Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([O:13][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)[CH2:11]I)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[O:13][C@@H:14]2[N:17]([C:16](=[O:18])[CH2:15]2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:8][CH2:9][C@@H:10]1[O:13][C@H:14]2[N:17]([C:16](=[O:18])[CH2:15]2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CI)OC1CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN2C(=O)C[C@@H]2O1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN2C(=O)C[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %
Yield: 41 %

Procedure:
A mixture of 4-[(S)-1-(tert-butyldimethylsilyl) oxymethyl-2-iodoethoxy]-azetidin-2-one which was prepared by the known method (6.8 g, 17.7 mmole), and powdered K2CO3 (6.1 g, 44 mmole) in DMSO (100 ml) was stirred at room temperature overnight and then diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by repeated silica gel column chromatography using hexane-ethyl acetate (9:1) as eluent. The title compounds (3R, 5S)-3-(tert-butyldimethyl silyl)oxymethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (Ref. 1A) (1.85 g, yield 41%) and its isomer (3R, 5R)-3-(tert-butyldimethyl silyl)oxymethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (Ref. 1B) (1.28 g, yield 28%) were obtained as oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH:16](=[O:20])[CH:17]([CH3:19])[CH3:18].Cl>O1CCCC1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CC(C)C=O
Reactant: CCOc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)C(C)C)cc1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
A solution of p-bromophenetole (2.01 g, 0.01 mol) in tetrahydrofuran is cooled to −65° C., treated dropwise with a 2.5 M solution of n-butyllithium in hexane (4 mL), stirred for 20 minutes at −55 to −65° C., treated dropwise with a solution of isobutyraldehyde (0.91 mL, 0.01 mol) in tetrahydrofuran, stirred overnight at room temperature, diluted with an ice-water mixture, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a tan oil (1.95 g) which is identified by NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1COCC1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-nitroaniline (4-7) (10.0 g, 72 mmol) and anhydrous potassium carbonate (20 g, 1.44 mmol) in anhydrous THF (240 mL) and benzoyl chloride (9.1 mL, 78 mmol) was stirred at RT overnight. The resultant solution was poured into 10% aq. HCl (200 mL) and cooled to 0° C. The yellow solid precipitated was filtered, washed successively with water (200 mL) and hexane (200 mL). Further drying under vacuum overnight provided the required 4-nitro-N-benzoylaniline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: OB(O)c1ccccc1F
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3F)c2cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 379(MH+).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)[N:14]=[N:13][C:12]=1[C:27]([NH:29][CH:30]1[CH2:32][CH2:31]1)=[O:28])C1C=CC=CC=1>CO.C(O)(=O)C.[C].[Pd]>[CH:30]1([NH:29][C:27]([C:12]2[N:13]=[N:14][N:15]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=3)[C:11]=2[CH2:10][CH2:9][OH:8])=[O:28])[CH2:31][CH2:32]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCO)cc1
Yield: 82.4 %

Procedure:
5-[2-(Benzyloxy)ethyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (737 mg, 1.70 mmol) obtained in Example 107 was dissolved in methanol-acetic acid (25:1, 26 ml), and the mixture was stirred at room temperature for 63 hr in the presence of 10% palladium carbon (wet, purity 50%, 150 mg) under a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst, the filtrate was concentrated to dryness, and ethyl acetate-diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (480 mg, 1.40 mmol, 82.2%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[N:4]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:3]1=[O:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccncc3F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CC(F)(F)F)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (example 72, 78 mg, 261 μmol) in DMF (700 μl) under an argon atmosphere was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (66.5 mg, 39.6 μl, 287 μmol) and cesium carbonate (93.4 mg, 287 μmol). After 3 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by trituration with diethyl ether/heptane. The title compound was obtained as white foam (36 mg).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:17]2[C:18]([Cl:25])=[C:19]([Cl:24])[C:20]([OH:23])=[C:21]([Cl:22])[C:16]=2[O:15][N:14]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:17]2[C:18]([Cl:25])=[C:19]([Cl:24])[C:20]([O:23][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:21]([Cl:22])[C:16]=2[O:15][N:14]=1
Reactant: Oc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 12.5 g of 3-(2-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole is added 80.0 g of pyridine hydrochloride. The mixture is immersed in an oil bath at 200° C. for thirty minutes with stirring. The melt is poured into one liter of iced-hydrochloric acid solution, stirred for thirty minutes, and the resultant precipitate collected and dried to yield 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, mp 110° C. (dec). To 50 ml of dry dimethylformamide is added 12 g of 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, 4.4 ml of ethyl bromoacetate and 20 g of potassium carbonate. The reaction is stirred at 70° C. for 2 hrs, filtered and solvent evaporated to afford an oil, which is stirred with 500 ml water for ten minutes and then extracted with ether/ethyl acetate. The organic extract is washed with water (2X), saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate followed by recrystallization from 95% ethanol yields ethyl {[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate, mp 140°-3° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH2:1][Br:11]
Reactant: COc1cccc(C)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(C)c1CBr
Temperature: 25 °C

Procedure:
0.50 g (3.68 mmol) of 2,3-dimethylanisole was dissolve in 10 ml of carbon tetrachloride. The resultant solution was then added with 0.72 g (4.04 mmol) of N-bromosuccinimide, and the obtained solution was subjected to irradiation of light (Infrared lamp 375WR manufactured by Toshiba) for 45 min. at the reflux temperature. The solution was then cooled down, and the temperature thereof was maintained at a room temperature to cause the precipitation. The precipitated succinimide was separated by filtration, and the obtained filtrate was condensed under reduced pressure to produce a crude product of 2-methoxy-6-methylbenzyl bromide.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])=[CH:22]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:21]([CH3:26])=[CH:20][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CB(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 2,2-dimethylethenylboronic acid (98.0 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (14 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (270 mg, 89.1%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5])=O.[NH2:12][C:13](N)=[O:14]>O>[OH:14][C:13]1[N:12]=[CH:1][C:3]2[C:4](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[N:5]=1
Reactant: NC(N)=O
Reactant: COc1ccc(C=O)c(N)c1
Solvent: O
Product: COc1ccc2cnc(O)nc2c1
Temperature: 175 °C
Reaction time: 1 h

Procedure:
2-Formyl-5-methoxyaniline (11.93 g, 79.5 mmol, 1.0 eq) and urea (38.0 g, 0.636 mol, 8.0 eq) were mixed, ground into a fine powder and placed into a 1 L 2-neck flask equipped with a mechanical stirrer and an air condenser. The flask was placed into a preheated (160° C.) oil bath. The reaction mixture melted and was stirred at 170-180° C. for 1 hour until it solidified forming yellowish-brown solid. The reaction mixture was cooled to RT, crushed, mixed with 70 mL of H2O and stirred for ˜1 hour at RT. The solid was filtered, washed with 150 mL of H2O and 20 mL of ice cold Et2O. The yellow solid thus obtained was dried over P4O10 under high vacuum for several hours and the crude material (12.57 g) was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1Cl
Reaction time: 0.5 h

Procedure:
To a reaction solution of 4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.26 g) in tetrahydrofuran (16 ml) was added sec-butyllithium (14.6 ml) dropwise in nitrogen atmosphere at −78° C. After the mixture was stirred at the same temperature for 30 minutes, a solution of benzyl chloroformate (2.1 ml) in tetrahydrofuran (16 ml) was added dropwise to the reaction mixture at −78° C. Furthermore, the reaction solution was stirred at −78° C. for 15 minutes, neutralized with saturated aqueous ammonium chloride (12 ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (17 ml), 1M tetrabutylammonium fluoride/tetrahydrofuran solution (16.9 ml) was added, and the mixture was stirred at ambient temperature for 3 hours. To the reaction solution were added ethyl acetate and water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate) to obtain benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (690 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9]1.C[O:21][C:22](=[O:46])[CH:23]([NH:34][C:35](=[O:45])[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=1[CH3:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH:23]([NH:34][C:35](=[O:45])[C:36]3[C:37]([CH3:44])=[CH:38][C:39]([CH3:43])=[CH:40][C:41]=3[CH3:42])[C:22]([OH:46])=[O:21])=[CH:26][CH:27]=2)[CH2:9]1
Reactant: COC(=O)C(Cc1ccc(B(O)O)cc1)NC(=O)c1c(C)cc(C)cc1C
Reactant: c1ccc(NCC2CNC2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(N3CC(CNc4ccccn4)C3)cc2)C(=O)O)c(C)c1
Reaction time: 20 h

Procedure:
153 mg (0.203 mmol) TFA salt of (10) together with 150 mg (0.406 mmol) 2-(2,4,6-trimethylbenzoylamino)-3-(4-boronophenyl)propionic acid methyl ester (12), 844 μl (6.1 mmol) triethlamine and 74 mg (0.406 mmol) Cu(OAc)2 were stirred in 2.5 ml DCE for 20 min under ultrasonification and then stirring was continued for another 20 h at room temperature. The reaction mixture was filtered over a pad of Celite, the solvent was removed under reduced pressure and the residue was dissolved in acetonitrile to be filtered over another pad of Celtite. After the solvent was removed, the crude methyl ester was dissolved in 9 ml methanol and stirred with 4 ml 0.5 M NaOH over the weekend. Solids were removed by filtration and the reaction mixture was purified by reversed phase HPLC using a water/acetonitrile gradient containing 0.1% TFA yielding the TFA salt of (11) after lyophilization as a white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10](F)[N:9]=1>C(OC)(C)(C)C>[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10]([O:6][CH2:3][C:4]#[CH:5])[N:9]=1
Reactant: Nc1nc(F)c(C(F)(F)F)cc1Cl
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: C#CCOc1nc(N)c(Cl)cc1C(F)(F)F

Procedure:
3.9 g (0.153 mol) of sodium hydride were introduced, under nitrogen, into 250 ml of methyl tert-butyl ether, with stirring, and 20 ml of propargyl alcohol were then added dropwise with stirring at 25°-30° C. over 20 minutes. After the mixture had been stirred for 30 minutes at 25° C., 32.9 g (0.153 mol) of 2-amino-3-chloro-6-fluoro-5-trifluoromethylpyridine in 100 ml of methyl tert-butyl ether were added in the course of 10 minutes and the mixture was stirred for 14 hours at 25° C. The reaction mixture was extracted with water, dried and concentrated, giving 37.8 g (99% of theory) of the title compound as a colorless oil of ηD24 =1.5217 (Table I, No. 1.035).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]3)[NH:13][CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]3)[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:23]([CH:24]=3)[O:22][CH2:21][CH2:20][OH:19])[CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Cc1ccc(C=O)cc1OCCO
Reactant: c1cc2[nH]ncc2cc1NC12CCC(CC1)NC2
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2CC3)cc1OCCO

Procedure:
Reaction of Intermediate 26 with 3-(2-hydroxyethoxy)-4-methylbenzaldehyde affords the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:38]1[CH:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:42])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[O:40][N:39]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (191 mg) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (211 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (92 mg).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:11]1[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[S:2]
Reactant: CSC(=S)NN=Cc1nc(-c2ccccc2)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12

Procedure:
A mixture of 73.4 gm. of 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester and 500 ml. of diphenyl ether is reacted as described in Example 23 giving the desired product as purple crystals, m.p. 237.5°-239° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 4 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and methoxyacetyl chloride. LCMS (M+H)+: m/z=568.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][C@H:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4=[O:34])[C:22]=3[O:35][CH3:36])(=[O:20])=[O:19])[C:14](O)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH:37]1(NC)[CH2:39][CH2:38]1.[B-](F)(F)(F)F.CCOC([C:52](C#N)=[N:53]OC(N(C)C)=[N+](C)C)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][C@H:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4=[O:34])[C:22]=3[O:35][CH3:36])(=[O:19])=[O:20])[C:14]([NH:53][CH2:52][CH:37]3[CH2:38][CH2:39]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1c(N2CCCCC2=O)cc(F)cc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)O
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CNC1CC1
Agent: F[B-](F)(F)F
Product: COc1c(N2CCCCC2=O)cc(F)cc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)NCC1CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Intermediate 17 (350 mg, 0.63 mmol) and cyclopropyl-methylamine (45 mg, 0.63 mmol) were coupled using the procedure described in example 1; 1.9), where only 25% conversion of starting materials was discovered. Heating to 50° C. did not lead to further conversion. Then TOTU (246 mg, 0.75 mmol) was added and after stirring for 1 h at RT conversion was completed. The mixture was purified by preparative HPLC. Yield after lyophilization: 162 mg, 43%, colorless, amorphous solid.
Reaction SMILES: [ClH:1].CO[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](=[NH:17])[O:14][CH2:15][CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:18][O:19]C1C=CC=CC=1C1(C#N)CC1>>[ClH:1].[CH3:18][O:19][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[C:10]1([C:13](=[NH:17])[O:14][CH2:15][CH3:16])[CH2:11][CH2:12]1
Reactant: COc1ccccc1C1(C#N)CC1
Reactant: CCOC(=N)C1(c2ccc(OC)cc2)CC1
Agent: Cl
Product: CCOC(=N)C1(c2ccccc2OC)CC1

Procedure:
The title compound (50 mg, oil) was prepared by a method analogous to the one used for Intermediate 48 but using 1-(2-methoxyphenyl)cyclopropanecarbonitrile.