Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH2:15](Br)[CH:16]=[CH2:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:17]([N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)[CH:16]=[CH2:15]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 70 °C
Yield: 93.1 %

Procedure:
A mixture of 4-pyrazoleboronic acid pinacol ester (3.0 g, 15.6 mmol), allyl bromide (6.9 g, 77 mmol) and sodium bis(trimethylsilyl)amide (20.5 mL of a 1.5N solution in THF, 30.7 mmol) in THF (20 mL) was heated to 70° C. overnight. After cooling to r.t. the reaction was quenched with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (3.4 g, 94%) as a yellow oil. δH (CDCl3) 1.20 (12H, s), 4.61-4.67 (2H, m), 5.06-5.24 (2H, m), 5.79-6.01 (1H, m), 7.60 (1H, s), 7.69 (1H, s).
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.O=C1CCC(=O)N1[O:26][C:27](=O)[CH2:28][C:29]#[N:30]>C(O)C>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:27](=[O:26])[CH2:28][C:29]#[N:30])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCO
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a stirred solution of the product from Method B (1.0 g) dissolved in 30 mL of ethanol was added 0.82 g of cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester and the resulting mixture stirred at room temperature for 2 h. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with saturated, aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to dryness in vacuo affording 1.1 g (86%) of the title compound as a yellow foam. LRMS: 313 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH:18]=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[Cl-].[C:21]([O:25][C:26]([N:28]1[CH2:36][CH2:35][C:31]2([CH2:34][NH2+:33][CH2:32]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH2:18][N:33]2[CH2:34][C:31]3([CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:36][CH2:35]3)[CH2:32]2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[NH2+]C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(CN3CC4(CCN(C(=O)OC(C)(C)C)CC4)C3)c12
Reaction time: 2 h

Procedure:
To a solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (25.0 mg, 0.098 mmol), 7-(tert-butoxycarbonyl)-7-aza-2-azoniaspiro[3.5]nonane chloride (39.0 mg, 0.15 mmol), and triethylamine (0.054 mL, 0.39 mmol) in 1,2-dichloroethane (2 ml) was added sodium triacetoxyborohydride (41.0 mg, 0.20 mmol). After 2 h, the reaction was quenched with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give tert-butyl 2-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]methyl}-2,7-diazaspiro[3.5]nonane-7-carboxylate. LRMS (ESI) calculated for C25H35N6O3 [M+H]+, 467.3; found 467.1.
Reaction SMILES: C1([C:7]2[O:11][C:10]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=[O:15])=[N:9][N:8]=2)C=CC=CC=1.[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH2:21]([C:7]1[O:11][C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[N:9][N:8]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccccc1-c1nnc(-c2ccccc2)o1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(Cc2nnc(-c3ccccc3C(=O)O)o2)cc1

Procedure:
The same procedure is used as that for the preparation of 2-(5-phenyl-1,3,4-oxadiazole-2-yl) benzoic acid, Example 7, Method IIIb. The quantities of reagents used differ and p-anisoyl chloride was used in place of benzoyl chloride.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C@H:20]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][CH:17]=1
Reactant: CCCC1CCC(C(CO)CO)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)cc3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl) propane-1,3-diol, 1.4 g (0.01 mol) of 4-fluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was continuously removed from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.1 g (0.004 mol) of trans-2-(4'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR25## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:27]1([C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[N:4]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: O=C(Nc1ccccc1)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1C(=Nc1ccccc1)n1nnc2ccccc21
Yield: 58.1 %

Procedure:
A solution of 4-oxo-N-phenyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.153 g, 0.426 mmol), 1H-benzo[d][1,2,3]triazole (0.201 g, 1.69 mmol) and thionyl chloride (0.06 mL, 0.82 mmol) in methylene chloride (2 mL) was heated under microwave heating conditions at 80 watts of power for 10 min. After that time, the reaction was concentrated and the crude product purified by flash column chromatography (silica gel, hexanes to ethyl acetate) to give 0.114 g (58%) of 3-[1H-benzotriazol-1-yl(phenylimino)methyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale red solid that was used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Product: Cc1ccc(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c(N)c1
Yield: 82 %

Procedure:
Starting from 2-amino-4-methylbenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (116 mg; 82% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1.[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1
Reactant: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reaction time: 15.5 h

Procedure:
2-(2'-Hydroxy-5'-hydroxyethylphenyl)-2H-benzotriazole (150 g, 0.59 mol), methacrylic acid (55 ml, 0.65 mol), hydroquinone (2.4 g), p-toluenesulfonic acid monohydrate (3 g) and toluene (2 l) were placed in a 3 liter flask equipped with a Dean and Stark receiver. After 1.5 hours of refluxing the mixture, another 2.7 g of p-toluenesolfonic acid monohydrate was added and the refluxing was continued for another 15.5 hours. Approximately 10 ml of water was collected (theoretical: 10.6 g) and the yield of the desired compound was 93.7% as judged by a gas chromatography. Another 1 g of p-toluenesolfonic acid monohydrate was added and the reflusing was continued for another 3 hours. A yield of 95.6% was shown by a gas chromatography. After cooling the reaction mixture, it was washed with aqueous sodium hydrogen carbonate solution, water, 5% hydrochloric acid and water. The organic layer was dried with anhydrons magnesium sulfate and chromatographed through an alumina (Fisher, 80-200 mesh) column. After evaporation of the solvent, the residue was recrystallized from distilled methanol twice. Yield: 141.8 g (74%); Purity: >99.9% (G.C.). The IR and NMR data were consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 5-methyl-2-oxindole (59 mg), 3-methylindole-2-carbaldehyde (56 mg) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 72 mg (74%) of 5-methyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[C:26]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:30][CH:29]=1)#[N:27].C(N(C(C)C)CC)(C)C>C(#N)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:34][C:35](=[O:36])[NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)=[O:33])=[CH:37][CH:38]=1)#[N:27]
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
In a similar manner to Example 1, starting material step (a), the p-toluenesulphonate salt of ethyl 4-aminophenoxyacetate (12.9 g, preparation described by Coutts, I. G. C. et al (1985), J. Chem. Soc. Perkin I, 1829), 4-cyanobenzoyl isocyanate (5.9 g), acetonitrile (400 ml total) and diisopropylethylamine (6.5 ml) were reacted to give, after stirring at ambient temperature for 1.5 hours, a solid, which was crystallised from acetonitrile/ethanol to give ethyl 4-[3-(4-cyanobenzoyl)ureido]phenoxyacetate (10.16 g) as an off-white solid: m.p. 200°-203° C.; NMR Spectrum (DMSO-d6) 1.22 (3H, t), 4.17 (2H, q), 4.75 (2H, s), 6.93 (2H, d), 7.49 (2H, d), 8.02 (2H, d), 8.13 (2H, d), 10.49 (1H, br s), 11.17 (1H, br s); Mass Spectrum m/Z 368 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[NH2:23]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:23][C:22]3[CH:21]=[C:20]([F:19])[C:26]([F:27])=[C:25]([F:28])[CH:24]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)c(F)c1
Yield: 11.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 113 mg of 3,4,5-trifluoroaniline in place of the 2,4-difluoroaniline. 33 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(3,4,5-trifluorophenyl)acetamide are obtained, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[OH:17].C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12]3[C:11](=[O:17])[NH:10][CH:15]=[CH:14][C:13]=3[NH:8][C:4]=2[CH:3]=1
Reactant: NNc1cccc(Br)c1
Reactant: Oc1ccnc(O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2[nH]c3cc(Br)ccc3c12
Temperature: 232 °C
Reaction time: 0.75 h

Procedure:
(3-Bromophenyl)hydrazine HCl (20.5730 g, 92.4 mmol) was dissolved in 6.25 N aqueous NaOH (16 mL, 100 mmol), ethanol (80 mL) and water (60 mL), and extracted with EtOAc (200 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. CH2Cl2 (150 mL) was added, dried over MgSO4, filtered and concentrated in vacuo to give (3-bromophenyl)hydrazine as a light orange oil. To a heterogeneous solution of (3-bromophenyl)hydrazine (17.19 g, 92 mmol) in Phenyl ether (82 mL) was added pyridine-2,4-diol (5.11 g, 46.0 mmol). A Dean-Stark trap was set up, and the reaction was heated at 232° C. for 4 hours. A strong effervescence and gas evolution occurred often for 45 min. The solution turned homogeneous with decrease in frequency of strong effervescence and gas evolution. The reaction mixture was cooled to room temperature; precipitation ensued. HPLC and LCMS showed completion of reaction (86784-071-01). Toluene (100 mL) was added, and the mixture stirred overnight at room temperature. The mixture was filtered and the precipitate was collected. Methanol (40 mL) was added, and the solution was stirred for 20 min. The precipitate was filtered and washed with methanol, dried to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one as a tan solid. Methanol (60 mL) was added, and the mixture was stirred for 7 h. The precipitate was collected to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol, 36.7% yield) a light tan solid. The precipitate was collected to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol, 36.7% yield) a light tan solid. The product had an HPLC Retention Time=2.585 min[mixture of rotamers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM; LC/MS+1 263.04; 265.04
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].N[C:18](C1C=CC=CC=1)(C)C(O)=O>>[CH3:16][O:15][C:13]([NH:12][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)([CH3:18])[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: CC(N)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C)(C(=O)O)c1ccccc1

Procedure:
2-Methoxycarbonylamino-2-phenyl-propionic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using 2-Amino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.96 (M+H+)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:2]1.[H-].[Na+].I[CH3:23].CO>CN(C=O)C>[CH3:23][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:2]1
Reactant: c1cc(-c2c[nH]c3ncccc23)c2ccncc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc3cnccc23)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
53 mg (0.216 mmol) of 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline are added to a suspension, kept under an argon atmosphere, of 26 mg (0.65 mmol) of sodium hydride, (60% suspension in paraffin oil) in 1 ml of DMF, and the reaction mixture is stirred at room temperature for 1 hour. 18 μl (0.65 mmol) of iodomethane are then added, and the reaction mixture is stirred at room temperature for a further 17 hours. 0.5 ml of methanol is then added, and the reaction mixture is subsequently evaporated in vacuo. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline as colourless solid; MS (EI): 259 [M]+;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:25]=[C:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[O:16]=[C:15]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:17]([O:19][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:18])[CH2:13][CH2:14]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
100 g of (S)-1-(benzyloxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid was dissolved in dehydrated dichloromethane (2 L), and under ice cooling, concentrated sulfuric acid (10 mL) and 213 g of isobutene were added, followed by stirring overnight at +20° C. or less. The reaction mixture was added to cold aqueous sodium carbonate solution while paying attention to effervescence, followed by liquid separation of the organic phase, washing with saturated brine and drying over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=7/3), and crystallized with hexane/ethyl acetate to afford 80 g of the title compound as a colorless crystalline powder (yield 67%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=2/1, flow rate 1 mL/min., retention time 4.2 min.).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: COC(=O)C(C)=Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)=Cc1ccc(OCCCCl)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Methyl 4-hydroxy-α-methylcinnamate (16.3 g), DMF (50 ml) and anhydrous potassium carbonate (11.7 g) were mixed, and stirred at 90° C. for 1 hour. The reaction solution was allowed to cool to 50° C., added 1-bromo-3-chloropropane (8.4 ml) thereto, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water (200 ml), and the mixture was extracted with ether (150 ml), washed with water (150 ml) 2 times, and then, dried over anhydrous magnesium sulfate. The ether layer was concentrated urder reduced pressure to give methyl 4-(3-chloropropoxy)-α-methylcinnamate (20 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCCCCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Product: CCCCCCOc1ccc2cc(C3(O)CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 32.3 %

Procedure:
Beginning with 0.257 gm (1.2 mMol) 1-(4-indolyloxy)-3-chloropropane and 0.400 gm (1.2 mMol) 4-hydroxy-4-(6-hexyloxynaphth-2-yl)piperidine, 0.194 gm (32%) of the title compound was recovered as a white solid by the procedure described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=O)[CH:7]=[CH:6][S:5]2.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:9]5[N:8]6[C:4]([S:5][CH:6]=[CH:7]6)=[N:3][C:2]=5[CH3:1])=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Cc1nc2sccn2c1C(=O)O
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c1C(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reaction time: 20 h
Yield: 19 %

Procedure:
A mixture of 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid (Bionet) (61 mg, 0.33 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol), EDC (77 mg 0.39 mmol) and HOAt (54 mg, 0.39 mmol) was stirred in DMF (3 ml) at 80° C. for 1 h then at ambient temperature for 20 h. The mixture was reduced in vacuo and the residue was partitioned between EtOAc and saturated NaHCO. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was purified by preparative LC/MS to give 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (29 mg). (LC/MS Basic: Rt 2.56 [M+H]+ 463).