Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:31])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[NH2:3].C1C=CC2[N:40]([OH:41])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C>[OH:41][NH:40][C:28](/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:9][CH2:10][N:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)=[O:31])=[CH:21][CH:22]=1)=[O:29]
Reactant: NC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.2 %

Procedure:
(E)-3-(4-{(E)-3-[4-(4-Carbamoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (316 mg, 0.716 mmol) was suspended in DMF (5 ml). HOBT (193 mg, 1.43 mmol), EDC (273 mg, 1.43 mmol), TEA (0.200 ml, 1.43 mmol) and NH2OTHP (100 mg, 0.86 mmol) were added. The mixture was stirred at room temperature for 72 h and then partitioned between water and hot AcOEt. The organic extract was dried over Na2SO4, evaporated in vacuo and the crude product was crystallized from DCM/Et2O. The resulting solid was suspended in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off, giving 103 mg of 4-(4-{(E)-3-[4-((E)-2-hydroxycarbamoyl-vinyl)-phenyl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid amide as its hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Brc1ncnc2nc[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C

Procedure:
A mixture of 6-bromopurine (2.0 g, 10 mmol), 3,4-dihydro-2h-pyran (1.0 ml, 11 mmol), and p-toluenesulfonic acid monohydrate (0.050 g, 0.26 mmol) in EtOAc (30 mL) was stirred at reflux under a reflux condenser for 48 h. The reaction mixture (suspension) was allowed to cool to room temperature and the solid was removed by suction filtration and washed with EtOAc (50 mL). The combined wash was concentrated in vacuo to afford 2.1 g as oil. The oil was chromatographed through a Redi-Sep® pre-packed silica gel column, eluting with a gradient of 30% to 60% EtOAc in hexane, to provide product.
Reaction SMILES: ClC1C=CC(C2C3C=CC(N)=NC=3C3C(C)=NOC=3C[N:14]=2)=CC=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[C:29]3[C:45]([CH3:46])=[N:44][O:43][C:30]=3[CH2:31][N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C:34]=2[N:35]=1.ClC1C=CC2C(C3C=CC(Cl)=CC=3)=NCC3ON=C(C)C=3C=2N=1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[C:34]3[N:35]=[C:25]([NH2:14])[CH:26]=[CH:27][C:28]=3[C:29]3[C:45]([CH3:46])=[N:44][O:43][C:30]=3[CH2:31][N:32]=2)=[CH:37][CH:38]=1
Reactant: Cc1noc2c1-c1ccc(Cl)nc1C(c1ccc(Cl)cc1)=NC2
Reactant: Cc1noc2c1-c1nc(N)ccc1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Product: Cc1noc2c1-c1ccc(N)nc1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine (Compound 228) was followed, except that 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine (Compound 240) was used as starting material instead of 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine. LC/MS m/z 325 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8.72 Hz, 1H), 7.38 (td, J=2.10, 8.70 Hz, 2H), 7.33 (td, J=1.90, 8.70 Hz, 2H), 6.76 (d, J=8.7 Hz, 1H), 6.39 (s, 2H), 4.60 (br. s, 2H), 2.46 (s, 3H).
Reaction SMILES: CO[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])/[CH:5]=[CH:6]\[C:7]([O:9]C)=O.CN(C=O)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:7](=[O:9])[CH:6]=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC=C(/C=C\C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 250 mL round-bottomed flask was charged with (Z)-dimethyl 4-(methoxymethylene)pent-2-enedioate (2.70 g, 13.5 mmol) and 50 mL of DMF. 4-fluorobenzenamine (1.43 ml, 14.8 mmol) was added dropwise at rt. After stirring at rt for 15 min, the yellow mixture was heated to reflux overnight. The reaction was then diluted with water (200 mL) and extracted with ether (3×100 mL). The combined extracts were dried with MgSO4 and concentrated to give a solid. Purification by MPLC gave methyl 1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate as a slightly yellow solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[F:15][C:16]([F:37])([F:36])[CH2:17][N:18]1[C:23](=[O:24])[C:22](Cl)=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:20]=[N:19]1.N>C1COCC1>[F:37][C:16]([F:15])([F:36])[CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:21]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:20]=[N:19]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by adding 1.0 M benzylmagnesium chloride in ether (0.53 mL, 0.53 mmol) to a THF (20 mL) solution of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared according to the method of Example 193E, at 0° C., then allowing the mixture to warm to room temperature over 2 hours. After an aqueous work-up, the crude material was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate) and crystallized from ethyl acetate/hexanes to provide white, crystalline product (yield: 74 mg, 43%). mp 112-114° C. 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 3.94 (s, 2H), 4.85 (q, J=12 Hz, 2H), 6.99 (dd, J=7.5 Hz, 3 Hz, 2H), 7.2 (m, 3H), 7.48 (d, J=9 Hz, 2H), 7.72 (s, 1H), 8.06 (d, J=9 Hz, 2H).: MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.60; H, 4.13; N, 6.57.
Reaction SMILES: Cl.CC1C=CC([N+]([O-])=O)=CC=1NC(N)=N.[N+]([O-])(O)=O.CC1C=CC([N+]([O-])=O)=CC=1NC(N)=N.[C:34]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)(=[O:36])[CH3:35].CO[CH:45](OC)[N:46]([CH3:48])[CH3:47]>>[CH3:45][N:46]([CH3:48])[CH:47]=[CH:35][C:34]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:36]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Agent: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: Cl
Solvent: O=[N+]([O-])O
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Methyl 5-amino-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (393 mg, 1.08 mmol) was dissolved in trifluoroacetic acid (5 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (148 mg, 2.15 mmol) was added with stirring to give a dark red mixture. After 10 minutes, solid sodium azide (699 mg, 10.8 mmol) was added followed by diethyl ether (5 mL). After and additional 20 minutes the reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 5-azido-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (350 mg) as a solid. 1H NMR (CDCl3) δ ppm 8.42 (2H, d, J=9.16 Hz), 8.02 (2H, d, J=9.16 Hz), 7.03 (2H, d, J=8.85 Hz), 6.96 (2H, d, J=9.16 Hz), 4.07 (3H, s), 3.88 (3H, s), 3.85 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:42])[C:17]([C:22]([O:24][C@@H:25]2[C@@H:29]([CH2:30][O:31][C:32]([C:34]3[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:33])[O:28][C@H:27](Cl)[CH2:26]2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>CN(C)C=O>[C:16]1([CH3:42])[C:17]([C:22]([O:24][C@@H:25]2[C@@H:29]([CH2:30][O:31][C:32]([C:34]3[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:33])[O:28][C@@H:27]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)[CH2:26]2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@H](Cl)C[C@@H]1OC(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](Oc2ccc3c(C)cc(=O)oc3c2)C[C@@H]1OC(=O)c1ccccc1C

Procedure:
7-Hydroxy-4-methylcoumarin (226 mg, 1.28 mmol) and sodium hydride (64 mg of a 60% dispersion in mineral oil, 1.6 mmol) were stirred at room temperature for 30 minutes in dry dimethylformamide (4 ml). Then the chloride (423 mg, 1.09 mmol) from Example 16 was added and after 24 hours the mixture was processed as in Stage 1 of Example 17 and the product isolated by flash chromatography on silica gel (eluting with 2% acetone in dichloromethane) to afford an oil which crystallized from hot methanol as colourless crystals (305 mg, 53%). 1H nmr indicated them to be a 91:9 mixture of the title compound and its α-anomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH2:15]I)[CH:11]=[C:6]1[C:5]2=[O:24].[CH3:25][Mg]Cl.[Li+].[B-](CC)(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH3:15])[CH:11]=[C:6]1[C:5]2([CH3:25])[OH:24]
Reactant: C[Mg]Cl
Reactant: COC(C)(CI)COc1cnc2oc3ccc(Br)cc3c(=O)c2c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)COc1cnc2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-bromo-3-(3-iodo-2-methoxy-2-methylpropoxy)-5H-chromeno[2,3-b]pyridin-5-one (4.10 g, 8.13 mmol) in 100 mL THF was cooled to −40° C. and was treated with methylmagnesium chloride (5.42 mL, 16.27 mmol). After stirring for two hours, the reaction mixture was allowed to warm to room temperature and superhydride (40.7 mL, 40.7 mmol) was added. After stirring for an additional 2 hours the reaction mixture was cooled to 0° C. and was quenched with MeOH. The reaction mixture was poured into saturated NH4Cl solution and was extracted with EtOAc. The organics were washed with water, brine, dried over MgSO4 and concentrated yielding 7-bromo-3-(2-methoxy-2-methylpropoxy)-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:7]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([C:5]2[O:4][C:3]([CH2:2][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: C1CCNC1
Reactant: COc1cc(-c2nnc(CCl)o2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(-c2nnc(CN3CCCC3)o2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To 2-(chloromethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,3,4-oxadiazole (Example 26, step C) (1.01 g, 3.75 mmol) in dioxane (10 mL) was added pyrrolidine (0.800 mL, 9.58 mmol). The reaction was stirred at rt overnight. Upon completion by TLC, the reaction mixture was treated with BOC-anhydride (0.371 g, 1.69 mmol) and cooled to 0° C. The mixture was treated with TEA (0.279 mL, 2.00 mmol). Purification by flash chromatography provided the title compound of step A (1.13 g, 3.70 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.72 (m, 4H), 2.56 (br. s., 4H), 3.92-3.96 (m, 2H), 3.98-4.02 (m, 3H), 7.64-7.69 (m, 1H), 7.79 (br. s., 1H), 8.01-8.06 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)c(C)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated salt solution 50 ml, saturated sodium bicarbonate solution 50 ml, and saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 350 ml of hexane:ethyl acetate=1:1) and concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 2 ml/hexane 5 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 322.9 mg.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g of (6-bromo-pyridin-2-yl)-methanol was dissolved in 50 mL of dimethylformamide and 2.72 g of imidazole was added thereto. Under cooling with ice, 5.21 g of tert-butyldimethylsilyl chloride was added thereto followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[NH2:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.N1C=CC=CC=1>[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=2[N:14]=1)[CH3:16]
Reactant: CNc1c(N)cc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(N)c2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a mixture of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine (1.3 g), 2-ethylsulfanylbenzoic acid (1.3 g), and pyridine (12 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (86 mg) were added at room temperature. The mixture was stirred at room temperature for 5 hours, then heated to 110° C., and stirred with heating for 8 hours. After the reaction mixture was allowed to cool to room temperature, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 339 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-6-trifluoromethyl-3H-benzimidazole-4-ylamine (hereinafter, Present Compound 336).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][O:10]CC1C=CC=CC=1)[CH3:6])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][OH:10])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC(C)CCCO
Yield: 98.8 %

Procedure:
10% palladium-active carbon (48 mg) was added to a mixed solution of 5-benzyloxypent-2-yl acetate (419 mg, 1.78 mmol) in methanol (1.86 mL) in an ice bath in an argon atmosphere, followed by stirring at room temperature in a hydrogen atmosphere. After completion of the reaction, filtration was carried out and the filtrate was concentrated under reduced pressure. 257 mg of the title compound (yield: 87%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=O)[N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]2[C:5](=O)[NH:4]1.B.C1COCC1.Cl>CO>[CH2:5]1[NH:4][C@@H:3]([CH2:2][OH:1])[CH2:8][N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]12
Reactant: O=C1NC(CO)C(=O)N2CCNCC12
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1CN2CCNCC2CN1
Temperature: 80 °C

Procedure:
To a flask containing (3S,9aS or 9aR)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione and (3S,9aR or 9aS)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D83, Diastereoisomer 1 plus D84, Diastereoisomer 2, 976 mg, 4.9 mmol) was added 1M BH3-THF solution (49 mL) under nitrogen and the reaction was brought to reflux (80° C.) overnight. The reaction flask was cooled to 0° C. and treated with 25 mL of MeOH. Conc. HCl was added and the resulting solution was heated to 60° C. for 5 h. The reaction was checked by direct MS (m/z=184 (M+BH3)). The reaction mixture was purified by SCX, obtaining 528 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][C:16]([F:20])([F:19])[CH2:17]O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[N:14]2[CH2:15][C:16]([F:20])([F:19])[CH2:17]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(F)(F)CO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)c1cccc2nc3n(c12)CC(F)(F)CN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of 3-{2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl}-2,2-difluoropropan-1-ol (Reference example 154, 48.9 mg, 0.110 mmol) in pyridine (1.5 mL) was added methanesulfonyl chloride (25.6 μL, 0.330 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs. The starting material wasn't consumed completely. To the mixture was added methanesulfonyl chloride (25.6 μL, 0.330 mmol) at 0° C. and the mixture was stirred at room temperature for 14 hrs. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting mesylate was dissolved into N,N-dimethylformamide (1.5 mL) and to the solution was added potassium carbonate (30.4 mg, 0.220 mmol) at room temperature. The mixture was stirred at 40° C. for 1 hr. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from hexane to give the title compound as a solid (24.0 mg, 0.0564 mmol, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][C:19]=4[Cl:29])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][C:19]=4[Cl:29])[CH3:31])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To solution of 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.0 g, 57.3 mmol), Cs2CO3 (37.40 g, 114.7 mmol) in DMF (600 mL), CH3I (30 mL, 479.8 mmol) was slowly added. The reaction mixture was stirred at room temperature overnight. Concentration removed about 200 mL of DMF, and then water (100 mL) was added to the mixture. The resulting precipitate was filtered, washed with water, dried to give 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.50 g, yield: 99%). ESI-MS: 519.4. 1H NMR (DMSO-d6, 400 MHz): δ7.72-7.68 (m, 2H, ArH), 7.52-7.49 (m, 1H, ArH), 7.30-7.20 (m, 3H, ArH), 6.76 (s, 1H, ═CH), 4.19 (s, 2H, CH2), 3.29 (s, 3H, CH3), 3.00 (s, 3H, CH3), 2.96 (s, 2H, CH2), 2.93 (s, 3H, CH3).