Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[N:25]1([C:31]([NH:1][C:2]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCOCC1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
After neutralizing 203 g (500 mmol) of phenylmethyl 1-aminocyclohexanecarboxylate.p-toluenesulfonate with a 10% sodium carbonate solution, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solid material was filtered off, and after adding 56 g (550 mmol) of triethylamine to the chloroform layer, 75 g (500 mmol) of 4-morpholinecarbonyl chloride was added dropwise, and the mixture was heated in an oil bath (60° C.) for 3 days. After completion of the reaction, the reaction mixture was washed successively in the order of water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting crystals were washed with ether to obtain 151 g (Yield: 87%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=[CH:19][C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([Cl:37])[CH:27]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:33]([O:32][C:30](=[O:31])[C:29]1[CH:35]=[CH:36][C:26]([NH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:23][CH3:24])(=[O:9])=[O:10])[C:15]=3[CH:16]=2)=[O:22])=[CH:27][C:28]=1[Cl:37])[CH3:34]
Reactant: CCOC(=O)c1ccc(N)cc1Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1Cl
Temperature: 60 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41 mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si](C(C)C)(C(C)C)C(C)C)[C:14]=3[O:30][CH3:31])[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:62][C:63]([O:65][CH3:66])=[O:64]>>[CH3:66][O:65][C:63](=[O:64])[CH2:62][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]2[N:10]([C:32](=[O:33])[C:34]3[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=3[F:40])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:12]2)[C:14]=1[O:30][CH3:31]
Reactant: COC(=O)CBr
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1OC
Reaction time: 12 h

Procedure:
[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (3.31 mmol), prepared as described in example 4, is treated with tetrabutylammonium fluoride (1 M in THF) (4.97 mmol) at room temperature for 40 minutes. Methyl bromoacetate (4.97 mmol) is then added. After 12 hours, the reaction is complete as determined by LC/MS. Purification is accomplished by silica flash chromatography (25% EtOAc/hexane) to give {3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 3H), 7.04 (m, 3H), 6.95 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.82 (dd, J1=8 Hz, J2=1.6 Hz), 6.76 (m, 2H), 4.7 (s, 2H), 4.1 (s, 3H); LC/MS (ES+): 505.1 (M+1)+.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][N:21]([CH3:3])[CH2:20][CH:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:19][CH2:18]2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CNCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A 37% aqueous solution of formaldehyde (5 ml; 67 mmol) and sodium cyanoborohydride (314 mg; 5.0 mmol) were added to a solution in acetonitrile (20 ml) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]amine (1.0 g; 2.4 mmol) synthesized by the above process, and the mixture was stirred at room temperature for 15 minutes. Acetic acid was then added to the solution to adjust the pH to about 5, and the mixture was stirred further for 48 hours at room temperature. The reaction mixture was brought to pH about 10 by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 989 mg (yield: 95%) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]methylamine as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)(Cl)Cl.O1CCOCC1>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(N)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (50 mg, 0.108 mmole) was added 4-methoxyaniline (16 mg, 0.129 mmole, 1.2 eq) followed by cesium carbonate (70 mg, 0.216 mmole, 2 eq) and Xantphos (6.2 mg, 0.0108 mmole, 10 mole %). Dioxane (1.2 mL) was added and the flask flushed twice with nitrogen. Pd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added and the flask was flushed again with nitrogen (×3) and heated at 80° C. for 2 hours. The reaction was cooled and diluted with ethyl acetate (10 mL). The solution was washed with water (3 mL) and with brine, dried and evaporated to leave a gum. This was applied in chloroform to a 1 mm, 20×20 cm silica prep plate which was eluted with 9:1 dichloromethane:ethyl acetate. The product band was recovered with acetone. Solution evaporated and residue azeotroped with ethanol to leave the title compound (37 mg, 68%). 1H-NMR (d6-DMSO, 500 MHz): δ 1.45 (s, 9H), 1.60 (s, 9H), 3.72 (s, 3H), 6.78 (d, J=0.63 Hz, 1H), 6.87 (d, J=9.14 Hz, 2H), 7.39 (t, J=0.95 Hz, 1H), 7.48 (d, J=9.14 Hz, 2H), 8.02 (d, J=0.63 Hz, 1H), 8.41 (d, J=0.95 Hz, 1H), 8.43 (d, J=0.63 Hz, 1H), 8.73 (br s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][NH:13]2)=[CH:8][C:7]=1[F:23])(=[O:5])[CH3:4].Br[CH2:25][CH2:26][F:27]>CN(C)C=O>[C:3]([C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH2:25][CH2:26][F:27])=[CH:8][C:7]=1[F:23])(=[O:5])[CH3:4]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(C(C)=O)c(F)cc2c1=O
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2c(F)c(C(C)=O)c(F)cc2c1=O
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To 1.62 g (34.0 mmol) of sodium hydride (50% dispersion in oil, pentane washed) in 250 ml of dimethylformamide was added 10.0 g (34 mmol) of the ethyl 7-acetyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate dissolved in 100 ml of dimethylformamide at room temperature. The mixture was stirred for two hours, and 13.0 g (2.4 eq) of 1-bromo-2-fluoroethane was added. The mixture was stirred overnight at 50° C. It was concentrated, and partitioned between water and dichloromethane. The dichloromethane was then concentrated and the residue purified by column chromatography to give 3.75 g of ethyl 7-acetyl-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3quinoline carboxylate, mp 155°-156° C. This material was hydrolyzed with 2N hydrochloric acid and 2-propanol as co-solvent to give 2.95 g of the 7-acetyl-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 215°-216° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[C:27]([CH3:38])=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:30]=2)=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].Br[CH2:42][C:43]([O:45]CC)=[O:44].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([C:24]([C:26]2[C:27]([CH3:38])=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:30]=2)=[O:25])[CH2:42][C:43]([OH:45])=[O:44])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)N(CC(=O)O)c1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide (2.1 g) and sodium hydride (60% content, 0.2 g) were reacted in dimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml) containing ethyl bromoacetate (1.0 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added tetrabutylammonium fluoride (2.0 g), tetrahydrofuran (20 ml) and acetonitrile (20 ml) and the mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-ethyl acetate was added to the residue to allow crystallization. The crystals were recrystallized from hydrous isopropanol to give the title compound (0.2 g), melting point: 124–125° C.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:17]=2[N:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[ClH:1].[CH3:24][C:22]1[C:21]([CH3:25])=[CH:20][C:18]2[NH:19][C:15]([CH2:14][N:11]3[CH:4]=[C:3]([CH2:2][C:5]4[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=4)[N:13]=[N:12]3)=[N:16][C:17]=2[CH:23]=1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: Cc1cc2nc(CN=[N+]=[N-])[nH]c2cc1C
Agent: Cl
Product: Cc1cc2nc(Cn3cc(Cc4c[nH]c(N)n4)nn3)[nH]c2cc1C
Yield: 49.7 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.047 g, 0.295 mmol) was reacted with 2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.071 g, 0.354 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(5,6 Dimethyl-1H-benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine dihydrochloride (0.029 g, 25%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.09 (s, 1H), δ 7.45 (s, 2H), δ 6.52 (s, 1H), δ 6.08 (s, 2H), δ 3.93 (s, 2H), δ 2.35 (s, 6H) ppm; 13C (75 MHz, CD3OD) δ 142.2, 136.9, 136.6, 124.5, 124.3, 113.8, 113.4, 110.0, 100.4, 85.8, 80.6, 75.3, 74.1, 45.0, 20.9, 19.28 ppm; HRMS (ESI) calcd for C16H18N8 (M+) 323.1727. found 323.1734.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[C:24]([N:27]([CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:24]([N:27]([C:28]1[CH:33]=[CH:32][C:31]([NH:34]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)[CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])(=[O:26])[CH3:25]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Product: CC/C(Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][C:51]([CH2:54]O)=[CH:50][CH:49]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:54][C:51]3[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1ccncc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2ccncc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
1,4-Diethylazodicarboxylate (205 μL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 4-pyridylmethanol (273 mg) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then poured into 0.5 N aqueous NaOH solution (25 mL). The mixture is extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol, 50/1; 20/1) followed by recrystallization from ethanol to afford 107 mg (21%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[ClH:26].[NH2:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:25]
Reactant: Cc1ccc(NC(=O)c2c(C)cccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(NC(=O)c2c(C)cccc2N)cc1
Temperature: 18 °C
Reaction time: 3.5 h

Procedure:
A stirred solution of N-(4-methylphenyl)-2-{[(1,1-dimethylethoxy)carbonyl]amino}-6-methyl-benzamide (1.67 g, 4.90 mmol) in methanol (4 mL) under an argon atmosphere, is treated with a saturated solution of hydrogen chloride in dioxane (30 mL) and stirred at 18° C. for 210 minutes. The solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from methanol-di-isopropyl ether to give the title compound as a colourless crystalline solid, m.p. 217–220° C.
Reaction SMILES: [C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.[Pd]>[C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(CCc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1

Procedure:
37.7 g (0.1 mol) of the 4-diphenylamino-4'-methoxystilbene prepared in Synthesis Example 1-1 was dissolved in 250 ml of dioxane. To the thus obtained mixture, 4 g of 5% Pd/C powder and then 2.4 l of hydrogen were added. A solvent was distilled away from the reaction mixture, whereby 1-(4-diphenylaminophenyl)-2-(4-methoxyphenyl)ethane was obtained as an oily transparent compound of light yellow in color.
Reaction SMILES: [CH2:1]([CH:8]([C:11]#[N:12])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19]>CN(C)C=O>[CH2:1]([C:8]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([C:9]#[N:10])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccc1
Yield: 17.3 %

Procedure:
Using 0.50 g of benzylmalononitrile, 10 ml of N,N-dimethylformamide, 0.14 g of sodium hydride (60% in oil), and 0.63 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.14 g of 2-benzyl-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (12)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH2:33][N:34]4[CH2:39][C@H:38]([CH3:40])[O:37][C@H:36]([CH3:41])[CH2:35]4)[S:31][CH:32]=3)=[O:27])[C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:14]=3)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CN1CCOCC1.Cl[CH2:50][CH2:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:41][C@H:36]1[O:37][C@@H:38]([CH3:40])[CH2:39][N:34]([CH2:33][C:30]2[S:31][CH:32]=[C:28]([C:26]([NH:25][C:12]3[C:13]4[C:17]([CH:18]=[C:10]([C:4]5[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][S:52]([CH:51]=[CH2:50])(=[O:54])=[O:53])[CH:3]=5)[CH:11]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)=[O:27])[N:29]=2)[CH2:35]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cc1N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-[6-[5-Amino-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (250 mg) was dissolved in DCM (6 ml) and N-methylmorpholine (0.143 ml) was added. The reaction was cooled to 0° C. in an ice bath, then 2-chloroethanesulfonyl chloride (0.047 ml) was added dropwise. The reaction was left to warm to RT overnight. Reaction had blown dry, so was redissolved in DCM (6 ml). Further 2-chloroethanesulfonyl chloride (0.047 ml) was added and stirred at RT for 2 hours. Water (6 ml) was added to the reaction. The DCM was separated, passed through a hydrophobic frit, then evaporated to dryness to give crude title compound (250 mg) used directly in the next step without further purification.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].N([O-])=O.[Na+].[BrH:30]>O1CCOCC1.O.[Cu]Br>[Br:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Br
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br

Procedure:
In a solution of 0.50 g of 3-(4-amino-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 1.0 ml of 1,4-dioxane and 2.0 ml of water, 1.0 ml of 47% hydrobromic acid was added, and stirred under reflux with heat for 1 hour. Then, the reaction mixture was cooled with ice, and a solution of 0.10 g of sodium nitrite in 1.0 ml of water was slowly added dropwise with stirring at a temperature of 5° C. or less, after the completion of the addition dropwise, continued to stir at the same temperature for further 1 hour. The diazo mixture was slowly added dropwise in a mixture of 1.0 ml of 47% hydrobromic acid and 0.28 g of copper (I) bromide at 60° C. with stirring, after the completion of the addition dropwise, continued to stir at 60° C. for further 2 hours. After the completion of the reaction, 10 ml of water was added in the reaction mixture, extracted with ethyl acetate (20 ml×2), the organic phases together were washed with water, then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:10) to obtain 0.43 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(F)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1noc2cc(F)c([N+](=O)[O-])cc12
Reaction time: 1 h

Procedure:
A mixture of 6-fluoro-3-methyl-1,2-benzisoxazole (23.5 g, 0.156 mol) in concentrated sulfuric acid is cooled with an ice-bath, treated dropwise with 90% nitric acid (8.50 mL) while maintaining the reaction mixture temperature below 15° C., stirred for one hour at ice-bath temperature, treated with additional 90% nitric acid (5.80 mL), warmed to and stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is air-dried and dissolved in methylene chloride. The resultant organic solution is dried over anhydrous magnesium sulfate, diluted with hexanes, and filtered to give the title product as a purple solid which is identified by 1H NMR spectral analysis.