Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](CCOC[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1)(C)C.FC(F)(F)S(O[CH:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=O)=O>C(Cl)Cl>[N:9]1[CH:10]=[CH:11][C:12]([O:15][CH:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1ccc(=O)cc1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(Oc1ccncc1)C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of benzyl lactate (6.0 g, 33 mmol) and N-methyl morpholine (2.7 mL, 33 mmol) in 100 mL anhydrous CH2Cl2 at −20° C. was added trifluoromethanesulfonyl anhydride (5.6 mL, 33 mmol). After stirring at −20° C. for 1 h, the reaction mixture was diluted with 100 mL hexane and washed with dilue aqueous sodium hydrogen sulfate and brine/saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% ether in hexane to give benzyl 2-trifluoromethanesulfonyloxypropionate (6.4 g), which was used immediately for the ensuing reaction. Thus, a mixture of N-trimethylsilylethoxymethyl-4-pyridone (Step A, 3.4 g, 15 mmol) and benzyl 2-trifluromethanesulfonyloxypropionate (4.7 g, 15 mmol) was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was dissolved in CH2Cl2 and loaded onto a silica gel column, which was eluted with 5% MeOH in CH2Cl2 to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.57 (d, 2H), 7.42 (d, 2H), 7.4-7.3 (m, 5H), 5.44 (q, 1H), 5.24 (ABq, 2H), 1.72 (d, 3H). LC-MS: m/e 258 (M+H)+ (1.8 min).
Reaction SMILES: N1(C2N=CN=C3C=2N=CN3[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)CCOCC1.N1(O[C:48]2[C:49]3[N:50]=[CH:51][N:52]([C:83]=3[N:84]=[CH:85][N:86]=2)[C@@H:53]2[O:82][C@H:72]([CH2:73][O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C@@H:63]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[C@H:54]2[O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])C2C=CC=CC=2N=N1.[CH2:87]([NH2:94])[C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[Si:56]([O:55][C@@H:54]1[C@H:73]([O:74][Si:75]([C:78]([CH3:79])([CH3:80])[CH3:81])([CH3:77])[CH3:76])[C@@H:72]([CH2:63][O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:66])[CH3:67])[O:82][C@H:53]1[N:52]1[C:83]2[N:84]=[CH:85][N:86]=[C:48]([NH:94][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)[C:49]=2[N:50]=[CH:51]1)([C:59]([CH3:62])([CH3:60])[CH3:61])([CH3:57])[CH3:58]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 88 %

Procedure:
As described for the synthesis of 6-(morpholin-4-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]purine, this benzyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)inosine (27) (71.8 mg, 0.099 mmol) and benzylamine (21.8 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 7 h. Chromatographic purification (SiO2, elution with 3% EtOAc in hexanes followed by 20% EtOAc in hexanes) afforded 61.0 mg (87% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.39. 1H NMR (500 MHz, CDCl3): δ 8.40 (s, 1H, Ar—H), 8.09 (s, 1H, Ar—H), 7.38 (d, 2H, Ar—H, J=7.3), 7.34 (t, 2H, Ar—H, J˜7.3), 7.28 (app t, 1H, Ar—H, Japp˜8.5), 6.02 (d, 1H, H-1′, J=5.4), 5.95 (br s, 1H, NH), 4.86 (br s, 2H, CH2), 4.70 (t, 1H, H-2′, J=4.9), 4.32 (t, 1H, H-3′, J=3.9), 4.12 (q, 1H, H-4′, J=3.4), 4.03 (dd, 1H, H-5′, J=11.2, 4.1), 3.78 (dd, 1H, H-5′, J=11.2, 2.9), 0.95, 0.93, 0.80 (3 s, 27H, tert-Bu), 0.13, 0.12, 0.11, 0.10, −0.04, −0.22 (6 s, 18H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 154.7, 153.0, 149.4, 139.1, 138.6, 128.6, 127.7, 127.4, 120.4, 88.4, 85.4, 75.6, 72.1, 62.6, 44.8, 26.0, 25.8, 25.7, 18.4, 18.0, 17.8, −4.4, −4.7, −5.1, −5.4.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[Na+].[CH2:19]([S:37][CH3:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[Br-].[Na+]>C(C(C)=O)C>[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[CH3:38][S+:37]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCCCCCCCCCCCCCCCCCSC
Reactant: O=C(CBr)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Br-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCC[S+](C)CC(=O)c1ccccc1

Procedure:
In a 100 mL Erlenmeyer flask were combined 10 g (0.05 mol) phenacyl bromide, 12.93 g (0.05 mol) sodium hexafluoroantimonate, 15 g (0.05 mol) methyl octadecyl sulfide and 40 mL methyl ethyl ketone (2-butanone). The reaction mixture was heated to boiling and maintained at this temperature for 30 minutes. During this time, sodium bromide was observed to precipitate. The reaction mixture was filtered to remove the inorganic salts and the resulting solution placed on a rotary evaporator to remove solvents. The product crystallized to give the desired salt, m.p. 80-82° C. Recrystallization from isopropanol gave a very light tan salt with a melting point of 79-80° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH:33]3[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)([C:25]#[N:26])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([CH2:25][NH2:26])([N:27]2[CH2:32][CH2:31][N:30]([CH:33]3[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) suspension of LAH (9.24 mmol, 3.0 equiv.) in THF (2 ml/mmol) was added dropwise conc. H2SO4 (4.62 mmol, 1.5 equiv.) in THF (1 ml/mmol) and the resulting suspension was stirred at room temperature for 1.5 h. A solution of 1-benzyl-4-(4-cyclopropylpiperazin-1-yl)piperidine-4-carbonitrile (3.08 mmol, 1.0 equiv.) in THF (2 ml/mmol) was added dropwise to the reaction mixture and it was heated to 50° C. for 12 h. The mixture was quenched with sodium sulfate solution, filtered through celite and washed with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to yield the desired product. Yield: 90%
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:19]=[C:20]2[C:29]=1[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:22][C:21]2=[O:30])[CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.Cl.[OH-].[Na+]>C(#N)C>[OH:1][CH:2]([C:17]1[N:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:19]=[C:20]2[C:29]=1[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:22][C:21]2=[O:30])[CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)c2c3c(nn2-c2ccccc2)c(=O)[nH]c2ccccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=c1[nH]c2ccccc2c2c(C(O)CC3CCNCC3)n(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Tert-butyl 4-[2-hydroxy-2-(4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]piperidine-1-carboxylate (100 mg, 0.2 mmol) was combined with concentrated hydrochloric acid (1 mL) and stirred at ambient temperature for 30 min. The reaction was poured over ice and the pH of the ice slurry was brought to 12 with 50% aqueous sodium hydroxide. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-60% CMA in chloroform) to provide an oily solid. The oily solid was stirred in acetonitrile. A solid was isolated by filtration to provide 40 mg of 1-(1-hydroxy-2-piperidin-4-ylethyl)-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tan powder, mp 258-261° C. MS (APCI) m/z 389 (M+H)+; Anal. calcd for C23H24N4O2.0.6H2O: C, 69.19; H, 6.36; N, 14.03. Found: C, 69.02; H, 6.23; N, 14.11.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5].C([Li])(C)(C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]=[O:31])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N:21]2>C(OCC)C.O1CCCC1.[Cl-].[NH4+]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]([OH:31])[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:32][C:33](=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N:21]2
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: C=C(C)CCI
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)CCC(O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
A solution of 4-iodo-2-methylbut-1-ene (942 mg, 4.8 mmol) in diethyl ether (5 mL) was added to a solution of tert-butyllithium (1.7 M in pentane, 5.65 mL, 9.6 mmol) in diethyl ether (15 mL) at −78° C. The reaction mixture was stirred at −78° C. for 35 minutes and then N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (400 mg, 0.96 mmol) in diethyl ether (5 mL) and tetrahydrofuran (4 mL) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for 15 minutes, then allowed to warm to 0° C. and stirred at 0° C. for 1 hour. The mixture was allowed to warm to room temperature, then stirred at room temperature for 15 minutes. The mixture was diluted with a saturated aqueous solution of ammonium chloride (35 mL) and extracted with ethyl acetate (3×35 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated to afford a yellow oil. Purification via silica gel chromatography (Gradient: 0% to 90% ethyl acetate in heptane) afforded the product as a white solid. Yield: 108 mg, 23%. LCMS m/z 487.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.22 (br d, J=6.8 Hz, 2H), 7.31-7.53 (m, 4H), 6.68-6.96 (m, 2H), 4.72-4.73 (m, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.80-3.87 (m, 1H), 3.76 (br s, 1H), 3.61-3.65 (m, 1H), 3.56 (br d, J=8.2 Hz, 1H), 3.13 (br s, 1H), 3.03 (dd, J=12.7, 4.1 Hz, 1H), 2.68 (m, 1H), 2.0-2.29 (m, 4H), 1.74 (s, 3H), 1.59-1.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][C:9]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:5][CH:6]=1.CC1C=CC(S(NN)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][C:9]=2[O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:5][CH:6]=1
Reactant: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of mL (E)-methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)acrylate (500 mg, 1.36 mmol), 4-methylbenzenesulfonohydrazide (1.27 g, 6.8 mmol), and toluene (15 mL) was heated at reflux for 12 hours, cooled to room temperature and concentrated. The residue was purified by silica gel (20 to 30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:28][OH:29]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:28][OH:29])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)CC(C)C
Reactant: NO
Agent: Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(CC(C)C)=NO

Procedure:
By the general method described in Part F of Example 30, 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylheptan-4-one was reacted with hydroxylamine hydrochloride to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylheptan-4-one oxime in about a 5 to 1 mixture of E and Z isomers as a white solid after recrystallization from aqueous methanol, mp 207-209° C.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:20][C:21](=[O:38])[C:22]([CH3:37])([CH3:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[CH3:19]>O.CN(C=O)C>[CH2:18]([O:20][C:21](=[O:38])[C:22]([CH3:37])([CH3:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:19]
Reactant: c1cc2c(s1)CCNC2
Reactant: CCOC(=O)C(C)(C)CCCCC(Br)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 75 °C
Reaction time: 44 h
Yield: 47.6 %

Procedure:
The hydrochloride salt of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (3.2 g, 18.9 mmol) was dissolved in water (120 mL) and 50% sodium hydroxide solution (10 mL) was added. The corresponding free base was extracted with dichloromethane (2×25 mL), which was dried over sodium sulfate, filtered, and concentrated. The remaining oil (2.58 g, 18.9 mmol) was dissolved in DMF (10 mL) under an argon atmosphere. Potassium carbonate (5 g) and 7-bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester (7.0 g, 18.63 mmol) were added and the mixture stirred for 44 hours at 75° C. The flask was cooled to room temperature and water (50 mL) was added. The product was extracted with dichloromethane (2×75 mL), which was dried over sodium sulfate, filtered, and concentrated. The remaining brown oil (8.94 g) was purified by column chromatography on silica gel (140 g), eluting with heptane-ethyl acetate (4:1 to 2:1). The product containing fractions were combined, concentrated, and dried to a constant weight under high vacuum at room temperature to provide 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester (Compound Ih, 3.85 g, 49% yield) as a clear oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.53 (dd, 1H, J=7.5, 1.2 Hz), 7.40 (dd, 1H, J=7.8, 1.2 Hz), 7.31-7.18 (m, 2H), 7.08 (d, 1H, J=5.1 Hz), 6.74 (d, 1H, J=5.1 Hz), 4.22 (dd, 1H, J=8.7, 4.5 Hz), 4.12 (q, 2H, J=7.2 Hz), 3.83 (d, 1H, J=14.1 Hz), 3.49 (d, 1H, J=14.1 Hz), 2.92-2.68 (m, 4H), 2.08-1.73 (m, 2H), 1.46 (m, 2H), 1.30-1.19 (m, 7H), 1.15 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=178.00, 139.41, 134.99, 134.26, 133.62, 129.53, 128.13, 128.03, 126.87, 125.51, 122.67, 63.69, 60.37, 50.79, 48.15, 42.33, 40.84, 33.11, 26.19, 25.40, 14.55. HRMS (DIP-CI): Calculated for (M+H+): 434.1921, found 434.1871.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:31])=[CH:18][CH:19]=2)[N:14]=1>O>[CH3:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(C)c1Oc1ccc2ccc(N)nc2n1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4c(C)cccc4C)nc3n2)cc1
Temperature: 4 °C
Yield: 28.5 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (16.7 g), N,N'-carbonyldiimidazole (17.8 g) and 2-amino-7-(2,6-dimethylphenoxy)-1,8-naphthyridine (21.2 g). The reaction mixture is poured into water and extracted with methylene chloride. After concentration of the organic phases to dryness under reduced pressure (4 kPa), the solid residue (33 g) is dissolved in boiling acetone (170 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetone (10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). By recrystallisation of the solid produced (11.5 g; m.p. approximately 100° C.) in acetone (50 cc), N-[7-(2,6-dimethylphenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (9.1 g) is produced, m.p. 174° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([N:27]3[C:23]([CH3:22])=[N:24][N:25]=[N:26]3)=[CH:29][CH:30]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.41 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=1)[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:25].[CH3:26][NH2:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[NH:27][CH3:26])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=1)[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:25]
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(O)c3)c12
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(O)c3)c2c1C
Temperature: 60 °C
Reaction time: 144 h
Yield: 74.8 %

Procedure:
6,7-Difluoro-1-(4-fluoro-3-hydroxyphenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (403 mg) and an aqueous solution (about 40%; 2.0 g) of methylamine were added to pyridine (2.0 g), and the mixture was stirred at 60° C. for 6 days. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (5 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (311 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[O:13].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:11]/[C:12]([C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-methoxybenzaldehyde (1.0 g, 7,3 mmol) and 3,4,5-trimethoxyacetophenone (1.54 g, 7.3 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with chloroform (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, and the solvent concentrated under vacou. The product was finally purified by column chromatography. Mass Spectrum m/e (M+1) 329.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:17][C:18]([OH:20])=O)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[N:10][N:11]([CH2:17][C:18]([NH2:33])=[O:20])[C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(N)=O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Example 10) (0.24 g, 0.54 mmol) in THF (6 mL) was added 0.10 g of 1,1'-carbonyldiimidazole at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), 6 mL conc. ammonium hydroxide was added and the mixture stirred at 25° C. for 18 hours. The reaction mixture was diluted with water, extracted with two portions ethyl acetate and the organic layer washed successively with dilute aqueous HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.15 g, 34%). Elemental analysis for C19H15N3F4SO3Calc'd: C, 51.70, H, 3.42, N, 9.52. Found: C, 51.46, H, 3.35, N, 9.39.