Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]3)=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN1CCCC1=O.C(N(CC)C(C)C)(C)C>[C:39]([NH:43][C:44](=[O:45])[N:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]2)=[CH:27][CH:26]=1)[CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][CH:19]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CC(c2ccc(CNCCc3ccc(Oc4ccccc4)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)(C)NC(=O)N(CCc1ccc(Oc2ccccc2)cc1)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Reaction time: 1 h

Procedure:
5-[4-([2-(4-Phenoxyphenyl)ethyl]aminomethyl)phenyl]isothiazolidin-3-one 1,1-dioxide trifluoroacetate (6.5 mg, 0.012 mmol) was dissolved in N-methyl-pyrrolidinone (100 μL) with N,N-diisopropylethylamine (10 μL). A solution of t-butylisocyanate in N-methyl-pyrrolidinone (100 μL) was added and the mixture stirred for 1 h. The mixture was purified by preparative LCMS to give the desired product. White solid, (6.5 mg, 100%). LCMS found for C22H21N2O5S (M+H)+: m/z=536.
Reaction SMILES: O.[CH:2]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](C=O)[C:4]=2[CH:3]=1.S(=O)(O)[O-:13].[Na+]>C(#N)C>[OH:13][C:5]12[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]1[CH2:3][CH2:2]2
Reactant: O=S([O-])O
Reactant: O=Cc1cccc2c1C=C2
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: OC12C=CC=CC1CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of the thus prepared permonophosphoric acid (18 mL, 1.2M) in acetonitrile was added to a flask equipped with ice bath, stirrer and water-cooled condenser. To the stirred solution was added 3-benzocyclobutene aldehyde (5 g, 0.037 moles) dropwise over a period of 30 minutes. The reaction mixture was stirred for an additional 2 hours and cooled to 0° C. Water (20 mL) was added to the cooled reaction mixture, followed by the addition of sodium bisulfite solution until the reaction mixture was free from permonophosphoric acid, as tested with starch iodide paper. The organic solvent was removed by rotary evaporation, and sodium hydroxide was added until the reaction mixture became alkaline. The reaction mixture was cooled to 0° C., acidified and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate and brine. Drying and removal of the solvent was followed by flash chromatography using 10 percent ethyl acetate in hexanes to afford 3.19 g 3-hydroxybenzocyclobutene as a solid. This represents a yield of approximately 70 percent. The 3-benzocyclobutene phenol was recrystallized from pentane. The 3-benzocyclobutene phenol product has a melting point of 47° C. Product analysis indicated substantially complete conversion of 3-benzocyclobutene aldehyde with the product, other than the desired 3-hydroxybenzocyclobutene, comprising unidentified polymer-like substance with substantially no formation of 3-benzocyclobutene carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[O:16]=[C:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.[I-].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18][C:17]2=[O:16])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cc1
Temperature: 120 °C
Yield: 93.4 %

Procedure:
To a stirring solution of 1-bromo-4-(heptyloxy)benzene (447 mg, 1.65 mmol) in dioxane (5 mL) were added tert-butyl 3-oxopiperazine-1-carboxylate (330 mg, 1.65 mmol), copper I iodide (31.4 mg, 0.17 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (234 mg, 1.65 mmol) and potassium carbonate (456 mg, 3.30 mmol). The reaction mixture was heated at 120° C. for 16 h. The reaction mixture was passed through a plug of celite, eluted with EA (50 mL). The organics were washed with ammonium chloride (25 mL), water (25 mL) and brine (25 mL) then dried over MgSO4 and concentrated to afford 602 mg (89%) of tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate. LCMS-ESI (m/z) calculated for C22H34N2O4: 390.5. found 319.0 [M+H]+, tR=2.90 min. (Method 4).
Reaction SMILES: CN(C=O)C.[CH3:6][N:7]1[CH:11]=[C:10](B(OCC)OCC)[CH:9]=[N:8]1.Br[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=1[O:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CO.[Cl-].[NH4+].[Fe]>[CH3:30][O:29][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[C:10]1[CH:9]=[N:8][N:7]([CH3:6])[CH:11]=1)[NH2:26]
Reactant: CCOB(OCC)c1cnn(C)c1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(N)ccc1-c1cnn(C)c1

Procedure:
A DMF solution of diethyl 1-methyl-1H-pyrazol-4-ylboronate, 4-bromo-3-methoxy nitrobenzene together with Pd(dppf) and K2CO3 were heated at reflux overnight. The product obtained was reduced with Fe in MeOH/ammonium chloride to provide the title compound. LC-MS (M+H)+=204.2. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.84 (1H, s), 7.66 (1H, s), 7.19 (1H, J=8.2 Hz, d), 6.29 (1H, s), 6.18 (1H, J=2.0, 8.2 Hz, dd), 5.31 (2H, br s), 3.80 (3H, s), 3.75 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]Br>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Clc1cccc(CCBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3cccc(Cl)c3)C2=O)cn1
Yield: 27 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-chlorophenethyl bromide. Yield: 27%. MS M+H calculated 414.13; found 414.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.20 μM.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].BrC[CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C>CN(C=O)C>[C:9]([CH:8]([C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)[CH2:13][CH2:14][OH:15])#[N:10]
Reactant: N#CCc1cccs1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCO)c1cccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (650 mg) was added in an ice bath to a DMF solution (25 ml) of thiophene-2-acetonitrile (1 g) and (3-bromopropoxy)-tert-butyldimethylsilane (2.06 g). After 20 minutes, the organic layer was separated by adding an aqueous saturated ammonium chloride and ethyl acetate were added thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The resulting residue was dissolved in acetonitrile (20 mL), a 1 M tetrabutylammonium fluoride/tetrahydrofuran solution (9.7 ml) was added thereto, and the mixture was stirred at a room temperature. After 18 hours, the organic layer was separated by adding water and ethyl acetate. The resulting organic layer was rinsed with water and brine, and dried over magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system), to give the title compound as a red oil (637 mg, 43%). 1H-NMR (400 MHz, CDCl3) δ 2.08-2.16 (m, 1H), 3.08 (t, J=7.0 Hz, 2H), 3.75 (t, J=7.0 Hz, 2H), 4.15-4.20 (m, 1H), 7.14 (dd, J=3.8 Hz, 4.8 Hz, 1H), 7.65 (dd, J=0.8 Hz, 4.8 Hz, 1H), 7.75 (dd, J=0.8 Hz, 3.8 Hz, 1H).
Reaction SMILES: [C:1]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)#[N:2].[SH2:12].C(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:3][C:1]([NH2:2])=[S:12])[N:9]=1
Reactant: S
Reactant: Cc1cc(C)nc(NC#N)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(N)=S)n1
Reaction time: 1 h

Procedure:
A suspension of 10 g of 2-cyanoamino-4,6-dimethylpyrimidine in 50 ml of pyridine was saturated with hydrogen sulfide and stored for 1 hour at 25°. The H2S treatment was repeated twice more, and the mixture was allowed to stir at 25° for 16 hours. Methylene chloride was added, and the product was filtered and washed with methylene chloride to afford 8 g of 4,6-dimethylpyrimidin-2-yl thiourea, m.p. >260°. IR (Nujol) 3280, 3180, 3120, 1610 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([O:8][C:9]2[C:44]([F:45])=[C:43]([F:46])[C:12]([C:13]([C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([O:33]CC5C=CC=CC=5)[CH:25]=4)=[C:17]([F:41])[C:16]=3[F:42])=[O:14])=[C:11]([F:47])[C:10]=2[F:48])=[CH:6][C:5]=1[O:51]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:18]2[C:17]([F:41])=[C:16]([F:42])[C:15]([C:13]([C:12]3[C:11]([F:47])=[C:10]([F:48])[C:9]([O:8][C:7]4[CH:49]=[CH:50][C:4]([NH2:1])=[C:5]([OH:51])[CH:6]=4)=[C:44]([F:45])[C:43]=3[F:46])=[O:14])=[C:20]([F:21])[C:19]=2[F:22])=[CH:25][C:26]=1[OH:33]
Reactant: [H][H]
Reactant: O=C(c1c(F)c(F)c(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c(F)c1F)c1c(F)c(F)c(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(F)c(C(=O)c3c(F)c(F)c(Oc4ccc(N)c(O)c4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 72 h
Yield: 95 %

Procedure:
32.5 g of 4,4'-bis(4-nitro-3-benzyloxyphenoxy)octafluorobenzophenone prepared as described in Example 3 (0.04 mol) are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 3 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and 100 ml n-hexane is added, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nccnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
To a solution of 3-chloropyrazine-2-carboxylic acid (2.0 g, 12.70 mmol, 1.0 eq.) and TEA (3.50 mL, 25.40 mmol, 2.0 eq.) in THF (50 mL) was added methyl chloroformate (1.2 mL, 15.20 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (0.97 g, 25.40 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with NH4Cl(aq) solution, and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloropyrazin-2-yl)methanol (400 mg, 22%) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.58 (d, J=2.5 Hz, 1H), 8.38 (d, J=2.5 Hz, 1H), 4.84 (s, 2H). LRMS (M+H+) m/z 145.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1.Cl.C([O-])([O-])=[O:20].[Na+].[Na+]>OO>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[OH:20])=[O:17])=[CH:10][CH:11]=1)[CH3:16]
Reactant: CCc1ccc(C(=O)c2cnccc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCc1ccc(C(=O)c2cnccc2O)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Next, to a solution of (4-chloropyridin-3-yl)-(4-ethylphenyl)methanol (3.2 g, 0.0129 mol) in chloroform (45 mL), Dess-Martin periodine (6.5 g, 0.0154 mol) was added under ice cooling and the reaction mixture was stirred at room temperature for 5 hours. After filtration to remove the precipitated insoluble materials, the filtrate was washed with 1M NaOH (40 mL) and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by NH silica gel chromatography (ethyl acetate) to give 4-chloro-3-(4-ethylbenzoyl)pyridine (3.4 g) as a yellow oil. A mixture of 4-chloro-3-(4-ethylbenzoyl)pyridine (3.4 g), 3M HCl (35 mL) and 30% H2O2 (2 drops) was heated under reflux for 6.5 hours. After cooling to room temperature, the reaction mixture was neutralized with Na2CO3. The resulting precipitate was filtered and washed with ethyl acetate to give 3-(4-ethylbenzoyl)-4-hydroxypyridine (2.9 g, 92% for 2 steps) as a light-yellow crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[NH:9].[CH2:11]([CH:19]1[CH2:21][CH:20]1[C:22](Cl)=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH2:11]([CH:19]1[CH2:21][CH:20]1[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[NH:9])=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N=C(N)NCCCCCN
Reactant: CCCCCCCCC1CC1C(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC1CC1C(=O)NCCCCCNC(=N)N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 350 mg. of 1-amino-5-guanidinopentane suspended in 70 ml. of dry pyridine was added 700 mg. of 2-(n-octyl)cyclopropanecarbonyl chloride. This mixture was stirred at room temperature for 2 days, after which the solid was filtered and the filtrate concentrated to a brown oil (1.19 g.). The entire bulk of this oil was chromatographed on silica gel eluting with MeOH:CHCl3 (2:3) and collecting 10 ml. fractions. Fractions 20-40 gave 28.8 mg. of desired products. Mass spectrometry (EI): M+ m/e 324 for C18H36N4O.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1.[NH2-].[Na+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)[C:3]([N:2]([CH3:13])[CH3:1])=[N:4]1)=[O:19]
Reactant: CN(C)c1n[nH]c2cc(Cl)ccc12
Reactant: CN(C)C(=O)Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)n1nc(N(C)C)c2ccc(Cl)cc21

Procedure:
0.04 mol of 3-dimethylamino-6-chloroindazole and 0.04 mol of sodium amide in 50 ml of toluene are heated to the boil for 1 hour. 0.04 mol of dimethylcarbamic acid chloride is added dropwise at 60° C and this temperature is maintained for 7 hours, while stirring. After cooling, the solution is filtered and evaporated in vacuo. Distillation of the residue gives 3-dimethylamino-6-chloroindazole-1-carboxylic acid dimethylamide (boiling point0.35 170° C, melting point: 65°-66° C; 75% of theory).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=O)(C)(C)C.OC1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClC(Cl)C.CO.C(O)(=O)C>[N:8]1([CH:6]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: OC1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and 4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200 ml) with acetic acid (4 ml) at RT for 30 minutes. Sodium triacetoxyborohydride (23 g) was then added and the mixture stirred at RT overnight. The mixture was evaporated to dryness and the residue taken into water, extracted with diethyl ether (3×200 ml), the aqueous was basified to pH 9-10 and extracted with dichloromethane (3×200 ml). The dichloromethane extracts were combined, dried (MgSO4) and evaporated to leave an oil (19 g; same compound as Example 9 step 1). The oil was dissolved in methanol (300 ml) and treated with concentrated hydrochloric acid (5 ml). The mixture was stirred overnight and then evaporated to dryness to leave the title compound as the hydrochloride salt (15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:18][C:19](=[O:23])[CH2:20][CH:21]=[CH2:22])=[N:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:18][C:19](=[O:23])[CH2:20][CH:21]=[CH2:22])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CCC(=O)Nc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ccc12
Solvent: C1COCCO1
Product: C=CCC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 19 °C
Reaction time: 17 h
Yield: 74.2 %

Procedure:
10 cm3 of 4N hydrochloric dioxane are added to 240 mg of N-(6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazol-3-yl)-3-butenamide described previously. The mixture is stirred at about 19° C. for 17 hours. The crystalline product is filtered off on a sinter funnel, rinsed with 2×5 cm3 of ethyl acetate and with 2×5 cm3 of diethyl ether and then dried under reduced pressure (90 Pa; 40° C.). 125 mg of N-(6-chloro-1H-indazol-3-yl)-3-butenamide, in the form of the hydrochloride and melting at 150° C., are thus obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]([N:15]2[C:23](=[O:24])[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]2=[O:25])=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.Cl[CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O.[I-].[Na+].C1OCCOCCOCCOCCOCCOC1>[F:3][C:4]1[C:14]([N:15]2[C:23](=[O:24])[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]2=[O:25])=[CH:13][C:7]2[N:8]([CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Reactant: C[Si](C)(C)CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To N,N-dimethylformamide (10 ml) is added at an ambient temperature sodium hydride (0.1 g), sodium iodide (5 mg), 18-crown-6 (5 mg) and 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.63 g). Thereafter the whole is stirred for 15 minutes, treated with a solution of chloromethyltrimethylsilane (0.61 g) in N,N-dimethylformamide (5 ml), and stirred at 100°-110° C. for an hour. The reaction mixture is evaporated to dryness in vacuo, admixed with water (30 ml), and extracted twice with dichloromethane (30 ml). The combined extract is dried over sodium sulfate and evaporated in vacuo to obtain an oily end product 2-[7-fluoro-4-trimethylsilylmethyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.7 g). nD20 1.5596.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]2[C:15]=1[F:26].Cl.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([N:28]3[CH2:31][CH:30]([OH:32])[CH2:29]3)=[O:25])=[C:16]2[C:15]=1[F:26]
Reactant: OC1CNC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)c(F)c12
Agent: Cl
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)c(F)c12)N1CC(O)C1

Procedure:
The title compound was prepared by the method substantially similar to that mentioned in Example-12, using (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid (prepared by the method mentioned in the Example 248) and 3-azetidinol hydrochloride to afford the crude compound. The crude compound was purified by Preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 100% EtOAc as eluent) to afford 12 mg of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([C:22]([C:16]2([C:13]3[CH:12]=[CH:11][C:10]([S:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: O=C(O)C1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Product: O=C(N1CCCC1)C1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Yield: 40 %

Procedure:
The title compound (228 mg, 40%) was prepared using 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxylic acid and pyrrolidine similarly to the procedure used for example 149.
Reaction SMILES: [OH:1][C@@H:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][O:4][C:3]1=[O:9].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:7][C:6]([CH3:8])([CH2:5][OH:4])[C@@H:2]([OH:1])[CH2:3][OH:9]
Reactant: CC1(C)COC(=O)[C@@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)[C@@H](O)CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
(R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (3.21 g, 24.7 mmol) was added to 30 mL THF and cooled to 0° C. Lithium aluminum hydride (24.7 mL, 24.7 mmol) was added slowly and the reaction was warmed to ambient temperature and heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed. The reaction was cooled to ambient temperature, and 1 mL water was added, followed by the addition of 1 mL of a 15% NaOH aqueous solution (w/v) and 3 mL of water, and the reaction was stirred overnight. The reaction was passed through Celite and filtered, rinsed with copious amounts of ethyl acetate, then dried over Na2SO4. The mixture was filtered, the filtrate was concentrated, and excess water was azeotroped with toluene-DCM (1-1). The residue was dried under high vacuum for 1 hour to yield 2.4 g of the desired product as a clear thick oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reactant: C1COCCN1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(N3CCOCC3)cc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=563.3 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, morpholine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.