Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]=[O:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([CH:10]([OH:11])[CH3:24])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(C)O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
The product from Example 21A (450 mg, 1.28 mmol) in THF (20 mL) was treated dropwise with methylmagnesium bromide (0.85 mL, 2.55 mmol) at −40° C. The reaction was stirred at −40° C. for 1.5 hrs, quenched with saturated NH4Cl and the mixture was extracted with EtOAc (2×). The organics were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 10-80% ethyl acetate/hexane) to afford 220 mg (47%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.64 (d, J=6.44 Hz, 3 H) 1.67 (s, 9 H) 3.70-3.78 (m, 1 H) 3.93 (s, 3 H) 5.19 (q, J=6.44 Hz, 1 H) 6.93 (d, J=8.90 Hz, 1 H) 7.37 (dd, J=8.59, 2.76 Hz, 1 H) 7.97 (s, 1 H) 8.06 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 369 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:8][CH:7]=1)C.[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:4]([N:28]([CH2:27][CH:26]([O:30][CH3:31])[O:25][CH3:24])[CH3:29])=[O:23])=[CH:11][CH:10]=1
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Product: COC(CN(C)C(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)OC
Temperature: 120 °C

Procedure:
Ethyl[4-[3-(trifluoromethyl)phenoxy]-phenyl]carbamate (7.1 grams; 0.02 mol) and N-(2,2-dimethoxyethyl) methanamine (15 ml) were charged into a glass reaction vessel equipped with mechanical stirrer, thermometer and reflux condenser. The mixture was refluxed for about 36 hours at a temperature of about 120° C. The product was recrystallized from ethyl acetate, then recrystallized from hexane giving the desired product having a melting point of 86°-88° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([O:15]CC)=O.[NH2:18][NH2:19]>C(O)C>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([NH:18][NH2:19])=[O:15]
Reactant: CCOC(=O)c1nc(-c2cccnc2)[nH]c1C
Reactant: NN
Solvent: CCO
Product: Cc1[nH]c(-c2cccnc2)nc1C(=O)NN
Temperature: -10 °C

Procedure:
A solution of 32 g of 5-methyl-2-(3-pyridinyl)-1H-imidazole-4-carboxylic acid, ethyl ester (prepared as described above) in ethanol was heated to boiling. A 79 ml portion of hydrazine was added. This mixture was stirred at reflux for 14 hours and then cooled to -10° C. The mixture was taken to dryness in vacuo and then evaporated to dryness in vacuo twice from 125 ml portions of methyl cellosolve. The residue was shaken with 100 ml of ethanol and the solids collected, washed with 100 ml of ethanol and two 100 ml portions of ether and dried at 60° C. in vacuo, giving 18.7 g of 5-methyl-2-(3-pyridinyl)-1H-imidazole-4-carboxylic acid, hydrazide.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3]([CH:9]=O)=[CH:2]2.[ClH:11].[NH2:12][OH:13]>CO.C(O)(C)C>[ClH:11].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3]([CH:9]=[N:12][OH:13])=[CH:2]2
Reactant: O=CC1=CN2CCC1CC2
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: ON=CC1=CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
1-Azabicyclo[2.2.2]oct-2-ene-3-carboxaldehyde (1 g, 7.29 mmol) was dissolved in 50 ml of methanol. Hydroxylamine hydrochloride was added to the solution and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to afford a white crystalline residue. The crystalline residue was suspended in 50 ml of isopropanol and refluxed for 15 minutes A crystalline material separated to afford the desired oxime (1.08 g, 75%), mp 227°-229° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.[C:9]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:33](O)=[O:34])[CH3:32])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:33](=[O:34])[C@H:31]([CH3:32])[NH:30][C:28](=[O:29])[C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[S:6][N:5]=1
Reactant: COc1nsc(N)n1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nsc(NC(=O)[C@H](C)NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-3-methoxy-[1,2,4]thiadiazole (0.37 g, 2.8 mmol) and N-carbobenzyloxy-L-phenylalanyl-L-alanine, N-Cbz-Phe-Ala-OH, (1.0 g, 2.7 mmol) in DMF (25 mL) was added 1,3-dicyclohexylcarbodiimide, DCC, (0.56 g, 2.7 mmol). After stirring for 30 min, 1-hydroxybenzotriazole hydrate, HOBT, (0.36 g, 2.7 mmol) was added and the resulting mixture was stirred at room temperature for 20 h. Volatile materials were removed in vacuo and the residue was purified by column chromatography on silica gel using a solvent mixture of dichloromethane and methanol (96/4) thereby affording the title compound as a white solid (1.2 g). Further purification by cristallization and chromatography on silica gel gave 3-methoxy-5-(N-carbobenzyloxy-L-phenylalanyl-L-alaninamido]-[1,2,4]thiadiazole (0.87 g, 67% yield). M.p. 161-162° C.; 1H-NMR (CDCl3) 7.14-7.38 (m, 12H, 10Ar—H and 2 NH), 5.92 (br. s, 1H, NH), 5.06 (s, 2H, OCH2), 4.38 (m, 1H, CHCH2Ar), 4.00 (m, 1H, CHCH3), 3.97 (s, 3H, OMe), 3.00-3.08 (m, 2H, CHCH2Ar), 1.34 (d, J=8.9 Hz, 3H, Me); MS (m/z) 484 (M++1), 416, 361, 316, 285, 185, 132, 75. The latter compound was also prepared by using diphenylphosphoryl azide and triethylamine instead of DCC/HOBT in 27.7% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1ccc(-c2oncc2CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(C)cc1
Yield: 79 %

Procedure:
A mixture of 3-[5-(4-methylphenyl)-4-isoxazolyl]propionic acid (4.00 g), conc. sulfuric acid (2 ml) and methanol (80 ml) was refluxed for 1 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-methylphenyl)-4-isoxazolyl]propionate (3.35 g, yield 79%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:7, volume ratio). NMR (CDCl3) δ: 2.41 (3H, s), 2.63 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 3.68 (3H, s), 7.30 (2H, d, J=8 Hz), 7.59 (2H, d, J=8 Hz), 8.20 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Yield: 16 %

Procedure:
Using a procedure similar to that of Example 5, with 7-(4-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and methanesulfonyl chloride as starting materials, 30 mg (16%) of the desired product was Isolated. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1 H), 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.10 (s, 3H); ES-MS m/z 510.17 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 110 °C
Reaction time: 24 h
Yield: 141.7 %

Procedure:
In 300 mL of dimethyl sulfoxide were suspended 181.8 g (560 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 100.0 g (374 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate and 79.18 g (747 mmol) of sodium carbonate, which were then heated to 110° C. while bubbling a nitrogen gas and stirred for 24 hours. After cooling to room temperature, 1000 mL of ethyl acetate and 1000 mL of water were added, followed by separation into two layers. The organic layer was washed with 500 mL of water twice and concentrated under reduced pressure. To the residue was added 500 mL of ethanol and concentrated under reduced pressure to yield 294.6 g of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily material (HPLC purity area percentage 76.6%). This oily material was dissolved in 700 mL of ethanol, and 29.88 g of sodium hydroxide dissolved in 300 mL of water was added thereto. The reaction solution was heated to 60° C. and stirred for 1 hour. The reaction solution was concentrated under reduced pressure. To the residue were added 1000 mL of water and 1000 mL of ethyl acetate, followed by separation into two layers. The aqueous layer was washed with 500 mL of ethyl acetate twice, and 1000 mL of ethanol was added to the aqueous layer. The aqueous layer was adjusted to about pH 6 by the addition of 500 mL of 1N hydrochloric acid and stirred at room temperature for 30 minutes and at 10° C. for 1 hour. The crystals formed were collected by filtration, washed with 400 mL of water and 400 mL of ethanol:water (1:1), and dried to yield 159.5 g of the title compound. HPLC purity area percentage 98.0%, Yield 74.1%.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([S:1][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
Combine 4-mercapto-benzaldehyde (0.45 g, 3.3 mmol), 6-chloro-nicotinamide (0.52 g, 3.3 mmol), potassium carbonate (0.7 g, 5.1 mmol), and dimehtylformamide (15 mL) then heat at 70° C. overnight. Cool to room temperature, pour into water, and then extract with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (1 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-formyl-phenylsulfanyl)-nicotinamide (120 mg). 1H NMR (DMSO-D6, 300.00 MHz): 10.08 (s, 1H), 8.91 (dd, 1H, J=2.3, 0.7 Hz), 8.18-8.12 (m, 2H), 8.03-7.98 (m, 2H), 7.83-7.78 (m, 2H), 7.61 (s, 1H), 7.34 (dd, 1H, J=8.4, 0.8 Hz). Step 3 6-[4-(Benzylamino-methyl)-phenylsulfanyl]-nicotinamide
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with THF (15 mL), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.00 g, 3.73 mmol), 3-aminopyridine (351 mg, 3.73 mmol) and sodium tert-butoxide (789 mg, 8.21 mmol). After bubbling nitrogen through the resulting solution for 30 min, Pd2Br2(t-Bu3P)2 (29 mg, 0.037 mmol) was added, and the reaction mixture was stirred at room temperature for 2.5 h. After this time the reaction was partitioned between ethyl acetate (50 mL) and water (50 mL) and filtered. The aqueous layer was separated and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 35% yield (370 mg) of 112a as a brown solid: mp>250° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.08 (d, 1H, J=2.5 Hz), 8.32 (m, 1H), 8.24 (dd, 1H, J=5.0, 1.5 Hz), 7.40 (s, 1H), 7.36 (dd, 1H, J=8.5, 4.5 Hz), 3.45 (s, 3H); MS (APCI+) m/z 281.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:24][CH2:25][O:26][C:27]4[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=4[C:29]([OH:31])=[O:30])[CH2:21][CH2:22]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3cccs3)c2c1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3cccs3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.1 g (0.33 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole (example 82, part B) and 0.092 g (0.42 mmol) 2-(2-chloro-ethoxy)-benzoic acid acid methyl ester. The crude mixture was purified by HPLC-MS using a C-18 column.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)c1
Reaction time: 5 h

Procedure:
A microwave vial was charged N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 650 mg, 2.02 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 403 mg, 2.22 mmol) and DIPEA (1058 μl, 6.06 mmol) in dry DMSO (6.7 ml). The reaction was subjected to microwave irradiation at 120° C. for 2 hours and then at 140° C. for 5 hours. Upon cooling the mixture was partitioned between ethyl acetate and water, washing with water and brine, dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by column chromatography (basic silica 0-100% DCM/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH2:21])=[N:18][C:17]=2[CH3:22])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>CN(C)C=O>[CH2:1]([NH:3][C:4]([NH:21][C:19]1[S:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:15][CH:14]=2)=[C:17]([CH3:22])[N:18]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 85 °C

Procedure:
Ethyl isocyanate (0.09 ml, 1.1 mmol) is added to a stirred solution of 5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.10 g, 0.37 mmol) in dimethylformamide (1.0 ml). The mixture is heated at 85° C. for 90 minutes followed by removal of the solvent. The residue is crystallised from ethyl acetate—methanol to afford the title compound. MH+ 340.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH2:40][CH2:41][CH:42]1[CH2:44][CH2:43]1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:40][CH2:41][CH:42]2[CH2:44][CH2:43]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: NCC1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCC2CC2)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and (aminomethyl)cyclopropane.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:38]2[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=2)OCCCO1>O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1cncc(B2OCCCO2)c1
Solvent: O
Product: CCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 59.2 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (9.24 g, 18.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (3.39 g, 20.8 mmol) were coupled according to the method described in Examples 118–121. Additional reagents were added after the reaction was heated for 16 hours, and the reaction was continued for 16 hours. Water (20 mL) was added, and the n-propanol was removed under reduced pressure. The remaining mixture was extracted with chloroform (2×200 mL), and the combined organic fractions were purified by column chromatography on silica gel (eluting with chloroform and chloroform:CMA). The resulting solid was recrystallized from acetonitrile to provide 5.44 g of tert-butyl 4-{[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as a white, fluffy solid, mp 229–231° C.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6](C)=[C:5]([C:10]#[CH:11])[CH:4]=1.[OH-].[K+].[CH3:16]O>O>[C:8]1([CH3:16])[CH:3]=[CH:4][C:5]([C:10]#[CH:11])=[CH:6][CH:7]=1
Reactant: C#Cc1cc([Si](C)(C)C)ccc1C
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C#Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
34.7 g (0.184 mol) of 4-trimethylsilyl ethynyl toluene was dissolved in 500 ml of methanol in a 1 L round-bottomed flask equipped with a stirrer. 10 ml of 20% KOH in water was added to the resulting solution. The reaction mixture was then stirred at room temperature for 5 hours. After the reaction was completed, water were poured into the flask. The reaction mixture was then extracted with ethyl ether several times. The combined extract was washed with water several times, and then dried with anhydrous magnesium sulfate. The solvent was removed, to give 21 g (98% yield) of yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][OH:12]>C1COCC1>[CH3:1][C:2]1[O:6][C:5](/[CH:7]=[N:9]/[C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)o1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(/C=N/[C@@H](CO)c2ccccc2)o1
Temperature: 25 °C

Procedure:
73.8 ml of 5-Methylfuran-2-carbaldehyde are added to 100 g of (R)-2-amino-2-phenyl-ethanol dissolved in 800 ml of THF. A reaction mixture obtained is heated at reflux for 5.5 hours and after cooling to rt solvent is evaporate. The title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1)([CH3:9])[O:4][Si](C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.[F-].Cl>O.O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1)([CH3:9])[OH:4]
Reactant: CC(O[Si](C)(C)C)(c1ccnc(-c2nc(=O)o[nH]2)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1ccnc(-c2nc(=O)o[nH]2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.1 %

Procedure:
To 3 ml of tetrahydrofuran was added 12 g of 3-{4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridin-2-yl}-1,2,4-oxadiazol-5-one, and 1.3 ml of tetrabutylammonium=fluoride (1M tetrahydrofuran solution) was added at 0° C. After stirring at room temperature for 4 hours, water and 10% HCl were added to the reaction solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.29 g of 3-[4-(2,2,2-trifluoro-1-methyl-1-hydroxyethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (62)).