Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=1.[CH3:20][CH:21]([O:23][C:24](=[O:49])[NH:25][CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]([C:45](=[O:47])[CH3:46])[CH:28]([CH3:48])[CH2:27]1)[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.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][CH:21]([O:23][C:24](=[O:49])[NH:25][C@H:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]4[C:17](=[O:18])[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[C:10]4=[O:19])[CH:6]=3)[CH:34]=2)[N:29]([C:45](=[O:47])[CH3:46])[C@@H:28]([CH3:48])[CH2:27]1)[CH3:20]
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(Br)cn1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(NC(=O)OC(C)C)CC1C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cnn(CCN4C(=O)c5ccccc5C4=O)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
2-[2-(4-bromo-1H-pyrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28) (80 mg, 0.250 mmol) and 1-methylethyl[1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (Intermediate 12, 150 mg, 0.360 mmol) were mixed with potassium carbonate (69.1 mg, 0.500 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.44 mg, 0.012 mmol), dissolved in ethanol (1 mL) and toluene (1 mL) and stirred under nitrogen at 90° C. for 1 hour. The mixture was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine, 30 mL), dried (MgSO4), filtered and evaporated to dryness to give a yellow solid which was loaded on to a 12+M Biotage silica column and eluted with cyclohexane:ethyl acetate (3:1 to 1:2). Product-containing fractions were evaporated to dryness to give a solid (39 mg). LCMS (Method C): Rt=0.95, MH+=530
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.CO.[CH:17]([NH2:19])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:19][CH:17]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto ice/water 1/1 (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31]O)[CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O.Cl>O1CCCC1.CS(C)=O>[F:34][C:24]([F:23])([F:33])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:26]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: OCc1cc(C(F)(F)F)ccn1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C1N(Cc2cc(C(F)(F)F)ccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a solution of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.753 g, 2.55 mmol), [4-(trifluoromethyl)pyridin-2-yl]methanol (Ashimori et al., Chem. Pharm. Bull. (1990) 38:2446-2458) (0.655 g, 3.70 mmol) and tri-n-butylphosphine (0.93 mL, 3.7 mmol) in anhydrous tetrahydrofuran (20 mL) and anhydrous dimethylsulfoxide (0.2 mL) at ambient temperature was added over a period of 10 min a solution of diethyl azodicarboxylate (0.64 mL, 4.1 mmol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and was poured into 1 M hydrochloric acid (50 mL). The mixture was extracted with diethyl ether (3×50 mL) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 80% to 100% gradient of dichloromethane in hexanes, followed by a 0% to 20% gradient of ethyl acetate in dichloromethane and recrystallization from methanol afforded 1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.164 g, 10%) as a colorless solid: mp 154-155° C. (methanol); 1H NMR (300 MHz, CDCl3) δ8.76 (d, J=5.1 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J=5.1 Hz, 1H), 7.24-7.16 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.04 (d, J=16.1 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.23-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.8, 157.3, 155.3, 150.8, 144.8, 141.9, 139.8, 138.5, 132.3, 129.0, 124.1, 123.9, 121.1, 118.7, 117.6, 111.8, 109.3, 99.5, 80.1, 64.7, 64.0, 58.2, 45.8; MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([C:16](O)=[O:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][OH:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C(O)c1cc2ccc(Br)cc2c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1cc2ccc(Br)cc2c2ccccc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.8 %

Procedure:
A solution of 3-bromo-phenanthrene-9-carboxylic acid (6.27 g, 20.8 mmol) in 100 ml of THF was cooled to 0° C. and a solution of borane in THF (1.0M, 25 ml, 25 mmol) was added dropwise. The cooling bath was removed, and the solution was stirred at room temperature for 19 hours and was then quenched by the cautious addition of methanol (25 ml). The solution was evaporated to dryness in vacuo and the residue was dissolved in methanol--CH2Cl2 (1:1) and again evaporated. After one repetition of this dissolution-evaporation process, 5.96 g (100%) of the title compound was obtained as a brown solid which was used in the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[C:16]([CH2:18][OH:19])[S:15][CH:14]=2)([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34][C:3]1[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[C:16]([CH2:18][OH:19])[S:15][CH:14]=2)([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=1[OH:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2csc(CO)c2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3csc(CO)c3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-23; 0.67 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.74 mmol), potassium carbonate (2.7 mmol) in DMF (5 mL), mp 76-80° C. MS (APCI): 503 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cn1ncc2c(-c3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4[nH]ncc34)nc21
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 4-(methanesulfonyl)benzene boronic acid (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 115. NMR (CDCl3): 3.19 (3H, s), 4.36 (3H, s), 7.58 (1H, m), 7.67 (1H, d), 7.84 (1H, d), 7.87 (1H, s), 8.06 (2H, d), 8.19 (1H, s), 8.20 (2H, d), 8.96 (1H, s), 10.20 (1H, br). MS: MH+ 404
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (1.76 g, 6.0 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as an off-white (2.59 g, 96%). MS (ISP) 451.0 [(M+H)+]; mp 258° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2C#N)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(C2CCCNC2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
To a stirred solution of tert-butyl 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.170 g, 0.431 mmol) in dioxane (30 mL) was added 4N HCl in dioxane (3 mL). The mixture was stirred at room temperature for 12 hrs. The resulting precipitates were collected by filtration and the filtrate was washed with dioxane to give 2-amino-6-(2-hydroxyphenyl)-4-(3-piperidinyl)-nicotinonitrile hydrochloride(0.075 g, yield; 53%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16][OH:17])[O:11][C:10]([CH3:22])([CH3:21])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:18]([CH3:19])[CH3:20])[CH2:15][CH2:16][O:17][C:37](=[O:40])[CH2:38][CH3:39])[O:11][C:10]([CH3:21])([CH3:22])[N:9]2[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)Cl
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCC[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
1.0 g (2.43 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 50 ml of methylene chloride is treated with 0.38 ml (2.7 mmol) of triethylamine and 0.24 ml (2.7 mmol) of propionyl chloride and stirred at room temperature for 12 hours. After the usual working-up the crude product is purified by flash chromatography on silica gel with a 1:5 mixture of ether and petroleum ether, whereby there is obtained 1.0 g (88%) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-isopropyl-4-(propionyloxy)butyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 452 (M-CH3)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][C:23]([C:25]([NH:27][C@@H:28]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:29](O)=[O:30])=[O:26])=[CH:24][C:19]2=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@H:28]([NH:27][C:25]([C:23]2[NH:22][C:20]3=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=[C:19]3[CH:24]=2)=[O:26])[C:29](=[O:30])[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:38][CH:37]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2ccc(Cl)nc2[nH]1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCCC1)c1cc2ccc(Cl)nc2[nH]1

Procedure:
To pyrrolidine (11.5 mg, 0.14 mmol) was added a solution of DIPEA (60 μL, 0.35 mmol) in DMF (500 μL) followed by 2-(S)-[(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl) propionic acid (EXAMPLE 272, 50 mg, 0.14 mmol) in DMF (500 μL) and HOBt (23 mg, 0.15 mmol) in DMF (500 μL) and the mixture stirred. After 5 min EDCI (34.5 mg, 0.18 mmol) in DMF (500 μL) was added and the reaction stirred for 16 hr. Solvent was removed in vacuo then crude material purified by mass-directed purification to give the title compound. m/z (ES+)=414.93 [m+H]+; RT=3.77 min.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O>[C:14]([NH:5][CH2:4][CH2:3][Br:2])([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
Twenty point five g (0.10 mole) of 2-bromoethylamine hydrobromide was dissolved in 140 ml of water. At 0° C., 15.3 g (0.089 mole) of benzylchloroformate was added, followed by 18.5 g (0.1 moles) of sodium bicarbonate, and the mixture was stirred for 15 minutes at 0°. The mixture was then stirred overnight at room temperature. The mixture was extracted with diethylether (3×250 ml), the combined portions of which were washed thrice with 150 ml portions of saturated sodium bicarbonate, dried with magnesium sulfate and evaporated to yield 20.98 g of the crude N-carbobenzyloxy-2-bromoethylamine (NCBA).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:21](I)[CH3:22].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:21][CH3:22])[CH2:13][C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(NCC(F)(F)C(F)(F)F)ncn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CC(F)(F)C(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.8 %

Procedure:
In 2 ml of N,N-dimethylformamide were dissolved 73 mg of 4-(2-butynyloxy)-6-(2,2,3,3,3-pentafluoropropylamino)pyrimidine and 47 mg of ethyl iodide, to which 12 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3.5 hours. Then, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 43 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-(2,2,3,3,3-pentafluoropropyl)amino)pyrimidine (the present compound (112)).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C(#N)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1ncc[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1F
Yield: 52 %

Procedure:
2-Methylimidazole (9.02 g, 0.11 M) and N,N-diisopropylethylamine (32.2 g, 0.25 M) were dissolved in acetonitrile (160 ml), and 3,4-difluoronitrobenzene (15.9 g, 0.1 M) added. The mixture was stirred and heated to reflux under nitrogen for 24 hours. Solvent was evaporated, the residue dissolved in ethyl acetate (300 ml), washed with water (150 ml), brine (150 ml), and dried (magnesium sulfate). The residue was recrystallised from a mixture of ethyl acetate (25 ml) and cyclohexane (150 ml) with the addition of charcoal to give the title compound (11.5 g), mp 106–107°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](N)[C:3]=1[NH:9][CH2:10][CH2:11][OH:12].Cl.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([OH:27])[C:23](=[NH:26])OC>C(O)C.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][OH:12])[C:23]([CH:22]([C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[Cl:14])[OH:27])=[N:26][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N)c1NCCO
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCO)c12
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a stirred solution of 2-[(2,6-diaminophenyl)amino]ethanol (3.63 g, 21.7 mmol) in ethanol (43 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (7.04 g, 26.0 mmol) at room temperature. After 12 h, the reaction mixture was diluted with aqueous sodium hydrogen carbonate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound as an orange amorphous solid (7.58 g, 21.5 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([O:11][C:14]2[C:13]([Cl:12])=[CH:31][C:17]3[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]([C:22]([F:24])([F:25])[F:23])[O:21][C:16]=3[CH:15]=2)=[C:2]([Cl:1])[CH:3]=1)([OH:7])=[O:6]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chloro-4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to Example 183, Step 3, an additional equivalent of potassium carbonate was added.) mp >300° C. 1H NMR (acetone-d6/ 300 MHz) 8.18 (d, 1H, J=2.0 Hz), 8.03 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.93 (s, 1H), 7.78 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 6.77 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). ESHRMS m/z 446.9625 (M−H, Calc'd 446.9650). Anal. Calc'd for C18H9Cl2F3O6: C, 48.13; H, 2.02; Cl, 15.79. Found: C, 47.96; H, 1.90; Cl, 15.65.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].O1CCC[CH2:30]1.CCOCC.C[Mg]Br>C(OCC)(=O)C>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]([OH:27])[CH3:30])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCN(c1ccc(C)c2cc(-c3ncc(C(C)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 4 h
Yield: 65 %

Procedure:
To a mixed solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4-methyl-1H-indol-7-yl]thiophene-2-sulfonamide (0.30 g) and tetrahydrofuran (30 mL) was added ether solution (0.60 mL) of 3M-methylmagnesium bromide under ice-cooling, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed successively with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2-2:1), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (201 mg, yield 65%) as pale-yellow prism crystals. melting point 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>>[C:14]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:3]([C:16]3[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)#[N:15]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2N)CC1
Agent: [K+]
Product: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 1-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-cyclohexanecarbonitrile (as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) according to the procedure of Example 1, step (f). Mass spectrum (ESI, m/z): Calcd. for C32H43N5O2Si, 558.3 (M+H), found 557.8.