Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[N:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12](O)[CH3:13]>>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:12][CH3:13])=[O:9])=[N:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cnc(C(=O)O)c(O)n1
Reactant: CCO
Product: CCOC(=O)c1ncc(C)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-6-methylpyrazine-3-carboxylic acid (32.5 g), prepared as described in J. Chem. Soc. 1955, 1379, was suspended in 500 mL of ethanol. The solution was cooled in an ice bath and hydrogen chloride gas was bubbled into the solution for 15 minutes. The mixture was stirred overnight at ambient temperature and then refluxed for 2 hours. The ethanol was removed under reduced pressure and the residue obtained crystallized from ethanol/ether to give 21.48 g of the title compound. m.p. 153° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([C:18](OC)=[O:19])[CH2:16][O:15][C:14]3=[O:22])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][OH:19])[CH2:16][O:15][C:14]3=[O:22])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC[C@@H](CO)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Methyl (4S)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-2-oxo-1,3-oxazolidine-4-carboxylate (0.20 g, 0.52 mmol), prepared in step 2 of Example 70, was dissolved in 5 mL of tetrahydrofuran and cooled to 0° C. Lithium borohydride (2M solution in tetrahydrofuran, 0.57 mL, 1.14 mmol) was added and the mixture was stirred for 2 h. The mixture was allowed to warm to 25° C. and stirred for an additional 30 min, quenched with H2O and then 2 mL of 2N HCl was added. The mixture was diluted with 10 mL of water and poured into ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (25% acetone/hexane) afforded the title compound (124 mg, 69%) as a white solid. mp 189-192° C. HRMS: calcd for C13H11BrN2O3S+H+, 354.97465; found (ESI, [M+H]+), 354.9742. Analytical HPLC: retention time 9.2 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][N:16](CC=C)[CH2:15][CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][NH:16][CH2:15][CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CCN1CCC=C(c2ccc([N+](=O)[O-])c(OC)c2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(C2=CCCNC2)ccc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Nitrogen was bubbled through dichloromethane (100 mL) for 10 minutes followed by the addition of N-dimethylbarbituric acid (15.4 g, 98.4 mmol) and Pd(PPh3)4 (1.9 g, 1.6 mmol). After the addition of 5-[3-(methyloxy)-4-nitrophenyl]-1-(2-propen-1-yl)-1,2,3,6-tetrahydropyridine, the reaction was heated to 35° C. and stirred for 3 h. To the cooled solution was added saturated aq. Na2CO3 (100 mL), and the mixture was allowed to stir at RT for 30 min. After extraction with dichloromethane (2×50 mL), drying (Na2SO4), and concentration, chromatography on SiO2 afforded 5-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (5.3 g, 70% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.31 (d, J=4.0 Hz, 2 H), 3.02 (t, J=5.7 Hz, 2 H), 3.29 (s, 1H), 3.71 (d, J=1.8 Hz, 2 H), 3.97 (s, 3 H), 6.32 (t, J=4.0 Hz, 1 H), 6.95 (d, J=8.4 Hz, 1H), 6.98 (s, 1 H), 7.85 (d, J=8.4 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:50][CH3:51])=[C:32]([CH:49]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:50][CH3:51])=[C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]5[CH2:48][CH2:47]5)=[O:45])[N:42]=4)[N:39]=3)[CH:49]=2)=[O:12])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CCC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 72.3 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (43 mg, 0.21 mmol), oxalyl chloride (23 μL, 0.27 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (60 mg, 0.18 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (68 mg, 74%) was obtained as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1.[Na].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].[I-].[Na+]>O1CCCC1>[CH3:14][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[O:13][N:12]=1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCOc2ccc([N+](=O)[O-])cc2)on1
Temperature: 80 °C

Procedure:
A mixture of 3.0 g (0.0115 mole) of 5-(7-bromoheptyl)-3-methylisoxazole and 1.85 g (0.0115 mole) of the sodium salt of 4-nitrophenol in 50 ml of dry tetrahydrofuran containing a few crystals of sodium iodide was heated at 80° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue triturated with 100 ml of methylene dichloride and 40 ml of water. The organic phase was dried and concentrated, and the residue crystallized from ether to give 3.5 g of 3-methyl-5-[7-(4-nitrophenoxy)heptyl]isoxazole, colorless solid, m.p. 58° C.; MIC vs. polio-2 virus in vitro=1.5 μg/ml.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14](O)([CH3:16])[CH3:15])[CH2:9]2)=[CH:5][CH:4]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>>[C:14](=[C:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:9]1)([CH3:16])[CH3:15]
Reactant: COc1ccc(CN2CCCC(C(C)(C)O)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCCC(=C(C)C)C2)cc1
Yield: 76.2 %

Procedure:
Combine 2-{1-(4-Methoxy-benzyl)-piperidin-3-yl]-propan-2-ol (0.564 g, 2.14 mmol) and 1:1 Et3SiH:TFA (8 mL) at room temperature. Reflux the reaction for 72 hours under a Nitrogen atmosphere and then concentrate under reduced pressure and flash chromatograph using 3% 1N NH3-MeOH in CH2Cl2 to give 400.0 mg (76% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5-1.6 (8H, d), 2.2 (2H, t), 2.5 (2H, br s), 3.0 (2H, br s), 3.5 (2H, br s), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 246
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])[C:27]([Cl:44])=[CH:26][N:25]=1>>[Cl:44][C:27]1[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])=[N:29][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:25][CH:26]=1
Reactant: CC1(C)CC(NC(=O)C(F)(F)F)C(=O)Nc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (67 mg, 24%) LCMS 564.12 (M−C3NH4), 1H-NMR (CDCl3, 400 MHz) δ 9.71 (bs, 1H), 9.60 (d, J=7.9 Hz, 1H), 9.43 (bs, 1H), 9.20 (s, 1H), 8.93 (bt, 1H), 7.50-7.47 (m, 2H), 7.37-7.34 (m, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 4.26-4.22 (m, 4H), 4.03-3.99 (m, 2H), 2.18-2.13 (m, 2H), 1.35 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [NH:1]([C:3](=[O:32])[CH2:4][CH2:5][N:6]1[C:19](=[O:20])[C:9]2([CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[O:8][C:7]21[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH2:2].[CH3:33][CH:34]1[CH2:44][CH2:43][CH:37]2[C:38]([O:40][C:41](=O)[CH:36]2[CH2:35]1)=[O:39].O.CCCCC>C1(C)C(C)=CC=CC=1>[CH3:33][CH:34]1[CH2:44][CH2:43][CH:37]2[C:38]([N:2]([NH:1][C:3](=[O:32])[CH2:4][CH2:5][N:6]3[C:19](=[O:20])[C:9]4([CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[O:8][C:7]43[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[C:41](=[O:40])[CH:36]2[CH2:35]1)=[O:39]
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Reactant: CC1(C)CC2(CC(C)(C)N1)OC1(CCCCCCCCCCC1)N(CCC(=O)NN)C2=O
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCCCC
Product: CC1CCC2C(=O)N(NC(=O)CCN3C(=O)C4(CC(C)(C)NC(C)(C)C4)OC34CCCCCCCCCCC4)C(=O)C2C1

Procedure:
The hydrazide of Example 1, 13.5 g (0.03 mole), was added to 225 ml xylene at 75° C. Added dropwise to this was 4-methylhexahydrophthalic anhydride, 5.1 g (0.03 mole) in 25 ml xylene. The apparatus was fitted with a Dean Stark water separation assembly and the reaction mixture was heated to reflux for 4 hours with azeotropic removal of water as it formed. The xylenes were stripped using aspirator vacuum and the residual sticky solid was slurried with 300 ml pentane. The solid was filtered and dried for 2 hours on the filter funnel. The white solid product weighed 11.7 g and had a melting range of 210°-212° C. The infrared spectrum (mull) showed two carbonyl bands at 1690 and 1730 cm-1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([F:30])[C:28]=1[F:29])[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([F:30])[C:28]=1[F:29])[NH:25][N:24]=[C:23]2[NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2c(F)c(F)c(Br)cc12
Yield: 40.3 %

Procedure:
9.4 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 700 mg of N-[5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 100 cm3 of ethyl acetate and 75 cm3 of saturated sodium hydrogen carbonate solution are added and the organic phase is then washed successively with 75 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 850 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 8 cm3 of diisopropyl ether, filtered off, washed with 3 cm3 of diisopropyl ether, dried under reduced pressure (90 Pa; 45° C.) to give 200 mg of N-(5-bromo-6,7-difluoro-1H-indazol-3-yl)butanamide in the form of white crystals melting at 220° C.
Reaction SMILES: [F-].[K+].[C:3]1([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].O.C(OCC)(=O)C>CN(C=O)C>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:14][C:13]3[N:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:10]=[C:11]([CH3:15])[CH:12]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)nn1-c1ccccc1)C2=O
Reaction time: 0.08 h
Yield: 7.5 %

Procedure:
To a mixture of 460 mg (7.9 mmol) of KF in DMF (25 ml) was added under nitrogen at room temperature 2,4-dihydro-2-phenyl-5-methyl-3H-pyrazol-3-one (1.38 g; 7.98 mmol) with stirring (5 minutes) followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.1 g, 3.63 mmol) and the resulting mixture was stirred at room temperature for 6 hours and then poured into water/ethyl acetate. The above mixture was extracted with ethyl acetate (3×75 ml) and the organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue (yellow foam, 1.3 g) was purified by flash chromatography (silica gel; 10-20% ethyl acetate in hexane) to afford 120 mg of 4-isopropyl-6-methoxy-2-(1-phenyl-3-methylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white foam, m.p. 65°-670° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([F:26])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:38])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([F:26])[CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (0.21 mmol) of the compound from Example 40 were introduced into 5 ml of dichloromethane at 0° C., 53.0 mg (0.22 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. Methanol was added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 58.8 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][C:8]([C:21]1[CH:20]=[CH:19][C:18]([O:23][CH3:24])=[C:17]([CH2:16][CH2:15][C:14]([O:13][CH3:12])=[O:25])[CH:22]=1)=[O:9]
Reactant: COC(=O)CCc1ccccc1OC
Reactant: COC(=O)CCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCCC(=O)c1ccc(OC)c(CCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.1g of glutaric acid monomethyl ester chloride and 5g of 3-(2-methoxyphenyl)-propionic acid methyl ester are added with ice cooling in succession to a suspension of 10g of aluminum chloride in 100 ml of dichloromethane and the mixture is stirred for 16 hours at room temperature. The reaction mixture is poured on ice/2n hydrochloric acid, shaken out with dichloromethane, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate (0-30% ethyl acetate). 4.45g of 5-[4-methoxy-3-(2-methoxycarbonylethyl)-phenyl]-5-oxo-pentanoic acid methyl ester is obtained as oil, that is heated together with 47.5g of pyridinehydrochloride for 5 hours to 180° C. for further reaction. After cooling to 90° C. the reaction mixture is mixed with water, acidified to pH 1 with concentrated hydrochloric acid, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 3.9g of 5[3-(2-carboxyethyl)-4-hydroxyphenyl]-5-oxopentanoic acid of melting point of 169°-166° C. is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a mixture of ethyl 3-[{[4-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (667 mg) obtained in Example A75(4) in tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (2.6 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (4 mL), and 1N hydrochloric acid (2.6 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min, and the resulting precipitate was collected by filtration to give the title compound (509 mg, 81%) as a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCNCC
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and diethylamine. Yellow solid. MS (ESI): 336.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:25])[CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[F:26][C:27]([F:33])([F:32])[S:28](O)(=[O:30])=[O:29].O>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:25])[CH2:11][CH:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)CC1CCC(c2ccc(O)cc2)CC1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Reaction time: 5 h
Yield: 91.1 %

Procedure:
Triethyl amine (8.1 mL, 57.99 mmol) was added dropwise to [4-(4-hydroxyphenyl)cyclohexyl]acetic acid methyl ester (9.6 g, 38.66 mmol) dissolved in CH2Cl2 and trifluoromethane sulphonic acid (8.1 mL, 48.32 mmol) solution at 0° C. The reaction mixture was warmed up to reach ambient temperature and stirred for 5 hours. The reaction mixture was poured into 200 mL water and extracted with CH2Cl2. The organic phase was washed with saturated sodium bicarbonate solution, brine and anhydrous Na2SO4. The solvent was reduced under reduced pressure, the residue was purified in silica gel using CH2Cl2 as an eluent to obtain [4-(4-trifluoromethanesulfonyloxyphenyl)cyclohexyl]acetic acid methyl ester (13.4 g, 91%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]=[CH:23][O:22]2)=[CH:16][CH:15]=1>C(OCC)C.O=P(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][CH2:20][C@@H:21]2[O:22][C@@H:23]([O:12][CH:3]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[CH2:2][Br:1])[CH2:24][CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Reactant: Clc1ccc(COCC2CCC=CO2)cc1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(COC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Yield: 69.2 %

Procedure:
102 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and the 82 mg of 2-(4-chlorobenzyloxymethyl)-3,4-dihydro-2H-pyran prepared above were then dissolved in 2 ml of diethyl ether, and one drop of phosphorus oxytrichloride was then added. The mixture was then allowed to react at room temperature for 4 days, after which it was treated and the product purified essentially as described in Example 34(a), to give 121 mg of trans-6-(4-chlorobenzyloxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.C([O-])([O-])=O.[K+].[K+].[Li+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=3)=[N:27][N:28]3[CH:29]=[C:30]([F:34])[CH:31]=[CH:32][C:33]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: N[n+]1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.1 %

Procedure:
To a solution of N-[3-(2-chloro-pyrimidin-4-ylethenyl)-phenyl]-2,2,2-trifluoro-acetamide (See Example 1, step B) (5.0 g) in DMF (40 mL) were added 1-amino-3-fluoropyridinium nitrate (5.4 g) and K2CO3 (6.0 g). The reaction was kept stirring at RT for 1.5 h. The DMF solution was poured into 5% LiCl solution (60 mL) and extracted with EtOAc (2×30 mL). The combined organic phase were dried (Na2SO4) and concentrated. The crude products were separated through silica gel column chromatography to afford two products. The first to elute was N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (2.0 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (d, 1H, J=5.49 Hz), 7.45 (d, 1H, J=7.68 Hz), 7.55 (t, 1H, J=7.96 Hz), 7.73-7.79 (m, 1H), 7.83 (d, 1H, J=0.91 Hz), 7.95 (t, 1H, J=1.74 Hz), 8.41 (dd, 1H, J=9.97, 5.76 Hz), 8.49 (d, 1H, J=5.49 Hz), 9.27 (dd, 1H, J=4.30, 2.29 Hz). ES-LC/MS m/z=436 [M+H]+.