Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH:10]([CH:12]([C:14](O)=O)O)O)(O)=O.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.CC1C=CC(S(OCCC#C)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>C(#N)C>[CH2:7]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[CH3:17])[CH2:10][C:12]#[CH:14]
Reactant: C[C@@H]1CCCN1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: C#CCCN1CCC[C@H]1C
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A sealed pressure tube was charged potassium carbonate powder (18.4 g, 133.2 mmol, 325 mesh), milled (2R)-2-methylpyrrolidine tartrate (20.9 g, 88.8 mmol), 3-butynyl 4-methylbenzenesulfonate (15.7 mL, 88.8 mmol), and acetonitrile (105 mL). The mixture was heated at 85° C. and stirred for 16 hours. The completion of the reaction was monitored by gas chromatography until all the tosylate was consumed. The reaction mixture was cooled to room temperature, diluted with CH3CN (50 mL), and filtered. The filtrate was used in the next step without further purification. GC-MS m/z 138 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40].C(N(CC)C(C)C)(C)C.[CH2:56]([O:58][C:59](=[O:64])[CH2:60][CH2:61][CH2:62]Br)[CH3:57]>C(#N)C.ClCCl>[CH2:56]([O:58][C:59](=[O:64])[CH2:60][CH2:61][CH2:62][NH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:15][CH2:16]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40])[CH3:57]
Reactant: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
To a solution of 3-((R)-2-amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (3-58) (55 mg, 0.086 mmol) in acetonitrile (2 mL) were added N,N-diisopropylethylamine (37 μl, 0.271 mmol) and 4-bromo-butyric acid ethyl ester (15 μl, 0.086 mmol) in the order, followed by stirring at 95° C. for 12 hrs. The solution was cooled to room temperature, diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was separated and concentrated. The residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 21 mg of the compound as a colorless oil (yield 33%). 1H NMR (300 MHz, CDCl3) δ 1.19 (3H, t), 1.65 (2H, m), 2.24 (4H, m), 2.33 (3H, s), 2.37-2.50 (4H, m), 2.74 (2H, m), 3.60 (4H, m), 4.02-4.09 (4H, m), 4.16 (1H, m), 5.40 (2H, dd), 7.20-7.40 (7H, m), 7.49 (1H, t), 7.53 (1H, d), 7.76 (1H, d), 8.10 (1H, dd), 8.18 (1H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].ClCCl.C1(C)C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:40]3[CH:39]=[C:38]([CH:42]([C:44]4[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=4)[OH:43])[CH:37]=[CH:36][CH:41]=3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[N:10]=1
Reactant: Cc1cccnc1C(O)c1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)c4ncccc4C)c3)cc12

Procedure:
415 mg (0.87 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, 40 mg (49 μmol) of dichloro[1,1′-bis(diphenyl-phoshino)ferrocene]palladium(II) dichloromethane adduct and 240 mg (0.86 mmol) of (3-bromo-phenyl)-(3-methyl-pyridin-2-yl)-methanol were place in a microwave vial. 6 mL of acetonitrile, 2 mL of toluene and 6 mL of a saturated aqueous solution of sodium carbonate were added. The vial was sealed and irradiated in a Personal Chemistry® Optimizer to 145° C. for 30 main. The resulting mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford a yellow oil. MS: m/z 553.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:15]O>S(=O)(=O)(O)O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:15])=[O:11]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1C(F)(F)F

Procedure:
A solution of 2-trifluoromethylphenylacetic acid (5.0 g) in methanol (30 ml) containing 5 drops of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate (100 ml), washed with 1 N sodium hydroxide (25 ml) then with brine (25 ml), dried over magnesium sulphate and evaporated to give the title compound (5.04 g) as a colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][CH:29]2[NH2:34]>>[CH2:1]([C:3]1[C:4]([NH:34][CH:29]2[C:30]3[C:25](=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:27][CH2:28]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: COc1cccc2c1CCCC2N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCCc3c(OC)cccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.66, 7.19, 7.00, 6.78, 5.47, 4.54, 3.87, 2.83, 2.68, 2.54, 2.06, 2.02, 1.97, 1.31; 13C NMR (100 MHz, CDCl3) δ 157.50, 153.66, 161.36, 140.81, 139.90, 129.80, 127.37, 126.82, 121.33, 108.49, 55.75, 48.72, 29.44, 28.55, 26.08, 23.59, 19.62, 13.93, 11.14; HRMS (FAB) calcd for C19H25N3O+H 312.2076, found 312.2066.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:25][C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][C:27]=1[O:35][C:36]([F:39])([F:38])[F:37]>>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:33]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:11]([CH3:23])([CH3:22])[C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:24])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:34])[CH:29]=[CH:28][C:27]=1[O:35][C:36]([F:39])([F:38])[F:37]
Reactant: C[C@@H]1NCCN(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: C[C@H]1C(=O)N(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Yield: 53 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3,3-dimethyl-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 28) and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethoxy-benzene (intermediate 17) gave the titled compound in 53% yield as light yellow foam. MS: 575.22 (MH+, Cl).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:1][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of benzyl 4-formylpiperidine-1-carboxylate (3 g) and tert-butyl piperazine-1-carboxylate (2.2 g) in dichloromethane (100 ml) was added sodium triacetoxyborohydride ((2.6 g). The resulting solution was stirred at room temperature for 18 hours and then washed with 2M sodium hydroxide (2×50 ml) and 2M hydrochloric acid (2×50 ml), dried over Magnesium sulphate, filtered and evaporated to afford tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (4.9 g) as an oil. Tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (4.9 g) was dissolved in ethanol and purged with argon. 20% Palladium hydroxide on carbon (500 mg) was added. The reaction mixture was purged with argon, evacuated and filled with hydrogen from a balloon. The reaction mixture was stirred at room temperature for 2 hours. A white solid precipitate formed. The reaction mixture was warmed to 40° C. and stirred at this temperature for a further 1 hour until the precipitate dissolved. The reaction mixture was allowed to cool to room temperature and stirred for a further 18 hours. The reaction mixture was purged with argon, filtered through celite and evaporated to afford tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (3.2 g) as a solid. Mass spectrum: M+H+ 284
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](Cl)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:16]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Reactant: NCCCO
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(NCCCO)nc21
Yield: 82 %

Procedure:
2-Chloroderivative (2) (0.5 mmol) and 3 ml of 3-aminopropanol were heated for 3 hours to 160° C. (sealed ampoule). Excess of the amine was evaporated at a temperature below 70° C. and the residue was purified by column chromatography (stepwise 0; 1; 2% MEOH in CHCl3) and crystallized from diethyl ether afforded the product in 82% yield; m.p. 98-101° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].BrC[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][N:10]=1>CN(C=O)C>[N:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][CH:9]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Yield: 298.1 %

Procedure:
A solution of the 4-bromo-2-(2-phenethyl)phenol (1.25 g, 14.5 mmol in DMF (10 ml) was treated with K2CO3 (0.82 g, 5.96 mmol) and methyl 2-bromomethyl-5-pyridine carboxylate (1.14 g, 4.96 mmol). The reaction was stirred at ambient temperature and then evaporated in vacuo. The residue was partitioned between ethyl acetate/H2O and the combined organic extracts were washed with at NaCl solution, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give methyl 2-(2-phenethyl)-4-bromophenoxy methyl)-5-pyridinecarboxylic acid (1.82 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[CH:3]=1.[ClH:22]>ClCCl>[ClH:22].[ClH:22].[CH3:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cnn1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(N2CCC(N)CC2)cnn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 121.1 %

Procedure:
To a solution tert-butyl 1-(6-methylpyridazin-4-yl)piperidin-4-ylcarbamate (2.14 g, 7.32 mmol) in dichloromethane (36 mL) was added HCl (2 M in diethylether, 18.3 mL, 36.6 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethylether and dried to afford the title compound (2.35 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([N:11]=O)[CH2:7][CH2:6]1.[C:14]([NH:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1)(=[O:16])[CH3:15].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:14]([NH:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22]([NH:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH:2]([CH3:13])[CH3:1])[CH2:6][CH2:7]2)=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1)(=[O:16])[CH3:15]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Reactant: CC(C)CCN1CCN(N=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(CCC(C)C)CC1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
N-(3-methyl-butyl)-N'-nitroso-piperazine (2.5 g.) was added to 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride (prepared from 3.5 g. of corresponding acid and thionylchloride) and triethylamine (5 ml.) in anhydrous toluene (250 ml.). After 1 hour, 10% sodium hydroxide (5 ml.) was added and the toluene layer separated, dried and evaporated to give 4-acetylamino-5-chloro-2-methoxy-N-[4-(3-methylbutyl)-1-piperazinyl]benzamide (3 g., 52%), m.p. 128°-30° (ex-ethylacetate/light petroleum.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:23])[NH:11][C:12]1[NH:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)[CH3:9])(C)(C)C.O1CCOCC1.[ClH:31]>>[ClH:31].[ClH:31].[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][C:12]1[NH:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Reaction time: 3 h

Procedure:
To 100 mg (0.30 mmol) of the product of Step A [1-(5-phenyl-2H-pyrazol-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester was added 1 ml of 4N HCl dioxane solution (Aldrich) at ambient temperature. The reaction was allowed to stir for 3 hours. After evaporation to dryness and trituration with ether, 73 mg of amino-N-(5-phenyl-2H-pyrazol-3-yl)-propionamide dihydrochloride was obtained as a white powder (80%) (MS: 231[P+1]/229 [P−1])(RF=0.2 on silica TLC (9/1 Chloroform/Methanol).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([CH2:24][OH:25])[CH:23]=1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][C:22]=3[CH2:24][OH:25])[CH2:31][CH2:30]2)=[O:13])=[CH:14][CH:15]=1
Reactant: Cc1ccc(N2CCNCC2)c(CO)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(CO)c1
Yield: 27 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (550 mg) described in Preparation Example 16 and [5-methyl-2-(piperazin-1-yl)phenyl]methanol (470 mg) described in Preparation Example 99 and by the reaction and treatment in the same manner as in Example 87, the title compound (264 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:25]=1[C:26](O)=[O:27].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH:18][C:26]([C:25]3[N:24]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[CH:23]=[N:22][C:21]=3[Cl:20])=[O:27])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (667 mg, 1.828 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (506 mg, 1.828 mmol) and diisopropylethyl amine (0.669 mL, 3.83 mmol) in DMF (20 ml) was added HATU (695 mg, 1.828 mmol) and the mixture was stirred for 30 minutes. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (589 mg, 0.944 mmol, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.40-7.51 (m, 2H), 7.37 (t, 1H), 7.09 (t, 1H), 7.01 (t, 1H), 5.46 (s, 2H), 4.46 (d, 2H), 3.35 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[S:15](=[O:19])(=[O:18])(N)[NH2:16]>O1CCOCC1.C(OC(C)C)(C)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([S:15]([NH2:16])(=[O:19])=[O:18])[CH3:1])([CH3:11])([CH3:13])[CH3:12]
Reactant: CNCCCCNC(=O)OC(C)(C)C
Reactant: NS(N)(=O)=O
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CN(CCCCNC(=O)OC(C)(C)C)S(N)(=O)=O
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A mixture of tert-butyl 4-(methylamino)butylcarbamate (4 g, 19.77 mmoles) and sulfuric diamide (7.6 g, 4 eq) in dioxane (10 mL) was heated at 100° C. in a microwave oven during 30 minutes. The RM was then concentrated in vacuo, and DCM was added. The resulting white precipitate of sulfuric diamide in excess was filtered off, and the filtrate was successively washed with diluted HCl, then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 3.55 g (64% yield) of tert-butyl 4-(methyl(sulfamoyl)amino)butylcarbamate 10b as a white solid; m/z 282 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([Br:41])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Br:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(Br)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (5 g), 2-bromo-1-(3-bromo-4-methoxyphenyl)ethanone (4.4 g) and N,N-dimethylformamide (300 mL) was added 60% sodium hydride (0.57 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (3.4 g, 43%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(O)C>[N:10]1[CH:9]=[N:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:7]2
Reactant: NCCCCCCO
Reactant: Clc1ccc2ncnn2n1
Solvent: CCO
Product: OCCCCCCNc1ccc2ncnn2n1
Yield: 117.8 %

Procedure:
2.03 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was dissolved in 20 ml of ethanol; 3.85 g of 6-amino-1-hexanol was added, followed by heating and refluxing for 19 hours. After cooling, the crystal obtained was collected by filtration, washed with ethanol and dried to yield 3.64 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:30][CH2:29][CH2:28][C@@:15]3([C:19](=[O:20])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[CH2:17][CH2:16]3)[CH2:14]2)=[N:11][CH:12]=1.N1C=CC=CC=1.C(Cl)Cl>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:17][CH2:16][C@:15]2([CH2:28][CH2:29][CH2:30][N:13]([C:10]3[N:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][CH:9]=3)[CH2:14]2)[C:19]1=[O:20]
Reactant: Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5S)-7-(5-aminopyridin-2-yl)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one (18.5 mg, 0.0000478 mol) and pyridine (13 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 0.5 h at rt. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 415.1/417.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH2:26][CH3:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[CH2:26]([C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1)[CH3:27]
Reactant: CCc1cncc2cccc(NC3CCC(NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: CCc1cncc2cccc(NC3CCC(N)CC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 86 (133 mg) and 10% hydrogen chloride/methanol solution (2 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (80.9 mg).