Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][C:8](=[O:10])[CH3:9].[H-].[Na+].[CH2:13](I)[CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[CH2:13]([N:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:8](=[O:10])[CH3:9])[CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)Nc1cccn1C
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(C(C)=O)c1cccn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
N-(1-Methylpyrrol-2-yl)acetamide (3.20 g, 0.0231 mol) in dry dimethylformamide was maintained at a temperature less than 0° C, with stirring under nitrogen, during the slow addition of 50% sodium hydride/oil (1.11 g, 0.0231 mol). After the addition, the mixture was stirred at 0° C. for 30 minutes and then the temperature allowed to rise to 15° C. when n-butyl iodide (8.50 g, 0.0461 mol) was added. The mixture was stirred at room temperature overnight and then poured into water (200 ml) and the mixture extracted with ether (4 × 50 ml). The combined extracts were washed with water (3 × 50 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the resulting oil distilled to give a colourless oil 3.72 g (83%) b.p. (airbath) 100° C/0.4 mm.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:18]=[C:19]1[C:24](=[O:25])[CH:23]2[CH2:26][CH2:27][N:20]1[CH2:21][CH2:22]2>C(O)C.C(O)(=O)C>[O:25]=[C:24]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:21][CH2:22]2)[CH:19]1[CH2:18][C:7]([CH3:6])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CC1C(=O)C2CCN1CC2)C(=O)OCC
Reaction time: 16 h

Procedure:
Ethanolic sodium ethoxide, previously prepared from 2.9 g of metallic sodium and 100 ml of ethanol, was added to diethyl methyl-malonate, 50 g, and the mixture was refluxed for 30 min. then cooled to 5°. A solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml, was then added dropwise and with stirring. After 16 hrs. at room temperature, the resulting solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml was added and the mixture was extracted with chloroform. Evaporation of this solvent gave diethyl (3-oxo quinuclidin-2-yl)-methyl-methylmalonate, 72 g (81%), m.p., 58.4° (from petroleum ether). A solution of the foregoing compound, 72 g, in ethanol, 50 ml, was treated at 5° and with stirring with a solution of sodium borohydride, 3.55 g, in ethanol, 600 ml. The borohydride solution was added in small increments over a period of six hours. After 20 hours, the mixture was neutralized with concentrated hydrochloric acid, then subjected to evaporation at reduced pressure. The residue was taken up in 200 ml of water and extracted with chloroform. Evaporation of this solvent left a syrupy residue, 55 g, which consisted of the compound diethyl (3-hydroxyquinucldin-2-yl)methyl-methylmalonate; its methiodide salt, prepared with methyl iodide in acetone, has a m.p. of 228.2°.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC#CCOc1cc(N(CCC)CCC)ncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 2 ml of dimethylsulfoxide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 152 mg of dipropylamine, followed by stirring at 80° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 179 mg of 4-(2-butynyloxy)-6-(dipropylamino)pyrimidine (the present compound (113)).
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 87.4 %

Procedure:
Using the general method of Example 146. Part B, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine (4.0 g, 12.3 mmol) was reacted with phenyl isocyanate (1.34 mL, 12.3 mmol) to provide 4.77 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30](Cl)[N:29]=[CH:28]2>>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11])[N:29]=[CH:28]2
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ncc2cc(Br)ccc2n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3cc(Br)ccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+[M+2]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([CH2:38][CH:39]5[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])[CH2:41][CH2:40]5)[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 75 °C
Yield: 13.2 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) (147 mg, 0.37 mmol) and triethyamine (52 μL, 0.37 mmol) in DMF (3 mL, anhydrous) was added tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (103 mg, 0.37 mmol). The reaction mixture was stirred at 75° C. until LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (high pH) to afford a brown solid (28.9 mg, 0.049 mmol, 13%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]2[O:15][CH2:16][O:17][C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+].O>CS(C)=O>[C:18]([CH2:2][C:3]1[C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]2[O:15][CH2:16][O:17][C:5]=2[CH:4]=1)#[N:19]
Reactant: [C-]#N
Reactant: CC(=O)NCCc1cc2c(cc1CCl)OCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NCCc1cc2c(cc1CC#N)OCO2

Procedure:
4.7 g of N-(6-chloromethyl-3,4-methylenedioxyphenethyl) acetamide was dissolved in 10 ml of DMSO and 1.32 g (0.028 mole) of sodium cyanide added to the stirred solution. Within a few minutes, the temperature rose from 25° to 32° C. After 1.5 hrs at ambient temperature the mixture was poured into ice and water. The suspension was extracted with three 50-ml portions of benzene. The benzene layers were washed with saturated brine six times, then with water, the solution dried, and the solvent distilled in the rotary evaporator leaving the above-named product as a crystalline solid, m.p. 153.3-155.5.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].C[N+:24](C)(C)[CH2:25][C:26]1C=CC=C[CH:27]=1.C(#N)C=C>C1C=CC=CC=1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:26]([CH3:27])[C:25]#[N:24])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C=CC#N
Solvent: c1ccccc1
Product: CCCCCCc1ccc(N=Nc2ccc(OC(C)C#N)cc2)cc1

Procedure:
In 2 ml of benzene, 0.4 g of 4-hexyl-4'-hydroxyazobenzene and a catalytic amount of trimethylbenzylammonium hydroxide were dissolved. To the resultant solution, 8 ml of acrylonitrile was slowly added. The resultant mixture was heated for 22 hours and then subjected to vacuum distillation for expulsion of the solvent. The residue of the distillation was extracted with benzene. Then, it was purified by silica gel column chromatography, to obtain 0.25 g of 2-[4-(4-hexylphenylazo)phenoxy]propanenitrile. This compound was converted to a corresponding carboxylic acid by hydrolysis with acetic acid containing hydrochloric acid. The carboxylic acid was converted into an acid chloride with thionyl chloride. The aminated quartz plates were treated with the acid chloride in the same manner as in Example 18. The absorption spectrum of the quartz plates indicated that the plates had azobenzene bonded thereto. A sandwich cell was produced by interposing the same mixed such a manner that the direction of rubbing perpendicularly intersected. When this cell was exposed alternately to an ultraviolet light and a visible light, it showed a reversible change in transmittance, indicating a change in the arrangement of liquid crystals between the homeotropic mode and the twisted mode.
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=O.[NH3:23]>CO>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]1=[O:22]
Reactant: N
Reactant: COC(=O)C1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Solvent: CO
Product: CN1C(=O)CCc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 55 °C
Yield: 84 %

Procedure:
To a stirred solution of 3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 4, 150 mg, 0.49 mmol) in MeOH (1 mL) is added 2.0 M NH3 in MeOH (1 mL, 2.0 mmol). The reaction mixture is then heated at 50-60° C. until all of the solid disappears. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give the title compound as a white solid (120 mg, 84%), 1H NMR (300 MHz, DMSO) δ 7.85 (br S, 1H), 7.60 (br S, 1H), 7.45-7.08 (m, 3H), 5.01 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.50 (m, 2H); MS for C14H15N3O4 m/z 290.5 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]1=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11].[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:20]1=[O:37]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoate (410 mg) was dissolved in 30% TFA/DCM (5 mL), the mixture was stirred on a magnetic stirrer for 4 hrs at room temperature. White foam was obtained after reduced pressure distillation to distill off the solvent. The foam was dissolved in DCM (30 mL). The resultant solution washed with aqueous saturated sodium bicarbonate solution and brine (30 mL), dried over anhydrous magnesium sulfate, and filtered. Title compound was obtained as a white solid (260 mg) after rotary evaporation. 1H NMR (CDCl3, ppm) δ 7.87-7.91 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.25 (dd, 1H, J=4.8, 13.2 Hz), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 1H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H). MS (m/e): 402 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)=[O:4].[C:38](O)(=[O:41])[CH:39]=[CH2:40].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([NH:5][C:3]([CH2:2][NH:1][C:38](=[O:41])[CH:39]=[CH2:40])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)CN
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)NCC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 27 %

Procedure:
320 mg of 2-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-acetamide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.06 ml of acrylic acid, 0.1 ml of pyridine and 234 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 5 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (96 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C@@H:25](Cl)[CH3:26]>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C@@H:25]([C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[CH3:26])=[CH:4][CH:3]=1
Reactant: C[C@H](Cl)c1ccc(Cl)cc1Cl
Reactant: Brc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(Br)cc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 6-bromoindazole (3.4 g, 17.0 mmol) and Cs2CO3 (15.8 g, 48.5 mmol) in 1-methyl-2-pyrrolidinone (NMP, 11 mL) at 85° C. was added crude (S)-2,4-dichloro-1-(1-chloroethyl)benzene (3.2 g, 15.4 mmol) dropwise. The reaction mixture was heated for 10 min, and cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with deionized water and brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-indazole (2.2 g, 6.0 mmol, 39%).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=1>CS(C)=O.[NH4+].[Cl-].[Cu]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=1)([F:9])[F:8])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Clc1cccc(I)c1
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a mixture of copper bronze (2.93 g, 46.1 mmol) in DMSO (5.0 mL) was added ethyl bromodifluoroacetate (3.2 mL, 25 mmol) under argon at room temperature (see Sato, K. et al; Chem. Pharm. Bull. 47:1013-1016, 1999). After stirring for 1 h, 1-chloro-3-iodobenzene (2.57 mL, 20.8 mmol) was added under argon at room temperature. After shaking for 3 days, the mixture was diluted with saturated NH4Cl (50 mL) and extracted with ether (25 mL). The biphasic mixture was filtered through a pad of Celite, and the filter cake was washed with ether (25 mL). The organic layer was separated from the filtrate, and the aqueous layer was extracted with ether (25 mL). The combined organic layers were washed with saturated NH4Cl (2×15 mL) and brine (15 mL), dried (Na2SO4), and concentrated to afford the title compound (4.77 g, 97%) as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.63-7.59 (m, 1H), 7.53-7.45 (m, 2H), 7.43-7.36 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:32]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:32][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:17][N:16]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Yield: 61.4 %

Procedure:
15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat. NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33. Found: 418. (M+H+).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:29][NH:30][CH2:31][CH2:32][NH:33][CH3:34]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:13]3[CH:14]=[N:15][C:16]([N:30]([CH3:29])[CH2:31][CH2:32][NH:33][CH3:34])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CNCCNC
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2oc(Cl)cc2c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(N(C)CCNC)nc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 16, step C described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70 mg, 1.0 eq) was reacted with N,N′-dimethylethane-1,2-diamine (150 mg, 10 eq) to give the desired product (Z/E=1/1). m/z=462[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:5]([Cl:17])=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>COCCOC.CCO>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:1]=2)[C:6]=1[CH2:8][P:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:16]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOP(=O)(Cc1nc(N)ccc1Cl)OCC
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(CP(=O)(OCC)OCC)c(Cl)ccc2n1
Yield: 13 %

Procedure:
Following the procedure for Example 17, the residue from Example 28 was combined with ethyl bromopyruvate (0.468 g, 2.4 mmol) in DME (25 mL). After the resulting salt was refluxed in abs EtOH (30 mL) for 6 h, workup and puricication produced 0./114 g (13% of title compound).
Reaction SMILES: Cl.[CH2:2]1[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[N:16][N:15]=1.C(N(CC)CC)C>C(O)C>[CH2:4]1[O:5][C:6]2([CH2:11][CH2:10][N:9]([C:17]3[C:18]4[C:23](=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:14]=[N:15][N:16]=3)[CH2:8][CH2:7]2)[O:12][CH2:2][CH2:3]1
Reactant: COc1cc2cnnc(Cl)c2cc1OC
Reactant: C1COC2(CCNCC2)OC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2cnnc(N3CCC4(CC3)OCCCO4)c2cc1OC
Yield: 71.5 %

Procedure:
4-Piperidone trimethylene ketal hydrochloride (20 g), 1-chloro-6,7-dimethoxyphthalazine (10 g), triethylamine (50 ml) and ethanol (300 ml) were heated together under reflux for 70 hours. The resulting mixture was evaporated in vacuo and the residue was partitioned between chloroform (2×100 ml) and water (60 ml). The chloroform extracts were combined, dried (MgSO4) and evaporated in vacuo to give a crude brown oil which on trituration with ethyl acetate (100 ml) at boiling point gave 1-[6,7-dimethoxyphthalazin-1-yl]piperid-4-one trimethylene ketal (11 g), m.p. 194°-6°. A second crop of the product (3 g) was obtained by evaporating the ethyl acetate trituration liquors.
Reaction SMILES: [Cl:1][C:2]1([C:10](=[O:12])[CH3:11])[CH2:7][CH:6]([CH2:8][CH3:9])OC1=O.[ClH:13]>>[Cl:1][CH:2]([CH2:7][CH:6]([Cl:13])[CH2:8][CH3:9])[C:10](=[O:12])[CH3:11]
Reactant: Cl
Reactant: CCC1CC(Cl)(C(C)=O)C(=O)O1
Product: CCC(Cl)CC(Cl)C(C)=O

Procedure:
The title compound is prepared according to the method described in Example 1 starting from 49 g (0.26 moles) of α-chloro-α-acetyl-γ-ethyl-γ-butyrolactone and 98 cm3 of abs. hydrochloric acid. After distillation 22 g (47%) of the title compound is obtained. Its boiling point is 68°-70° C. at a pressure of 133.3 Pa, nD20 =1,4600.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3,4-difluoro phenyl isocyanate (0.041 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 51 as a colorless solid (0.096 g, 80%). LCMS m/z (%)=467 M+H+ (81Br, 88), 465, M+H+ (79Br, 95)1H NMR (400 MHz, DMSO-d6) δ: 8.816 (bs, 1H), 8.681 (bs, 1H), 7.5 (s, 1H), 7.412 (d, J=2.51 Hz, 2H), 7.389 (d, J=2.51 Hz, 2H), 7.199 (t, 1H), 7.167 (s, 1H), 6.983 (t, 1H), 3.989 (m, 1H), 3.596 (s, 3H), 1.225 (d, J=6.61 Hz, 3H), 1.078 (d, J=6.61 Hz, 3H).