Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:12]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22]>C(O)(=O)C.Cl.O.C(O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][N:12]=[C:24]([C:25](=[O:27])[CH3:26])[C:21](=[O:23])[CH3:22])=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(OC(F)F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(OC(F)F)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 4-(difluoromethoxy)aniline (1000 mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-{[4-(difluoromethoxy)phenyl]hydrazono}pentane-2,4-dione (1400 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[C:5]([OH:47])=[C:6]([CH:46]=1)[CH2:7][C:8]1[C:9]([OH:45])=[C:10]([CH:42]=[CH:43][CH:44]=1)[C:11]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:29]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28](=[O:41])[N:19]2[C:20]=1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:12].C(Cl)(Cl)(Cl)Cl>C(C(O)=O)(F)(F)F.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[C:5]([OH:47])=[C:6]([CH:46]=1)[CH2:7][C:8]1[C:9]([OH:45])=[C:10]([CH:42]=[CH:43][CH:44]=1)[C:11]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:29]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28](=[O:41])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])=[O:12]
Reactant: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(Cc3cc(Cl)cc(Cc4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3cccc(Cc4cc(Cl)cc(Cc5ccccc5O)c4O)c3O)CS[C@H]12
Yield: 90 %

Procedure:
A solution of 17 (3.93 g, 4.99 mmol) in CF3CO2H (35%) in CH2Cl2 (45 mL) was stirred at room temperature for 13 h. The solution was condensed under reduced pressure and then CCl4 (30 mL) was added to the residue and evaporated. The resultant solid was crystallized from a mixture of EtOH and ether (2:1) to afford pure 19 (3.28 g, 4.49 mmol) as a white crystal in 90% yield: mp 196-198° C.; 1H NMR (DMSO-d6 /D2O) d 3.60 (br s, 4H, 2×CH2), 3.68, 3.79 (AB, Jgem =19 Hz, 2H, CH2S), 4.65 (s, 2H, OCH2CO), 4.95, 5.21 (AB, Jgem =14 Hz, 2H, CH2O), 5.15 (d, J=5.1 Hz, 1H, HC(6)), 5.76 (d, J=5.1 Hz, 1H, HC(7)), 6.80-7.35 (m, 14H, 4×ArH); IR (nujol): 3300-3450 (OH, NH, CO2H), 1785 (β-lactam), 1720 (ester), 1685 (amide), 1610 (C=O) cm-1. Anal. (C37H31N2O10SCl) C, H, N, S Cl.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])c(Br)c2)C1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of 2-bromo-4-fluoro-1-nitrobenzene (1.5 g, 6.8 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (1.9 g, 10 mmol), and sodium bicarbonate (1.7 g, 20 mmol) in DMSO (40 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature, poured into excess water and the resulting precipitate was filtered. The solids were washed with aqueous ammonium chloride, brine and water to afford the desired product (2.5 g, 96%) as a yellow solid: 387 [C15H20BrN3O4+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31].CCCCC>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]([OH:11])[CH2:9][O:10][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOc1ccccc1OC(c1ccccc1)C(O)CO
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccccc1OC(c1ccccc1)C(O)CO[Si](C)(C)C
Temperature: -17 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpropanol from Example 2 (1.44 g, 5 mmole) and triethylamine ((0.77 mL, 5.5 mmole) were dissolved in ethyl acetate (15 ml) and cooled to −17° C. Trimethylsilyl chloride (0.64 mL, 5.0 mmole) dissolved in 5 mL of ethyl acetate was added over 10 minutes keeping the temperature below −15° C. a white precipitate formed during this addition. The mixture was stirred below −15° C. for 15 minutes, and 20 mL of pentane was added. The solids were removed by filtration and the filtrate was concentrated under vacuum to a cloudy oil. The oil was chromatographed on silica (230-400 mesh) eluting with 4:1 heptane-ethyl acetate. The product-containing fractions were concentrated to yield 1.80 g (88.5%) of the title compound as a clear colorless oil; 1H NMR (400.13 MHZ, CDCl3) d 0.09 (s, 9H), 1.47 (t, J=6.8 Hz, 3H), 2.82 (d, J=5.2, 1H), 3.80 (m, 3H), 4.0-4.11 (m, 4H), 5.08 (d, J=6.0, 1H), 6.76 (m, 2H), 6.85 (m, 2H), 7.2-7.45 (m, 5H); 13C NMR (100.62 MHZ, CDCl3) d 0.0, 15.54, 63.34, 65.06, 75.22, 83.71, 114.28, 118.60, 121.51, 122.95, 127.84, 128.49, 128.84, 138.93, 148.34, 150.40; MS (ei) m/e 360.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@@H:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@@H:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([O:20][CH3:21])=[O:19])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)c1ccccc1
Yield: 44.9 %

Procedure:
6-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 2.0 g, 7.29 mmol), (S)-methyl 2-amino-2-phenylacetate hydrochloride (2.20 g, 10.93 mmol) and DIPEA (3.82 mL, 21.86 mmol) in NMP (10 mL) were heated in the CEM microwave at 80° C. for 1 hr. The reaction was then quenched with ice-water and the resulting precipitate filtered. The crude solid was purified by column chromatography using hexane:ethyl acetate as eluent to give the title compound (1.32 g, 3.27 mmol, 44.9% yield) as a white solid. HPLC (condition B): retention time=0.93 min. LCMS (condition B): m/z 403.2, 405.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1 H, d, J=7.48 Hz), 8.31 (1 H, s), 7.88 (1 H, d, J=1.54 Hz), 7.11-7.72 (3H, m), 6.93 (2 H, d, J=1.76 Hz), 6.12 (1 H, d, J=7.70 Hz), 3.31 (3 H, s).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:17]=[C:16]2[C:6]([C:7]([OH:30])=[C:8]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:9](=[O:18])[C:10]32[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>O>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:17]=[C:16]2[C:6]([C:7]([OH:30])=[C:8]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:9](=[O:18])[C:10]32[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Yield: 48.8 %

Procedure:
1,1-Dimethylethyl N-((7-trifluoromethyl-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (1.29 g, 2.82 mmol) was stirred in TFA (3 mL, 40.4 mmol) at room temperature for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (550 mg). MS (m/e)=400.1 (M+H)+. Calculated for C18H16F3NO6 399.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([OH:21])=O)[S:8][C@H:7]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:32]=1.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH2:35])=[O:21])[S:8][C@H:7]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:32]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)CN1C(=O)[C@@H](CC(N)=O)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
A solution of trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetic acid (200 mg, 426 μmol), 1,1'-carbonyidiimidazole (143 mg, 853 μmol) and tetrahydrofuran (5 mL) was heated at reflux for 1.5 hours. The resulting reaction mixture was cooled to 0° C. and a solution of tetrahydrofuran saturated with anhydrous ammonia (5 mL) was added. After 0.5 hours the reaction mixture was warmed to ambient temperature, concentrated under reduced pressure and purified by flash column chromatography (1:1 hexanes/ethyl acetate) to provide 200 mg (quantitative) of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2](=[CH2:7])[CH2:3][NH:4][CH2:5][CH3:6].[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F)([O-:10])=[O:9]>>[CH3:7][C:2](=[CH2:1])[CH2:3][N:4]([CH2:5][CH3:6])[C:12]1[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C=C(C)CNCC
Product: C=C(C)CN(CC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Treatment of N-2-methylallyl-N-ethylamine with 2,4-dinitrofluorobenzene as described in Example 1 gave N-2-methylallyl-N-ethyl-2,4-dinitrobenzeneamine as a red oil (13.0 g).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Solvent: CCO
Product: CN1CCN(CC(O)COc2ccccc2C(=O)Nc2cccc3[nH]ccc23)CC1

Procedure:
1.8 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 36 ml of ethanol and 6.5 ml of N-methyl piperazine was refluxed for 1 hour and the solvents were eliminated under reduced pressure. The residue was chromatographed over silica (eluent:chloroformethanol, 9-1) to obtain 1.77 g of 2-[3-(4-methyl-1-piperazinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamid
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.CCCCCC.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28].[Cl-].[NH4+]>O1CCCC1>[F:15]/[C:9](=[CH:34]\[C:33]1[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C/c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of ethyl diethylphosphono-2-fluoroacetate (4.90 g, 20.2 mmol) in tetrahydrofuran (40 mL) was stirred under a nitrogen atmosphere at 0° C. and 1.6 M n-butyllithium/hexane solution (13.1 mL, 21.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, and a solution of 4-nitrobenzaldehyde (3.05 g, 20.2 mmol) in tetrahydrofuran (40 mL) was added dropwise. The mixture was stirred at room temperature for 16 hr, and ice-cooled aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3%-40% ethyl acetate/hexane) to give the title compound (3.46 g, yield 72%) as a yellow powder.
Reaction SMILES: [H-].[Na+].C(S(CC)=O)C.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:23][C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:10]=1.[N:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1>CS(C)=O>[N:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2([CH2:36][C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[S:23][C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: c1ccc2c(c1)Sc1ccccc1C2Cc1ccncc1
Agent: CCS(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)Sc1ccccc1C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A quantity of 0.38 g (8.0 mmole) of 50% sodium hydride oil dispersion was added slowly during 15 minutes to 20 ml of ethyl sulfoxide at room temperature. After completion of addition, the reaction mixture was heated at 45° for 30 minutes. It was cooled to 15° and a solution of 2.3 g (8.0 mmole) of 9-(4-pyridinylmethyl)thioxanthene in 10 ml of dimethylsulfoxide was added dropwise during 15 minutes at room temperature. After completion of addition, the reaction mixture was stirred 30 minutes at room temperature. Then a solution of 4-picolylchloride (8.75 mmole) in 5 ml of dimethylsulfoxide was added dropwise during 30 minutes at ambient temperature. The reaction was then heated at 40° for 30 minutes. The reaction was quenched by addition of water (50 ml). Trituration of the precipitated oil yielded a crystalline solid, which was filtered off, washed with water and dried. The tan solid was dissolved in benzene and decolorized by stirring with 1 g of Magnesol® for 30 minutes. Filtration and evaporation yielded a colorless product (2.0 g) which was recrystallized from ethylacetate, m.p., 201.4°-203.4°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])O1>>[F:20][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[N:7]=[C:2]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH:3]=[CH:4][CH:5]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(F)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Product: CC(C)(F)c1ccn2c(-c3cccc(-c4ccccc4C#N)n3)cnc2n1
Yield: 37 %

Procedure:
The product of Example 25 (0.34 g, 1.0 mmol) was coupled to 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile following the procedure in Example 2 to give 2-{6-[7-(1-fluoro-1-methyl-ethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile (0.133 g, 37%) as a white solid: δH (360 MHz, CDCl3) 1.80 (6H, d, J 22), 7.38 (1H, dd, J 7 and 2), 7.59 (1H, ddd, J 8, 7 and 1), 7.75 (1H, ddd, J 8, 7 and 1), 7.80-7.96 (5H, m), 8.38 (1H, s), 10.36 (1H, d, J 7); m/z (ES+) 358 (M++H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7](Cl)[N:6]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[OH-].[Na+]>O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([OH:16])[CH:18]=2)[N:6]=1
Reactant: OCCNc1nc(Cl)nc(NCCO)n1
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNc1nc(NCCO)nc(Nc2cccc(O)c2)n1

Procedure:
70.1 g (0.3 mol) of 2,4-bis-(2-hydroxyethylamino)-6-chloro-1,3,5-triazine, 32.8 g (0.3 mol) of 3-hydroxyaniline and 400 ml of water are placed in a 2 l flask equipped with a stirrer, a dropping funnel, a reflux condenser and a thermometer. The mixture is heated under reflux, with stirring. In the course of this, a solution of 12 g of sodium hydroxide in 60 ml of water is added dropwise slowly at such a rate that a slightly alkaline reaction mixture results. 300 ml of water are then added, as well as active charcoal for the removal of colour. The hot solution is then filtered and cooled. The resulting, virtually colourless crystals are filtered off with suction, washed free from chloride with a little water and dried. The product has a melting point of 142°-143° C. The yield is 70.8 g (=77% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(F)c2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 0 °C
Reaction time: 2.75 h
Yield: 56 %

Procedure:
A solution of 3-[3-(3-fluorophenylsulfonyloxy)-5-methylphenoxy]-propanol (840 mg, 2.5 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (0.90 mL, 25.2 mmol), anhydrous dimethyl sulfoxide (0.52 mL, 27.4 mmol), and anhydrous dichloromethane (25.9 mL) was cooled to 0° C. under nitrogen. Sulfur trioxide pyridine complex (830 mg, 5.2 mmol) was added in portions over 13 minutes. The solution was stirred at 0° C. for 2.75 hours, then the reaction was quenched with 10% aqueous citric acid (60 mL). Diethyl ether (60 mL) was added, and the mixture was extracted. The aqueous layer was extracted with diethyl ether (30 mL), and the combined organic layers were washed with 5% aqueous citric acid (100 mL). The aqueous layer was extracted with diethyl ether (30 mL), and the combined organic layers were washed with pH 7 buffer (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to an oil. The crude product was purified by flash column chromatography through silica gel (40% diethyl ether in hexane) to give the title compound as a pale yellow oil (468 mg, 56%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (t, 1H, J=1.4 Hz), 7.51-7.68 (m, 3H), 7.35-7.42 (m, 1H), 6.63 (br s, 1H), 6.44 (br s, 1H), 6.37 (br t, 1H, J=2.2 Hz), 4.20 (t, 2H, J=6.1 Hz), 2.87 (td, 2H, J=1.4, 6.1 Hz), 2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H15FO5S: 361.1 (M+Na). Found: 361.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:17](Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:9][S:17][N:8]=2
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(F)cc1N
Solvent: CCN(CC)CC
Product: Fc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
4-Fluoro-benzene-1,2-diamine (2.5 g, 19.8 mmol) was added into a 50-mL Schlenk flask. The system was flushed with argon before 200 mL of chloroform was added and followed by addition of triethylamine (11.05 mL, 79.3 mmol). A clear solution was observed after stirring at room temperature for 10 minutes. Thionyl chloride (5.18 g, 43.6 mmol) was added dropwise. The mixture was heated to reflux for 5 hours before being cooled down to room temperature. The organic layer was washed with brine (100 mL) and further dried over anhydrous MgSO4. After removal of the solvent, the product was purified by silica gel column with hexane/dichloromethane (v/v, 1/2) as the eluent. Removal of the solvent offered a colorless oil (1.35 g, 44.3% yield) after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ7.93 (d×d, 1H, J=9.0 Hz×5.0 Hz), δ 7.56 (d×d, 1H, J=9 Hz×2.5 Hz), δ 7.38 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1cccc(N)c1C
Product: Cc1cccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c1C
Yield: 58.8 %

Procedure:
Using the procedure of example 1, 2,3-dimethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 34 (50 mg, 59%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=8.0 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.18-7.13 (m, 3H), 7.02 (dd, J=8.0 Hz, 4.8 Hz, 1H), 2.37 (s, 3H), 2.20 (s, 3H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])=[CH:4][CH:3]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)Nc1ccc(Cl)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A solution of p-chlorophenylisocyanate (756 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (558 μl, 4 mmol) is added at 0° C., and the mixture is stirred at 0° C. for 30 minutes, and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and distilled under reduced pressure to remove solvent. The residue is recrystallized from dichloromethane/diisopropylether to obtain the objective compound 6y (1.48 g, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:23][C:24](N(OC)C)=[O:25])[CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:24](=[O:25])[CH2:23][CH:20]3[CH2:22][CH2:21]3)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)CC1CC1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(C(=O)CC3CC3)cc21

Procedure:
Prepared from 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester and 2-cyclopropyl-N-methoxy-N-methyl-acetamide using a procedure analogous to that of Preparation 263. MS: [M+H]+=331.