Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:20](CC2C=CC(OC)=CC=2)[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>C(Cl)Cl>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4)cnc23)nc1
Temperature: 160 °C

Procedure:
To a 2 dram vial was added 6-chloro-8-((4-methoxybenzyl)(5-methylpyridin-2-yl)amino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (32 mg, 0.064 mmol) and (trans)-cyclohexane-1,4-diamine (146 mg, 1.280 mmol). The reaction mixture was heated neat at 160° C. for 1 hour. The solution was diluted with DCM and washed with water. The organic layer was concentrated to dryness and then dissolved in neat TFA and heated to 80° C. for 2 hours. The solution was concentrated in vacuo and the residue was purified via preparative HPLC to give 6-((trans-4-aminocyclohexyl)amino)-8-((5-methyl-2-pyridinyl)amino)-N-4-pyridinylimidazo[1,2-b]pyridazine-3-carboxamide (14.2 mg, 0.031 mmol, 48.5% yield). HPLC Rt=2.19 minutes (Waters Sunfire C18 column 4.6×50 mm):0%-100% B. Solvent B: 90% MeOH, 10% H2O, 0.1% TFA). Solvent A: 10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min) [M+H]=458.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].O>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of trans-2-phenylcyclopropanamine (80 mg, 0.601 mmol) in methanol (10 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (102 mg, 0.601 mmol) and the reaction was heated to reflux for 2 minutes. After cooling back to the room temperature, sodium cyanoborohydride (75 mg, 1.201 mmol) was added to the reaction mixture and was stirred for 1 hour. Water (20 mL) was added. The reaction was concentrated and 20 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, and dried over MgSO4, filtered and evaporated. The resulting oil was purified on preparatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier). 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-Methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (95 mg, 0.250 mmol, 41.7% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 3.68 (s, 3H), 3.09 (d, J=7.07 Hz, 2H), 2.99 (dt, J=4.11, 7.45 Hz, 1H), 2.49 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.35 (tt, J=3.63, 12.28 Hz, 1H), 2.07 (dd, J=3.54, 13.39 Hz, 2H), 1.93 (dd, J=3.28, 13.14 Hz, 2H), 1.66-1.83 (m, J=3.57, 3.57, 7.70, 7.70, 15.36 Hz, 1H), 1.50-1.58 (m, 1H), 1.36-1.50 (m, 3H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.83 min; MS (ESI): 288.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[S:11](Cl)([CH3:14])(=[O:13])=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:14][S:11]([O:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:13])=[O:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of trans-ethyl 2-hydroxymethyl-1-cyclopropanecarboxylate (1.136 g, 7.88 mmol) in dry tetrahydrofuran (20 ml) was cooled to 0° C. (ice bath), treated dropwise with mesyl chloride (0.675 ml, 8.66 mmol) and then treated immediately with triethylamine (1.32 ml, 9.52 mmol). This solution was stirred at 0° C. for 1.5 h (tlc indicated no substrate left). After dilution with ether (200 ml), the solution was washed with water, saturated ammonium chloride (10 ml), brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a clear oil, 1.690 g (97%) which was used as such for the next step without purification. ir (film) νmax : 1720 cm-1 (C=O); 1Hmr (CDCl3) δ: 4.13 (2H, q, J=7, CH2 --CH3, 3.05 (2H, s, CH2 --OMs), 2.0~0.6 (4H, m, cyclopropyl), 1.27 ppm (3H, t, J=7, CH3 --CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]([CH3:33])[CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH:34](O)=O.C=O.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]([CH3:33])[CH2:26][CH:27]2[CH2:28][CH2:29][N:30]([CH3:34])[CH2:31][CH2:32]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: Cc1cc(CN(C)CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: O=CO
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(CN(C)CC2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 7-Methyl-5-[(methyl-piperidin-4-ylmethyl-amino)-methyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (30 mg, 0.065 mmol) in methanol (1.5 mL) was added formic acid (0.02 ml), formaldehyde (0.1 mL), and Sodium cyanoborohydride (0.2 mL, 0.1 M in THF) respectively. The mixture stirred at room temperature for 1 hour and was then diluted with water and extracted with ethyl acetate. The organics were washed with brin, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (15 mg, 38%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 2H), 7.21-7.14 (m, 4H), 4.78 (s, 2H), 4.22 (s, 2H), 3.48 (s, 2H), 2.94 (d, 2H), 2.75 (s, 3H), 2.33 (s, 3H), 2.23 (d, 2H), 2.16 (s, 3H), 2.01 (t, 2H), 1.84-1.80 (m, 2H), 1.54-1.51 (m, 1H), 1.25-1.20 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C=CC=CC=1.[CH3:18][O:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)(=O)C>[CH3:18][O:19][CH2:20][CH2:21][S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:24])=[O:23]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: COCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
Into a 1.0 L round bottom flask equipped with mechanical stirrer, addition funnel, thermometer and nitrogen inlet tube was placed 100 grams (0.67 Mol) of 5-amino-2-methylbenzoxazole and 350 mL of pyridine. The slurry was stirred in an ice/ethanol bath at 0° C. then 110 grams (0.69 Mol) of Intermediate 1 was added dropwise so as to maintain a reaction temperature below 7° C. The reaction was stirred at 0° C. for two hours then the resulting red colored mixture was poured into 1.0 L of ethyl acetate. The slurry was stirred for 30 minutes then filtered and the collected solids were discarded. The filtrate was extracted with 4×200 mL of 10% hydrochloric acid and the organic phase was collected and dried over magnesium sulfate. The solvents were removed in vacuo to afford 140 grams (0.52 Mol, 76.7% yield) of desired product as a tan solid.
Reaction SMILES: CCOCC.[CH2:6]([Mg]Cl)[CH2:7][CH3:8].[C:11]([N:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:17]1=[O:27])(=[O:15])[CH:12]=[CH:13][CH3:14]>C1COCC1>[CH3:14][C@H:13]([CH2:6][CH2:7][CH3:8])[CH2:12][C:11]([N:16]1[C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][O:18][C:17]1=[O:27])=[O:15]
Reactant: CCC[Mg]Cl
Reactant: CC=CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC[C@@H](C)CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
To the copper (1) bromide dimethylsulfide complex (13.34 g, 64.87 mmol) in dry THF (150 mL) at −30° C. under Nitrogen was added a 2M ether solution of Propylmagnesiumchloride (64.87 mL, 129.7 mmol) and stirred for 20 minutes. (R)-3-But-2-enoyl-4-phenyl-oxazolidin-2-one (15.0 g, 64.87 mmol) in THF (60 mL) was added over a 15 minute period at −35° C. and let slowly warm up to room temperature over 4 hours. The mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The suspension was extracted into ether, washed with 5% ammonium hydroxide solution and then with brine and dried over MgSO4. The solution was concentrated under reduced pressure to afford the titled compound (13.34 g; 100% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (m, 6H) 1.2 (m, 3H) 1.6 (s, 1H) 2.0 (m, 1H) 2.7 (dd, J=16.1, 8.5 Hz, 1H) 3.0 (dd, J=15.9, 5.4 Hz, 1H) 4.3 (dd, J=8.9, 3.8 Hz, 1H) 4.7 (t, J=8.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 7.3 (m, 5H). MS, m/z (relative intensity): 276 [M+1H, 100%].
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>O1CCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in tetrahydrofuran were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in tetrahydrofuran at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6](=[O:13])[CH2:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6](=[O:13])[CH2:5]2
Reactant: O=C1Cc2cc(Br)ccc2C(=O)O1
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)Cc3cc(Br)ccc3C2=O)cc1
Yield: 82.7 %

Procedure:
A mixture of 6-bromo-isochroman-1,3-dione (0.6 g) (product of step ii)) and 4-methoxybenzylamine (0.313 g) in toluene:acetic acid (4:1, 20 mL) was heated at reflux for 17 hours. The reaction mixture was evaporated and the residue was dissolved in dichloromethane before washing with 2N hydrochloric acid. The organic phase was dried, filtered and evaporated then triturated with diethyl ether to yield the sub-title compound (680 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:33]([NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Yield: 73.1 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.200 g, 0.642 mmol) in anhydrous dichloromethane (20 ml) under an atmosphere of nitrogen was added dry triethylamine (0.098 ml, 0.706 mmol) and the mixture was stirred until dissolution was complete. To this solution was then added phenyl isocyanate (0.077 ml, 0.706 mmol) and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (150 ml) and 1M aqueous citric acid (75 ml). The organic layer was successively washed with 1M aqueous citric acid (1×75 ml), saturated sodium bicarbonate solution (2×75 ml) and saturated brine (1×75 ml), then dried (MgSO4) and evaporated. The crude product was recrystallised from methanol to give the title compound as colourless crystals (0.185 g), m.p. 228°-229° C. (dec). δ (DMSO, 360 MHz) 1.67 (1H, ddd, J=12.7, 12.4 and 3.5 Hz, CHACHBHCCHD), 2.34 (1H, dm, J=12.7 Hz, CHACHBHCCHD), 3.73 (3H, s, CO2CH3), 4.00 (1H, dd, J=12.4 and 2.9 Hz, CH ACHBHCCHD), 4.94 (1H, m, CHACHBHCCHDNHCO), 6.53 (1H, d, J=6.4 Hz, CHDNHCONAr), 6.72 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.88-6.93 (3H, m, 6-H or 8-H, ArH and ArNH), 7.20-7.25 (2H, m, ArH) 7.39 (2H, d, J=8.0 Hz, ArH), 8.15 (1H, s, CHDNHCONHAr); m/e 393 (M+), 198 (100%, M-NHCONHPh, CO2CH3 and H); Found C, 54.76; H, 4.39; N, 10.48; C18H17Cl2N3O3 requires C, 54.84; H, 4.35; N, 10.66%.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(C(=O)C2CC2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1cc(OC)ncn1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.13 g) in THF (100 ml) was added ethyl diethylphosphonoacetate (13.2 mL) at 0° C. To the obtained solution was added cyclopropyl(6-methoxypyrimidin-4-yl)methanone (entire amount) obtained in Example 2, step C, and the mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give an isomer mixture of the title compound (E:Z=93:7 or 7:93, 5.57 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.Cl>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
2,3,4-Trifluoronitrobenzene (1.01 g) and ethyl pyruvate (1.15 g) were dissolved in ethanol (8 ml). After adding 5% Pd-C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.38 g) was obtained as slightly yellow oily substance. Various spectral data of this product was identical with those obtained in Example 7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (130 mg, 0.5 mmol) according to the general procedure K. Obtained as an amorphous yellow substance (166 mg).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+]>C(Cl)Cl>[OH:15][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a 250 mL Erlenmeyer flask was added methyl 4-amino-2-methoxybenzoate (7.5 g, 41.4 mmol) and a 25% solution of sulfuric acid (40 mL, 188 mmol). The solution was cooled to 0° C. and a saturated solution of sodium nitrite (4.29 g, 62.2 mmol) was added drop wise. The orange mixture was stirred for 15 minutes. The resulting diazonium solution was then very slowly poured into a 1 L flask containing 500 mL of 3% sulfuric acid. The solution was stirred for 5 minutes then transferred to a separatory funnel. The reaction mixture was diluted with 150 mL of DCM, extracted, dried over magnesium sulfate and concentrated. to a red solid. The resulting solid was triturated with hexane to give 5.71 grams of the desired phenol as a red powder (73% yield). The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.67-3.72 (m, 3H), 3.74 (s, 3H), 6.39 (dd, J=8.66, 2.13 Hz, 1H), 6.45 (d, J=2.13 Hz, 1H), 7.59 (d, J=8.66 Hz, 1H). LCMS Rt=1.070 min., m/z 183.09 (M+H), 96% purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][C:14]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:22])[CH2:9]1)=[O:21]
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (160 mg, 0.49 mmol, 1 eq), 1-Chloro-3-chloromethyl-benzene (95 mg, 0.59 mmol, 1.2 eq), Cesium carbonate (325 mg, 1 mmol, 2 eq) in DMF (2 ml) was stirred at room temperature overnight. It was concentrated, dissolved in acetonitrile and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 450.2
Reaction SMILES: [Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)=[CH:25][CH:24]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc2c(Br)ncc(Br)n12
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(Br)n12
Yield: 52.6 %

Procedure:
5,8-Dibromo-3-methylimidazo[1,2-a]pyrazine (270 mg, 0.93 mmol) and 4-morpholinoaniline (200 mg, 1.1 mmol) are combined in nBuOH (10 mL) and DIPEA (240 μL, 1.4 mmol) is added. The mixture is heated at reflux for 10 h, cooled and the solvent removed under reduced pressure. The residue is purified by silica chromatography, eluting with 12% -100% EtOAc in cyclohexane, to afford the title compound as a red-brown solid (190 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37](I)([CH3:39])[CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH:37]([CH3:39])[CH3:38])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2cnn(C(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 95717.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) and isopropyl iodide (0.16 mg) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.47 g) was obtained. By the reaction and treatment of this compound, in the same manner as in Example 17 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.22 g) was obtained. melting point: 185° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][C:20]([NH2:21])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=1>CCOCC>[C:1]([CH2:3][C:4]([NH:21][C:20]1[CH:22]=[C:23]([Cl:24])[C:17]([Cl:16])=[CH:18][C:19]=1[N+:25]([O-:27])=[O:26])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of cyanoacetic acid (1.70 g, 20 mmol) in CH2Cl2 (50 mL) oxalyl chloride (2.2 mL, 25 mmol) was added. The mixture was stirred for 2 h, more oxalyl chloride (2.2 mL, 25 mmol) was added and the mixture was refluxed while stirring for 3 h. The mixture was cooled to room temperature and evaporated twice with ethanol-free CHCl3 (20 mL) to remove excess of (COCl)2. To the residue was added 4,5-dichloro-2-nitroaniline (1.035 g, 5 mmol) and CH2Cl2 (10 mL) and the resulting mixture was stirred for 3 h, then diluted with ether (50 mL). The precipitate was filtered, washed with ether (5×10 mL) to give 0.891 g (65%) of the title compound as an orange solid: mp 156°-158° C. (from EtOH); IR (KBr) 3369, 3118, 2928, 2261, 1694, 1609, 1576, 1498, 1346 and 1280 cm-1 ; 1H NMR (DMSO-d6) δ4.00 (s, 2H), 7.94 (s, 1H), 8.31 (s, 1H), 10.70 (s, 1H, N--H). HRMS Calcd for C9H5N3O3Cl2 : 272.9708. Found: 272.9712.