Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].ClC[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>[O-]CC>[C:1]([NH:4][C:5]([C:29]1[CH:30]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:28]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOC(=O)COc1cccc(CCl)c1
Agent: CC[O-]
Product: CCOC(=O)COc1cccc(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Temperature: 0 °C

Procedure:
Diethyl acetamidomalonate (2.60 g) and ethyl 3-(chloromethyl)phenoxyacetate (Robertson, J. Chem. Soc. (1933), 492; U.S. Pat. No. 3,933,895) (2.39 g) were dissolved in ethanolic ethoxide (prepared from sodium (230 mg) and absolute ethanol (10 ml)) and the mixture refluxed for 19 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract evaporated. The residual gum was crystallised from ether/hexane to give diethyl acetamido-(3-ethoxycarbonylmethoxyphenyl)malonate as white prisms, m.p. 98.5°-101.5°. This derivative (1.90 g) was refluxed with 10% aqueous hydrochloric acid (25 ml) for 31/2 hours and the cooled solution was evaporated to dryness in vacuo. The residual white solid was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (15 ml) and thionyl chloride (1.64 g). The resulting solution was set aside at room temperature for 18 hours, refluxed for 1 hour, cooled, and poured into ice-water, adjusting the pH to 9-10 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated, giving ethyl 2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate as a colourless oil, which was used without further purification in Examples 20 and 21.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][N:38]=2)=[CH:30][CH:29]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][N:38]=2)=[CH:30][CH:29]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Reactant: CCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2ncc(CCCCCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.95 g) is added in small portions to a solution of (E)-hex-2-en-1-ol (0.40 g), 2-(4-hydroxyphenyl)-5-octylthiazole (0.70 g), diethylazodicarboxylate (0.60 g) in dry tetrahydrofuran (40 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.15 g of 2-(4-[(E)-hex-2-enyloxy]phenyl)-5-octyfthiazole.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].CO[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:29][CH2:28][C:27]=3[CH:26]=2)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(c3)CCCC4)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting 5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with 70% EtOAc/hexanes afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=23)[CH:6]=1.C1COCC1.C([Li])CCC.CCCCCC.[CH:40]1([CH:46]=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([CH:46]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=34)[CH:6]=2)[OH:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=CC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-n3cc(Br)cn3)ccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(C(O)C4CCCCC4)cn3)ccnc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in THF (2.0 mL, 0.025 mol) under a nitrogen atmosphere was cooled to −78° C. and 1.6 M n-butyllithium in hexane (0.10 mL, 0.00016 mol) was added slowly. The mixture was stirred for 15 min and then treated with cyclohexanecarboxaldehyde (25.0 μL, 0.000208 mol). After 20 min at −78° C., the reaction was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the cyclohexyl[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]methanol as a crude residue, LC/MS (M+H)+: 427.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:19](=[CH:20][CH:21]=1)[O:18][C:12]1([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:22].CC(O)=O.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:19](=[CH:20][CH:21]=1)[O:18][C:12]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:13]1)[CH2:11][C:10]2=[O:22]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCNC1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
(−)-(E)-3-[4-Oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (505 mg, 1.49 mmol) was suspended in DCM (50 ml). TEA (0.208 ml, 1.49 mmol) was added and the pH was adjusted to 5 with AcOH. Benzaldehyde (190 mg, 1.794 mmol) and NaBH(OAc)3 (475 mg, 2.24 mmol) were added and the mixture was stirred at RT for 3 h. The resulting solution was washed with 5% NaHCO3 and brine, then dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (eluent:petroleum ether:EtOAc 9:1 to 7:3) to give (−)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (547 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:14][N:15]1CCCC1=O.Cl>O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]#[N:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Clc1ccccc1C1=CCCCC1
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: O
Product: N#Cc1ccccc1C1=CCCCC1
Yield: 68 %

Procedure:
A mixture of 19.3 g. (0.1 mol) o-(1-cyclohexenyl)-chlorobenzene and 16.4 g. (0.18 mol) cuprous cyanide in 100 ml. N-methylpyrrolidinone was heated to 200° C. for 15 hours. For working up, the brown-black product was introduced into a solution of 40 g. ferric chloride, 10 ml. concentrated hydrochloric acid and 60 ml. water and the mixture heated for 0.5 hours to 60° to 70° C. The N-methylpyrrolidinone phase was separated off and the aqueous phase was extracted several times with toluene. The combined organic phases were successively washed with 2N hydrochloric acid, water and 10% aqueous sodium hydroxide solution and subsequently dried with anhydrous sodium sulphate and evaporated. Fractional distillation gave the desired benzonitrile derivative. Yield 68% of theory; b.p. 90-92° C./0.1 mm.Hg; nD26 =1.5648.
Reaction SMILES: [O-2:1].[Mg+2:2].[O-2].[Ca+2:4].[Mg].[O-2].[Ca+2].[C:8](=[O:10])=[O:9]>O>[C:8](=[O:1])([OH:10])[O-:9].[Mg+2:2].[C:8](=[O:1])([OH:10])[O-:9].[C:8](=[O:1])([OH:10])[O-:9].[Ca+2:4].[C:8](=[O:1])([OH:10])[O-:9]
Reactant: O=C=O
Reactant: [O-2]
Agent: [Ca+2]
Agent: [Mg+2]
Agent: [Mg]
Solvent: O
Product: O=C([O-])O
Reaction time: 5 h

Procedure:
A mixture of magnesium oxide and calcium oxide, prepared from calcination of dolomite at 900° C. for 2 hours, is hydrated for 5 hours at 50° C. The weight ratio of water to magnesium/calcium oxide is 5:1. Then water is added into the mixture to prepare slurry at a weight ratio of water to magnesium/calcium oxide of 190:1. After that, carbon dioxide (75 vt %) is introduced into the slurry to react for 2 hours at 25° C. Subsequently, a pure aqueous solution of magnesium bicarbonate and calcium bicarbonate (MgO+CaO (90 wt % MgO): 5.1 g/L, Fe: 1.1 ppm, Al: 0.7 ppm) is obtained after clarification and filtration.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[NH2:23][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]1=[O:18]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: NC(=C1Sc2ccccc2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
35.1 gm (0.138 mol) of 2-benzoyl-benzo[b]thiophen-3-ol were dissolved in 35 cc of glacial acetic acid, followed by the addition of 39.0 gm (0.506 mol) of ammonium acetate and refluxing for two and a half hours. The still warm mixture was stirred into 300 cc of ice water, whereby a reddish product was precipitated. The solid was filtered off, dried in the air and recrystallized once from 60 cc of toluene. For further purification, it was dissolved in 30 cc of ethyl acetate, and just enough petroleum ether was added to ensure that no further precipitate forms (about 20 cc), after which 20 gm of activated carbon was added, followed by boiling and hot filtering. The pure end product was obtained from the cool filtrate by cooling to +10° C., adding 60 cc of petroleum ether, allowing the mixture to stand for two hours, and then suction-filtering. By concentrating the mother liquors to a volume of 30 cc and prolonged cooling to +10° C., 2.0 gm more of the desired product of the same quality were obtained. The combined crystalline product was thoroughly washed with a total of 20 cc of petroleum ether and freed from solvents in a circulating air drier at +70° C. 23.0 gm (66% of theory) of egg yellow crystals were obtained, m.p. 121.6°-122.5° C., and were found to be identical with the product of Example 1 based on elemental analysis, IR and UV spectra.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH:17]C(=O)OC(C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>C(O)(C)C>[N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([NH2:17])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Product: Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 90b; 1.7 g, 5 mmol) is treated with a solution of hydrogen chloride in isopropanol (30 mL of 4 M) and heated at 60° C. for 5 h. The solvent is evaporated off under reduced pressure and the residue is treated with aqueous sodium hydrogen carbonate solution (80 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether—hexane to afford the title compound as yellow crystalline solid, m.p. 96-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[Al](C)C.CCCCCC.C([O:20][C:21]([C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=1)=O)C>O1CCOCC1>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:21]([C:23]2[C:28]([Br:29])=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=2)=[O:20])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution 3-Amino-1-methyl-pyrazole (1.39 g, 14.3 mmol, 3.5 equiv.) in 25 ml of dry dioxane were added 7.17 ml of a 2M solution of trimethyl aluminium in hexane (14.3 mmol, 3.5 equiv.) and the mixture was stirred for 1 h at r.t. Then 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (1.00 g, 4.1 mmol) were added and the reaction was refluxed for 2 h. After allowing the reaction to cool to r.t., the reaction was quenched with water (0.5 ml), stirred for 10 min, dried by addition of magnesium sulfate and filtered over Dicalite which was further washed with methylene chloride. The filtrate was concentrated in vaccuo. The residue (1.66 g, yellow oil) was purified by flash chromatography (heptane/ethyl acetate 2:3) to yield the title compound as a yellow solid (total 0.99 g, 82%), MS (ISP): m/e=295.2, 297.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li][CH2:12]CCC.CI>C1COCC1>[CH3:12][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A solution of oxindole (665 mg, 5.0 mmol) in THF (10 ml) was treated dropwise with n-BuLi (4.4 ml, 11.0 mmol) at −78° C., stirred for 30 min. at −78° C. To the reaction methyliodine (2 ml) was added dropwise at −78° C. The resulting solution was warmed up to room temperature. The mixture was quenched with water. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered and concentrated under vacumm. Purification on silica gel with 30% ethyl acetate/hexane to provide the title compound (630 mg, 86%). MS (DCI/NH3) m/e 148 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[N:18]=[N:19][NH:20][N:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C1COCC1>[Br:1][C:2]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3cnc(-c4nn[nH]n4)cn3)CC2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1
Reaction time: 1 h

Procedure:
To a mixture of 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-5-(2H-tetrazol-5-yl)pyrazine from Step 6 (5.00 g, 11.9 mmol) and triethylamine (3.32 mL, 23.8 mmol) in THF (50 mL) at 60° C. was added tert-butyl bromoacetate (3.48 g, 17.9 mmol). After a period of 1 h at 60° C., the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. To the solid was added 50 mL of acetone followed by slow addition of 100 mL of hexane. The resulting solid was filtered to provide tert-butyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][NH:15]C(=O)C(F)(F)F)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.CN>CO>[NH2:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:23][CH:22]=1
Reactant: Nc1nccc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: CN
Solvent: CO
Product: NCc1ccc(COc2ccnc(N)n2)cc1
Temperature: 25 °C

Procedure:
50 mg (1.53 mmol) N-[4-(2-Amino-pyrimidin-4-yloxymethyl)-benzyl]-2,2,2-trifluoro-acetamide (5) is dissolved in 1 mL methanol and treated with 2 mL methylamine (33% in ethanol). The reaction mixture is stirred at room temperature over night and all volatiles are removed in vacuo. The product is used without further purification in the next step. ESI-MS m/z 231.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=2)[N:5]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH:9]([C:8]2[C:4]([CH2:3][O:2][CH3:1])=[N:5][N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]=3)[CH:7]=2)[OH:10])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution (100 mL) of 3-(methoxymethyl)-1-[6-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbaldehyde (5.3 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (25.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (4.6 g, 67%) as a pale-yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][Si:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][C:9](O)=[O:10]>ClCCCl>[CH3:5][Si:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][C:9]([Cl:3])=[O:10]
Reactant: C[Si](C)(C)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: C[Si](C)(C)CCC(=O)Cl
Temperature: 40 °C

Procedure:
13.5 g (0.11 mol) of thionyl chloride were added dropwise at room temperature to a solution of 10 g (0.068 mol) of 3-trimethylsilylpropionic acid in 50 ml of 1,2-dichloroethane. The mixture was heated at 40° C. for 2 hours, and the excess thionyl chloride was distilled under vacuum. A solution of 3-trimethylsilylpropionic acid chloride was obtained in 1,2-dichloroethane, which solution was used as is in the next step.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Cl:35])=[C:9]([Cl:26])[C:10]2[N:11]([C:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][N:15]=2)[CH:12]=1)=[O:6].CO.O.Cl>O>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:8]2[C:7]([C:5]([OH:6])=[O:4])=[CH:12][N:11]3[C:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:14][N:15]=[C:10]3[C:9]=2[Cl:26])=[C:29]([Cl:35])[CH:30]=1
Reactant: COC(=O)c1cn2c(CNCC(=O)OC(C)(C)C)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cn12
Yield: 84.8 %

Procedure:
Sodium hydroxide (1.0 M aqueous solution, 0.16 mL, 0.16 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (60) (15 mg, 0.026 mmol) in 4:1 MeOH/water (5 mL). When the reaction was complete, the solution was diluted with water, acidified to pH 3 by addition of 1.0 M aqueous HCl, and extracted with ethyl acetate. The organic extracts were dried over NaSO4, filtered, concentrated in vacuo to provide the desired product as a white crystalline solid (12 mg, 84%). MS (APCI−) m/z 541, 543, 545 (M-; Cl, Br pattern) detected.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16].[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>CO>[C:22]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: C=C1CC(=O)O1
Reactant: C=C(C)C(=O)NCCCN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
Triethylamine (24 g, 0.24 mole) was added dropwise at 0° C. to a solution of N-(3-aminopropyl)methacrylamide hydrochloride (40 g, 0.24 mole) and diketene (20 g, 0.24 mole) in methanol (800 ml). After addition, the temperature was maintained at 0° C. for 2 hours under stirring. Stirring was continued at 20° C. for 20 hours. The solvent was then removed. The residue was dissolved in chloroform (1 liter), washed with 5% hydrochloric acid (200 ml), washed with saturated NaHCO3 (200 ml), dried over anhydrous magnesium sulfate, and filtered. Excess solvent was removed. The residue was recrystallized from benzene (500 ml) and ethyl ether (500 ml) to give N-(3-acetoacetamidopropyl)methacrylamide (m.p.=93°-94° C.) at a yield of 50%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:4]=1)(=[O:16])[CH3:15]
Reactant: BrCc1cccc(-c2ccsc2)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1cccc(-c2ccsc2)c1
Yield: 41.8 %

Procedure:
A stirred solution of 8.7 g (0.034 mol) of 3-(3-bromomethylphenyl)thiophene and 5.1 g (0.051 mol) of potassium acetate in 65 mL of glacial acetic acid was heated under reflux for three hours. The reaction mixture was cooled and transferred to a separatory funnel, and 150 mL of water was added. The mixture was extracted with two portions of 120 mL each of methylene chloride. The combined extracts were washed with 150 mL of a saturated solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally 100 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give an oil residue. The residue was subjected to column chromatography on silica gel, eluting with hexane:methylene chloride (3:2). The appropriate fractions were combined to give 3.3 g of 3-(3-thienyl)phenylmethyl acetate.