Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:8]=[C:9]([Cl:21])[C:10]=1[O:11][C:12]([F:20])([F:19])[CH:13]([F:18])[C:14]([F:17])([F:16])[F:15])[NH:5][CH2:6][CH3:7].[F:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27].CCCCCCC.C(OCC)(=O)C>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([N:5]([CH2:6][CH3:7])[C:29]([NH:28][C:26](=[O:27])[C:25]2[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:24]=2[F:23])=[O:30])[CH:8]=[C:9]([Cl:21])[C:10]=1[O:11][C:12]([F:19])([F:20])[CH:13]([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCNc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Solvent: ClCCCl
Solvent: CCCCCCC
Solvent: CC(Cl)Cl
Product: CCN(C(=O)NC(=O)c1c(F)cccc1F)c1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Temperature: 40 °C
Yield: 110.1 %

Procedure:
To a solution of 1.00 g 3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)-N-ethyl aniline in 2 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature there was added 0.54 g 2,6-difluorobenzoyl isocyanate dissolved in 6 mL dichloroethane dropwise over a 10 minute period. The mixture was stirred and warmed to 40° C. for a 1.5 hour period. Analysis by thin layer chromatography silica gel 4:1 heptane/ethyl acetate indicated incomplete reaction. To the mixture was added 0.13 g 2,6-difluorobenzoyl isocyanate in 1.5 mL 1,2-dichloroethane, and the mixture was warmed at 40° C. for 2.5 hour. Analysis by TLC indicated complete reaction. The reaction mixture was concentrated under vacuum to give an oil 1.64 g, which was chromatographed using a Michel-Miller low pressure silica gel column eluted with 4:1 heptane/ethyl acetate. Like fractions were pooled and concentrated under vacuum to give a white solid 0.87 g, mp 106°-14° C. Proton nmr and mass spectra were consistent with the proposed structure. Anal. calcd C19H11Cl2F9N2O3 : C, 40.95; H, 1.99; N, 5.03. Found: C, 40.89; H, 1.92; N, 5.03.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[CH2:24](Br)[C:25]#[CH:26]>>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([N:8]([CH2:26][C:25]#[CH:24])[CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:23])(=[O:11])=[O:10])=[CH:17][CH:16]=1)[C:20]#[C:21][CH3:22]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: C#CCBr
Product: C#CCN(C(C(=O)OC)C(C)C)S(=O)(=O)c1ccc(OCC#CC)cc1
Yield: 99.9 %

Procedure:
According to the procedure of Example 5, 0.800 g (2.36 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.53 g (4.72 mmol) of 80% propargyl bromide gave 0.89 g of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-3-methylbutanoate as a colorless oil. Electrospray Mass Spec 378.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=2)[N:9]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
tert-Butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate (55.7 g, 128 mmol) was dissolved in dichloromethane (200 mL) and trifluoroacetic acid (215 ml) was slowly added (careful: immediate gas evolution!). The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere and evaporated to dryness. To the residue were added equal amounts of water and dichloromethane (300 mL). The obtained emulsion was basified to pH 9 with 33% aq. NaOH. The emulsion was cleared by the addition of methanol, and the layers were separated. The aqueous layer was extracted with dichloromethane (200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield crude 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol. The crude material was purified by column chromatography (SiO2, 2% methanol in dichloromethane) to yield 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (44 g, 97%) as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 8.52 (dd, J=2.1, 8.1 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.37 (dt, J=1.5, 7.2 Hz, 1H), 7.22 (dd, J=1.5, 9.0 Hz, 1H), 7.04 (dd, J=1.2, 6.9 Hz, 1H), 6.92 (dt, J=1.2, 7.2 Hz, 1H), 4.49-4.39 (m, 2H), 3.34 (dt, J=2.4, 12.2 Hz, 2H), 3.12-3.02 (m, 1H), 2.54 (s, 3H), 2.09-2.00 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.25 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CC(OC)(C)C>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1F
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(O)c1cc(-c2ccccc2)ccc1F

Procedure:
5-Bromo-2-fluoro-benzoic acid (49) (2.0 g, 9.00 mmol) was coupled to phenyl boronic acid (1.23 g, 10.00 mmol) using method F, except that after the 2 hour reaction, water (50 mL) and TBME (50 mL) were added. The mixture was filtered and the aqueous layer was washed with TBME. The aqueous layer was then acidified with 1N HCl and the precipitated solid was collected and dried. Yield: 1.6 g, 82%
Reaction SMILES: F[C:2]1C=C(C=CC=1)N.C(C1C=CC(C(O)=O)=CC=1)(=O)C1C=CC=CC=1.C(NCC)C.[F:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:54])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:41]=2)[CH:35]=[CH:36][CH:37]=1.[H-].[Na+]>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([N:38]([CH3:2])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:41]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Nc1cccc(F)c1)c1cccc(C(=O)c2ccccc2)c1
Agent: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CN(C(=O)c1cccc(C(=O)c2ccccc2)c1)c1cccc(F)c1
Reaction time: 0.08 h

Procedure:
Following Procedure A with the substitution of 20 g (88 mmol) 3-benzoylbenzoic acid [579-18-0] and 8.5 mL (88 mmol) 3-fluoroaniline for 4-benzoylbenzoic acid and diethyl amine, the product N-(3-fluorophenyl)-3-benzoylbenzamide was generated (28 g, 88 mmol) as a clear oil. The oil was dissolved in 50 mL dry THF to which a 10 mL THF slurry of 2.1 g (90 mmol) NaH was slowly added. The mixture was allowed to stir for 5 min then 5.6 mL (90 mmol) of Mel was added and continued stirring for 16 h. The reaction was carefully quenched with water and partitioned between water and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered, and concentrated to yield 29.3 g (88 mmol) product. MS m/z (MH+) 334.
Reaction SMILES: C([O-])(=[O:3])C.[K+].Cl[C:7]1[N:12]=[N:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:32])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[C:33]([C:35]1[CH:44]=[C:43]([CH3:45])[C:38]2[NH:39][C:40](=[O:42])[O:41][C:37]=2[CH:36]=1)=[O:34]>C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:22]2[NH:21][C:20](=[O:32])[N:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:10]4[N:11]=[N:12][C:7](=[O:3])[CH:8]([C:33]([C:35]5[CH:44]=[C:43]([CH3:45])[C:38]6[NH:39][C:40](=[O:42])[O:41][C:37]=6[CH:36]=5)=[O:34])[CH:9]=4)[CH2:18][CH2:17]3)[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(C3=CC(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)C(=O)N=N3)CC1)C(=O)N2
Reaction time: 7 h

Procedure:
0.10 g (1.0 mmol) potassium acetate were added to 0.13 g (0.20 mmol) 3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (mixture) in 3 mL acetic acid and the mixture was boiled under a nitrogen atmosphere for 7 h. Then the reaction mixture was evaporated down and the residue was triturated with water, suction filtered and dried. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:45]([Si:49](Cl)([CH3:51])[CH3:50])([CH3:48])([CH3:47])[CH3:46].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:51])[CH3:50])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To a solution of 4-[6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (3.15 g, 5.90 mmol) in dichloromethane (22 ml) were added imidazole (0.96 g, 14.17 mmol) and tert-butyl(chloro)dimethylsilane (1.07 g, 7.08 mmol). The reaction mixture was stirred at room temperature for 5 hours, water and dichloromethane were then added. The aqueous layer was separated and the organic layer was washed with water, brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of EtOAc (0-30%) in cyclohexane to yield the title compound as a yellow foam (2.05 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][C@H:12]2[C@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:18]2[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][C@H:12]2[CH2:11][NH:10][C:8]([C:3]2[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])=[CH:20][C:21]=1[F:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(3-aminopyridin-2-yl)carbonyl]amino}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (110 mg) in DMF (3 ml) was added 60% sodium hydride at 0° C., and the mixture was stirred for 30 min. Methanesulfonyl chloride (53 μL) was added, and the mixture was warmed to room temperature, and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44.4 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 73.7 %

Procedure:
In the same manner as in Example 259 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (130 mg, 0.84=mol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (91 μL, 1.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (220 mg, 75%) was obtained as a white solid.
Reaction SMILES: [N+]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1I)=[CH:7][CH:8]=[N:9]2)([O-])=O.C(Cl)(=O)C(Cl)=O.COC1C=C(C(I)=CC=1OC)C(O)=O.CN(C)CCNC1C2C(=CC=CC=2[N+]([O-])=O)N=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[CH:13][CH:12]=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cccc([N+](=O)[O-])c23)cc1OC
Agent: CN(C)CCNc1ccnc2cccc([N+](=O)[O-])c12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4ccccc4ncc3c2cc1OC
Yield: 73 %

Procedure:
Synthesis of N-(quinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8d). Oxalyl chloride (2.1 g, 16.2 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (1.5 g, 4.87 mmol) in anhydrous methylene chloride (40 mL), and the stirred mixture was refluxed for 4 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 40 mL of anhydrous methylene chloride, and this solution was added to a solution of 7d (870 mg, 4.05 mmol) and triethylamine (4.0 g, 40.0 mmol) in methylene chloride (30 mL), and the resulting mixture was stirred at reflux for 2 hours. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×75 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 1.45 g of the amide, in 73% yield; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.63 (m, 2H), 3.07 (s, 3H), 3.68 (s, 3H), 3.93 (m, 1H), 4.62 (m, 1H), 6.26 (s, 1H), 7.00 (s, 1H), 7.44 (d, 1H, J=4.4), 7.69 (m, 2H), 8.11 (m, 2H), 8.75 (d, 1H, J=4.4); 13C NMR (CDCl3) δ 45.6, 47.0, 55.3, 56.0, 56.7, 82.5, 110.2, 121.6, 122.8, 125.8, 127.6, 130.0, 130.5, 130.6, 133.8, 146.9, 148.1, 149.6, 149.8, 150.8, 169.8; IR (CHCl3) 1650;
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5])C.Cl.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:24]([C:21]2[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=2)[N:25]=1
Reactant: CSc1ccc(NN)cc1
Reactant: CCOC(C)=NC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CSc1ccc(-n2nc(C)nc2-c2ccccc2)cc1
Reaction time: 8 h
Yield: 61 %

Procedure:
N-(1-ethoxy-ethylidene)-benzamide 400 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and (4-methylsulfanyl-phenyl)-hydrazine hydrochloride 439 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=1:1). As a result, 3-methyl-1-(4-methylsulfanyl-phenyl)-5-phenyl-1H-[1,2,4]triazole (359 mg, yield: 61%) was obtained as a liquid phase.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.O>CN(C)C=O.C(OCC)(=O)C>[C:29]1([C:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[CH2:24][CH:25]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Reactant: O=S(=O)(Nc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)N(CCCN1CC=C(c2ccccc2)CC1)c1ccccc1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A solution of N-phenylbenzenesulphonamide (2.34 g) in dry N,N-dimethylformamide (10 cc) is added dropwise to a suspension of sodium hydride (0.24 g, 80% suspension in oil) in N,N-dimethylformamide (50 cc). After 15 minutes' stirring, a solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (2.34 g) in N,N-dimethylformamide (20 cc) is added. The reaction mixture is heated to 140° C. for 1 hour and then cooled and poured into a mixture of water (200 cc) and ethyl acetate (200 cc). The organic phase is washed with water, is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 40-cm height) and eluted with dichloromethane and with a mixture of dichloromethane and ethanol (98-2 and 96-4 by volume), fractions 250-cc being collected. Fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from isopropyl ether (150 cc), N-[3-(4-phenyl-1,2,3,6-tetrahydropyridyl)propyl]-N-phenylbenzenesulphonamide (2.4 g) is obtained, melting at 112° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(C)(C)C)[C:5]([CH3:13])=[CH:4][CH:3]=1>ClCCCl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)nc1NC(C)(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Br)nc1N
Yield: 93.2 %

Procedure:
A solution of (6-bromo-3-methylpyridin-2-yl)-tert-butylamine (500 mg, 2.06 mmol) in DCE (2 mL) and TFA (2 mL) was heated at 120° C. for 10 min in a microwave reactor, and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH to give 6-Bromo-3-methylpyridin-2-ylamine as a white solid (359 mg, 93%). 1H NMR (400 MHz, CHCl3-d): δ 7.11 (d, J=7.5 Hz, 1 H); 6.77 (d, J=7.5 Hz, 1 H); 4.50 (s, 2 H); 2.07 (s, 3 H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]([OH:13])[CH2:14][CH3:15])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Mg+]
Reactant: O=Cc1ccn(-c2ccccc2)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(O)c1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
1-Phenyl-1H-pyrazole-3-carbaldehyde (779 mg, 4.53 mmol) was dissolved in anhydrous THF (9 mL) and chilled in an ice bath. EtMgBr (3.0 M in Et2O, 4.5 mL) was added dropwise. After 1.5 hours, the reaction mixture was allowed to warm to ambient temperature. TLC (2:1 hexanes:EtOAc indicated complete consumption of aldehyde starting material. The reaction mixture was quenched with water and extracted with EtOAc (2×). The EtOAc layers were washed with brine (1×), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (2:1 hexanes:EtOAc) to provide the title compound (631 mg, 69%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 1H, J=2.4 Hz), 7.65 (d, 2H, J=7.6 Hz), 7.42 (t, 2H, J=7.6 Hz), 7.27 (d, 1H, J=7.2 Hz), 6.38 (d, 1H, J=2.4 Hz), 4.79 (dd, 1H, J=12, 5.6 Hz), 2.38 (d, 1H, J=4.8 Hz), 1.98-1.81 (m, 2H), 1.01 (t, 3H, J=7.2 Hz). MS (ES) m/z 203.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:43][C:44]1[N:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>>[NH2:24][C:19]1[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:4]2[CH:3]=[C:2]([C:47]3[CH:48]=[N:49][C:44]([CH3:43])=[CH:45][CH:46]=3)[CH:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[N:18]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: Cc1ccc(B(O)O)cn1
Product: COc1ccc(Nc2ncc(-c3ccc(C)nc3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 6-methylpyridin-3-ylboronic acid (40.5 mg, 0.296 mmol) (Frontier Scientific), and was isolated as a yellow crystalline solid (56%). m/z (ESI, +ve ion) 401.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.85 (1H, s); 9.03 (1H, d, J=2.7 Hz); 8.77 (1H, d, J=2.2 Hz); 8.67 (1H, d, J=2.5 Hz); 8.56 (1H, d, J=2.7 Hz); 8.20 (1H, dd, J=8.8, 2.7 Hz); 7.99 (1H, dd, J=8.1, 2.2 Hz); 7.91 (1H, br. s.); 7.77 (1H, br. s.); 7.38 (1H, d, J=8.2 Hz); 6.85 (1H, d, J=8.8 Hz); 3.86 (3H, s); 2.52 (3H, s); 2.46 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].Cl.[CH3:15][NH:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:17])[C:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added dimethylamine hydrochloride (10.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (26.0 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-[(dimethylamino)carbonyl]-cyclohexanecarboxylate (20.1 g). APCI-MS M/Z:214[M+H]+