Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C=[C:6]([Cl:8])[N:5]=[CH:4][NH:3]1.C[CH2:10][N:11](C(C)C)C(C)C.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOCC>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH:34][C:10]3[N:11]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH:27]=[N:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: ClC1=CN(Cl)NC=N1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To 2,4-dichloro-1,2,5-triazine (526.1 mg, 3.51 mmol) in DMF (15 mL) at O2C was added DIEA (0.733 mL, 4.21 mmol). The resulting yellow solution was stirred at 0° C. for 20 min and 1-benzyl-1H-indazol-5-ylamine (Step 2) (783.5 mg, 3.51 mmol) was added in one portion followed by 2×2.5 mL DMF flask rinses. The resulting mixture was stirred at 0° C. for 30 min, at RT for 4.5 h, then diluted with EtOAc. The organic layer was washed twice with water and once with brine. The aqueous layer and washings were extracted with EtOAc. The combined organics were dried, concentrated, and purified by chromatography (SiO2, elution with 1:1 EtOAc-hexanes) to give a slightly impure pinkish solid. Trituration with Et2O gave (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine as a light pink solid: MS m/z=337 [M+H]+. Calc'd for C17H13ClN6: 336.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.CN1CCOCC1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>CN(C)C=O.O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:6]([C:12]#[N:13])=[CH:7][N:8]=[C:9]3[C:4]=2[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:11]=[N:10]3)[CH:20]=[CH:19][CH:18]=1
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cnc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of 1.4 g (4.12 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 1.67 g (16.5 mmol) of N-methyl-morpholine in a mixture of 6 ml of N,N-dimethylformamide and 35 ml of tetrahydrofuran was added with stirring at 0° C. a solution of 0.52 g (5.76 mmol) of acryloyl chloride in 10 ml of tetrahydrofuran over 10 min. After 3 hr at 0° C., the most of the solvent was removed saturated sodium bicarbonate was added. Solid was collected and washed with water. After air drying, the solid was extracted with 500 ml of boiling tetrahydrofuran. The tetrahydrofuran was removed and the residue was purified on a silica gel column eluting with ethyl acetate-methanol mixtures giving 0.29 g of the title compound as a yellow solid: mass spectrum (electrospray, m/e): M+H 394, 396.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1([CH3:43])[O:30][CH:29]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][O:27]1.[N+](C1C=CC(C=CC2C=CC=CC=2)=CC=1)([O-])=O>O.CN(C)C=O>[CH3:25][C:26]1([CH3:43])[O:30][CH:29]([CH2:31][C:2]2[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[CH2:28][O:27]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(C=Cc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)cc2)O1

Procedure:
A mixture of 120.5 g of 4-hydroxy-4'-nitrostilbene, 69 g of anhydrous potassium carbonate, 143 g of 2,2-dimethyl-4-(4-methyl phenyl sulphonyloxymethyl)-1,3-dioxolane, prepared in accordance with the specification of K. Freudenberg and H. Hess in Liebigs Annalen der Chemie Vol. 448 (1926), p. 121, and 1 l of dimethyl formamide (DMF) was boiled for 30 minutes with refluxing. After cooling the reaction mixture was poured, with vigorous stirring, into 5 l of water. The precipitated crystals were filtered off and after-washed with 5 1 of water. The crude product after drying was crystallized from 4 l of acetone. Obtained were 135 g of 4-((2,2-dimethyl)-1,3-dioxa-4-cyclopentyl)methyl)-4'nitrostilbene in the form of yellow acicular crystals having a melting point of 146°-147° C.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:12])[NH2:5].[CH3:23][N:24]=[C:25]=[S:26]>>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]2[NH:5][C:25](=[S:26])[N:24]([CH3:23])[C:3]2=[O:22])=[O:12])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccc(C)cc1
Reactant: CN=C=S
Product: Cc1ccc(COC(=O)NCCCCC2NC(=S)N(C)C2=O)cc1

Procedure:
Using an analogous procedure to Example 1 Nε-p-methylbenzyloxycarbonyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[CH:3]1.OS(O)(=O)=O.[CH3:16]O>>[O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:16])=[O:9])=[CH:5][CH:4]=[CH:3]1
Reactant: O=C(O)c1cccc(=O)[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(=O)[nH]1

Procedure:
A mixture of commercially available 6-oxo-1,6-dihydropyridine-2-carboxylic acid (4.000 g; 28.75 mmol) and concentrated H2SO4 (3.5 ml) in anh. MeOH (65 ml) was refluxed, under nitrogen, for 22 h. MeOH was removed under reduced pressure, and the residue was basified by addition of a solution of 10% aq. NaHCO3. The mixture was then extracted with DCM (3×), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 6-oxo-1,6-dihydropyridine-2-carboxylate as a beige solid. LC-MS (conditions D): tR=0.54 min.; no ionisation.
Reaction SMILES: BrC1N=C2C=CN(COCC[Si](C)(C)C)C2=NC=1.CN.[CH3:21][NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1.[CH:40]1([N:46]=[C:47]=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CS(C)=O.ClCCCl>[CH:40]1([NH:46][C:47](=[O:48])[N:22]([CH3:21])[C:23]2[N:24]=[C:25]3[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]3=[N:27][CH:28]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Reactant: O=C=NC1CCCCC1
Agent: CN
Agent: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CN(C(=O)NC1CCCCC1)c1cnc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 150 °C
Yield: 27 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (0.328 g, 1.00 mmol) was dissolved in DMSO (2.5 mL). A solution of methylamine (33 wt % in EtOH, 2.5 mL, 20 mmol) was added and the resulting solution was heated at 150° C. in the sealed tube overnight, then cooled to RT. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to give a mixture of impure Methyl-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine, which was dissolved in 1,2-dichloroethane (3 mL). Cyclohexylisocyanate (0.38 mL, 3.00 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, concentrated, purified by SiO2 chromatography (12 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 0.110 g of 3-cyclohexyl-1-methyl-1-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (27% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([CH:17]=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC.O1[CH2:43][CH2:42]OCC1>[Cu](I)I.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>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:1]4[C:2]([C:24]5[N:25]=[CH:26][CH:27]=[CH:28][N:29]=5)=[N:3][CH:4]=[CH:42][CH:43]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:5]=1
Reactant: C1COCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1cc(C)nc(N2CC3CN(C=O)CC3C2)n1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccnc4-c4ncccn4)CC3C2)n1
Yield: 64 %

Procedure:
To a solution of 2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Example 234) (50 mg, 0.14 mmol), 2-tributylstannylpyrimidine (50 mg, 0.14 mmol), and copper iodide (2.6 mg, 0.014 mmol) in 1,4 dioxane (1 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction was irradiated in a microwave reactor at 160° C. for one hour. The resulting solution was filtered through Celite®, washed with DCM, and concentrated. Purification (FCC) (MeOH(NH3)/DCM) gave the title compound (35 mg, 64%). MS (ESI): mass calculated for C22H23N7O, 401.20; m/z found 402.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.85 (s, 3H), 7.70 (d, J=6.7, 1H), 7.48-7.42 (m, 1H), 7.21 (d, J=4.4, 1H), 6.32-6.24 (m, 1H), 3.93-3.79 (m, 2H), 3.75-3.61 (m, 3H), 3.52 (s, 1H), 3.52-3.42 (m, 1H), 3.17 (dd, J=10.8, 5.0, 1H), 3.09-2.88 (m, 2H), 2.37-2.22 (m, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([OH:20])[C:15]([O:17]CC)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([O:28]C2C=CC=CC=2)C=CC=CC=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:47]1([NH:53][NH2:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>O.C(O)(=O)C.C(Cl)Cl>[CH3:21][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:12]=2)[O:20][C:22](=[O:28])[N:54]([NH:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:15]1=[O:17]
Reactant: CCOC(=O)C(C)(O)c1ccc(Oc2ccccc2)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC1(c2ccc(Oc3ccccc3)cc2)OC(=O)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.3 %

Procedure:
A mixture of 14.3 g of ethyl 2-(4-phenoxyphenyl)lactate (34 g of a mixture containing 14.3 g of ethyl 2-(4-phenoxyphenyl)lactate and 19.7 g of diphenyl ether), 9.7 g of 1,1'-carbonyldiimidazole and 100 mL of methylene chloride was agitated at 25° C. for 19 h. Water (0.30 mL) was added and the mixture was agitated for 15 min. Then, 5 mL of acetic acid and 7.4 g of phenylhydrazine were added. After agitating at 25° C. for 24 h, 100 mL of water was added. The pH was lowered to 2 with hydrochloric acid, and the aqueous layer was removed. After washing the methylene chloride layer with 50 mL of water, the solvent was evaporated under vacuum. The oily residue was mixed with 150 mL hexane and 15 mL of ethyl acetate, heated to 65° C., cooled to 20° C., and then filtered. The solids were washed with 100 mL of a mixture of 20 mL ethyl acetate and 80 mL of hexane and then dried. The title product (15.2 g) was obtained with a m.p. of 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH:18]([CH3:20])[CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(Cc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of isopropyl-(2-nitro-benzyl)-carbamic acid tert-butyl ester (730 mg, 2.48 mmol) in ethyl acetate (10 ml) was added acetic acid (0.156 ml, 2,73 mmol) and catalytic amount of palladium 10 wt. % on activated carbon. The mixture was stirred overnight under hydrogen atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (15% ethyl acetate-hexane) to afford (2-amino-benzyl)-isopropyl-carbamic acid tert-butyl ester (f) (568 mg, 2.15 mmol, 87%) as reddish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[C:19]4[N:11]([C:12](=S)[NH:13][C:14](=[O:20])[C:15]=4[CH:16]=[N:17]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].OO.[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[C:19]4[N:11]([C:12]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[N:13][C:14](=[O:20])[C:15]=4[CH:16]=[N:17]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Reactant: CC(C)CN
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(=O)c2cnn3c2n1CC=C3c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution or 3.00 g of 8-(3-fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (Example 10) in 60.0 ml of N,N-dimethylformamide was added 10 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath, then 3.40 ml of 30% hydrogen peroxide was added to the mixture dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then 6.0 ml of isobutylamine was added in one portion and the mixture was allowed to warm to room temperature, then was stirred for 2 hours. The solid was collected by filtration, washed with water, then ether to give 1.24 g of the desired product as a white solid, m.p. 256°-259° C. Following the procedure of Example 52 and reacting 8-(3-fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one with the appropriate primary aliphatic amine or cyclic secondary amine, the products of Examples 53-57 were obtained as set forth in Table VI.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)[OH:19].[Cl-].[Na+]>>[C:13]([CH2:12][S:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:19])[CH:4]=1)([OH:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CSCCCC1C(=O)C=CC1O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2-[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[C:29]1([CH3:39])[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([NH:37][NH2:38])=[O:36])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH:38][NH:37][C:35](=[O:36])[C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:39])[CH:30]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: Cc1cccc(C(=O)NN)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)NNC(=O)c4cccc(C)c4)s3)c2cc1OC
Yield: 3.8 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and m-toluic acid hydrazide (15.0 mg, 0.1 mmol, Lancaster) gave 3-Methyl-benzoic acid N′-[4-(3-chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carbonyl]-hydrazide (2.1 mg, 3.8%) as a white solid. MS m/z 548 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=[O:19])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C=O)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26.2 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (1g) (30 mg, 0.08 mmol) was dissolved in methanol (0.5 mL). A 4 N hydrochloric acid/ethyl acetate solution (2.5 mL) was added, and the mixture was stirred at room temperature for 4.5 hours. Following concentration under reduced pressure, the residue was dissolved in DMF (2 mL). Diisopropylethylamine (0.054 mL, 0.31 mmol) was added, and the mixture was stirred at 140° C. using a microwave reactor for one hour. Saline was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by reverse phase high performance liquid chromatography (Develosil, 2 cm diameter×10 cm, 0.1% formic acid-containing acetonitrile/water mixed solvent) to obtain 6.6 mg of the title compound as a pale yellow solid (27%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=2)[NH:3]1.[F:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:13][CH2:12][O:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:10]4)[CH2:35][CH2:36]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)CC(=O)N3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2cc(OCCN3CCC(Cc4ccc(F)cc4)CC3)ccc2N1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A suspension of toluene-4-sulfonic acid 2-(2-oxo-2,3-dihydro-1H-indol-5-yloxy)-ethyl ester (0.77 g, 2.22 mmol), 4-(4-fluorobenzyl)piperidine (1.1 g, 5.63 mmol), and potassium carbonate (2.2 g, 15.92 mmol) in acetonitrile (75 ml) was refluxed overnight under argon. The reaction mixture was cooled to room temperature and the solid was filtered off and washed with THF (3×20 ml). The filtrate was evaporated, and the solid chromatographed on silica gel eluting with 35% methanol/ethyl acetate to give the title compound (0.62 g, 76%) as a solid, mp 149-150° C. Analysis calculated for C22H25FN2O2 ·0.14H2O: C, 71.21; H, 6.87; N, 7.55; F, 5.12. Found: C, 71.21; H, 6.68; N, 7.49; F, 5.26.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Br:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[Br:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br
Temperature: 110 °C
Reaction time: 24 h
Yield: 47.7 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (3.28 g, 10 mmol), 3-amino-4-bromophenol (2.82 g, 15 mmol), potassium carbonate (2.76 g, 20 mmol) and N,N-dimethylformamide (20 mL) was stirred at 110° C. for 24 hr, then at 150° C. for 24 hr. The reaction mixture was diluted with water and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→40/100) and recrystallized from ethyl acetate to give the title compound (1.85 g, yield 48%) as a pale-yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>ClCCl.N1C=CC=CC=1>[C:16]([O:1][CH2:2][C@@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 0 °C

Procedure:
The compound of Example 3D (0.58 g, 2.7 mmol) was dissolved in 4 mL of dichloromethane and 2 mL of pyridine; the solution was cooled to 0° C., and 0.39 mL of pivaloyl chloride was added dropwise over 5 minutes. The resultant mixture was stirred at 0° C. for 2.5 hours, then it was quenched with water, and the mixture was concentrated in vacuo with the bath maintained below ambient temperature. The crude material was partitioned between ether and 0.5 N aqueous HCl; the organic phase was washed with 0.5 N aqueous HCl, then brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue (0.96 g) was carried forward without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])CCC.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([CH:29]=[O:30])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(CNc2ccc(Br)cn2)cc1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41, 10.00 g, 0.03360 mol) in tetrahydrofuran (400.0 mL) under an atmosphere of nitrogen at −78° C. was added n-butyllithium (17.5 mL, 2.00 M in cyclohexane). After 90 minutes, tert-butyllithium (42.00 mL, 1.70 M in hexane) was added to the reaction. After 80 minutes, N,N-dimethylformamide (6.9 mL, 0.089 mol) was added to the reaction. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound, which was crystallized from tert-butoxyl methyl ether to provide compound (42, 7.66 g, 92.2%).