Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])#[N:24].C(=O)([O-])[O-].[K+].[K+].C1N2CCN(CC2)C1>O.CC(CC(C)=O)C>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1)#[N:24]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: C1CN2CCN1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 47.5 °C
Reaction time: 5.5 h
Yield: 91.8 %

Procedure:
Methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (98.4 g at 97.7% strength; prepared as described in WO 92/08703) was added to MIBK (210 g) and water (38.3 g) and heated to 45-50° C. 2-Cyanophenol (40.1 g), potassium carbonate (63.4 g) and DABCO (0.51 g) were added and the temperature was raised to 80° C. and held for 5.5 hours. Water (316 g) was added and agitation continued for 30 minutes before settling and separating the aqueous layer. Analysis of the MIBK solution revealed a 91.8% yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (azoxystrobin).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O[C:14]1[C:22]2N=NN[C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C[N:33]([CH:35]=[O:36])C>>[C:35]([NH2:33])(=[O:36])[C:14]1[CH:22]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1

Procedure:
Ester compound 3 is converted to the free carboxylic acid, and is then reacted with substituted aniline compound 4 to yield an arylamide of formula 5. For example, LiOH is added to a stirred solution of 3 in a mixture of solvents. The volatiles are removed under vacuum, and the residue is diluted with water and acidified to about pH 3. The resulting solids are filtered, washed with water and dried under vacuum to furnish a carboxylic acid intermediate. The intermediate is dissolved in a solvent such as DMF and the mixture is stirred to prepare a solution. To the stirred solution is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) followed by hydroxybenzotriazole (HOBt). After stirring, diisopropyl ethyl amine is added and stirred. Then substituted aniline 4 (representative of substituted aryl or heteroaryl) is added, and the reaction mixture is stirred. The solvent is removed under vacuum. The residue is diluted with water and stirred. The resulting solids are filtered and purified through column chromatography to provide benzamide compound 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([NH:26][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NN1CCCCCC1
Product: O=C(NN1CCCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-azepan-1-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.45 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 6.2 mmol of azepan-1-ylamine. LC/MS [8.99 min; 455 (M+1)]
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[CH3:12][CH:13]1[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:23])[CH:16]=[CH:15][CH2:14]1.C(NC(C)C)(C)C>C(Cl)Cl>[Br:1][C:16]1[C:17]([OH:23])=[C:18]([C:13]([CH3:12])=[CH:14][CH:15]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1C(=O)C=CCC1C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)c1c(C)ccc(Br)c1O

Procedure:
A solution of 1,3-dibromo-5,5-dimethylhydantoin (65 g) in DCM (150 mL) was added dropwise to a stirred and cooled solution of methyl 6-methyl-2-oxocyclohex-3-enecarboxylate (prepared in a similar manner to Hauser et al, Synthesis 1980 814, 75.16 g) and N,N-di-isopropylamine (6.15 mL) in DCM (500 mL) at 0° C. and the resultant mixture was stirred at room temperature for 3 days. The mixture was recooled to 0° C. and further 1,3-dibromo-5,5-dimethylhydantoin (11 g) was added and the mixture was stirred at 0° C. for 3 hours. The precipitate was removed by filtration and the filtrate was evaporated to dryness to give methyl 3-bromo-2-hydroxy-6-methylbenzoate (114.5 g) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH3:25])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CNCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)CCN(C)C)s2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1 eq), is dissolved in anhydrous DCM (50 ml). The reaction is put under nitrogen. N,N,N′-Trimethyl-ethane-1,2-diamine (0.58 ml; 5.94 mmol; 3 eq) and triethylamine (0.83 ml; 5.94 mmol; 4 eq) are added successively and the reaction mixture is stirred overnight at room temperature. The reaction mixture is washed with NH4Cl sat. (2 times), water (3 times), brine, and dried over MgSO4. After evaporation of the solvents, the crude product is suspended in ACN, filtered and dried under vacuum, affording Compound (5) as a beige solid (309 mg; 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=CC1CCCOC1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Yield: 69.1 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (18 g, 83.70 mmol), tetrahydro-2H-pyran-3-carbaldehyde (9.55 g, 83.70 mmol) and pyrrolidine (6.95 mL, 83.70 mmol) in MeOH (125 mL) was heated to reflux for 4.5 h. The mixture was allowed to reach r.t. and concentrated. The residue was dissolved in EtOAc (150 mL) and washed with 1M NaOH (80 mL), 1M HCl (80 mL), and brine (80 mL) successively. The organic phase was concentrated, the residue was purified by flash chromatography with a gradient of 10% EtOAc in heptane to 40% EtOAc in heptane to give the title compound (18 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.50 (m, 3H), 1.79 (m, 0.5H), 1.94 (m, 1.5H), 2.67 (m, 1H), 2.86 (m, 1H), 3.30 (m, 2H), 3.78 (m, 1H), 3.84 (m, 0.5H), 4.04 (dd, 0.5H), 4.44 (m, 1H), 7.05 (dd, 1H), 7.71 (m, 1H), 7.79 (d, 1H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:17])([F:16])[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(Cl)(Cl)Cl>[C:22]1([O:21][C:19](=[O:20])[NH:15][C:12]2[CH:11]=[N:10][C:9]([C:8]([F:7])([F:16])[F:17])=[CH:14][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (2.9 mL) was added to a solution of 2-trifluoromethyl-5-aminopyridine (1.95 g) in chloroform (15 mL), the mixture was cooled in ice, and phenyl chloroformate (1.8 mL) was added thereto. The resulting mixture was stirred at room temperature overnight, and the reaction mixture was concentrated under reduced pressure. The residue was washed with isopropyl ether to afford phenyl[6-(trifluoromethyl)pyridin-3-yl]carbamate (2.16 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:19]C(=O)C)=[CH:7]2.Cl>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2
Reactant: CC(=O)NCc1cc2cccc(F)c2nc1-c1ccccc1
Agent: Cl
Product: NCc1cc2cccc(F)c2nc1-c1ccccc1
Temperature: 25 °C

Procedure:
To N-((8-fluoro-2-phenylquinolin-3-yl)methyl)acetamide (28 mg, 95 μmol) was added hydrochloric acid (2M solution in water, 2 mL, 4000 μmol). The reaction was heated to 80 C for 24 h. The reaction was cooled to rt and quenched with 15% NaOH. The product was extracted into ether (2×10 mL) and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to afford (8-fluoro-2-phenylquinolin-3-yl)methanamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.48 (m, 4H), 7.39 (ddd, J=10.6, 7.8, 1.6 Hz, 1H), 4.05 (s, 2H), 2.03 (br s, 2H). Mass Spectrum (ESI) m/e=253.0(M+1).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21]Br)=[C:15]([Cl:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(#N)C.C(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:21])[CH2:23][N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)=[C:15]([Cl:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(CBr)Cc1ccc(C(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(Cc1ccc(C(C)(C)C)cc1Cl)CN1C[C@@H](C)O[C@@H](C)C1
Yield: 65 %

Procedure:
A solution of 23 g of 2,6-cis-dimethylmorpholine and 30.4 g of 3-(p-tert-butyl-o-chlorophenyl)-2-methylpropyl bromide in 150 ml of acetonitrile is refluxed for 4 hours. The crude product is dissolved in methylene chloride, the solution is washed with water, aqueous sodium bicarbonate solution and again with water, and dried over Na2SO4, the solvent is evaporated and the residue is distilled. There is obtained 22 g of N-[3-(p-tert-butyl-o-chlorophenyl)-2-methylpropyl]-2,6-cis-dimethylmorpholine (active ingredient no. 2); b.p. (0.05 mm) 133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17]C)[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(F)cc1)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(c2ccc(F)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 180 °C

Procedure:
A stirred mixture of 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone (1.2 g., 0.00354 mole) and pyridine hydrochloride (12 g.) is heated at 180° C. for one hour, then poured into water (500 ml.). The 2-(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone melts at 193°-200° C. and is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:15])[CH2:5][C:4]=2[CH:3]=1>CCCCCC.CCOC(C)=O>[F:15][C:10]1[C:11]2[C:12]3=[CH:13][C:14]4[C:2](=[CH:3][C:4]3=[CH:5][C:6]=2[CH:7]=[CH:8][CH:9]=1)[NH:1][C:4]([CH3:5])([CH3:12])[CH2:3][C:2]=4[CH3:14]
Reactant: Nc1ccc2c(c1)Cc1cccc(F)c1-2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=c2cc3c(cc2NC(C)(C)C1)=Cc1cccc(F)c1-3

Procedure:
This compound was prepared according to General Method 3 (EXAMPLE 16) from 2-amino-5-fluorofluorene (structure 15, where R2, R4-6=H, R3=F, X=CH2) (360 mg, 1.72 mmol) to 125 mg (26%) of Compound 126 as a light brown solid. Data for Compound 126: Rf=0.63 (silca gel, hexane/EtOAc, 3:1); 1H NMR (400 MHz, acetone-d6): 7.55 (s, 1H), 7.25 (d, J=7.3, 1H), 7.12 (m, 1H), 7.02 (d, J=10, 10, 1H) 6.73 (s, 1H), 5.39 (s, 1H), 3.81 (s, 2H), 2.87 (s, 3H), 1.28 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=C3C(=CC=2)[NH:46][C:45](=[O:53])[CH2:44][O:43]3)OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]5[C:23](=[CH:24][CH:25]=4)[NH:46][C:45](=[O:53])[CH2:44][O:43]5)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=C1COc2c(ccc3c(=O)c(I)c(-c4ccccc4)oc23)N1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c5c(ccc4c3=O)NC(=O)CO5)cc2)CCC1
Yield: 44 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-6-phenyl-1H-4,5-dioxa-1-aza-phenanthrene-2,8-dione was reacted to give the title compound as a yellow oil (92 mg, 44%). LCMS (Method H): RT=−4.71 min, [M+H]+=539.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14].[H-].[Na+].BrC[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[N+:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:1][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3](=[O:14])[NH:4]2)([O-:13])=[O:12]
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC(=O)OCC)C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (5.25 g, 29.5 mmol, described in Intermediate 17) in DMF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol) and the resulting mixture was stirred for 30 min. Ethyl bromoacetate (3.60 mL, 32.4 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. A further equivalent of sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol) was added, stirring was continued for 1 h, then ethyl bromoacetate (3.00 mL, 27.1 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then quenched with saturated aqueous NH4Cl (125 mL) and H2O (500 mL). The mixture was extracted with EtOAc (3×300 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=351 (M+1).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[F:16][C:17]1[C:22]([F:23])=[C:21]([OH:24])[CH:20]=[CH:19][C:18]=1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:36]=2)=[CH:27][N:26]=1.[C:46](O)(=[O:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>CN(C1C=CN=CC=1)C.ClCCl>[C:46]([O:24][C:21]1[CH:20]=[CH:19][C:18]([C:25]2[N:30]=[CH:29][C:28]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:36]=3)=[CH:27][N:26]=2)=[C:17]([F:16])[C:22]=1[F:23])(=[O:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Reactant: CCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OC(=O)CCCCCC)c(F)c3F)nc2)cn1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
2.7 mmol of DCC are introduced at room temperature into 50 ml of dichloromethane, and 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine, 2.7 mmol of heptanoic acid and 0.24 mmol of DMAP are added. The reaction mixture is left to stand overnight with exclusion of light, precipitated dicyclohexylurea is then filtered off, and the solvent is removed in vacuo. The crude product is chromatographed on silica gel 60 using dichloromethane/ethyl acetate 20:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 1.0 g (84%) of colorless crystals, X 88 SC 165 SA 167.5 I.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH2:32][CH2:33][OH:34]>>[OH:34][CH2:33][CH2:32][C:31]1[N:35]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: NC(CCO)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: O=C(N1CCSCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(CCO)no2)C1

Procedure:
According to General Method 6A, 1.00 g (2.390 mmol) of the compound from Example 25A and 323 mg (3.107 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 848 mg (69% of theory)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([O-:16])=O)[S:13][C:6]=12.[Li+]>>[CH3:1][N:2]([CH3:3])[C:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[Cl:4])[CH:11]=1)=[O:16]
Reactant: CNC
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from dimethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 239/241 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:37][C:38]([F:42])([F:41])[CH2:39]O>C(Cl)Cl>[F:37][C:38]([F:42])([F:41])[CH2:39][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cnc2ccc(CO)cn12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(COCC(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (59) (460 mg, 2.2 mmol) and DIEA (0.78 mL, 4.4 mmol) in DCM (5 mL) was added MsCl (303 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up to give a residue. The crude product was dissolved in 2,2,2-trifluoroethanol (2 mL) and was added K2CO3 (608 mg, 4.4 mmol). The reaction mixture was heated at 80° C. for 2 hours. Once complete, the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was purified by silica chromatography to yield ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (97). 1H NMR (400 MHz, CDCl3) δ 9.33 (m, 1H), 8.32 (s, 1H), 7.76 (dd, J=0.8, 9.2 Hz, 1H), 7.47 (dd, J=2.0, 9.2 Hz, 1H), 4.76 (s, 2H), 4.44 (q, J=7.2 Hz, 2H), 3.92 (q, J=8.4 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). MS m/z 303.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[F:11].[O:12]1C[CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:15][CH:14]([CH2:13][OH:12])[O:8][N:7]=2)=[CH:4][C:3]=1[F:11]
Reactant: ON=Cc1ccc(Br)c(F)c1
Reactant: C1CCOC1
Product: OCC1CC(c2ccc(Br)c(F)c2)=NO1
Reaction time: 4 h

Procedure:
4-Bromo-3-fluoro-benzaldehyde oxime (55.7 g, 265.3 mmol) and ally alcohol (44 ml) were added to tetrahydrofuran (300 ml) and then bleach (1791 ml) was added. The reaction was stirred for four hours followed by extraction with tetrahydrofuran (2×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (66 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([CH3:22])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:20]([NH2:36])[CH3:22]
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(N)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Temperature: 140 °C

Procedure:
1-{[6-Chloro-1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(4-fluorophenyl)acetone (500 mg, 1.21 mmol), ammonium acetate (35b, 934 mg, 12.11) and cyanoborohydride on polymer support (1.82 g, 3.63 mmol) were mixed in methanol (3 ml) and heated in micro at 140° C. for 10 min. The mixture was concentrated and treated with NaHCO3 and DCM. The organic phase was concentrated and the crude product was purified by flash chromatography (EtOAc/heptane followed by EtOAc/methanol). The diasteromers were separated on preparative HPLC (Kromasil column, water buffered with 2 g NH4OAc/l, pH set to 5.5 with HOAc, and MeCN, 25%-75%) to give the syn-isomer (1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine (35a-rac-1) as first eluated isomer (assignment by 1H-NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31](Cl)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Reactant: Nc1ccn(CCCO)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (83 mg, 88%) as a white foam: [α]30589=−88.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.78-2.32 (m, 10H, 5×CH2), 3.34 (brs, 5H, OCH2 and SO2CH3), 3.95 (m, 1H, ArCHCO), 4.02 (t, J=6.5 Hz, 2H, NCH2), 4.56 (t, J=4.7 Hz, 1H, OH), 6.41 (s, 1H, Ar), 7.56 (s, 1H, Ar), 7.61 (d, Jo=8.3 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1 H, NH).