Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2].C(NC(NC1C=C(C2SC=C(C(F)(F)F)N=2)C(B2OC(C)(C)C(C)(C)O2)=CN=1)=O)C.[F:55][C:56]1[CH:64]=[CH:63][C:62](I)=[CH:61][C:57]=1[C:58]([OH:60])=[O:59].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCOCC1.O.CCOC(C)=O>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:62]2[CH:63]=[CH:64][C:56]([F:55])=[C:57]([CH:61]=2)[C:58]([OH:60])=[O:59])=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc(F)c(C(=O)O)c2)cn1
Temperature: 0 °C
Yield: 60 %

Procedure:
6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 0.261 g, 0.72 mmol, Intermediate 17) and 2-fluoro-5-iodobenzoic acid (0.175 g, 0.66 mmol, aldrich) were combined in dioxane (1 ml). A solution of cesium carbonate (0.364 g, 1.12 mmol) in water (0.658 ml) was added followed by tetrakis(triphenylphosine)palladium(0) (0.076 g, 0.07 mmol, strem) and additional dioxane (2.63 ml). The flask was placed in an oil bath preheated to 100° C. and was heated for 1h., then cooled to 0° C. and 1 N HCl was added until the pH was ˜3. EtOAc (5 ml) was added and a solid crashed out and was collected by filtration and washed with EtOAc, then dried to give a grey solid 5-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-2-fluorobenzoic acid (0.180 g, 60.2%).
Reaction SMILES: C([O:4][C@@:5]1([CH2:38][CH3:39])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([S:26][CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])(=O)C.NN.Cl>CO.O1CCOCC1>[CH2:38]([C@:5]1([OH:4])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([S:26][CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])[CH3:39]
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CCC(C)C)C(SC)=N3
Agent: Cl
Agent: NN
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CCC(C)C)C(SC)=N3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.2 %

Procedure:
To a solution of (9S)-9-acetoxy-9-ethyl-1-(3-methylbutyl)-2-methylthio-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (43.0 mg, 0.08 mmol) in methanol (2 ml) and 1,4-dioxane (2 ml) was added anhydrous hydrazine (200 μl). The mixture was stirred at room temperature for 2.5 hr. 10% HCl in methanol was added dropwise to acidify the reaction mixture and the mixture was stirred at room temperature for 2 hr. After concentrated under reduced pressure, the obtaining residue was partitioned between dichloromethane and water. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=100/1) to give the product (33.2 mg, 84%) as an orange powder.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:28])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(OCC)(=O)C>Cl>[Cl:28][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(Cl)cc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.8 %

Procedure:
Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (221 g, 0.511 mol) was dissolved in hydrogen chloride in ethyl acetate (2.4 N, 1.6 L, 3.84 mol) and the resulting solution was stirred at ambient temperature for 16 hours. The solution was concentrated to give 198 g of crude 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)-benzoic acid. The crude product was recrystallized by dissolving in hot isopropyl acetate (0.5 L) and diluting with hexanes (1.1 L). After 48 hours, the crystals were collected and wash with hexanes. The resulting white solids were dried under high vacuum to give 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (169 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.9 Hz, 2H), 7.38 (s, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.60 (s, 1H), 4.21-4.31 (m, 4H), 3.75 (t, J=5.4 Hz, 1H), 2.31-2.37 (m, 1H), 2.08-2.15 (m, 1H), 1.32 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[C:9]2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:28])C(=O)C1.O>C1COCC1>[Br:28][C:12]1[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]([CH3:20])=[C:10]([S:13]([NH:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH:11]=1
Reactant: Cc1c(S(=O)(=O)NC2CC2)ccn1CC1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(S(=O)(=O)NC2CC2)cc(Br)n1CC1CCCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of compound 3c (3.0 g, 10.0 mmol) in THF (80 mL) at −78° C. was added a solution of NBS (1.78 g, 10.0 mmol) in THF (50 mL) and the solution was stirred for 2 h at −78° C. Water was added and the solution was extracted with EA twice. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified CC (EA/PE=1/5) to give compound 3d (3.2 g, 85%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].C(O)C[OH:23].B(F)(F)F.CCOCC.[OH-].[Na+]>C1COCC1.O>[O:3]1[CH2:1][CH2:2][O:20][CH:4]1[C:5]1[CH:6]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:15]=[C:16]([CH:17]=1)[C:18]([OH:23])=[O:19]
Reactant: OCCO
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C2OCCO2)c1
Reaction time: 1.5 h

Procedure:
Mix 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (580 mg, 2.1 mmol), ethane-1,2-diol (0.35 mL, 6.3 mmol), and boron trifluoride diethyl etherate (0.2 mL, 1.6 mmol) in THF (5 mL) and stir for 1.5 h. Add additional ethane-1,2-diol (0.35 mL, 6.3 mmol) and stir for 20 min. Add 1 N NaOH (10 mL) and stir for 1 h. Add additional 5 N NaOH (1 mL) and stir for 30 min. Dilute the reaction mixture with water (10 mL) and wash with diethyl ether (2×10 mL). Acidify the aqueous layer with 0.5 N HCl to about pH=5. Extract with dichloromethane (3×20 mL), dry (sodium sulfate) and concentrate to give the title compound as a crude residue that is used in the next step without further purification.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1(N)[CH:11]=[C:10]([OH:12])[N:9]=[N:8]1.[CH3:14][CH:15](O)[CH3:16]>>[CH:15]([O:12][C:10]1[NH:9][N:8]=[C:7]([NH2:6])[CH:11]=1)([CH3:16])[CH3:14]
Reactant: NC1(N)C=C(O)N=N1
Reactant: CC(C)O
Agent: CS(=O)(=O)O
Product: CC(C)Oc1cc(N)n[nH]1
Temperature: 120 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
Methanesulfonic acid (25 mL) was added to a 2-propanol (250 mL) solution of 3-amino-5-hydroxypyrazolamine (25 g), and stirred at 120° C. for 2 days. The reaction liquid was left cooled, and the solvent was evaporated off under reduced pressure. Aqueous saturated sodium hydrogencarbonate solution was added to the residue, then extracted with ethyl acetate, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure to give the intended product (5.35 g, 15%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH2:16](O)[CH:17]=C>>[CH2:1]([O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH:16]=[CH2:17]
Reactant: C=CCO
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Product: C=CCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and allyl alcohol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.62 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](Cl)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH:13][C:38]([C:34]3[C:33](=[O:41])[N:32]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH:37]=[CH:36][CH:35]=3)=[O:39])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A solution of Example A1 (0.147 g, 0.572 mmol) in THF (1 mL) was treated with Et3N (0.120 mL, 0.858 mmol) and a suspension of Example A3 (0.216 g, 0.858 mmol) in THF (2 mL). The mixture was layered with argon and stirred at RT overnight. The mixture was cooled to RT, the solid removed via filtration, rinsed with THF and the filtrate concentrated to dryness. The residue was triturated with MeCN, sonicated and the resulting solid collected via filtration and dried to afford N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (104 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 8.71-8.61 (m, 2H), 8.38 (d, J=5.8 Hz, 1H), 8.23 (dd, J=6.6, 2.2 Hz, 1H), 7.69 (m, 3H), 7.49 (m, 2H), 7.25 (d, J=2.3 Hz, 1H), 7.13 (dd, J=5.8, 2.3 Hz, 1H), 6.82 (m, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].CCO>O>[I:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)N1CCc2ccc(I)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Ic1ccc2c(c1)NCC2
Yield: 63.6 %

Procedure:
1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16 g, 29 mmol), EtOH (8 mL), and H2O (6 mL) are heated at 90° C. overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is extracted into aqueous HCl. The aqueous layer is in turn basified with NaOH, and is extracted with EtOAc. The organic layer is dried and concentrated. Hexane trituration yields 6-iodoindoline (577 mg, 64%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1cc(O)ccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(Br)c(C2OCCO2)c1

Procedure:
To a solution of 2-bromo-5-hydroxy-benzaldehyde compound 1 (15.0 g, 74.62 mmol) in toluene (100 mL) was added ethylene glycol (12.5 mL, 223.86 mmol) and p-TSA (1.42 g, 7.46 mmol). The solvent was removed under reduced pressure to give crude product 2 (20.0 g crude), which was used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.38 (d, J=8.6 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.62 (d, J=8.2, 2.3 Hz, 1H), 6.01 (s, 1H), 4.20-4.01 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([S:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Sc1ccccc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2sc3c(c2c(Sc2ccccc2)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 65 °C
Yield: 55 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.032 g; 0.070 mmol) in methanol (1 mL) was added a solution of sodium hydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated at 65° C. for 18 h. After cooling, the organic volatiles were removed under reduced pressure and the aqueous phase was then acidified with a solution of hydrochloric acid 2N until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure to afford 0.017 g (50%) of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].[CH2:13](Cl)[CH:14]=[CH2:15].Cl>O>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:15][CH:14]=[CH2:13])[CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4]
Reactant: C=CCCl
Agent: CCOc1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CCc1ccc(O)c(OCC)c1
Reaction time: 3 h

Procedure:
To 34 ml of water were added in order 3.36 g of sodium hydroxide, 11.60 g of o-ethoxyphenol, 0.716 g of cupric chloride (CuCl2.2H2O; catalyst) and 7.07 g of allyl chloride. The reaction took place at 83° C and with stirring, for 3 hours. The reaction solution was then neutralized with hydrochloric acid and extracted with five portions of 30 ml of ether. The resulting ethereal extract was distilled to give 4.51 g of the desired o-ethoxy-p-allylphenol and 0.78 g of the unreacted o-ethoxyphenol. There was also obtained 6.56 g of by-product 1-allyloxy-2-ethoxybenzene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:32]([N:51]1[CH:55]=[C:54](B(O)O)[CH:53]=[N:52]1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:32]([N:51]1[CH:55]=[C:54]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([C:28]([F:29])([F:31])[F:30])(=[O:26])=[O:27])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[CH:53]=[N:52]1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1)C(F)(F)F
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)cc1)C(F)(F)F
Yield: 94.6 %

Procedure:
150 mg 6-bromo-4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl] quinoline (compound in Production Example 456) and 134 mg 1-trityl-1H-4-pyrazolylboronic acid were reacted in the same manner as in Example 9, to give 205 mg 6-(1-trityl-1H-pyrazol-4-yl)-4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl] quinoline. This product was reacted in the same manner as in Example 67, to give 90 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([C:41]([F:44])([F:43])[F:42])[CH:34]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([C:41]([F:42])([F:43])[F:44])[CH:34]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (200 mg, 0.57 mmol) was dissolved in DMF (4 mL) and triethylamine (200 μL, 1.43 mmol) added, followed by 4-bromomethyl-1-methoxy-2-trifluoromethyl-benzene (154 mg, 0.57 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 244 mg of the title compound 18 as a yellow solid. 1H NMR (CDCl3): δ 8.14-8.11 (m, 1H), 8.07-8.03 (m, 1H), 7.86-7.80 (m, 1H), 7.70-7.64 (m, 1H), 7.50-7.47 (m, 1H), 7.42-7.37 (m, 1H), 6.96-6.91 (m, 1H), 3.93-3.79 (m, 4H), 3.42 (s, 2H), 2.91-2.80 (m, 2H), 2.03-1.85 (m, m, 5H), 1.53-1.44 (m, 2H), 1.02-0.96 (m, 2H), 0.83-0.76 (m, 2H). LC: 100%. MS (EI): m/z 537 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[N:35]1([CH2:2][C:3]([NH:5][C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]4[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=5)[CH:18]=[CH:19][CH:20]=4)=[N:10][N:9]3[CH:34]=2)=[O:4])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 87 %

Procedure:
Using N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (120 mg, 0.244 mmol), morpholine (1 mL) and acetonitrile (3 mL) as starting materials and in the same manner as in Example 398, the title compound (116 mg, 87%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH:23][O:24][CH3:25])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:23]([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:24][CH3:25])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCCCc1ccc(F)cc1
Product: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[3-(4-fluorophenyl)-propyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 90-91° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.77 (6H, s, CH3), 1.98 (2H, m, CH2), 2.64 (2H, t, J=7.9 Hz, CH2), 3.71 (2H, t, J=7.6 Hz, NCH2), 3.73 (3H, s, OCH3), 6.41 (1H, broad s, CH), 6.98 (2H, m, aromatics), 7.16 (2H, m, aromatics). Anal. calcd for C17H20FNO5: C, 60.53; H, 5.98; N, 4.15. Found: C, 60.43; H, 5.99; N, 4.09.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CC(=O)OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CC(=O)O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of methyl 2-[3-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.44 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.35 g, 81%) of 2-[3-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4C)CC3)c(OC)nc2c1
Yield: 93 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 93%). H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.99-3.02 (m, 4H), 3.73-3.76 (m, 4H), 3.91 (s, 3H), 4.15 (s, 3H), 7.00-7.22 (m, 7H), 7.76-7.79 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:12]([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C>O1CCCC1>[OH:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[CH3:12])=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cnc(O)c(Cl)c1
Reactant: O=C([O-])CC(=O)[O-]
Agent: CCC(C)(CC)O[Mg+2]
Solvent: C1CCOC1
Product: CC(=O)c1cnc(O)c(Cl)c1
Yield: 93.3 %

Procedure:
7.2 g (37.5 mmol) of 5-chloro-6-hydroxynicotinoyl chloride in 10 ml of absolute tetrahydrofuran are added to a boiling solution of 8.55 g (37.5 mmol) of diethyl ethoxymagnesium-malonate (prepared in accordance with Org. Synth. Coll. Vol. IV (1963), 285) in 120 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. After neutralization with 2N sulphuric acid, the organic phase is separated off and evaporated. The residue is heated under reflux in a mixture of 30 ml of glacial acetic acid, 20 ml of water and 5 ml of concentrated sulphuric acid for 4 hours. The mixture is stirred into ice-water, brought to pH 4 and extracted with ethyl acetate. Drying and evaporation gives 6 g (93%) of the title compound, melting point: 188° to 189° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].S(Cl)([Cl:15])(=O)=O>>[Cl:15][CH:5]([C:4](=[O:11])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)COC
Product: CCOC(=O)C(Cl)C(=O)COC

Procedure:
The title compound was prepared in a manner analogous to Intermediate 124 starting from ethyl 4-methoxy-3-oxobutanoate (Intermediate 5) and sulfuryl chloride.