Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>C(Cl)Cl>[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC[C@@H]1CCCN1
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (S)-(+)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.12 (d, J=17 Hz, 1H), 3.90 (s, 3H), 3.85 (m, 2H), 3.51 (m, 2H), 3.44 (m, 2H), 3.15 (s, 1H), 2.38 (s, 3H), 1.94 (m, 3H), 1.72 (m, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2=[O:15])=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2([OH:15])[CH3:1])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=C1c2cc(Br)ccc2CCC1Cc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)c2cc(Br)ccc2CCC1Cc1cccnc1
Reaction time: 10 h

Procedure:
Methyl magnesium bromide (15 ml of a 3M solution in ether) was added dropwilse over 5 minutes to a stirred solution of 7-bromo-2-(3-pyridylmethyl)-1-tetralone (3.20 g) in dry tetrahydrofuran (50 ml). The resulting mixture was heated under reflux with stirring for 10 hours and then cooled. An excess of aqueous ammonium chloride solution was added and the mixture was extracted several times with ether. The combined ethereal extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave 7-bromo-1-hydroxy-1-methyl-2-(3-pyridylmethyl)-1,2,3,4-tetrahydronaphthalene (2.87 g) as a mixture of isomers which was used directly in the next stage.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH3:17])[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1.[Cl:27][C:28]1[N:33]=[C:32](Cl)[CH:31]=[CH:30][N:29]=1.O>C(COC)OC>[Cl:27][C:28]1[N:33]=[C:32]([C:12]2[C:13]([CH3:17])=[C:14]([C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH:15]=[O:16])[CH:31]=[CH:30][N:29]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccnc(Cl)n2)c(C)c1C=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
A 2 M aqueous solution of sodium carbonate (2.72 mL, 5.43 mol) and tetrakistriphenylphosphine palladium(0) (209 mg, 0.181 mmol) were added to a suspension of the 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde obtained in Example 4-1 (500 mg, 1.81 mmol) and 2,4-dichloropyrimidine (405 mg, 2.72 mmol) in dimethoxyethane (5.4 mL) at room temperature. The mixture thus obtained was stirred at 80° C. for 10 hours. Thereafter, the resulting solution was cooled to room temperature. Water was added to the reaction solution, and the precipitated crude product was collected by filtration and was then washed with water and diisopropyl ether to obtain the title compound (418 mg, yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)[NH:7][C:6]2=1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:28]=2[O:27][CH2:26]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:35]([C:32]4[CH:33]=[CH:34][C:28]5[O:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=5[CH:31]=4)=[O:36])[CH2:19][CH2:18]3)[NH:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N)CC1)CO3
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CO4)CC1)CO3

Procedure:
The titled compound is prepared as an off-white solid following Scheme 5 and in analogy to Example 27 using trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>CO>[CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: COC(=O)COc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc2cnccc12
Yield: 85 %

Procedure:
To an ice-cooled solution of 29.0 g of 5-hydroxyisoquinoline in 300 ml of DMF, 11.0 g of sodium methylate was added portionwise. After stirring for 30 min, 17.9 ml of methyl chloroacetate was added dropwise, and the resultant mixture was stirred at room temperature overnight and concentrated under reduced pressure. To the residue, 300 ml of toluene and 300 ml of water were added, and the whole mixture was filtered. The aqueous layer was extracted with 50 ml of toluene, and the combined toluene solution was treated with 2 g of charcoal and evaporated to give methyl 5-isoquinolyloxyacetate. The ester was dissolved in 100 ml of methanol, reacted with 80 ml of 3 N sodium hydroxide aqueous solution for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with 80 ml of water and 160 ml of acetone, and neutralized with 20 ml of concentrated hydrochloric acid. The precipitates formed were filtered, washed with 80 ml of 50% aqueous acetone, and dried to give 34.5 g (85% yield) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate (0.26 g) in methanol (2.6 mL) and ethyl acetate (1.3 mL), 10% palladium-carbon (0.26 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.13 g of tert-butyl 2-(2-hydroxy-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=[CH:4]1)[CH3:2]>CC(=O)OCC.[Pd]>[CH2:10]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[CH3:11]
Reactant: CCC1(CC)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1(CC)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.6 %

Procedure:
A solution of 4,4-diethyl-cyclohex-2-enone (10.7 g, 70.5 mmol) in EA (400 mL) is treated with Pd/C (1.0 g, 10% Pd). The suspension is stirred at rt for 24 h under 1 bar of H2. The mixture is filtered, and the filtrate is evaporated to give 4,4-diethyl-cyclohexanone (11.7 g) as a colourless solid; 1H NMR (CD3OD): δ 2.32 (t, J=7.0 Hz, 4H), 1.66 (t, J=7.0 Hz, 4H), 1.48 (q, J=7.6 Hz, 4H), 0.88 (t, J=7.6 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide (40 mg, 0.12 mmol) and diisopropylethylamine (0.1 mL, 0.59 mmol) in methylene chloride (1.0 mL) was added benzoyl chloride (15 uL, 0.13 mmol) and stirred at room temperature for 30 min. The crude reaction was purified by ISCO Companion (silica, (silica, 0-5% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-benzoylamino-ethyl)-amide (48 mg, 48%). LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.36 (1H, s) 8.55 (1H, s) 8.24 (1H, br. s.) 8.00 (1H, d, J=5.27 Hz) 7.73-7.85 (3H, m) 7.43-7.52 (2H, m) 7.35-7.42 (2H, m) 7.28 (1H, d, J=3.32 Hz) 6.82 (1H, d, J=5.47 Hz) 6.40 (1H, d, J=3.51 Hz) 3.39-3.45 (4H, m)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][S:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH2:13][CH2:14][S:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 83.8 %

Procedure:
9.5 g of N-benzyloxycarbonyl-DL-methionine, 3.4 g of triethylamine, 150 ml of chloroform, 3.7 g of ethyl chlorocarbonate and 3.4 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 10.3 g (yield: 84%) of 2-(N-benzyloxycarbonyl-DL-methionylamino)-1,3,4-thiadiazole as white crystals having a melting point of 155°-159° C.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]C)=[O:11])[C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>CO.O>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1noc(CC(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Cc1onc(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of methyl 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carboxylate (0.816 g, 3.25 mmol) and lithium hydroxide hydrate (0.136 g, 3.25 mmol) in methanol (18 mL) and water (9.00 mL) was stirred at room temperature overnight. HPLC and LCMS analysis indicated that the hydrolysis was complete. The reaction mixture was concentrated under reduced pressure, and the residue dissolved in 1N aqueous hydrochloric acid and extracted with ether. The organic layer was collected and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (0.746 g, 3.15 mmol, 97% yield) as an off-white solid. The product had an HPLC ret. time=2.00 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 0.93 (s, 3H), 1.97-2.09 (m, 1H), and 2.89 (d, J=7.28 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23](Cl)(=O)[C:24](Cl)=O.[CH2:29](Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([C:18]([F:20])([F:19])[F:21])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([O:6][CH:23]([CH3:24])[CH3:29])=[O:5]
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 60 °C
Yield: 70 %

Procedure:
To a solution of 4.3 g (0.012 mole) 2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorobenzoic acid in 50 mL methylene chloride was added 3.1 mL (0.036 mole) oxalyl chloride causing the evolution of gas. When this evolution ceased, one drop of DMF was added and the solution stirred until the gas evolution ceased. The solution was concentrated in vacuo and the resultant residue dissolved in 25 mL isopropanol and heated to 60° C. for 1 hour. The solution was cooled, poured into 200 mL cold water and the solid filtered and dried. The product was recrystallized from ethanol/water to yield 1.69 g (70%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzoic acid, 1-methylethyl ester as a white solid; mp 69° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].C(N(C(C)C)C(C)C)C.FC(F)(F)S(O[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])(=O)=O.C(C1N=C(C2CCN(C(=O)CN3C(C)=CC(C(F)(F)F)=N3)CC2)SC=1)(=O)C.[CH3:62][C:63]1[N:67]([CH2:68][C:69]([N:71]2[CH2:76][CH2:75][CH:74]([C:77]3[S:78][CH:79]=[C:80]([C:82](=[N:84][O:85]CCCCC4C=CC=CC=4)[CH3:83])[N:81]=3)[CH2:73][CH2:72]2)=[O:70])[N:66]=[C:65]([C:96]([F:99])([F:98])[F:97])[CH:64]=1>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]([O:5][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])[CH2:83][C:82]([C:80]1[N:81]=[C:77]([CH:74]2[CH2:75][CH2:76][N:71]([C:69](=[O:70])[CH2:68][N:67]3[C:63]([CH3:62])=[CH:64][C:65]([C:96]([F:98])([F:99])[F:97])=[N:66]3)[CH2:72][CH2:73]2)[S:78][CH:79]=1)=[N:84][OH:85]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(=NOCCCCc1ccccc1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(CC(O[Si](C)(C)C(C)(C)C)c3c(F)cccc3F)=NO)cs2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-difluorobenzaldehyde (0.177 g, 1.25 mmol) in dichloromethane (5 mL) was added N-ethyl-N-(1-methylethyl)-2-propane amine (0.436 ml, 2.5 mmol) and 1,1,1-trifluoro-methanesulfonic acid, (1,1-dimethylethyl)dimethylsilyl ester (0.430 mL, 1.875 mmol). The reaction was stirred for 15 minutes and a solution of 1-[4-(4-acetyl-2-thiazolyl)-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (i. e. the product of Example 1, Step D) (0.5 g, 1.25 mmol) dissolved in dichloromethane (2 mL) was added dropwise over 5 minutes. The resulting reaction was stirred for 6 hours and concentrated under reduced pressure. The residue was purified via silica gel chromatography (20% ethyl acetate: hexanes to 100% ethyl acetate eluant) to provide 0.62 g of the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5]1=O)(=O)[NH2:2]>C1COCC1>[NH2:2][CH2:1][CH:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: NC(=O)C1CCN(Cc2ccc(Cl)cc2)C1=O
Solvent: C1CCOC1
Product: NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 15 h
Yield: 66.7 %

Procedure:
To a solution of 3-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.45 g) in THF (15 mL) was added 1.0 N BH3 in THF (25 mL). The reaction mixture was stirred at 65° C. for 15 h. After cooling to room temperature, the solvent was removed under reduced pressure. Water (30 mL) and conc. HCl (10 mL) were added and the mixture was stirred at 100° C. for 2 h and room temperature for 1 h. 2 N NaOH aqueous solution (100 mL) was added and the mixture was extracted with AcOEt (50 mL×3). The combined organic layers were dried over K2Co3, filtered and concentrated. Column chromatography (SiO2, 15% CH3OH-5%. Et3N in CH2Cl2) afforded 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 19%) as a colorless oil.
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:17][O:18][NH:19][CH3:20].C(N(CC)CC)C>ClCCl>[CH3:17][O:18][N:19]([CH3:20])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([S:2]([F:15])([F:14])([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Yield: 51 %

Procedure:
4-(Pentafluoro-λ6-sulfanyl)benzoyl chloride (1.00 g, 3.751 mmol), O,N-dimethyl-hydroxylamine hydrochloride (0.402 g, 4.13 mmol), and triethylamine (0.835 g, 8.25 mmol) were stirred in dichloromethane for 2 hours at room temperature. The reaction was concentrated in vacuo and diethyl ether added. The solid was collected by filtration and purified by silica gel column chromatography to afford the title compound as a solid (0.557 g, 51% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[N:3]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=431.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[Cl-].[CH2:12]1[CH2:16]OC[CH2:13]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:16][CH:12]=[CH2:13])=[CH:4][C:3]=1[F:10]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: [Cl-]
Product: C=CCC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the aldehyde from Step F (7.97 g, 39.1 mmol) in 40 mL of THF at −78° C. under argon was added dropwise a solution of allymagnesium chloride in THF (23.4 mL, 46.9 mmol, 2M). After one hour, another portion of allymagnesium chloride solution was added (5 mL, 10 mmol). After an additional 30 minutes, the solution was quenched with saturated aqueous ammonium chloride, warmed to room temperature, and poured into ethyl acetate. The solution was washed with washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([O:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:16]([O:32][C:33]1[S:34][C:35]([CH:9]=[O:10])=[CH:36][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CN(C=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOc1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(C=O)s1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a cooled mixture of 27 g of N-methylformanilide and 27 g (0.176 mole) of phosphorus oxychloride is added 32.5 g (0.1 mole) of 2-hexadecyloxythiophene. The mixture is warmed to 70° C under vacuum (10 mm Hg). The mixture is allowed to stand at 60°-70° C for 7 hours, then overnight at room temperature after which the mixture is stirred into 100 g of ice. The mixture is extracted into benzene, washed with water, dried over sodium sulfate and distilled in vacuo to give 5-hexadecyloxy-2-thiophenecarboxaldehyde. The carboxaldehyde (7.1 g, 0.02 mole) is stirred vigorously with 4 g of potassium hydroxide in 2.6 ml of water for 24 hours. The mixture is diluted with water and extracted into ether. The aqueous layer is separated and acidified with hydrochloric acid precipitating 5-(hexadecyloxy)-2 -thiophenecarboxylic acid.
Reaction SMILES: [IH:1].[NH2:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[NH:5].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=O>C(O)(=O)C>[IH:1].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=[N:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[NH:5]
Reactant: N=C(NN)NCc1ccncc1
Reactant: Cc1cccc(C)c1C=O
Agent: I
Solvent: CC(=O)O
Product: Cc1cccc(C)c1C=NNC(=N)NCc1ccncc1

Procedure:
A mixture of 2.93 g. of 1-amino-3-(4-pyridylmethyl)guanidine hydriodide and 1.34 g. of 2,6-dimethylbenzaldehyde in 5 ml. of glacial acetic acid is heated at 100° C. After 2 hours the solidified reaction mixture is triturated with water and filtered. Crystallization from absolute ethanol gives the desired product as colorless granular crystals, m.p. 197°-200° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7](OC)(OC)[O:8]C.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CO>[CH3:14][O:3][C:2]([CH:4]1[CH2:6][CH2:5]1)([O:8][CH3:7])[CH3:1]
Reactant: CC(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)(OC)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 50 g (0.59 mol) of cyclopropyl methyl ketone, 82 g (0.77 mol) of trimethyl orthoformate, 200 ml of methanol and 0.25 g of p-toluenesulfonic acid was stirred at room temperature for 2 hours, and then 0.15 g of sodium methoxide was added. Then, under reduced pressure, the methanol was first distilled off (at about 400 mbar) and, finally (at about 250 mbar), the product (II) as a colorless liquid.