Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:16]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
To a solution of 3-hydroxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (630 mg, 1.45 mmol) (obtained as described in Reference Example 57(5)) in a mixture of methylene chloride (32 ml) and pyridine (12 ml) were added methanesulfonyl chloride (377 μl, 4.36 mmol) and triethylamine (611 μl, 4.36 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether, and the mixture was filtered off and washed with diisopropyl ether to afford 3-methanesulfonyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (766 mg, yield 100%) as a white solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)O[C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.NC1C=CC=CC=1S>>[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[CH:2]=1.[NH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[CH:2]=[CH:5]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccc1O
Agent: Nc1ccccc1S
Product: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: c1ccc2[nH]ccc2c1

Procedure:
reacting isatoic anhydride with 2-aminophenol or 2-aminothiophenol to obtain a 2-(2-aminophenyl)benzazole (wherein the term “benzazole” means benzoxazole or benzothiazole);
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[F:38][C:39]([Si](C)(C)C)([F:41])[F:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][C:34]([OH:37])([C:39]([F:41])([F:40])[F:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(=O)CC4)c3)cc2n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(O)(C(F)(F)F)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (140 mg, 0.28 mmol) in dry THF was treated successively with trifluoromethyltrimethylsilane (0.06 mL, 0.42 mmol) and tetra-n-butylammonium fluoride (1M solution in THF, 0.28 mL, 0.28 mmol). The reaction was stirred at rt overnight before it was partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give 4-hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (15 mg, 9%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.21 (1H, s), 8.25 (1H, s), 8.15 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.94 (1H, d), 6.66 (1H, t), 6.53 (1H, d), 6.02 (1H, s), 4.44 (2H, d), 4.07-4.17 (5H, m), 2.95-3.05 (2H, m), 1.55-1.63 (4H, m); m/z (ES+) 568 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8](O)[CH:7]=[C:6]([CH3:11])[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=1
Reactant: Cc1cc(O)nc(C(C)C)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(C(C)C)n1
Temperature: 110 °C

Procedure:
76.1 g of 2-isopropyl-6-methyl-4-pyrimidinol [2814-20-2] (500 mmol) are dissolved in 300 ml of toluene at 90° C. 80.5 g of phosphorus oxychloride (525 mmol) are added dropwise thereto at from 90 to 103° C., and the reaction mixture is heated at 110° C. for 2 hours. After cooling to 20° C., the reaction mixture is adjusted to pH 8 using 4M sodium hydroxide solution, with cooling. The aqueous phase is separated off and extracted with 100 ml of toluene. The combined organic phases are washed three times with 100 ml of water each time and dried at RT under 2 mbar. 89.7 g (105%; contains toluene) are obtained.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@@H:57]2[O:86][C@H:85]([CH2:87][O:88]CC3C=CC=CC=3)[C@@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]([O:68]CC3C=CC=CC=3)[C@H:58]2[O:59]CC2C=CC=CC=2)[C@@H:45]([CH2:96][O:97]CC2C=CC=CC=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl.CO>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:57]1([O:56][C@@H:46]2[C@@H:45]([CH2:96][OH:97])[O:44][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]3[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]2[OH:48])[O:86][C@H:85]([CH2:87][OH:88])[C@@H:76]([OH:77])[C@H:67]([OH:68])[C@H:58]1[OH:59]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O[C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
The compound (611 mg, 0.55 mmol) synthesized in Example 3 (3c) was dissolved in methanol (8 mL) and ethyl acetate (2 mL) and hydrochloric acid-methanol solution (2 mL) and 20% palladium hydroxide-carbon (400 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After the celite filtration, the solvent was distilled off under reduced pressure and methanol (2 mL) and 28% ammonia water (300 μL) were added thereto, followed by stirring of the mixture at room temperature for 10 minutes. After the solvent was distilled off under reduced pressure, the residue was purified by ion exchange resin (Dowex 50w×8) column (water −1.4% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (54 mg, 42%) as colorless amorphous matter.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=O)=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>[Cl-].[Na+].O.O1CCCC1>[CH2:23]([O:30][N:31]=[CH:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[C:8]([F:14])[C:9]=1[F:13])[C:4]([OH:6])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(C=NOCc2ccccc2)c1F
Yield: 100 %

Procedure:
2,4,5-Trifluoro-3-formylbenzoic acid (Horiuchi N., Yonezawa T., Chiba K., Yoshida H., PCT Int. Appl. [1999] WO 97-JP2918), (5.70 g, 27.9 mmol), triethylamine (11 mL, 78.9 mmol), O-benzylhydroxylamine hydrochloride (4.47 g, 28.0 mmol) and anhydrous tetrahydrofuran (150 mL) are stirred at room temperature for 50 hours. The mixture is poured into brine and the pH adjusted to 5.5–6.0 using 1.0 M hydrochloric acid. The mixture is extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered, and concentrated in vacuo to provide 3-(benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (8.63 g), which is used without further purification. 1H NMR (200 MHz, CDCl3): δ 9.82–9.18 (bs, 1H), 8.24 (s, 1H), 7.94–7.68 (m, 1H), 7.55–7.23 (m, 5H), 5.23 (d, 2H). MS (EI, M−1) m/z 308.
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].[C:7]([O-])(O)=O.[Na+].[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13].IC>O.CCO>[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25]([CH3:7])(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: CC(C)(C)c1nc2ccc(Cl)c(S(C)(=O)=O)c2o1
Temperature: 25 °C

Procedure:
A solution of 204 mg of Na2SO3 and 409 mg of NaHCO3 in 4 ml H2O is heated to 75° and treated portionwise with 0.5 g of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9). A mixture obtained is heated at 75° for 2 hours and 4 ml of EtOH are added followed by 0.11 ml of iodomethane. A mixture obtained is heated at 90° overnight and allowed to cool to rt. A mixture obtained is extracted with 3×30 ml of EtOAc and the combined organic extracts obtained are washed with brine, dried over MgSO4 and solvent is evaporated. The title compound is obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3ncn(C)c(=O)c23)cc1
Temperature: 110 °C

Procedure:
5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C, 125 mg, 0.60 mmol, 1 eq), p-toluenesulfonyl chloride (138 mg, 0.72 mmol, 1.2 eq) and triethylamine (126 μl, 0.90 mmol, 1.5 eq) were dissolved in acetonitrile (2 ml). The mixture was heated at reflux (oil bath at 110° C.) for 3 hours to yield 3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate (compound 1D). The product was confirm by LC-MS. Solvent was removed in vacuo and the crude product 3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate used in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH2:30][CH:31]2[CH:36]([OH:37])[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:32]2[CH2:33][CH2:34][CH2:35][C@@H:36]([OH:37])[C@@H:31]2[CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: OC1CCCNC1CN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCC[C@@H](O)[C@@H]1CN1CCCC1
Reaction time: 16 h

Procedure:
A solution of 3,4-dichlorophenylacetic acid (4.45 g) and 1,1'-carbonyldiimidazole (4.16 g) in dry tetrahydrofuran (60 ml) was stirred at room temperature for 20 min before adding a solution of the product of stage (i) (4.0 g, 60:40 mixture of trans:cis isomers) in dry tetrahydrofuran. This solution was stirred for 16 h under nitrogen and concentrated in vacuo. Column chromatography of the residue on UGI alumina (10 cm diameter, 20 cm length) with graded elution from dichloromethane to dichloromethane:methanol (9:1) removed polar material. The mixture obtained was converted to the hydrochloride salt and crystallised from ethyl acetate:methanol (1:2). The mother liquors were concentrated and the residue was crystallised from the same solvent. The mother liquors from this second recrystallisation gave the title compound upon concentration as an amorphous solid (2.8 g), m.p. 115°-120°, which contained a 93:7 mixture of trans:cis isomers by h.p.l.c.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:12]2[C:13](=[O:19])[NH:14][C:15]3=[CH:16][CH:17]=[CH:18][C:10](=[C:11]23)[O:9][CH2:8]1.Cl.O>CO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[N:12]2[C:13](=[O:19])[NH:14][C:15]3=[CH:16][CH:17]=[CH:18][C:10](=[C:11]23)[O:9][CH2:8]1
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccn1)CO3
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2cccc3c2n1C(C1CCCCN1)CO3
Reaction time: 144 h
Yield: 82.6 %

Procedure:
The tricycle intermediate, 4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.25 g, 0.98 mmol) from Example 13, was partially dissolved in methanol (50.0 mL) and 12.0 M hydrogen chloride in water (1.0 mL, 12 mmol) in a Parr bottle. The reaction was degassed with nitrogen, followed by addition of palladium (10% on carbon), and the reaction was charged to 55 PSI hydrogen and shaken for 6 days. The reaction was filtered to remove the catalyst and concentrated in vacuo to give 4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a dark oil (0.21 g, 82%). LCMS calculated for C14H18N3O2 (M+H)+: m/z=260.1. found: 260.1.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH3:14][S:15][C:16]1[N:21]=[CH:20][C:19]2=[CH:22][CH:23]=[C:24]([CH:25]=[O:26])[N:18]2[N:17]=1>C(OCC)(=O)C>[CH3:14][S:15][C:16]1[N:21]=[CH:20][C:19]2=[CH:22][CH:23]=[C:24]([CH:25]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:26])[N:18]2[N:17]=1
Reactant: CSc1ncc2ccc(C=O)n2n1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc2ccc(C(O)c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.00 M of Phenylmagnesium bromide in Tetrahydrofuran (1.552 mL, 1.552 mmol) was added to a solution of 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (250.0 mg, 1.294 mmol) in Tetrahydrofuran (8.0 mL, 99 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature with stirring for 3 hours. The mixture was then diluted with ethyl acetate and quenched with saturated ammonium chloride. The resulting mixture was washed with water and the organic layer was extracted, dried over sodium sulfate and reduced. The resulting oil was then purified via Isco flash column chromatography (hexanes/ethyl acetate) to afford 340 mg of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol. 1H NMR (400 MHz, DMSO, d6) δ 8.90 (s, 1H), 7.43 (m, 2H), 7.32 (m, 2H), 6.93 (m, 1H), 6.88 (m, 1H), 6.24 (m, 1H), 6.14 (m, 1H), 3.29 (s, 4H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:21]1[C:30]([O:31][CH3:32])=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].[C:33](=[O:36])([O-])[O-:34].[K+].[K+].[C:39](#[N:41])[CH3:40]>CN(C=O)C>[CH2:1]([O:3][CH:4]([C:21]1[C:30]([O:31][CH3:32])=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:40][CH:39]([NH:41][C:33](=[O:36])[O:34][C:28]([CH3:29])([CH3:23])[CH3:27])[CH:8]([CH3:13])[CH3:9])[CH2:17][CH2:16]1)[CH3:2]
Reactant: CC#N
Reactant: CCOC(c1nc2ccccc2cc1OC)n1c(NC2CCNCC2)nc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(c1nc2ccccc2cc1OC)n1c(NC2CCN(CC(NC(=O)OC(C)(C)C)C(C)C)CC2)nc2ccccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Intermediate (32) (0.1382 mol) was added at 55° C. to a mixture of (±)-1-[ethoxy(3-methoxy-2-quinolinyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine (0.0346 mol) and potassium carbonate (0.242 mol) in acetonitrile (108 ml) and DMF (20 ml) (1 equiv of intermediate (32) was added every hour). The mixture was stirred at 55° C. for 1 hour and filtered. The filtrate was poured out into H2O and the mixture was extracted with EtOAc. The organic layer was separated, washed with a saturated NaCl solution, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.4 and 96/4/0.5; 20–45 μm). Two fractions were collected and their solvents were evaporated, yielding 2.5-g (23%) of (±)-1,1-dimethylethyl [1-[[4-[[1-[ethoxy(3-methoxy-2-quinolinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]methyl]-2-methylpropyl]carbamate (comp. 38).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][C:13]([OH:15])([CH3:23])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC(=O)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(Br)n2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 114.3 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate (800 mg, 2.17 mmol) in THF (40 mL) at −78° C. was added CH3MgBr (169 mg, 1.44 mmol). The mixture was stirred at −78° C. for 2 hours, quenched with 10% NH4Cl solution (35 mL), extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM:MeOH (20:1˜10:1) as eluting solvents to afford tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (636 mg, 76%). MS (ESI) m/z: 386 [M+H]+.
Reaction SMILES: [CH:1]([N:4]=[C:5]1[CH:9]2[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:8]2[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[CH3:17][I:18]>>[I-:18].[C:5]1(=[N+:4]([CH:1]([CH3:3])[CH3:2])[CH3:17])[CH:9]2[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:8]2[CH2:7][CH2:6]1
Reactant: CI
Reactant: CC(C)N=C1CCC2c3ccccc3CC12
Product: CC(C)[N+](C)=C1CCC2c3ccccc3CC12
Product: [I-]

Procedure:
3,3a,8,8a-Tetrahydro-N-isopropylcyclopent[a]inden-1[2H]-imine (1.4 g) and methyl iodide (3 ml) were kept at room temperature overnight. The resultant solid mass was triturated with ether to give the quaternary salt as a buff solid, m.p. 168°-170°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([O:25][CH3:26])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[CH:16]=1)[CH3:10]>ClCCCl>[C:5]([C:21]1[CH:22]=[C:17]([C:15]2[CH:16]=[C:11]([CH2:9][CH3:10])[CH:12]=[CH:13][C:14]=2[O:25][CH3:26])[CH:18]=[CH:19][C:20]=1[OH:23])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCc1ccc(OC)c(-c2ccc(OC)cc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(OC)c(-c2ccc(O)c(C(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture was prepared by suspending 5.0 g of aluminium chloride into 25 ml of 1,2-dichloroethane. The mixture was added 1.0 ml of acetylchloride, stirred for 1 hour at room temperature. The reaction mixture, wherein 2.4 g of 5-ethyl-2,4'-dimethoxybiphenyl was added, was stirred for 2 hours with cooling by the ice bath and stirred from further 2 hours at room temperature. Ice water was added into the reaction mixture, and extracted with chloroform. The extract was washed with 10% water solution of sodium hydrogencarbonate and an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethyl acetate=50:1) to yield 1.6 g of 3'-acetyl-5-ethyl-4'-hydroxy-2-methoxybiphenyl.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.Cl.[CH3:38]CO>O1CCOCC1>[F:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:22][C:19]3[CH:20]=[CH:21][C:16]([C:13]4[S:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH2:7][CH3:38])=[O:5])=[O:10])=[N:15][CH:14]=4)=[CH:17][CH:18]=3)[S:28][C:29]=2[CH:35]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: CCO
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)c1ncc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)s1)C(C)C
Temperature: 80 °C

Procedure:
A solution of Methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 150 mg) and 2-chloro-6-fluorobenzo[d]thiazole (101 mg) in EtOH (3 ml) was heated at 55-60° C. to get clear solution. 4M aqueous HCl in 1,4-Dioxane (0.11 ml) was added to it and the reaction mixture was refluxed at 80° C. for 20 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc:Pet ether, 2:8). The solid was crystallized in EtOAc/pet ether to give the title compound. Yield: 120 mg (53%); 1HNMR (DMSO-d6, 300 MHz): δ 10.76 (s, 1H), 8.66 (d, 1H), 8.37 (s, 1H), 7.88 (d, 2H), 7.80 (d, 2H), 7.77 (d, 1H), 7.64 (dd, 1H), 7.2 (m, 1H), 4.29 (m, 1H), 4.16 (q, 2H), 2.27 (m, 1H), 1.22 (t, 3H), 0.95 (d, 6H); MS (ES+) m/z 499 (M+1).
Reaction SMILES: [C:1]12([N:6]3[CH:19]=[C:18]4[C:8]([C:9](=[O:20])[CH2:10][C:11]5([CH2:17]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]5)=[N:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[N:22]1>>[C:1]12([N:6]3[CH:19]=[C:18]4[C:8]([C:9](=[O:20])[CH2:10][C:11]5([CH2:17]4)[CH2:16][CH2:15][N:14]([C:30]([C:26]4[CH:25]=[C:24]6[C:29](=[CH:28][CH:27]=4)[NH:21][N:22]=[CH:23]6)=[O:31])[CH2:13][CH2:12]5)=[N:7]3)[CH2:4][CH:3]([CH2:2]1)[CH2:5]2
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: O=C1CC2(CCNCC2)Cc2cn(C34CC(C3)C4)nc21
Product: O=C1CC2(CCN(C(=O)c3ccc4[nH]ncc4c3)CC2)Cc2cn(C34CC(C3)C4)nc21

Procedure:
The title compound was prepared by a method analogous to that described in Example 1, using 2-(bicyclo[1.1.1]pentan-1-yl)-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(2H)-one and 1H-indazole-5-carboxylic acid. +ESI (M+H) 416.2; HPLC retention time 2.32 minutes (Method A).