Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.O.[NH3:12]>O>[NH2:12][C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(Cl)nn1
Reactant: N
Solvent: O
Product: CC(C)c1ccc(N)nn1
Temperature: 165 °C

Procedure:
3-Chloro-6-isopropylpyridazine (1.60 g, 10.2 mmol) and 28% ammonia water (15.0 ml) were introduced into a sealed tube reactor and stirred under pressure and heating at 140° C. for 24 hours and at 165° C. for 25 hours. The reaction solution was left and cooled, poured into water (30.0 ml), adjusted to pH 9, and extracted 3 times with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude crystals. The crystals, while being washed with diisopropyl ether-hexane, were filtered to give the title compound as pale brown crystals. The yield was 0.41 g (29.3%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][C@@H:10]1[NH:34][C:35]([C:37]1[S:38][C:39]2[CH2:40][N:41]([CH3:46])[CH2:42][CH2:43][C:44]=2[N:45]=1)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][OH:16])[CH2:11][C@@H:10]1[NH:34][C:35]([C:37]1[S:38][C:39]2[CH2:40][N:41]([CH3:46])[CH2:42][CH2:43][C:44]=2[N:45]=1)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCc2nc(C(=O)N[C@H]3C[C@H](CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC[C@@H]3NC(=O)OC(C)(C)C)sc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](CO)CC[C@@H]3NC(=O)OC(C)(C)C)sc2C1
Yield: 67.5 %

Procedure:
(1S,2S,4R)—N1-tert-Butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (1.25 g) was dissolved in tetrahydrofuran (30 ml), and tetrabutylammonium fluoride (1 M solution, 2.5 ml), and the mixture was stirred at room temperature for 3 days. After the solvent was distilled off under reduced pressure, dichloromethane was added, and the reaction mixture was washed with water, the resultant organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:20→1:10) to obtain the title compound (540 mg) as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[O:16][CH2:17][CH2:18][C:19]=23)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3c2CCO3)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 2,3-dihydro-benzofuran-4-carboxylic acid. LC-MS (acidic): tR=1.01 min; [M+H]+=359.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[Cl:1][C:2]1[N+:7]([O-:27])=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(Cl)nnc1Oc1c(C)cccc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(Cl)[n+]([O-])nc1Oc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 384 h
Yield: 56.8 %

Procedure:
3.42 g (12.9 mmol) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine, dichloromethane (110 mL) and 3.34 g (15.4 mmol) of 80% m-chloroperbenzoic acid were mixed, and the mixture was stirred at at room temperature for 16 days. The reaction mixture was poured into ice-cold saturated aqueous sodium sulfite solution, and extracted with dichloromethane. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 2.06 g (7.33 mmol, Yield: 56.8%) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1>Cl>[C:11]1([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ncc(-c2ccccc2)c(OC)n1
Agent: Cl
Product: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Yield: 80 %

Procedure:
2,4-Dimethoxy-5-phenyl-pyrimidine was suspended in 6N HCl and heated to 100 C for 24 h. Solution was cooled in an ice bath to afford title compound as a white solid 119 mg (80% yield). HNMR (500 MHz, dmso): 111.25 (1H, s), 11.15 (1H, d), 7.65 (1H, d), 7.55 (2H, d), 7.35 (2H, m), 7.25 (1H, t).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH:19]=O>>[CH3:25][O:24][C:22]1[CH:21]=[C:18]([CH:19]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=2)=[O:3])[CH:17]=[C:16]([O:15][CH3:14])[CH:23]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C=CCOc1ccc(C(C)=O)cc1
Product: C=CCOc1ccc(C(=O)C=Cc2cc(OC)cc(OC)c2)cc1
Reaction time: 18 h
Yield: 91.3 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 3,5-dimethoxy-benzaldehyde were dissolved in 10 ml of dry freshly distilled ethanol under an inert atmosphere (argon), and the solution was admixed with 100 mg of sodium hydroxide and left under stirring for 18 h. The reaction mixture was filtered to give 2.96 g (99%) of 3,5-dimethoxy-4′-prop-2-enyloxychalcone which was recrystallized from methanol, m.p. 88.5-90° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1([CH3:15])[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1.Cl>CC(C)=O.[Cl-].[Na+].O>[CH3:15][C:5]1([C:4]#[C:3][Si:2]([CH3:16])([CH3:1])[CH3:17])[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1
Reactant: CC1(C#C[Si](C)(C)C)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C#C[Si](C)(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of 6 (2.1 g, 8.3 mmol) in acetone (25 mL) was added 10% aqueous HCl solution (15 mL). The solution was cloudy. Thus, to the cloudy solution, was acetone dropwise (total 12 mL) until the solution was clear. The clear solution was stirred at room temperature for 5 h. The mixture was diluted with brine (250 mL). The aqueous mixture was extracted with methylene chloride/ether (1:2, 200 mL×3). The extract was washed with saturated aqueous bicarbonate solution (2×100 mL) and brine (100 mL×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 7 as a crystalline solid (1.7 g, 98%): 1H NMR (CDCl3) δ 2.75, 2.29, 2.04, 1.65 (each 2H, m), 1.32 (3H, s), 0.17 (9H, s); 13C NMR (CDCl3) δ 211.8, 110.8, 86.9, 39.2, 38.8, 32.9, 28.8, 0.4.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6](OCC)=[O:7])=O.Cl.[NH2:16][NH2:17]>C(O)C.O.Cl>[CH2:13]([O:12][C:2]([C:3]1[NH:16][N:17]=[C:6]([OH:7])[CH:4]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: NN
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 5 g Diethyl Oxalacetate sodium salt in 100 ml ethanol, 1.5 g hydrazine monohydrochloride were added and the reaction mixture was heated to 80° C. for 3 h. Then the solution was diluted with 100 ml of water containing 3 ml of halfconcentrated HCl and extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification; Yield: 3.4 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH:1]1[C:11](=[O:12])[CH2:10][O:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]1=2
Reactant: Nc1ccncc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cnccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
4-amino-3-pyridinol (650 mg, 5.904 mmol) was dissolved in anhydrous N,N-dimethyl formamide (15 ml) under nitrogen atmosphere, and chloroacetyl chloride (0.52 ml, 6.494 mmol) solution was added thereto dropwise at room temperature and then stirred for 30 minutes. Then, potassium carbonate (2.0 g, 14.760 mmol) was added thereto dropwise at room temperature, and the reaction mixture was heated at 100□ for 18 hours. The reaction mixture was cooled to room temperature and water was added to quench the reaction. The organic layer was extracted with ethyl acetate and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid. The obtained white solid was recrystallized from ethyl acetate and n-hexane to obtain white solid (520 mg, 59%).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccc(Br)c(Cc2ccccc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 720 mg of 2-benzyl-3-bromo-6-(2-methoxyethyloxy)pyridine, 340 mg of 3-ethynyl-3-quinuclidinol, 130 mg of tetrakis(triphenylphosphine)palladium(0), 42 mg of cuprous iodide, 0.93 ml of triethylamine and 3 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 80° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 500 mg of the target compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][O:47][CH2:48][CH2:49]Br>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][CH2:49][CH2:48][O:47][CH3:46])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: COCCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(COCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-methoxy-ethyl bromide there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(2-methoxy-ethoxymethyl)-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 687 (M+NH4)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>>[Cl:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2nc(Cl)[nH]c2c1
Reaction time: 8 h

Procedure:
To 21 0 mL of fuming HNO3, 2-chlorobenzimidazole (13.42 g, 87.95 mmole) was added portionwise over a period of 10 min with stirring and ice-H2O cooling. After the addition, the cooling bath was removed and stirring was continued at room temperature overnight. This reaction mixture was cooled to ~ 0° C., poured into 300 mL of ice, and neutralized carefully with conc. NH4OH to ~ pH 8. The resulting suspension was filtered. The yellowish solid product was washed with portions of H2O and air-dried. The filtrate and washings were combined and extracted with EtOAc (200 mL×2). The EtOAc solution was washed with sat. NaCl solution (200 mL×2), dried (Na2SO4), and evaporated to give 1.3 g of a yellowish solid. The solid was combined with the major part of the product and was recrystallized from MeOH to give 16.34 g (5 crops, 94%) of 19 as yellowish crystals. mp 235°-237° C. MS (El) m/e 196.9984 (100%, M+ =196.9992). 1H NMR (DMSO-d6) d 14.06 (br. s, 1, 1-NH), 8.41 (s, 1, 4-H), 8.14 (dd,. 1, 6-H, J6-4 =2.0 Hz, J6-7 =9.0 Hz), 7.71 (d, 1, 7-H).
Reaction SMILES: Cl[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:14])[C:3]=1[F:15].[F:16][C:17]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:18]=1[NH2:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:15][C:3]1[C:4](=[O:14])[N:5]2[C:9](=[C:10]([C:11]([OH:13])=[O:12])[C:2]=1[NH:19][C:18]1[CH:20]=[CH:21][C:22]([I:24])=[CH:23][C:17]=1[F:16])[CH2:8][CH2:7][CH2:6]2
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
Compound 1d (240 mg, 1.04 mmol) and 2-fluoro-4-iodoaniline (493 mg, 2.08 mmol) stirred in dry THF (10 ml) at 0° C. under nitrogen. LiHMDS (1M in THF, 3.11 mL, 3.11 mmol) was added dropwise, and the reaction stirred 4 h while warming to RT. The solution was quenched with 1N HCl and extracted with 10% MeOH/CH2Cl2 (3×). Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (10% to 16% MeOH/CH2Cl2) gave 238 mg (53%) of Example 1 as a tan solid. 1H NMR (400 MHz, MeOD-d4): δ 7.22-7.31 (m, 2H), 6.67 (t, 1H, J=8.0 Hz), 4.06 (t, 2H, J=7.6 Hz), 3.45 (t, 2H, J=7.6 Hz), 2.05-2.15 (m, 2H). MS (ES) [m+H] calc'd for C15H11F2IN2O3, 433. found 433.
Reaction SMILES: [Si](Cl)(C)(C)C.[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[C:14](Cl)(=[O:22])[O:15][CH2:16][O:17][C:18](=[O:21])[CH2:19][CH3:20]>CCOCC>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:14](=[O:22])[O:15][CH2:16][O:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: CCC(=O)OCOC(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Product: CCC(=O)OCOC(=O)Nc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
Me3SiCl (2.3 mL, 18 mmol) is added to 4-chloroaniline (4.6 g, 36 mmol) in Et2O (50 mL) at room temperature with stirring during 20 min. Following an additional 30 min Stirring 7c (4.05 g, purity 90%, 22 mmol) in Et2O (30 mL) is slowly (1 h) added. The stirring is continued overnight. The precipitate is filtered off and the filtrate extracted with ice-cold 0.1N HCl (50 mL), H2O (3×50 mL), dried (MgSO4) and evaporated. The residue (4.9 g) is extracted with hexane (50 mL) to leave 3.3 g (71%) of the title compound, mp 90°-91° C.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.NC1[C:19]([Br:20])=[CH:18][NH:17][N:16]=1>C(O)(=O)C>[Br:20][C:19]1[CH:18]=[N:17][N:16]2[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:13]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: Brc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 0.01 mole of 3-amino-4-bromopyrazole in glacial acetic acid is heated at reflux temperature for 8 hours. The solvent is removed to give the product of the example, m.p. 243°-244° C.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC>C1COCC1.CCCCCC>[CH2:1]([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1[B:15]([OH:20])[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(Br)c1Cc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ncc(B(O)O)c1Cc1ccccc1
Temperature: -78 °C
Yield: 39 %

Procedure:
5-Benzyl-4-bromo-1-methyl-1H-pyrazole (0.27 g; 1.06 mmol) was dissolved in 5.0 ml anhydrous THF and cooled down to −78° C. Afterwards was added Triisopropyl borate (0.46 ml; 2.01 mmol) and n-BuLi; 1.6 mol/1 in Hexane; (0.69 ml; 1.11 mmol). It was stirred for 1 hour within the desired product was formed. It was warmed to 25° C. and quenched with water. It was purified with reverse phase chromatography by using basic conditions.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][N:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[N:4][CH:5]=2)=[N:13]1
Reactant: CN1CCNCC1
Reactant: CC1(C)COC(c2ccc(Cl)nc2)=N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C3=NC(C)(C)CO3)cn2)CC1
Yield: 67 %

Procedure:
2-Chloro-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridine hydrochloride was transformed into its free base by dissolving 8.0 g (32 mmol) in saturated sodium bicarbonate solution and extracting the base into dichloromethane. The solvent was evaporated and the residue was dissolved in toluene. After addition of 11.35 g (113 mmol) N-methylpiperazine, the mixture was refluxed for 36 h. After cooling to room temperature water (50 ml) and ethyl acetate (150 ml) were added and the aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layers were extracted two times with 1 N hydrochloric acid, the acidic aqueous layer was made alkaline with 28% sodium hydroxide solution and extracted two times with dichloromethane. The organic layer was dried (magnesium sulfate) and evaporated. The residue was crystallized from ethyl acetate/hexane to yield 6.0 g (67%) of a white crystalline compound.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:18]2[CH:19]=[C:20]([CH2:1][OH:4])[CH:21]=[CH:22][CH:23]=2)=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(CO)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakis-triphenylphosphine palladium (14 mg), and (3-hydroxymethyl)-phenylboronic acid (90 mg) under an argon atmosphere, and the mixture was stirred 80° C. overnight. The reaction solution was cooled to room temperature, a 1 N aqueous sodium hydroxide solution was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (20 mg, yield 43%).
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3].P(Br)(Br)[Br:15]>CCOCC>[Br:15][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc2nccnc2c1
Solvent: CCOCC
Product: CC(Br)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 6-(1-hydroxyethyl)quinoxaline (0.4 g, 0.23 mMol) in ether (4 mL) and hexanes (2 mL) at zero degrees was added phosphorus tribromide (0.196 mL, 2.07 mMol) and the mixture stirred at zero degrees for one hour and then allowed to warm to room temperature. After two hours at room temperature the reaction mixture was poured over ice and then partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was discarded and the organics washed with saturated sodium bicarbonate, then dried (MgSO4), and concentrated to dryness to yield 20 mg (37% yield) of 6-(1-bromo-ethyl)-quinoxaline as a light yellow oil. 1H NMR (CDCl3): δ=8.79 (m, 2H), 8.06 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=2.2 Hz), 7.85 (dd, 1H, J=9.0, 2.2 Hz), 5.34 (q, 1H, J=6.9 Hz), 2.10 (d, 3H, J=6.9 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mL×2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give colorless oil (3.01 g, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:13]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12])=[N:8][C:7]=2[CH:32]=1)#[N:2].[CH3:33][Mg]Cl>C1COCC1>[C:28]([O:27][C:25]([N:17]1[C:18]2[C:14](=[C:13]([C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][C:7]=4[N:8]=3)([OH:12])[CH3:33])[C:21]([O:22][CH3:23])=[CH:20][C:19]=2[CH3:24])[CH:15]=[CH:16]1)=[O:26])([CH3:29])([CH3:31])[CH3:30]
Reactant: C[Mg]Cl
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2cc(C#N)ccc2o1
Solvent: C1CCOC1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2o1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-(5-cyanobenzo[d]oxazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (600 mg, 1.39 mmol) in THF (14 mL) at 0° C. methylmagnesium chloride, 3M in THF (1.39 mL, 4.17 mmol) was added. The reaction mixture was stirred for 15 min and then quenched with a saturated aq. solution of NH4Cl at 0° C. The layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was dried over MgSO4 filtered and concentrated. The resulting residue was absorbed onto silica and purified by flash chromatography (0-50% EtOAc:heptanes) to give the title compound. MS (ESI+) m/z 448.22 (M+H).