Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH:20]=[O:21]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([CH:20]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)[OH:21])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1cc(F)cc(F)c1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M in THF, 35 mL, 17.5 mmol) was added to a solution of 3,5-difluorobenzaldehyde (1.95 g, 13.7 mmol) in THF (50 mL) slowly via syringe at −78° C. The reaction mixture was stirred at this temperature for 3 hours and then quenched with saturated NH4Cl (aqueous). The mixture was extracted with EtOAc (60 mL×2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a colorless oil (3.9 g) as product M6.1, which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:28]([NH2:30])=[O:29])=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=4)[CH:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:28]([NH2:30])=[O:29])=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:34]([CH2:33][C:32]([F:39])([F:38])[F:31])(=[O:36])=[O:35])[CH:22]=4)[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cccc(N)c4)cnc3C(N)=O)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(NS(=O)(=O)CC(F)(F)F)c4)cnc3C(N)=O)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 65A (18 mg, 0.045 mmol) in dichloromethane (0.4 mL) and pyridine (0.1 mL) was added to a cooled to 0° C. 2,2,2-trifluoroethanesulfonyl chloride (9 mg, 0.05 mmol). The reaction mixture was stirred slowly warming to ambient temperature over 18 hours and concentrated under reduced pressure. The crude material was purified by RP-HPLC (10 mM ammonium acetate/acetonitrile) to afford the title compound. 1H NMR (DMSO-d6) δ ppm 10.27 (s, 1H), 8.21 (d, J=3.0, 1H), 8.14 (d, J=1.9, 1H), 7.68-7.63 (m, 1H), 7.52-7.40 (m, 2H), 7.40-7.33 (m, 2H), 7.30-7.23 (m, 1H), 7.20-7.14 (m, 2H), 7.00-6.94 (m, 2H), 4.54 (q, J=9.8, 2H), 3.13 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H); MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[C:19]([C@@H:21]5[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]5)[N:18]=[N:17]4)[CH:14]=3)[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([C:19]2[N:18]=[N:17][N:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[NH:9][N:8]=[C:7]4[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:20]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2cn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2n[nH]c3ccc(-n4cc([C@@H]5CCCNC5)nn4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the crude (R)-tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate dissolved in CH2Cl2 (30 mL) was added TFA (2 mL and Et3SiH (0.2 mL) and stirred at room temperature overnight under a stream of nitrogen. Evaporated the solvent and column purified (10% MeOH in CH2Cl2) to give the (R)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (0.61 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:34])[O:32][CH3:33].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:34])[O:32][CH3:33])[N:3]=2)[N:6]=1)=[O:29]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 60.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), methyl chlorocarbonate (33 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as starting materials and in the same manner as in Example 388, the title compound (104 mg, 61%) was obtained as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]([OH:16])([CH2:14][OH:15])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH:17]12[CH2:25][CH:21]([CH2:22][NH:23][CH2:24]1)[CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:29]([O:28][C:26]([N:19]1[CH2:18][CH:17]2[CH2:25][CH:21]([CH2:22][N:23]([CH2:2][C:3]([OH:16])([CH2:14][OH:15])[CH2:4][O:5][C:6]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=3)[CH2:24]2)[CH2:20]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(OCC(O)(CO)CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)(CO)COc3ccc(C#N)cc3)C2)C1
Yield: 31 %

Procedure:
A mixture of 4-(3-chloro-2-hydroxy-2-hydroxymethylpropoxy)benzonitrile (180 mg; 0.74 mmol; from step (b) above), tert-butyl 3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate (230 mg; 1.0 mmol; see Example F above) and K2CO3 (140 mg; 1.0 mmol) in MeCN (5 mL) was refluxed for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in diethyl ether and the solution was acidified with KHSO4 (aq.). The aqueous layer was collected and NaHCO3 (satd.) was added followed by ether extraction. The organic layer was collected, dried, concentrated and subjected to column chromatography (DCM:MeOH; 20:1) to give the title compound in a 31% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:5].[CH3:13]OS(OC)(=O)=O>O1CCCC1>[CH3:3][C:4]([O:12][CH3:13])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:5]
Reactant: CC(C)=CCCC(C)(C)O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC=C(C)C
Reaction time: 16 h

Procedure:
To sodium hydride (93.5 g, 3.9 mol) suspended in tetrahydrofuran (300 mL) was added 2,6-dimethylhept-5-en-2-ol (500 g, 3.5 mol) in tetrahydrofuran (1000 mL). The mixture was heated at reflux until gas evolution was complete. Dimethylsulfate (274 mL, 2.9 mol) in tetrahydrofuran (226 mL) was added to the cold (0~C) mixture. After standing for 16 h, the mixture was heated at reflux for 7 hours. Aqueous workup yielded 2,6-dimethyl-2-methoxyhept-5-ene, bp40 65-68~C (461.5 g); NMR(CDC13) 1.2(s,6H), 1.4-1.6(m,2H), 1.6(s,3H), 1.7(s,3H), 1.9-2.1(m,2H), 3.2(s,3H), 5.1-5.2(m,1H); IR(neat) 2970, 2932, 1462, 1442, 1373, 1357, 1195, 1072 cm-1 ; MS(m/e) 41, 67, 73, 109, 124, 142.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.COC1C=CC(CS[C:19]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=CC=1>O1CCCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][S:31]/[C:19](/[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8](/[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)\[CH2:9][CH3:10])=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SCc1ccc(OC)cc1)SCc1ccc(OC)cc1
Reactant: CCCc1cc(Br)ccn1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)/C(SCc1ccc(OC)cc1)=C(/CC)c1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 10.1 mL, 16.2 mmol) to a stirred solution of diisopropylamine (2.3 mL, 16.4 mmol) in tetrahydrofuran (25.0 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, 0° C. for 15 min, and then recooled to −78° C. A solution of 4-bromo-2-propylpyridine (2, 2.94 g, 14.7 mmol) in tetrahydrofuran (25.0 mL) is added dropwise to this solution over a period of 30 min. The resulting deep red suspension is stirred at −78° C. for 1 h, after which time a solution of diethyl 2-[bis(4-methoxybenzylsulfanyl)methylene]malonate (1, 7.03 g, 14.8 mmol) in tetrahydrofuran (40.0 mL) is added dropwise over a period of 15 min. The resulting yellow solution is stirred at −78° C. for 1.5 h, −15° C. for 1.5 h, and room temperature for 30 min to give a dark orange solution. The reaction mixture is quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give 3 an orange oil. The product is purified by flash column chromatography (eluting with 5% ethyl acetate in methylene chloride.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(-n2ccnc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
90 mg of 1-(3-hydroxymethylphenyl)imidazole was dissolved in 10 ml of chloroform, and 100 microliters of thionyl chloride was added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl ether and water. The organic layer was separated, washed successively with a 5% aqueous solution of sodium hydrogen carbonate and then with water, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration and then ethyl ether was evaporated to give 1-(3-chloromethylphenyl)imidazole as a pale yellow oily product.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH2:14]1[CH2:18]OC[CH2:15]1>[Cu]I>[CH3:18][C:14](=[CH2:15])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C=Cc1ccccc1
Reactant: C1CCOC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Product: C=C(C)C(CC(C)=O)c1ccccc1
Reaction time: 2 h

Procedure:
The organo magnesium compound is then added to a solution of 10 g (0.068 mole) of benzalacetone and 7% (0.97 g) of CuI in 250 ml of THF. The mixture rapidly assumes a brown colouring. After addition, it is left for a few minutes at reflux and then 12 hours at ambient temperature. Hydrolyzing takes place by the addition of the reaction mixture to crushed ice and ammonium chloride, accompanied by very vigorous stirring. After 2 hours, the mixture assumes a blue lavender shade. Extraction takes place with ether and the product is dried on sodium sulphate.
Reaction SMILES: [N:1]([CH:4]([CH2:21][CH:22]=[CH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[NH2:1][CH:4]([CH2:21][CH:22]=[CH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: C=CCC(Cc1ccccc1-c1noc2ccccc12)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(N)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a stirred solution of 631 mg of 3-[2-(2-azido-4-pentenyl)phenyl]-1,2-benzisoxazole in 10 ml of anhydrous tetrahydrofuran at -40° C. under a nitrogen atmosphere was added 2.07 ml of a 1 M solution of lithium aluminium hydride in diethyl ether. The reaction mixture was warmed to room temperature then heated to 60° C. for 1 h. After cooling to room temperature and careful quenching with 4 N sodium hydroxide, 50 ml of water was added and the product extracted with 100 ml then 50 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent removed by evaporation to give crude product which was purified by chromatography on silica gel eluting with 10% methanol in dichloromethane, to give 315 mg of 3-[2-(2-amino-4-pentenyl)phenyl]-1,2-benzisoxazole. The product was dissolved in 1 ml of methanol and 131 mg of fumaric acid was added. Addition of diethyl ether and cooling to 4° C. led to crystallisation of 313 mg of 3-[2-(2-amino-4-pentenyl)phenyl]-1,2-benzisoxazole (E)-edioate, melting at 170-172° C.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cc(CO)no1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)C)on2)cc1
Reaction time: 5 h
Yield: 20.5 %

Procedure:
4.24 g of (5-i-propyl-isoxazol-3-yl)methanol was dissolved in 10 ml of pyridine, and 6.67 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.82 g of (5-i-propyl-isoxazol-3-yl)methyl 4-toluenesulfonate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][CH:20]([OH:25])[CH2:21]4)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH:18]4[CH2:24][CH2:23][CH:22]3[CH2:21][CH:20]([OH:25])[CH2:19]4)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Agent: [Pd]
Solvent: CO
Product: NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)methanone (1.1 g, 0.0035 mol) in methanol (15 mL) was added 10% Pd/C (0.17 g) and the mixture hydrogenated at 3 kg pressure for 1 h. The catalyst was filtered over celite and the filtrate was concentrated to give [1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)methanone (0.87 g, 86%). MS-ES I m/z 315 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[Si:24]([O:1][CH2:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)c1ccccc1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of phthalide (26.8 g) in methylene chloride (600 ml) were successively added N,O-dimethylhydroxylamine hydrochloride (58.5 g) and aluminum chloride (40.0 g) under ice-cooling, and triethylamine (139 ml) was added dropwise over 40 min. The mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into diluted hydrochloric acid, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-hydroxymethyl-N-methoxy-N-methylbenzamide. The obtained 2-hydroxymethyl-N-methoxy-N-methylbenzamide was dissolved in N,N-dimethylformamide (300 ml), and imidazole (9.53 g) and tert-butyldimethylchlorosilane (21.1 g) were added. The mixture was stirred at room temperature for 3.5 hr and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (42.0 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[N:31]([O-])=O.[Na+].O>C(O)(=O)C>[NH2:31][C:12]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:9]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[N:10][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=N[O-]
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (3.0 g, 7.31 mmol) was dissolved in acetic acid (20 ml), an aqueous solution (1 ml) of sodium nitrite (605 mg, 8.78 mmol) was dripped in under water cooling, and agitation was done for 30 minutes at room temperature. After adjusting the pH to approximately 4.0 with a 2N NaOH aqueous solution, extraction was carried out 2 times using dichloromethane. After washing with water, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. The residue was dissolved in a methanol (40 ml)-ethyl acetate (40 ml) mixture solvent, 300 mg of Pd/C was added, and catalytic hydrogenation was done for 2 hours under atmospheric pressure. The Pd/C was filtered using celite, and the filtered liquid was distilled away under reduced pressure. The residue was washed with ether, and 1.63 g (52% yield) of 5-amino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 63 are shown below.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15](=[O:38])[NH:16][C:17]1[C:18]([C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:24]=3[N:23]=2)=[N:19][NH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.CO>Cl.O1CCOCC1>[NH2:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([NH:16][C:17]1[C:18]([C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:24]=3[N:23]=2)=[N:19][NH:20][CH:21]=1)=[O:38]
Reactant: Cn1c(-c2n[nH]cc2NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)nc2cc(N3CCOCC3)ccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c(-c2n[nH]cc2NC(=O)C(N)c2ccccc2)nc2cc(N3CCOCC3)ccc21
Yield: 82.1 %

Procedure:
{[3-(5-Morpholin-4-yl-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl-carbamoyl]-phenyl-methyl}-carbamic acid tert-butyl ester (Example 232) (30 mg) was dissolved in 4M HCl/dioxane, and 3 ml of methanol and stirred at room temperature overnight. The solvent was removed in vacuo and residue triturated with diethylether to give 2-amino-N-[3-(5-morpholin-4-yl-methyl-1H-benzimidazol-2-yl-)-1H-pyrazol-4-yl]-2-phenyl-acetamide (AT8162) as a white solid (20 mg, 83%). (LC/MS (acidic method): Rt 2.39 min, [M+H]+ 432).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.OC1C2N=NNC=2C=CC=1.[H-].CN(C)CCCN=C=NCC.[C:32]([C:34]1[CH:59]=[CH:58][CH:57]=[CH:56][C:35]=1[O:36][C:37]1[CH:38]=[C:39]([NH2:55])[C:40]([NH2:54])=[CH:41][C:42]=1[O:43][C:44]1[CH:45]=[N:46][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:48][CH:49]=1)#[N:33]>C(OCC)(=O)C.CN(C)C=O>[C:32]([C:34]1[CH:59]=[CH:58][CH:57]=[CH:56][C:35]=1[O:36][C:37]1[C:42]([O:43][C:44]2[CH:45]=[N:46][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:48][CH:49]=2)=[CH:41][C:40]2[NH:54][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:55][C:39]=2[CH:38]=1)#[N:33]
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21 mg of pyrazine-2-carboxylic acid, 52 mg of hydroxybenzotriazole and 52 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydride were added to a dimethylformamide (2 ml) solution of 72 mg of 4-(2-cyano-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 196 (step 5), and the reaction liquid was stirred at room temperature for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in 1 ml of N-methylpyrrolidinone, and 20 mg of ytterbium trifluoromethanesulfonate was added to it, and the reaction liquid was stirred at 160° C. for 2 h ours. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=30/1) and through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a brown solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:26]([CH3:35])[CH:25]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:1][S:2]([O:34][CH2:33][CH2:32][O:31][C:27]1[C:26]([CH3:35])=[CH:25][C:24]([C:14]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:29][C:28]=1[CH3:30])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
TEA (0.24 mL, 1.70 mmol) followed by methanesulfonyl chloride (0.13 mL, 1.70 mmol) were added to a solution of 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.230 g, 0.57 mmol) in CH2Cl2 (10 mL). After stirring for 6 hours at room temperature, the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 8% MeOH in CH2Cl2, afforded 2-(2,6-dimethyl-4-(3-(4-(N-(methylsulfonyl)methylsulfonamido) phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)ethyl methanesulfonate (0.280 g, 77%).