Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:45][C@@H:46]([NH2:49])[CH2:47][OH:48]>CC(N(C)C)=O.ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:49][C@H:46]([CH3:45])[CH2:47][OH:48])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: C[C@@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (4.0 g, 0.0086 mol) in dimethylacetamide (10.0 mL) at −20° C. was added N-methylmorpholine (1.2 g, 0.012 mol), followed by the dropwise addition of a solution of isobutylchloroformate (1.58 g, 0.012 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred for 10 min. under argon atmosphere after which it was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0° C., and added R-2-amino-1-propanol (0.97 g, 1.01 mol). The resulting mixture was stirred at room temperature for 1.5 h, concentrated in vacuo, and the residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=522) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (20 mL), washed successively with 5% sodium bicarbonate (2×15 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (2.2 g, 49%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.91 (dd, 1H, J=1.6 Hz, & 6.4 Hz), 7.68 (d, 1H, J=1.6 Hz), 7.60 (m, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.57 (abq, 2H), 4.18 (m, 1H), 3.56 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), and 1.22 (d, 3H, J=6.8 Hz); ES-HRMS m/z 522.0860 (M+H calcd for C23H23N3O4F2 Br requires 522.0835). 19F NMR (CD3OD/400 MHz) −111.85 (m) and −115.90 (m).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH:8]1[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH:8]1[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CN1CCN(C)C(CCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C)C(CCCl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.5 mL) was added dropwise to an ice cooled methylene chloride (5 mL) solution of 3-(2-hydroxyethyl)-1,4-dimethyl-2-piperazinone (0.40 g, described in Example 1). The reaction mixture was stirred for 30 min and poured on an ice solution of 10% sodium bicarbonate. The mixture was extracted with methylene chloride, and the organic extract was dried and evaporated to give the title compound: IR (CHCl3) 1635 cm-1 ; and NMR (CDCl3) δ 2.35 (s, 3H) and 2.90 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:60]=[CH:59][C:11]([C:12]([O:27][CH2:28][C@@:29]2([CH:51]=[CH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58])[O:33][C@@H:32]([N:34]3[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[CH2:31][C@@H:30]2[O:43][SiH2:44][C:45]([CH3:50])([CH3:49])[CH:46]([CH3:48])[CH3:47])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([O:27][CH2:28][C@@:29]2([CH:51]=[CH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][S:2]([CH3:1])(=[O:4])=[O:3])[O:33][C@@H:32]([N:34]3[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[CH2:31][C@@H:30]2[O:43][SiH2:44][C:45]([CH3:49])([CH3:50])[CH:46]([CH3:47])[CH3:48])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]2[CH:59]=[CH:60][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCOS(C)(=O)=O)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Methanesulfonyl chloride (96 μL, 1.22 mmole) was added dropwise to Compound (4) (250 mg, 0.32 mmole) in dry pyridine (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 hours and the reaction was quenched by the dropwise addition of methanol (1.5 mL). The yellow solution was poured into water (20 mL) and the layers were separated. The organic phase was washed with brine (20 mL), dried over magnesium sulfate and concentrated to a white solid (0.41 g) under reduced pressure. (Routinely, this crude material was used directly in the next step). The crude product (0.41 g) was purified by column chromatography on silica gel using ethyl acetate/hexane mixtures for elution. 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl) silyl]-4'-(7-methanesulfonyloxy-1-hepten-1-yl)-thymidine (241 mg, 87.5%) was obtained as a white solid. Recrystallization from hexane/dichloromethane gave a sample with m.p. 72°-75° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].O=[CH:24][C@@H:25]([C@@H:27]([C@@H:29]([CH2:31]O)O)O)O>>[CH:25]1[CH:27]=[C:29]2[C:31](=[N:9][C:7]([NH:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])=[N:8]2)[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]([NH2:13])[C:20]([OH:22])=[O:21])[CH:24]=1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: N[C@@H](CCCCn1cccc2nc(NCCC[C@H](N)C(=O)O)nc1-2)C(=O)O
Temperature: 80 °C

Procedure:
Three liters containing 100 mM each of L-arginine, L-lysine and D-ribose, at pH 7.3, Were heated for 1 hr at 80° C. The cooled mixture was poured onto a Buchner funnel filled with Dowex 50×4-400 ion-exchange resin (Aldrich Chem. Co., Inc., Milwaukee, Wisc.) equilibrated according to conditions of Boas (Boas, N. F., J. Biol. Chem., 204, pp. 553-563, 1953). The resin was washed with 2 liters each of water and 1 M pyridine, followed by elution of pentosidine-containing material with 1 liter of 2 N NaOH. The material was then adjusted to pH 7.4 with HCl, concentrated by rotary evaporation, passed through a Bio-Gel P-2 column and purified by HPLC as described above. The material was also chromatographed on Whatman 17 Chr paper (Whatman Inc., Clifton, N.J.) using 1:1 water/pyridine. Upon elution from the paper, the material was reinjected and collected by reversed-phase HPLC using TFA as the counterion.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([F:15])([F:14])[F:13].P(Cl)(Cl)([Cl:19])=O>[NH4+].[OH-]>[Cl:19][C:3]1[C:2]([CH3:1])=[N:11][C:10]2[C:5]([N:4]=1)=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][CH:9]=2
Reactant: Cc1nc2cccc(C(F)(F)F)c2nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2cccc(C(F)(F)F)c2nc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-methyl-8-(trifluoromethyl)quinoxalin-2-ol (0.8292 g, 3.634 mmol) and phosphorous oxychloride (6.653 mL, 72.68 mmol) was stirred at 100° C. After 1.5 h, the mixture was cooled to room temperature. The mixture was poured into ice (˜50 mL) with stirring and neutralized with NH4OH (30 mL) and ice with stirring. The resulting precipitate was collected by filtration, rinsed with water (100 mL), and dried to give 3-chloro-2-methyl-5-(trifluoromethyl)-quinoxaline as a pink solid: 1H NMR (400 MHz, DMF) δ ppm 8.35 (1H, d, J=8.4 Hz), 8.25 (1H, d, J=7.4 Hz), 7.94-8.02 (1H, m), 2.80 (3H, s); LC-MS (ESI) m/z 247.0 [M+H]+. The pink solid was carried on crude without purification for the next step.
Reaction SMILES: [CH3:1]/[C:2](=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])/[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(C1C2C(=CC=CC=2)NC=1)(=[O:29])CCCCCC.Br[CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)=[O:44]>>[CH3:1]/[C:2](=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])/[C:3]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[O:44])[CH:5]=1)=[O:29]
Reactant: CCCCCCC(=O)c1c[nH]c2ccccc12
Reactant: CCCCCCCC/C=C(\C)Cc1c[nH]c2ccccc12
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Product: CCCCCCCC/C=C(\C)C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12

Procedure:
The procedure of Ex. 1 was repeated except that (E)-3-(2-methyl-2-undecenyl)indole obtained in Pre. Ex. 25 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate was used in place of 4-bromobutyrate to give (E)-4-methoxybenzyl 4-[3-(2-methyl-2-undecenoyl)-1-indolyl]butyrate as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.[OH:23]O>C(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]([OH:23])=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(C=O)ccc21
Reactant: OO
Solvent: O=CO
Product: Cn1c(COc2ccc(C#N)cc2)nc2nc(C(=O)O)ccc21
Reaction time: 12 h

Procedure:
1.25 g (4.3 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]imidazo[4,5-b]pyridine-5-carbaldehyde were dissolved in 10 mL formic acid and mixed at 0° C. with 1.0 mL hydrogen peroxide (33% strength). After 12 hours at 4° C., the white precipitate formed was suction filtered, washed with water, and dried at 40° C. Yield: 0.81 g (61% of theory), C16H12N4O3 (308.7).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:22]1(=O)NC(=O)C2=CC=CC=C12>C(O)C.[Ni]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(N)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Ni]
Agent: C=O
Solvent: CCO
Product: CNc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 2 h

Procedure:
A mixture of α-t-butoxycarbonylamino-p-aminophenylacetic acid (26.6 g, 0.1 mol), formaldehyde (8.1 ml of a 37% aq. solution) and phthalimide (14.7 g, 0.1 mol) in 200 ml of absolute ethanol is heated at reflux for 1 hour. After cooling to room temperature Raney nickel catalyst is added and the mixture is hydrogenated under 60 psi of H2 100° for 2 hours. The catalyst is filtered off and the solvent is evaporated in vacuo. Following chromatography on silica gel the desired product is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cccc3c2[C@@]1(CCCCN1CCc2ccccc2C1)CCC3
Yield: 100 %

Procedure:
(S)-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (120 mg, 0.40 mmol), 1,2,3,4-tetrahydroisoquinoline (59 mg, 0.44 mmol), and potassium carbonate (83 mg, 0.60 mmol) in anhydrous N,N-dimethylformamide (1 ml) were stirred at room temperature for 2 days. To the reaction mixture obtained was added ethyl acetate (80 ml), which was then washed with water and saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain a product. The product obtained was separated and purified by means of silica gel column chromatography, whereby 150 mg (0.40 mmol, yield 100%) of the above-described object compound could be obtained.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=2.ClC1C=NC2C(=CC=C(C(Cl)=O)C=2)N=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([N:4]([O:3][CH3:2])[CH3:5])=[O:27])=[CH:21][CH:20]=2
Reactant: CNOC
Reactant: O=C(Cl)c1ccc2ncc(Cl)nc2c1
Agent: Cl
Agent: O=C(Cl)c1ccc2nc(Cl)cnc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of O,N-dimethyl-hydroxylamine hydrochloride salt (29 g, 0.30 mol, 1.1 eq) and DIEA (182 mL, 1.08 mol, 4.0 eq) in DCM (300 mL) was added the mixture of 3-chloro-quinoxaline-6-carbonyl chloride and 2-chloro-quinoxaline-6-carbonyl chloride (52 g, 0.27 mol, 1.0 eq) at 0° C. The mixture was stirred at rt overnight, then concentrated. The residue was washed with water (300 mL×2) and extracted with EA (300 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting solid was triturated with EA/PE=1/1 (300 mL) to afford 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (16.5 g, 24.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (69 mg, 0.2322 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (73 mg, 0.357 mmol), 4 N HCl in dioxane (70 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and a solid precipitated out, which was filtered off. Purified solid with normal phase chromatography to yield a white solid (33.6 mg, 31%), 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. mp 295° C.; LCMS: m/z=465.41 (M+H+), 1H NMR (400 MHz, MeOD) δ 8.76 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 7.48 (m, 1H), 7.15 (m, 1H), 6.97 (d, 1H, J=8.3 Hz), 2.95 (s, 3H), 2.34 (m, 2H), 2.12 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)(Cl)Cl>[C:40]([NH:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:10])([F:9])[F:11])=[O:5])(=[O:42])[CH3:41]
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F

Procedure:
In a solution of 0.05 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2,2-trifluoroethyl) benzoic acid amide (Compound of the present invention No. 5-329) synthesized in Synthetic Example 12 and 0.15 ml of triethylamine in 2 ml of chloroform, 0.10 ml of acetic anhydride was added under cooling with ice with stirring, and stirred at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:8 to 1:1 gradient), and 0.045 g of the aimed product was obtained as pale yellow resinous substance.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 0 °C

Procedure:
methanesulfonyl chloride (3.130 g, 2.115 mL, 27.32 mmol) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol) and Et3N (5.027 g, 6.924 mL, 49.68 mmol) in DCM (50 mL) cooled to 0° C. on an ice-bath. The reaction was allowed to warm to ambient temperature over 3 hours. The reaction mixture was washed with water and 1M HCl, dried (MgSO4), filtered and concentrated in vacuo to give tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate as a yellow oil (7.9 g, Quantitative yield—some residual solvent). 1H NMR (400.0 MHz, CDCL3) δ 1.49 (s, 9H), 1.60-1.57 (m, 1H), 2.04-1.79 (m, 3H), 3.08 (s, 3H), 3.38-3.32 (m, 1H), 3.50-3.43 (m, 1H), 3.70-3.60 (m, 2H) and 4.74 (br s, 1H) ppm;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].C1C(=O)N([Br:24])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][Br:24])[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21

Procedure:
The mixture of 6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20 g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g, 1.8 mmol) and CCl4 (120 mL) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure to about 50 mL. The reaction was then filtered, and the solid was washed with Et2O (20 mL). The combined organic solution was then concentrated under vacuum to generate crude product. Crude 62.2 was generated as a brown oil and used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14](C(OCC)=O)[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.Cl.[C:30](=O)([O-])O.[Na+].C([O:37][CH2:38][CH3:39])C>O1CCCC1.O>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:38]([OH:37])([CH3:39])[CH3:30])[CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Ethyl 1-cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-8-carboxylate as synthesized in Example 102, 503 mg was suspended in 9 mL of tetrahydrofuran, and into the suspension 1.7 mL of 3M methylmagnesium bromide solution in diethyl ether was dropped, followed by 23 hours' stirring at room temperature under nitrogen atmosphere. The reaction liquid was poured into water, and of which pH was adjusted to 9 with diluted hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution. The precipitated crystals were recovered by filtration and washed with water. The crude product was heat-suspended in acetone and purified. The crude product was alkali-treated and thereafter its pH was adjusted to 10 by addition of diluted hydrochoric acid (i.e. the carboxylic acid was dissolved in water). Thus precipitated crystals were recovered by filtration, washed with water, heat-suspended in 2-propanol and purified. Further recrystallizing the same from N,N-dimethylformamide-water mixed solvent, 133 mg of the title compound was obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.[CH3:29][O:30][C:31]1[CH:65]=[CH:64][C:34]([CH2:35][N:36]2[C:40]3=[N:41][CH:42]=[CH:43][C:44]([O:45][C:46]4[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=4[F:53])=[C:39]3[C:38]([N:54]3[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][O:62][CH3:63])[CH2:56][CH2:55]3)=[N:37]2)=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]2[C:40]3=[N:41][CH:42]=[CH:43][C:44]([O:45][C:46]4[CH:51]=[CH:50][C:49]([NH:52][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:48][C:47]=4[F:53])=[C:39]3[C:38]([N:54]3[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][O:62][CH3:63])[CH2:56][CH2:55]3)=[N:37]2)=[CH:64][CH:65]=1
Reactant: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
EDCI (27 mg, 0.14 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (11 mg, 0.047 mmol, prepared according to the procedure described for Example 19, Step C) and HOBt-hydrate (22 mg, 0.14 mmol) in DMF (0.3 mL) at ambient temperature, and the reaction mixture was stirred for 15 minutes at ambient temperature. 4-(1-(4-Methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (12 mg, 0.024 mmol) and triethylamine (0.020 ml, 0.14 mmol) were then added, and the resulting mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with EtOAc and washed with water. The aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative TLC (0.5 mm) and eluted with 15% MeOH/DCM (Rf=0.74). The product was obtained as a waxy solid (2 mg, 10%).