Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=3)[C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate (3.00 g, 11.8 mmol) in anhydrous N,N-dimethylformamide (20 mL) under nitrogen atmosphere was added in one portion sodium hydride (60% in mineral oil, 0.57 g, 14.15 mmol). The mixture was stirred for 1 hour, then 4-(trifluoromethyl)benzyl bromide (3.39 g, 14.16 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added. The resulting reaction mixture was stirred for 16 hours, then was partitioned between ethyl acetate (200 mL), water (100 mL) and brine (50 mL). The aqueous layer was extracted with ethyl acetate (200 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with 10% ethyl acetate in hexanes to afford the title compound as a cream solid in 89% yield (4.32 g): 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 6.17 (s, 1H), 4.53 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.86-3.79 (m, 2H), 3.50-3.43 (m, 2H), 2.50 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 413.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].CN([CH:14]=[O:15])C>C1COCC1>[CH:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10])=[O:15]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C=O
Temperature: -50 °C

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (20 g, 102 mmol) in THF (500 mL) at −100° C. was slowly added a solution of n-Buli 1.6M in hexanes (70 mL, 112 mmol). DMF (11 mL, 143 mmol) was then added and the mixture was allowed to warm to −50° C. over 30 min. The reaction mixture was quenched with brine. The reaction mixture was diluted with EtOAc and extracted with brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 80:20) the residue was triturated in Et2O/hexane 90:10 to afford the title compound. tR: 0.86 min (LC-MS 2); Rf=0.40 (hexane/EtOAc, 8:2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13](C(O)=O)[CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[ClH:19]>ClCCl.O1CCOCC1>[ClH:19].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N[C@H]2CCNC2)nc1
Reaction time: 8 h

Procedure:
The above nitro compound (6.16 g, 20.0 mmol) was suspended in dichloromethane (200 mL) and hydrogen chloride in dioxane (4M, 25 mL) was added. The mixture was stirred overnight and solvents were evaporated to give (S)-5-nitropyridine-2-yl-pyrrolidine-3-yl-amine hydrochloride as an off white solid (5.92 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15]C)=[O:14])[C:8]2=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[C:8]2=[O:17])=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccn(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccn(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
A solution of methyl 1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (2.4 g, 9.2 mmol, 1.0 eq) in MeOH (25 ml) was treated with 5 N aqueous sodium hydroxide (4.6 mL, 24 mmol, 2.6 eq) at room temperature and the reaction mixture was stirred for 15 h. The reaction mixture was concentrated in vacuo, diluted with water and the solution was extracted with ethyl acetate (discarding the organic fraction). The aqueous fraction was cooled to 0° C. and acidified with concentrated HCl. The resulting solid was filtered, washed with water and the solid dried in vacuo to afford the product (1.6 g, 70%) which was sufficiently pure to use in the subsequent step without further purification. 1H NMR (DMSO-d6) δ 8.44–8.39 (m, 2H), 7.46–7.42 (m, 2H), 7.24–7.18 (m, 2H), 6.78 (d, 1H, J=6.98 Hz), 5.31 (s, 2H); HRMS(ESI), calcd.: 248.0723, found: 248.0718.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.Cl.[CH2:23]([N:25]([CH2:40][CH3:41])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:24]>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([NH:28][CH2:27][CH2:26][N:25]([CH2:40][CH3:41])[CH2:23][CH3:24])=[O:30])=[CH:32][CH:33]=3)=[N:7][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CCN(CC)CCNC(=O)c1ccc(B(O)O)cc1
Agent: Cl
Product: CCN(CC)CCNC(=O)c1ccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 4-{[2-(Diethylamino)ethyl]carbamoyl}benzeneboronic acid hydrochloride using Suzuki coupling conditions as described in Scheme 1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:6]([F:11])([F:10])[CH2:7][CH2:8][CH3:9])=[CH:4][F:5].[FH:14]>>[F:1][C:2]([F:12])([F:13])[CH:3]([C:6]([F:10])([F:11])[CH2:7][CH2:8][CH3:9])[CH:4]([F:14])[F:5]
Reactant: CCCC(F)(F)C(=CF)C(F)(F)F
Reactant: F
Product: CCCC(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,3,3-pentafluoro-2-hexanol may be prepared by fluorinating commercially available 3-hexanone to form 3,3-difluorohexane which may then be dehydrogenated to form 3,3-difluoro-2-hexene. CF3 may then be reacted with the 3,3-difluoro-2-hexene to form 2-trifluoromethyl-1,3,3-trifluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-hexene. The 2-trifluoromethyl-1,3,3-trifluoro-1-hexene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3-tetrafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3-tetrafluoro-1-hexene which may then be fluorinated to form 2-trifluoromethyl-1,1,1,2,3,3-hexafluorohexane. The 2-trifluoromethyl-1,1,1,2,3,3-hexafluorohexane may then be hydrolyzed to form 2-trifluoromethyl-1,1,1,3,3-pentafluoro-2-hexanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COCCCN
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCOC

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 3-methoxy-propylamine following general procedure B to afford 8-methoxy-4-(3-methoxy-propyl-amino)-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.57 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(3-methoxy-propyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (35 mg). LCMS: m/z 344 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:35]=[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:38][C:39]=1[CH3:40]>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:34]([CH3:33])[CH:35]=2)[CH2:46][CH2:45]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Product: Cc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1C
Yield: 14 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3,4-dimethyl-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (9.7 mg, 14%) as light yellow oil. MS m/e=519.4 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[CH:12])[C:8](=[O:13])[CH2:7][CH2:6]1)=O.[NH3:14]>CO>[O:13]=[C:8]1[N:9]([CH2:10][C:11]#[CH:12])[CH:5]([C:3]([NH2:14])=[O:2])[CH2:6][CH2:7]1
Reactant: N
Reactant: C#CCN1C(=O)CCC1C(=O)OC
Solvent: CO
Product: C#CCN1C(=O)CCC1C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-(2-propynyl)-2-pyrrolidinone (5.1 g) and sieve dried methanol (250 ml) was treated with anhydrous ammonia for ten minutes and was then allowed to stand overnight at ambient temperature. The solution was concentrated to afford an oil which crystallized (4.81 g). Recrystallization from 95% ethanol (20 ml) gave 3.07 g of almost colorless crystals, mp 145°-147° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:9])=[CH:4][C:3]=1[O:27][CH3:28].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:28][O:27][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(=O)c2c(-c3ccccc3)c(OC)c3ccccn23)ccc1N
Product: CCOC(=O)CNc1ccc(C(=O)c2c(-c3ccccc3)c(OC)c3ccccn23)cc1OC

Procedure:
This compound was obtained according to the method described in Example 192, by alkylating (4-amino-3-methoxyphenyl)(1-methoxy-2-phenylindolizin-3-yl)methanone, a compound of Example 95, with ethyl bromoacetate. A yellow powder is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[CH:5]=[C:4]([NH2:24])[N:3]=1.[N:25]([O-])=[O:26].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[CH:12][CH:11]=2)[C:5]([N:25]=[O:26])=[C:4]([NH2:24])[N:3]=1
Reactant: Nc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 76.9 %

Procedure:
Pyrimidine 37 (Example 20, 4.72 g, 13.7 mmol) is dissolved in 60 mL acetic acid (30%) and heated to 70° C. NaNO2 (1.4 g, 20.03 mmol) dissolved in 5 mL water is added drop wise until KJ-starch paper remains black. After cooling to 0° C. in an ice-bath, the purple precipitate is collected by filtration and recrystallized from acetone to yield 3.9 g (10.54 mmol, 77%) of a purple solid. 1H-NMR (400 MHz, DMSO-d6) δ=10.03 (d, J=4.0, 1H, 5-NHa), 10.00 (t, J=5.8, 1H, CF3CONH), 8.01 (d, J=4.0, 1H, 5-NHb), 7.86 (s, 1H, 1-NHa), 7.81 (s, 1H, 1-NHb), 7.51 (d, J=8.1, 2H, ArH), 7.30 (d, J=8.1, 2H, ArH), 5.54 (s, 2H, OCH2), 4.38 (d, J=5.8, 2H, CH2N) ppm.
Reaction SMILES: C(C(O)=[O:29])CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.ON1C(=O)CCC1=O.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(OCC)(=O)C>[C:46]([NH:45][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)([NH:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:29]
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2H,2H,3H,3H-Perfluoroundecanoic acid (1.354 g, 2.75 mmol), N-hydroxysuccinimide (348 mg, 3.02 mmol) and dicyclohexylcarbodiimide (622 mg, 3.02 mmol) were dissolved in ethyl acetate (120 ml) and stirred for 18 hours at ambient temperature. The white precipitate which formed (dicyclohexylurea, DCU) was filtered and the remaining solution was evaporated to dryness. The residue was recrystallised twice from ethyl acetate. Yield 1.00 g (62%) containing traces of DCU.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].C([Li])CCC.[CH3:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>O1CCCC1.CCCCCC>[OH:23][C:22]1([CH2:11][C:6]2[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:28])[N:18]1[CH3:17]
Reactant: CN1C(=O)c2ccccc2C1=O
Reactant: CNC(=O)c1ccccc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccccc1CC1(O)c2ccccc2C(=O)N1C
Reaction time: 2 h

Procedure:
A solution of 29.8 grams (0.2 mole) of N-methyl-o-toluamide in 600 milliliters of dry tetrahydrofuran is treated dropwise with 275 milliliters (0.44 mole) of n-butyl lithium in hexane, while maintaining the temperature at 0° C. to 10° C. After the addition is complete, the mixture is stirred at 0° C. to 10° C. for 2 hours. The cooling bath is removed and a solution of 32.2 grams (0.2 mole) of N-methyl phthalimide in 330 milliliters of tetrahydrofuran is added dropwise. The temperature is maintained at 20° - 25° C. during the addition, afterwhich it is stirred for 11/2 hours at room temperature. The resulting mixture is cooled in ice and quenched by the addition of saturated ammonium chloride. The layers are separated and the organic layer is washed with ammonium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is crystallized from ethyl acetate to give α-(1-hydroxy-2-methyl-3-oxoisoindolin-1-yl)-N-methyl-o-toluamide, m.p. 175.5 - 177.5.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:33][C:34]([CH3:36])=[O:35]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:34]([CH3:36])([OH:35])[CH3:33])(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(C)(=O)=O)ccc2n1CC1CC1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-(methylsulfonyl)-1H-benzimidazole (Step D, 8.22 g, 25.7 mmol) in tetrahydrofuran (200 mL) was added lithium bis(trimethylsilyl)amide (1.07 M in hexane, 28.8 mL, 30.8 mmol) at −40° C. under nitrogen atmosphere. After stirring for 10 min, acetone (20 mL) was added at −40° C. and the mixture was allowed to warm to room temperature. After stirring for 18 h, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2 as eluent) to afford the title compound (4.68 g, 48%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC[O-].[Na+].Cl>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][N:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cn2)noc1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)cn2)noc1/C=C/c1ccccc1
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a solution of 3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (1.05 g, 4.2 mmol) and benzaldehyde (0.42 mL, 4.2 mmol) in ethanol (6 mL) was added sodium ethylate (1.5 g, 4.6 mmol) and the reaction mixture was stirred at reflux for 30 min. Aqueous hydrochloric acid (1 M, 5 mL) was added and stirring was continued for 15 min. The precipitate was filtered and dried to afford the title compound (1.2 g, 85%) as an off-white solid. MS: m/e=309.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](I)([CH3:11])[CH3:10]>>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: Oc1cccc(F)c1
Product: CC(C)Oc1cccc(F)c1

Procedure:
3-fluoro-phenol and isopropyl iodide were reacted to form 3-fluoro-isopropoxy-benzene which was reacted with nitric acid to obtain 2-isopropoxy-4-fluoro-nitro benzene which was reacted as in Example 1 to obtain 0-(4-nitro-3-isopropoxy-phenyl)-hydroxylamine melting at 104° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:31][CH:20]5[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH:19]5[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:31][CH:20]5[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:23][CH:19]5[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CC3CN(C(=O)OC(C)(C)C)CC3C1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)cc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of Example 262C (˜3.93 mmol) in tetrahydrofuran (28 mL) and methanol (20 mL) was added 1M aqueous sodium hydroxide (23.61 mL, 23.61 mmol) and the mixture was stirred at 60° C. for 3 hours. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 6-15% methanol in dichloromethane to give the title compound. LC-MS: 450 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH:10][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:24])=[O:4]
Reactant: CNC(=O)c1sc(C(C)(C)C)cc1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 43 %

Procedure:
A solution of the N-methyl-3-amino-5-tert-butylthiophene-2-carboxamide (0.60 g, 2.83 mmol) and 4-methylphenyl isocyanate (0.36 mL, 2.83 mmol) in toluene (2 mL) was heated at the reflux temp. for 18 h. The resulting solution was concentrated under reduced pressure and the resulting solid was purified by flash chromatography (EtOAc/CH2Cl2) affording N-(2-methylcarbamoyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.42 g, 44%): mp 202-4° C.; 1H NMR (CDCl3) δ1.38 (s, 9H), 2.31 (s, 3H), 2.91 (d, J=4.9 Hz, 3H), 5.59 (bs, 1H), 7.11 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.90 (s, 1H), 10.53 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:27][CH3:28])=[C:12]([C:14]([CH3:26])([CH3:25])[CH2:15][C@:16]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:17](O)=[O:18])[CH:13]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:27][CH3:28])=[C:12]([C:14]([CH3:26])([CH3:25])[CH2:15][C@@:16]([C:20]([F:22])([F:23])[F:21])([OH:24])[CH2:17][OH:18])[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(C(=O)O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CO)C(F)(F)F
Temperature: 50 °C
Reaction time: 13 h
Yield: 44.5 %

Procedure:
A solution of lithium aluminium hydride (1M in tetrahydrofuran, 12.6 mL, 12.6 mmol) was introduced into a flask under a nitrogen atmosphere. The solution was heated to 50° C. under nitrogen. (2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl) pentanoic acid (2 g, 6.17 mmol) in tetrahydrofuran (4 mL) was then added dropwise using a syringe pump (50 mL/h addition rate). The solution was then stirred for 13 h at 50° C. The reaction mixture was then cooled to 0° C. and quenched with a slow addition (10 mL/h addition rate) of water (0.5 mL) keeping the temperature below 5° C. Once gas evolution stopped, the cloudy solution was allowed to warm to 20° C. and 15% aqueous sodium hydroxide solution (0.5 mL) followed by water (1.5 mL) were added dropwise (40 mL/h addition rate). The slurry was stirred for 15 min at room temperature, filtered and the inorganic salts were washed twice with ethyl acetate (2×10 mL). The organic liquors were then washed successively with 7.5% aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL). The organic liquor was split into two equal amounts, the first half was concentrated to dryness to afford the title compound (851 mg) and the second half was re-crystallised from methyl-cyclohexane to afford the title compound (595 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[CH2:5])[CH3:2].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1>C(O)CO>[CH3:5][C:4]1([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:16])[N:14]=3)[CH:11]=2)[O:38][CH2:2][CH2:1][O:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Solvent: OCCO
Solvent: Cc1ccccc1
Product: CC1(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OCCO1
Yield: 20.2 %

Procedure:
A mixture of 80 mg of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 2.5 mL of toluene, 280 μL of ethylene glycol and 170 mg of para-toluenesulfonic acid is placed over molecular sieves. The mixture is refluxed for 2 hours and then cooled, filtered and diluted with 20 mL of dichloromethane and 20 mL of water, and neutralized with 2N sodium hydroxide solution. The aqueous phase is washed with dichloromethane and the combined organic phases are dried and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a gradient of dichloromethane and ethyl acetate of from 0/30 to 70/30 to give 17 mg of 6-(2-methyl-1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.