Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:9]2[CH:14]3[CH2:15][C:16](=[O:18])[CH2:17][CH:10]2[CH2:11][O:12][CH2:13]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>[Pd].CCO>[CH:1]1([N:9]2[CH:14]3[CH2:15][C:16](=[O:18])[CH2:17][CH:10]2[CH2:11][O:12][CH2:13]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC2COCC(C1)N2C1C=CCCCCC1
Agent: [Pd]
Agent: O=C1CC2COCC(C1)N2C1/C=C\CCCCC1
Solvent: CCO
Product: O=C1CC2COCC(C1)N2C1CCCCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a manner similar to Example 32, the compound of formula MG, 9-((Z)-cyclooct-2-enyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one, was prepared from the compound of formula MF except that the compound of formula ME was used in place of the compound of formula JC (yield 90%). Under a hydrogen atmosphere, a mixture of the compound of formula MG, 5% palladium on carbon (1.0 g, Sigma-Aldrich), and EtOH (20 mL) was stirred at a temperature of about 25° C. for 4 h. After the Pd/C was filtered off, the filtrate was concentrated under reduced pressure to provide the compound of formula MH, 9-cyclooctyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>O.C(#N)C>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@:11]([CH2:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH3:23])([OH:12])[CH2:10]1
Reactant: Cc1ccccc1CBr
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1C[C@]1(O)C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO
Yield: 20.4 %

Procedure:
A 1.14 g quantity of potassium hydroxide was dissolved in a mixture of 33 ml of water and 16 ml of acetonitrile. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 1.50 g of 2-methylbenzyl bromide at room temperature with stirring. Then the same subsequent procedures as in Examples 4 and 5 were conducted, giving 0.29 g of the title compound in a yield of 20%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:7]1=[N:6]2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([NH:33][C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[O:18])[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Nc1nnn[nH]1
Reactant: Cc1sc(C)c2c(=O)n3cc(C(=O)O)ccc3nc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(C)c2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc12
Temperature: 105 °C
Yield: 62.6 %

Procedure:
A mixture of 0.6 g (0.0022 mol) of 1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (Example 48) and 0.84 g (0.005 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 90 ml of dimethylformamide is stirred and heated in a wax bath at 105° C. for eighty five minutes under nitrogen. The mixture is allowed to stand at room temperature for thiry minutes and then 0.225 g (0.0022 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for three and one-half hours. The solvent is evaporated and the residue suspended in hot methanol, cooled and 0.71 g of crude product is collected. This material is dissolved in hot pyridine, activated charcoal (Darco G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.47 g of 1,3-dimethyl-10-oxo-N-1H-tetrazol-5-yl- 10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with pyridine (1:0.2); mp >300° C. (dec).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:21][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: COc1cccc(CO)c1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COc1cccc(COc2cccc([N+](=O)[O-])c2C#N)c1
Yield: 83 %

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and 3-methoxybenzylalcohol in 83% yield. 1H NMR (400 MHz, d-DMSO) δ 3.75 (s, 3H), 5.38 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 4H), 7.93-7.87 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CCCN1c1ccc(Br)cc1C=O
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (15 g, 73.8 mmol) in DMSO (150 mL) and water (40 mL) were added 2-methylpyrrolidine (9.8 mL, 96 mmol) and sodium carbonate (15.7 g, 148 mmol). The resulting mixture was heated at 110° C. for 8 hours. The reaction mixture was cooled at RT, diluted with water (1000 mL) and extracted with MTBE (2×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a yellow oil (17 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 9.94 (1H, s), 7.75 (1H, s), 7.51 (1H, d), 6.93 (1H, d), 3.92 (1H, m), 3.68 (1H, m), 2.97 (1H, t), 2.49-2.18 (1H, m), 1.88 (1H, m), 1.57-1.68 (2H, m), 1.10 (3H, d).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: COCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A149) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: ON.Cl.[Br:4][C:5]1[CH:6]=[C:7]([C:11](=[O:17])[CH:12]=[CH:13][N:14](C)C)[CH:8]=[N:9][CH:10]=1>CO>[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[O:17][N:14]=[CH:13][CH:12]=2)[CH:8]=[N:9][CH:10]=1
Reactant: CN(C)C=CC(=O)c1cncc(Br)c1
Agent: Cl
Agent: NO
Solvent: CO
Product: Brc1cncc(-c2ccno2)c1

Procedure:
Hydroxyamine•hydrochloride (42 mg) was added to a methanol (2 ml) solution containing 1-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-ene-1-one obtained in the 1st step, followed by reflux for 2 hours. The solvent was distilled away under reduced pressure, and water was added to the obtained residue, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:3), and a white solid of 5-(5-bromopyridin-3-yl)isoxazole (59.5 mg) was thus obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl>[Br:14][C:8]1[CH:7]=[C:6]([NH:5][NH2:1])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A solution of sodium nitrite (3.16 g, 45.8 mmol) in water 30 ml was added dropwise over 30 minutes to a stirred suspension of 4-amino-2-bromoanisole (Desc. 4(a); 7.31 g, 36.2 mmol) in concentrated hydrochloric acid (50 ml), maintaining the temperature below 0° C. The mixture was stirred at ca. 0° C. for 30 minutes then added portionwise to a suspension of tin(II) chloride dihydrate (36.87 g, 163 mmol) in concentrated hydrochloric acid (50 ml) at -10° C. The resulting thick paste was stirred at -2° C. for 15 minutes, allowed to warm to room temperature over 20 minutes and stirred at room temperature for a further 20 minutes. The reaction mixture was recooled, basified with 10M sodium hydroxide solution and extracted with ethyl acetate (2×250 ml). The extracts were washed with brine (250 ml), combined, dried (MgSO4) and concentrated in vacuo to afford 3-bromo-4-methoxyphenylhydrazine (7.27 g, 93%); δH (250MHz, CDCl3) 3.84 (3H, s, ArOCH3), 6.75 (1H, dd, 8.8, 2.6Hz, 6-H), 6.83 (1H, d, 8.8Hz, 5-H), 7.11 (1H, d, 2.6Hz, 2-H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C@:5]1([CH:16]=[O:17])[CH2:7][C@H:6]1[C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].S(=O)(=O)(O)O>>[CH3:4][C@:5]1([C@H:16]([OH:17])[CH3:1])[CH2:7][C@H:6]1[C@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[Mg]Br
Reactant: C[C@@H](c1ccccc1)[C@@H]1C[C@]1(C)C=O
Agent: O=S(=O)(O)O
Product: C[C@@H](c1ccccc1)[C@@H]1C[C@]1(C)[C@@H](C)O
Reaction time: 1 h
Yield: 66.9 %

Procedure:
Under a nitrogen atmosphere, methyl magnesium bromide (0.97 mol/L, tetrahydrofuran solution, 8.5 ml, 8.25 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −10° C. (1S*,2S*)-1-Methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde (1.03 g, 5.5 mmol) was placed into the dropping funnel, and added dropwise in 5 minutes with the temperature kept at −10° C. After stirring for 60 minutes, a 20% aqueous sulfuric acid solution (4.5 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). (R*)-1-[(1S*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl]ethanol (0.75 g, 3.68 mmol, 67% yield) was obtained as the main isomer, and (S*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl]ethanol (0.205 g, 1.0 mmol, 18% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].Cl>O1CCCC1>[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-Aminocaproic acid (10.0 g) in a 1.27 M aqueous sodium hydroxide solution (60 ml) was added a solution of acryloyl chloride (7.8 ml) in tetrahydrofuran (20 ml) dropwisely while chilling in ice water. During the addition, the reaction mixture was adjusted to be pH 8 to 9 by addition of 4 N aqueous sodium hydroxide solution. After the addition, the resulting mixture was stirred for 2 hours while being gradually cooled to room temperature. Subsequently, the reaction mixture was adjusted to be pH 3 by addition of 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with distilled water and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and recrystallized from hexane to give the target compound (9.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1>O1CCCC1.C(N(CC)CC)C.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Fc1ccc(-c2onc3ccccc23)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a suspension of (16) (42.6 g, 0.2 mol) in 750 ml of dry tetrahydrofuran (THF) and 20 ml of triethylamine is added 5% palladium on charcoal (6 g). The vigorously stirred suspension is flushed with hydrogen gas and stirred at room temperature under a hydrogen atmosphere until absorption of hydrogen ceases (approximately 90-90% of the molar amount; 8-10 hours). The catalyst is removed by filtration through a bed of celite, and the solvent is removed under reduced pressure. The product (16) is recrystallized from toluene.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[CH2:6]([O:8][C:9](=[O:13])[CH2:10][C:11]#[N:12])[CH3:7].C(N(CC)CC)C>O>[CH2:6]([O:8][C:9](=[O:13])[CH:10]([C:11]#[N:12])[C:4](=[S:5])[NH:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOC(=O)CC#N
Reactant: CCN=C=S
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=S)C(C#N)C(=O)OCC
Temperature: 50 °C

Procedure:
4.25 ml of ethyl isothiocyanate is added to a mixture that consists of 5 g of cyanoacetic acid ethyl ester and 5 ml of triethylamine at 25° C. Then, it is allowed to stir for 6 more hours at 50° C. Then, the reaction mixture is concentrated by evaporation in a vacuum. The residue is taken up in ethanol and poured into 150 ml of ice-cold IN hydrochloric acid. It is allowed to stir for 3 more hours at 25° C., and then the residue is filtered off. The solid that is obtained is rewashed with water. 7 g of product is obtained.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[C:7]2[C:8](=[CH:14][N:15]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:16]=2)[C:9](=[O:13])[N:10]([CH3:12])[N:11]=1>C(O)C>[CH3:12][N:10]1[C:9](=[O:13])[C:8]2=[CH:14][N:15]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[CH:16]=[C:7]2[C:6]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:11]1
Reactant: CC(C)N
Reactant: Cn1nc(Cl)c2cn(Cc3cccc4ccccc34)cc2c1=O
Solvent: CCO
Product: CC(C)Nc1nn(C)c(=O)c2cn(Cc3cccc4ccccc34)cc12
Temperature: 200 °C
Reaction time: 24 h

Procedure:
Isopropylamine (1 ml) was added to a solution of 4-chloro-2,6-dihydro-2-methyl-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazine-1-one (0.095 g) in ethanol (4 ml) and the mixture was heated in a sealed tube at 200° C. for 3 days then at 250° C. for 24 hours. The mixture was evaporated and the residue was purified by column chromatography, eluting with ethyl acetate followed by recrystallisation from ethyl acetate/isohexane to give the title compound (0.013 g).
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[C:2]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([C:5]4=[O:12])[CH2:3]2)[CH2:9]3)[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1C2CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 154.1 %

Procedure:
To a stirred solution of compound 5-hydroxyadamantan-2-one (10.0 g, 60.2 mmol) in benzene (180 mL) was added trifluoromethanesulfonic acid (5.3 mL, 60.2 mmol) over a period of 30 minutes at r.t. After stirring the reaction mixture for 5 minutes at r.t, it was refluxed for 4 h. The reaction mixture was cooled to 0° C. and sat. aq. NaHCO3 (76 mL) was added over a period of 30 minutes. Two layers were separated, the aqueous layer was extracted with ether and the combined layer was washed with water and brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 5-Phenyladamantan-2-one (10.5 g) as a white solid in 80% yield. M.R: 53.8-60.9° C. m/z (M+1) 227; IR (cm−1): 2921, 2853, 1717, 1446, 1060, 758, 698. 1H NMR (CDCl3) 300 MHz δ 7.37-7.30 (m, 4H), 7.26-7.19 (m, 1H), 2.70-2.63 (m, 2H), 2.30-2.0 (m, 11H). 13C NMR (CDCl3) 75 MHz δ 217.8, 147.8, 128.3 (2C), 126.1, 124.6 (2C), 46.9 (2C), 44.3 (2C), 41.9, 35.9, 38.4 (2C), 28.0.
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][C:12]1([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.S(Cl)(Cl)=O>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([N:1]([CH2:8][C:9]([O:11][C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC1(OC(=O)CNc2ccccc2)CCCCC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC2(C)CCCCC2)c2ccccc2)c1
Yield: 11.4 %

Procedure:
The procedure is carried out in a manner analogous to that described in Example 1, but using 3.0 g of 1-methylcyclohexyl 2-anilinoacetate, 2.5 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 0.9 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 40 g of silica (0.063-0.200 mm) contained in a column 1.5 cm in diameter [eluent: cyclohexane/ethyl acetate (70/30 by volume)], collecting 20-cm3 fractions. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After-recrystallization from an acetonitrile/diisopropyl ether mixture (50/50 by volume), 0.6 g of 1-methylcyclohexyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 192° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].Cl[CH2:12][C:13]([CH3:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH2:12][C:13](=[O:14])[CH3:15]
Reactant: CC(=O)CCl
Reactant: Oc1c(Br)cc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)COc1c(Br)cc(Br)cc1Br
Temperature: 27 °C
Yield: 96.5 %

Procedure:
A mixture of 5 g 2,4,6-tribromophenol (15 mmol), 1.4 g 1-chloroacetone (15 mmol), 4.16 g anhydrous potassium carbonate (30 mmol) and 20 ml DMF is stirred at 27° C. Completion of the reaction is confirmed by TLC. The reaction mass is diluted with water and extracted with ethylacetate The organic layer is washed with water and brine, dried over anhydrous sodium sulphate and concentrated to obtain 5.6 g 1-(2,4,6-tribromo-phenoxy)-propan-2-one (97%).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18](B(O)O)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O.C1(C)C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:2]3[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: Cn1nccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1nccc1-c1cnn(-c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-iodo-1-methyl-1H-pyrazole (600 mg), [1-(4-fluorophenyl)-1H-pyrazol-4-yl]boronic acid (650 mg), tetrakistriphenylphosphine palladium (166 mg), 2 M sodium carbonate aqueous solution (2.9 mL), ethanol (3.0 mL) and toluene (6.0 mL) was stirred at 100° C. for 4 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=9:1 to ethyl acetate), so as to obtain the title compound (450 mg) in the form of a light yellow solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22](O)=[O:23])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([N:58]2[CH2:63][CH2:62][N:61]([C:64]3([CH2:70][N:71]4[CH2:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:72]4=[O:80])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][CH2:59]2)[CH2:57][CH2:56]1>ClCCl>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:67]2[CH2:66][CH2:65][C:64]([N:61]3[CH2:62][CH2:63][N:58]([CH:55]4[CH2:56][CH2:57]4)[CH2:59][CH2:60]3)([CH2:70][N:71]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[C:72]3=[O:80])[CH2:69][CH2:68]2)=[O:23])[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Reactant: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)N2CCC(CN3Cc4ccccc4C3=O)(N3CCN(C4CC4)CC3)CC2)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)ethoxy)acetic acid AC7 (0.306 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4.0 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of 2-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isoindolin-1-one AM13 (1.2 equiv) in dichloromethane (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 50%. MS, Rt=3.4 min, m/z=694.5 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=O)[OH:9])=[C:4]([CH3:19])[C:3]=1[CH3:20].N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([Cl:29])([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:4]([CH3:19])[C:3]=1[CH3:20]
Reactant: Cc1ccc(P(=O)(O)C(=O)c2ccccc2)c(C)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(P(=O)(Cl)C(=O)c2ccccc2)c(C)c1C
Temperature: 0 °C

Procedure:
250 g of the acid from Example 2 were suspended in 670 ml of toluene and dissolved with 102.6 g of pyridine. 1546 g of thionyl chloride were added dropwise to the reaction mixture at 60° C. over the course of 1 hour. After a post-reaction time of 3 hours, the red-brown emulsion was cooled to 0° C., and the rust-brown crystals were filtered off. The solution which remained was evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12]([NH:16][C:17]1[O:18][C:19]([C:26](Cl)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:13][C:12]([NH:16][C:17]1[O:18][C:19]([C:26]([NH:4][CH2:3][CH2:1][OH:2])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)NCCO)o1
Yield: 34.3 %

Procedure:
By the procedure of Example 38, a stirred mixture of 50 ml methylene chloride, 0.70 g (11.46 mmol) of ethanolamine, 1.27 g (12.61 mmol) of triethylamine, and 3.1 g (11.46 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride, was reacted for 64 hours at ambient temperature. The product was separated and then recrystallized to yield 1.16 g of a yellow solid product (m.p.=154°-156° C.) identified in Table 1.