% yield) as a yellow oil. The product was carried on without further purification. MS m/z 423 (M+23).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:32][CH:33]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (25.5 mg, 0.09 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (18.1 μL, 0.09 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoro-pyridine (13.2 mg, 0.09 mmol) described in manufacturing Example 41-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (23.6 mg, 67%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=1[CH3:30])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(F)cc1C
Yield: 11.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (2.75 g, 8.2 mmol) and 4-fluoro-2-methylaniline (1.34 g, 10.7 mmol) in acetonitrile (20 ml) was refluxed for 8 h. The solution was cooled and 1.52 g crystallized product was filtered off. The filtrate was evaporated and chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 0.4 g of the desired product. Total yield: 1.92 g (57%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:4]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:4]=2[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:6][C:7]=1[C:8]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:9]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2c(-c3ccc(OC)cc3)noc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)nc(-c4ccccc4)c23)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)-4-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (70 mg, 0.18 mmol) and glycine (539 mg, 7.18 mmol) were added to sodium methoxide solution (10.8 mL, 5.38 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in minimum amount of water and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 79 mg of crude solid. The solid was dissolved in 15 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and the precipitate was collected by filtration. The solid was dried under vacuum to afford 47 mg of the title compound. MS: (+) m/z 420.37 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:24]1([C@@H:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][C@H:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:35]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1ccc([C@@H]2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN[C@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 89.6 %

Procedure:
Working under the conditions of Example 20, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (51.6 g) and (R)-2-phenylpiperazine (31.7 g), (R)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (66.86 g) is obtained in the form of a yellow solid, m.p. 221° C.
Reaction SMILES: CC1C2C(=O)CCC=2N(S(C2C=CC(C)=CC=2)(=O)=O)C=1C(O)=O.O=C1C2C=C(C(OC)=O)NC=2CC1.BrC1C=C(C=CC=1)C[Mg]Br.Br[C:48]1[CH:49]=[C:50]([CH:74]=[CH:75][CH:76]=1)/[CH:51]=[C:52]1\[CH2:53][CH2:54][C:55]2[N:56]([S:64]([C:67]3[CH:73]=[CH:72][C:70]([CH3:71])=[CH:69][CH:68]=3)(=[O:66])=[O:65])[C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][C:59]\1=2.[F:77][C:78]([F:89])([F:88])[C:79]1[CH:84]=[CH:83][C:82](B(O)O)=[CH:81][CH:80]=1>>[F:77][C:78]([F:89])([F:88])[C:79]1[CH:84]=[CH:83][C:82]([C:48]2[CH:76]=[CH:75][CH:74]=[C:50]([CH2:51][CH:52]3[C:59]4[CH:58]=[C:57]([C:60]([O:62][CH3:63])=[O:61])[NH:56][C:55]=4[CH2:54][CH2:53]3)[CH:49]=2)=[CH:81][CH:80]=1.[S:64]([N:56]1[C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][C:59]2/[C:52](=[CH:51]/[C:50]3[CH:49]=[C:48]([C:82]4[CH:83]=[CH:84][C:79]([C:78]([F:89])([F:88])[F:77])=[CH:80][CH:81]=4)[CH:76]=[CH:75][CH:74]=3)/[CH2:53][CH2:54][C:55]1=2)([C:67]1[CH:68]=[CH:69][C:70]([CH3:71])=[CH:72][CH:73]=1)(=[O:65])=[O:66]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(Br)c1
Agent: Br[Mg]Cc1cccc(Br)c1
Agent: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)n2c3c(c(C)c2C(=O)O)C(=O)CC3)cc1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized in four steps. First, tosyl protected methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (methyl 4-oxo-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (1.50 g, 8.37 mmol) was reacted with 3-bromobenzylmagnesium bromide (15 mL, 3.75 mmol) according to General Procedure 3 to give exo olefin-containing compound (E)-methyl 4-(3-bromobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by coupling with 4-(trifluoromethyl)phenylboronic acid (0.178 g, 0.94 mmol) according to General Procedure 9.1 to give (E)-methyl 1-tosyl-4-((4′-(trifluoromethyl)biphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, then tosyl deprotection according to General Procedure 10.1 to give (E)-methyl 4-((4′-(trifluoromethyl)biphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Hydrogenation of (E)-methyl 4-((4′-(trifluoromethyl)biphenyl-3-yl)methylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate according to General Procedure 6 (with 5% Pd/C), then purification provided the title compound, which was used without purification in the next step. 0.047 g. 19F NMR (376 MHz, ACETONE-d6) δ ppm −63.27 (s, 3F); LCMS-MS (ESI−) 398.0 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:38])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O:35]CC)=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:38])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)O)c1
Yield: 101.9 %

Procedure:
To a stirred solution of 154 g of ethyl [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonyl-biphenyl-3-yloxy]acetate in 1.23 L of ethanol was added 275 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. To the reaction mixture was added dropwise 275 mL of 2 mol/L hydrochloric acid, and ethanol was removed under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was dried over anhydrous magnesium sulfate, and removed under reduced pressure to give 149 g of [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid.