Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]3=[O:22])=[CH:13][CH:12]=2)[CH2:21][CH2:20]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 28, the title compound was prepared from the compound obtained in step (e) of Example 1 and benzoyl chloride.
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:24]([Mg]Br)[CH3:25]>C1COCC1>[C:16]1([NH:15][C:6]2[C:5]([C:4](=[O:22])[CH2:24][CH3:25])=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
In a 250 mL round-bottomed flask, N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (1.73 g, 5.32 mmol) was combined with THF (20 mL) to give a brown solution and the solution was cooled to 0° C. Ethylmagnesium bromide (1.0 M in THF) (16 mL, 16.0 mmol) was added dropwise at 0° C. over 5 min. The reaction mixture was stirred in an ice bath for 2.5 hr and 1 hr at room temperature. Additional ethylmagnesium bromide (1.0 M in THF) (6 mL, 6.00 mmol) was introduced over 3 min and the mixture was stirred for 2 hr at room temperature. The reaction mixture was cautiously quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (1×50 mL), dried over MgSO4 and concentrated in vacuo to give 1.56 g of crude product as a yellow solid. The crude material was purified by flash chromatography (silica gel, 150 g, 15% ethyl acetate in hexanes) to give 1-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-propan-1-one (1.35 g, 86.3% yield) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 11.13 (s, 7H) 8.67 (d, J=8.2 Hz, 1H) 7.74 (d, J=7.8 Hz, 2H) 7.20-7.54 (m, 3H) 6.81-7.19 (m, 1H) 3.19 (q, J=7.2 Hz, 2H) 1.12 (t, J=7.1 Hz, 3H). MS calcd. for C15H13F3N2O [(M+H)+] 295.0, obsd. 295.0.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:12][S:13]([O:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCc2ccccc2C1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
2-tetralinol (0.86 g) in pyridine (5 ml) was stirred with cooling to 0°. Methylsulphonyl chloride (0.8 g) was added dropwise while maintaining the temperature at 0°. The mixture was then allowed to warm to room temperature and was stirred for 0.5 hour. The mixture was then poured on to ice and immediately a white precipitate formed; the mixture was allowed to stand overnight. The precipitate was then filtered off, washed with water and air-dried to give 2-methylsulphonyloxytetralin (0.72 g), m.p. 60°-62°.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:4]=1>CO>[NH2:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:4]=1
Reactant: Clc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Reactant: N
Solvent: CO
Product: Nc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Temperature: 130 °C
Yield: 69 %

Procedure:
A 7N ammonia in methanol (60 ml) was added to 6-chloro-4-(1H-5-indolylamino)pyrimidine (2.455 g, 10 mmol); and the reaction mixture was heated in a sealed tube at 130° C. for 90 hours. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); diethyl ether was added to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (1.563 g, 6.9 mmol, 69%) as pale brown crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:11][C:4]1[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.9 %

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridine (1.47 g, 7.61 mmol) in toluene (40 mL) was treated with, solid K2CO3 (1.26 g, 9.13 mmol) and 4-methyl-piperidine (0.90 mL, 7.6 mmol). The reaction was stirred at room temperature for 1.5 h, additional toluene (10 mL) was added, and the reaction was stirred an additional 5 h. The reaction was diluted with EtOAc and washed with water. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.00 g, 100%) as a waxy, bright yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.06 (d, 1H, J=4.0 Hz), 7.61 (d, 1H, J=4.0 Hz), 3.83-3.75 (m, 2H), 3.08-2.97 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (br s, 1H), 1.37-1.23 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C11H14ClN3O2, 256.1 (M+H), found 256.1.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[CH3:23][N:24]1[C:28](C(Cl)=O)=[CH:27][N:26]=[CH:25]1>>[CH3:23][N:24]1[C:28]([C:3](=[O:22])[CH2:4][C:5]2[N:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]3=[N:7][C:6]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:27][N:26]=[CH:25]1
Reactant: Cn1cncc1C(=O)Cl
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cncn2C)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid methyl ester 35a and 3-methyl-3H-imidazole-4-carbonyl chloride using the procedure of Method C described above. 1H NMR (400 MHz, CDCl3) 2.34 (s, 3H), 2.39 (s, 3H), 3.91 (s, 3H), 4.52 (s, 2H), 7.05 (dd, J=1.1, 9.1 Hz, 1H), 7.26 (m, 2H), 7.57 (m, 4H), 7.74 (s, 1H), 7.80 (s, 1H). Mass spectrum (m/e) 345 (M+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][C:12]1=[O:19])[CH2:8]2.I[CH3:21]>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[N:13]([CH3:21])[C:12]1=[O:19])[CH2:10]2
Reactant: CI
Reactant: O=c1[nH]c(C2CC2)cn1C1C2CC3CC(C2)CC1C3
Product: Cn1c(C2CC2)cn(C2C3CC4CC(C3)CC2C4)c1=O

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-cyclopropyl-1,3-dihydro-imidazol-2-one (obtained in example 15, 100 mg) by alkylation with iodomethane (82 mg). 1-Adamantan-2-yl-4-cyclopropyl-3-methyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (52 mg). MS (EI): 272.3 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)(C)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1

Procedure:
207 parts of 2,6-dichloro-4-nitro-aniline are introduced into 180 parts of isopropanol and 300 parts of water and 200 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C. resulting in the evolution of nitrogen. The mixture is cooled, 400 parts of water are added and the product is filtered off. 192 parts (a practically quantitative yield) of 3,5-dichloro-nitro-benzene, of melting point 60°-62° C., are obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])[CH2:14][CH2:13]2)[CH2:11]1
Reactant: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCOCC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(C1CCN(C2CNC2)CC1)N1CCOCC1
Temperature: 120 °C
Yield: 43.4 %

Procedure:
4-({1-[1-(Diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine (0.44 g, 1.0 mmol) was dissolved in ethanol and to the resultant solution was added palladium hydroxide on carbon (0.15 g) and ammonium formate (0.27 g, 4.2 mmol). The reaction mixture was heated for 2 min at 120° C. using microwave single node heating. The catalyst was filtered off by means of a phase separator and the filter cake washed with ethanol. The solvent was removed by evaporation and the residue was dissolved in methanol (1 mL) and THF (10 mL). The solution was loaded on a cation exchange sorbent (Isolute® SCX-2; 10 g). The column washed with THF and the product was then eluted with ammonia saturated methanol. The solvent of the collected fractions was removed by evaporation and there was obtained 0.11 g of the title compound as colourless oil. 1H NMR (500 MHz, CD3OD): 1.7-1.8 (m, 4H), 1.9-2.0 (m, 2H), 2.6-2.9 (m, 4H), 3.3-3.4 (m, 1H), 3.5-3.7 (m, 8H), 3.8-4.0 (m, 3H); LCMS: m/z 254 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.Cl>CN(C)C=O>[C:17]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]2=[O:14])=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NC(=O)C(c2ccc(O)cc2)C(=O)N1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)barbituric Acid (1.9 g) and tertbutyl dimethylsilyl chloride (4.68 g) in 20 ml of anhydrous dimethylformamide are added 4.4 g of imidazole and the mixture is heated to 55° C. for 5 hours. The temperature is then brought to room temperature and the reaction mixture is poured into 1 N hydrochloric acid and extracted twice with ethyl acetate. The pooled organic extracts are washed with water and dried over sodium sulfate. By concentration of the solution a white solid separates, which is kept at 0° C. overnight, then it is filtered to give 2.185 g of the product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12]/[C:11]/2=[N:31]/[C:30]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 6-phenoxy-2-phenylchroman-4-one (316 mg, 1 mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:15][C@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[CH:19]=2)([O:16][CH3:17])[C@H:13]([OH:37])[C@@H:12]([OH:38])[C@@H:11]1[OH:39])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C@@H:10]1[C@@H:11]([O:39][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:12]([O:38][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([O:37][CH2:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[CH:19]=2)([O:16][CH3:17])[O:15]1)([CH3:6])([CH3:7])[CH3:5]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 260.4 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 15i (1.37 g, 1.69 mmol) in anhydrous tetrahydrofuran (15 mL) was added sodium hydride (0.20 g, 8.45 mmol, 60% dispersion in Mineral oil) at 0° C. The mixture was stirred at 0° C. for 15 min, and then benzyl bromide (1.45 g, 8.45 mmol) and tetrabutylammonium iodide (0.06 g, 0.17 mmol) were added in turn. The mixture was further stirred at room temperature for 20 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated in vacuo to give the title compound 15j as yellow oil (1.9 g, 100%). This material was not further purified.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[O:9][N:8]=1.C(N(C(C)C)CC)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:27](=[O:29])[CH3:28])[CH2:14][CH2:13]2)[O:9][N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
50 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)-piperidinium hydrochloride and 77 μl (3 eq.) of diisopropylethylamine were dissolved in 1 ml of dichloromethane. 39 μl (1.2 eq.) of acetic anhydride were added dropwise and the reaction medium was stirred for 2 hours at room temperature. The reaction medium was evaporated and the residue was taken up in 15 ml of ethyl acetate. The organic phase was washed with aqueous 1N sodium hydroxide solution (3×30 ml), with aqueous 1N hydrochloric acid solution (3×30 ml) and with saturated aqueous NaCl solution (30 ml), dried over MgSO4 and concentrated under reduced pressure to give 41 mg (98%) of the expected compound.
Reaction SMILES: [F:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].C[Si](C)(C)[O-].[K+]>C1COCC1>[F:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(F)c1ccccn1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(F)(C(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of 0.89 g (4.9 mmol) of methyl 2-fluoro-2-pyridin-2-ylpropanoate from Step A in 2 mL of anhydrous THF was added 1.3 g (9.7 mmol) of potassium trimethylsilanolate. The mixture was allowed to stir for 3 h at ambient temperature then quenched with 1 mL of trifluoroacetic acid. The volatiles were evaporated in vacuo and the resulting residue was purified by reverse phase HPLC (YMC Pack Pro C18, 100×20 mm I.D. column, 0-60% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford the title compound as a light yellow oil (785 mg, 95%). LC-MS: m/z (E/S) 170 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([OH:11])=[O:10].[C:13]([C@@H:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)#[N:14]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([O:11][C@H:15]([C:13]#[N:14])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)=[O:10]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Yield: 79 %

Procedure:
Using the procedure of Example 1, 0.6 g of the acid of Step C of Example 27 and 0.73 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain 1.0 g of (S)α-cyano-3-phenoxybenzyl (1R,trans) 2,2-dimethyl-3-(3-chloro-1,2-propadienyl)cyclopropane-carboxylate with a specific rotation of [α]D20 =+26°±2° (c=0.75% in CHCl3).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C/c1cccc(CBr)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution prepared with t-butyl 3-(6-hydroxymethyl-pyridin-2-yl)-trans-acrylate (trans form, 2 g) described in Reference Example 10-(1) and carbon tetrabromide (4.23 g) in methylene chloride (20 mL) at ice temperature, triphenylphosphine (2.68 g) was added in small portions, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was transferred to a separating funnel, diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=10:1) to give 2.23 g of t-butyl 3-(6-bromomethylpyridin-2-yl)-trans-acrylate as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1([C:12]([NH2:14])=O)[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[C:12]([C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1)#[N:14]
Reactant: CC1(C(N)=O)COc2ccccc2O1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: CC1(C#N)COc2ccccc2O1
Yield: 69.9 %

Procedure:
A stirred mixture of 2-methyl-1,4-benzodioxan-2-carboxamide (8.17 g), phosphorus pentoxide (17 g) and anhydrous toluene (175 ml) was heated under reflux for 4 hours. On cooling the supernatant was decanted from the residue, the latter being washed by decantation with more toluene. Filtration and evaporation of the solvent gave a solid residue (5.18 g). Crystallisation from ethanol yielded the cyano compound (4.4 g); m.p. 88°-89°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1.C1CCCCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)([CH3:28])([CH3:27])[CH3:26]
Reactant: Brc1ccc(C2c3ccccc3-c3nccn32)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Temperature: 25 °C

Procedure:
To a solution of 5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (3.17 g) in THF (60 mL) at −78° C. was added LAD solution (10.19 mL, 1.5 M in cyclohexane) drop wise. After stirring for 5 minutes tert-butyl bromoacetate was added, cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h the reaction was quenched with aqueous saturated NH4Cl and layers were separated. Aqueous layer was extracted with EtOAc (2×). Combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography using a linear gradient of 1-50% EtOAc in hexanes afforded title compound as a white solid. Mass. found (M+H)+, 427.0.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=23)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[N:24]=1.Cl.[OH-].[Na+]>O>[NH2:29][C:25]1[N:26]=[C:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([CH2:16][CH2:17][OH:18])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[CH:23][N:24]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(CCO)c23)c(F)c1
Reactant: Nc1nccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nccc(Nc2ccc(Oc3ccnc4[nH]cc(CCO)c34)c(F)c2)n1

Procedure:
135 mg (0.47 mmol) of 2-[4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]ethanol and 79 mg (0.61 mmol) of 4-chloropyrimidine-2-amine are suspended in 6 ml of water. 0.6 ml (0.6 mmol) of 1N hydrochloric acid is added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is adjusted to pH 10, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 10:1).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)([CH3:5])[CH2:3][CH3:4].O.[OH-].[Na+]>CO>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a stirred solution of N-[4-(1,1-dimethylpropyl)-2-nitrophenyl]acetamide (Preparation 95, 15 g, 60 mmol) in MeOH:water (120 mL:80 mL) at 0° C. was added sodium hydroxide (5 g, 125.4 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo to afford the title compound (11 g, 88%).