Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[F-].[K+].CN1CCN(C)C1=O.[F:22][C:23]1[CH:24]=[C:25]([Br:30])[CH:26]=[CH:27][C:28]=1I>CN(C)C=O.[Cu]Br>[F:22][C:23]1[CH:24]=[C:25]([Br:30])[CH:26]=[CH:27][C:28]=1[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: Fc1cc(Br)ccc1I
Agent: [Cu]Br
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCN(C)C1=O
Product: Fc1cc(Br)ccc1C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
13.2 g (91.9 mmol) of copper(I) bromide were cooled to −5° C. in 80 ml of dry N,N-dimethylformamide. Under nitrogen, 14.7 g (76.7 mmol) of trimethyl-(pentafluoroethyl)silane were added. 4.45 g (76.7 mmol) of potassium fluoride (spray-dried) were added in portions over the course of 30 minutes at a rate such that the internal temperature remained below 0° C. The mixture was stirred at 0° C. for 1 hour and was then warmed to 20° C. over the course of 12 hours. Thereafter 10 ml of dry 1,3-dimethyl-2-imidazolidinone and 22 g (73.1 mmol) of 3-fluoro-4-iodo-bromobenzene were added. The contents were stirred at 75° C. for 14 hours. Then all of the volatile constituents were distilled off to dryness, the distillate being collected in a cold trap cooled with liquid nitrogen. The distillate was subsequently warmed to 20° C. and dissolved in 500 ml of diethyl ether. This solution was washed with four times 100 ml of water and then with two times 100 ml of saturated aqueous NaCl solution. The organic phase was then dried, and the solvent was removed on a Vigreux column. Subsequent distillation of the residue on a Vigreux column gave 16.1 g of product (boiling point: 86-87° C. (75 mmHg)) with a purity of 99% by weight.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([NH2:11])[CH2:9][NH2:10]>CCOCC.C(O)(C)C>[CH2:1]([NH:5][C:6]([NH:10][CH2:9][CH2:8][NH2:11])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NCCN
Reactant: CCCCN=C=O
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCNC(=O)NCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
A solution of n-butylisocyanate (19.83 g, 0.2 m) in Et2O (50 ml) was added over 40 minutes to a vigorously stirred solution of ethylenediamine (48.08 g, 0.8 m) in isopropanol (1000 ml). After stirring at 25° C. for 3 hours, and standing for about 16 hours, the mixture was filtered and the filtrate evaporated to dryness under reduced pressure initially using water aspiration and finally high vacuum at 70° C. The residue was stirred for 1 hour in 12N HCl (20 ml) and H2O (200 ml), filtered and the filtrate rendered alkaline with 40% NaOH and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel and eluted with 20% MeOH-CHCl3 saturated with NH3 to give 83 (19.7 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:8].[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C:30]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:31])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(C(F)(F)F)c1
Product: COc1cc(NC(=O)c2cc(Br)ccc2OC(=O)N2CCOCC2)cc(C(F)(F)F)c1
Yield: 85.8 %

Procedure:
Using 5-bromo-2-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [C:1]([C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>[OH-].[NH4+].C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of tert-butyl 4-cyano-4-isopropylpiperidine-1-carboxylate (90 mg, 0.357 mmol) in ammonium hydroxide (2 ml) and ethanol (4 ml) was added Raney nickel (100 mg, 1.167 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen and stirred overnight under a hydrogen balloon, at which point LC/MS analysis showed the desired product. The mixture was filtered through a plug of Celite, washing liberally with methanol, and then concentrated to a small volume and partitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate. The aqueous phase was extracted with 2×20 ml of ethyl acetate, and then the combined organics were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 50% methanol in dichloromethane over 10 column volumes to provide tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg). The title compound was then prepared from tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (57 mg, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 545.3 (M+1). 1H NMR (500 MHz, CDCl3): 8.33 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.14 (br t, J=6.0 Hz, 1H), 3.63 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 3.33 (br t, J=10.5 Hz, 2H), 1.83 (septet, J=7.0 Hz, 1H), 1.54-1.66 (m, 4H), 1.46 (d, J=7.0 Hz, 6H), 1.45 (s, 9H), 0.99 (d, J=7.0 Hz, 6H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.Cl[CH2:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:27][N:26]1[C:22]([CH2:21][N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:5][C:4]2=[O:3])=[N:23][CH:24]=[N:25]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: Cn1ncnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 281 mg, 7.0 mmol) was added to a solution of phenylmethyl 3-oxo-1-piperazinecarboxylate (1.5 g, 6.4 mmol) in dry dimethyl formamide (5 mL) and the mixture was stirred at room temperature for 30 minutes. 5-(Chloromethyl)-1-methyl-1H-1,2,4-triazole (WO0023449, 920 mg, 7.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (150 mL) and extracted with diethyl ether (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale oil (2 g, 94%). m/z (ES+) 330 (M+1).
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14]CC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53](C(O)=O)[CH2:54][CH2:55][CH2:56][CH2:57][NH:58]C(OC(C)(C)C)=O)(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:29]([OH:31])=[O:30])=[O:14])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CCCCN)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-Nε-tert-butoxycarbonyl-L-lysine (360 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 10 mg (12%) of the desired material.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:11][C:12]1[N:17]=[C:16]([NH:18][CH:1]=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: Cc1cccc(N)n1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(NC=O)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To stirred neat formic acid (3.83 mL, 101.7 mmol) was added acetic anhydride (6.98 mL, 74.0 mmol). The reaction mixture was heated under stirring at 70° C. for 2 hrs and allowed to room temperature. A solution of 6-methylpyridin-2-amine (5.00 g, 46.23 mmol) in tetrahydrofurane (30 mL), was added dropwise in order to prevent temperature from rising above 45° C. The reaction mixture was allowed to room temperature and stirred for further 1 hr. The reaction mixture was concentrated in vacuo and the residue was diluted in 100 mL of ethanol. The reaction mixture was stirred for 2 hrs at room temperature concentrated in vacuo, yielding to N-(6-methylpyridin-2-yl)formamide as a yellow solid [2.00 g, yield 32%; HPLC/MS: m/z=137 (M+H); logP(HCOOH)=0.45].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([C:12]#[C:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2].[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cncnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.2 %

Procedure:
tert-Butyl 4-(4-((4-((5-(2-ethoxy-2-oxoethyl)pyrimidin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I111) (0.108 g, 0.177 mmol) was dissolved in dry DMF (10 mL) under an atmosphere of nitrogen. Pd/C (10 wt. %; 0.040 g) in EtOAc (2 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with balloon and stirred at room temperature for 22 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×20 mL). The solvent was removed in vacuo to give a greyish semi-solid which was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I112) (0.096 g, 88% yield) as a pale yellow foam; 1H NMR (400 MHz, de-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 4.11-4.04 (m, 4H), 3.83 (s, 2H), 3.28-3.21 (m, 4H), 2.79 (brs, 2H), 2.68-2.58 (m, 1H), 1.74 (d, J=13.1 Hz, 2H), 1.52-1.38 (m, 11H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.65 min; m/z 615.1 [M+H]+.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[OH2:9].CC[O:12]CC>>[C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[CH3:1][C@@H:2]([OH:12])[C@H:3]([OH:9])[CH3:4]
Reactant: CCOCC
Reactant: O
Agent: N[C@@H]1CCCC[C@H]1N
Product: C[C@@H](O)[C@@H](C)O
Temperature: 25 °C

Procedure:
1.28 g (11.2 mmol) of (1R,2R)-(-)-1,2-cyclohexanediamine of α!D20 =-36.7° (c 4.1, H2O) and 1.00 g (11.1 mmol) of dl-threo-2,3-butanediol were added to 2 ml of ether and then heated/dissolved therein, and the solution was cooled to room temperature. Afterward, the precipitated crystals were collected by filtration and then recrystallized from 2 ml of ether twice to obtain 1.00 g of (1R,2R)-(-)-1,2-cyclohexanediamine·(2R,3R)-(-)-2,3-butanediol. Physical properties of the product are as follows.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[N:5]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:6]=1[C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)([CH3:9])[CH3:8].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.COC1C=CC=CC=1P(C1C=CC=CC=1OC)C1C=CC=CC=1OC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[CH2:26][S:25][C:4]1[N:5]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:6]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)([CH3:9])[CH3:8])=[C:2]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c(Br)nc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccccc1P(c1ccccc1OC)c1ccccc1OC
Solvent: O
Solvent: CCO
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1c(-c2ccccc2)nc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Yield: 17.1 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-6-fluorobenzylthio)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (100 mg, 0.166 mmol), phenylboronic acid (40.5 mg, 0.332 mmol), Pd(OAc)2 (2 mg, 0.008 mmol), tris(2-methoxyphenyl)phosphine (6 mg, 0.017 mmol), and K3PO4 (106 mg, 0.498 mmol) in EtOH—H2O (3 mL, 10:1 v/v) was refluxed overnight. The reaction mixture was filtered through Celite™. The filtrate was concentrated in vacuo, dissolved in DCM (5 mL) and washed with H2O (5 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (Hex/EtOAc=9:1) to give the title product (17 mg, 17%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.23 (s, 6H), 4.57 (s, 2H), 6.10 (m, 2H), 6.30 (t, 2H), 6.50 (dd, 1H), 6.75 (m, 1H), 6.80 (d, 1H), 6.85 (dd, 1H), 7.19 (m, 1H), 7.25 (t, 2H), 7.70 (s, 1H), 7.71 (s, 1H); MS (EI) m/z 601 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1([CH3:24])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:21](=[O:23])[CH3:22])[C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35]Br.CC(C)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1([CH3:24])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:21](=[O:23])[CH3:22])[C:15]([O:20][CH2:35][CH2:34][CH2:33][Br:32])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)OCC)CC2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c2c(cc(C(C)=O)c1OCCCBr)CCC(C)(CCC(=O)OCC)O2
Reaction time: 25 h

Procedure:
A mixture of 263 mg of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester, 222 mg of anhydrous potassium carbonate, 0.39 ml of 1,3-dibromopropane, 6 ml of anhydrous acetone, and 3 ml of anhydrous N,N-dimethylformamide was stirred and refluxed for 16 hours. An additional 0.25 g of anhydrous potassium carbonate was added and stirring, and refluxing were continued for 25 hours. The mixture was cooled and volatile materials were removed first under water aspirator pressure and then high vacuum. The residue was treated with ether and acetone and the solids were removed by filtration. Concentration of the filtrate in vacuo afforded 359 mg of racemic-6-acetyl-7-(3-bromopropoxy)-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as an orange oil.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][CH:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][CH:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49].Br[CH2:64][CH2:65][F:66]>>[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:64][CH2:65][F:66])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1NC1c2ccccc2CC1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino 2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 2969, 2932, 2907, 2877, 1608, 1563, 1545, 1483, 1447, 1392, 1353, 1207, 1177, 1123, 1042 cm−1; OAMS supporting ions at: ESI+ 483.2; MS (EI) m/z 482 (M+); HRMS (FAB) calcd for C27H32CLFN4O+H1 483.2327, found 483.2324. [α]25D=−79 (c 0.52, methylene chloride); Anal. Calcd for C27H32ClFN4O: C, 67.14; H, 6.68; N, 11.60. Found: C, 67.19; H, 6.90; N, 11.63.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([O-])=[O:13])[N:4]=1.[OH-].[NH4+:18]>>[F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:18])=[O:13])[N:4]=1
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Temperature: 100 °C

Procedure:
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (250 mg, 1 mmol) and 10 mL of ammonium hydroxide were added in a 20 mL sealed tube. The reaction mixture was heated to 100° C. and reacted for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (240 mg) as a white solid. The product was used directly in the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:16][S:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH3:15][O:14][N:12]([CH3:13])[C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:17][CH3:16])[CH:23]=2)=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)C=Cc1ccc(Br)cc1
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C=Cc1ccc(-c2cccc(SC)c2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 125.6 %

Procedure:
3-(4-Bromo-phenyl)-N-methoxy-N-methyl-acrylamide (11.7 g, 43.2 mmol) prepared in Step 1 of Preparation 1, 3-(methylthio)phenylboronic acid (14.5 g, 86.4 mmol), Pd(PPh3)4 (2.5 g, 2.2 mmol) and sodium carbonate (13.7 g, 129.6 mmol) were added to a mixed solvent of N,N-dimethylformamide (200.0 mL) and distilled water (50.0 mL). The reaction mixture was stirred at 80° C. for 7 hours and then extracted with ethyl acetate. The extract was washed with a saturated solution of ammonium chloride, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 17.0 g of the titled compound as a yellow solid.
Reaction SMILES: C(O)=[O:2].OO.[C:6]12(C)[C:12](C)(C)[CH:9]([CH:10]=[CH:11]1)[CH2:8][CH:7]2[S:15]([O-:18])(=[O:17])=[O:16].[NH+]1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>>[OH:2][CH:10]1[CH:11]2[CH:6]3[CH:7]([CH2:8][CH:9]1[CH2:12]3)[S:15](=[O:18])(=[O:17])[O:16]2
Reactant: O=CO
Reactant: CC1(C)C2C=CC1(C)C(S(=O)(=O)[O-])C2
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: OO
Product: O=S1(=O)OC2C(O)C3CC2C1C3
Temperature: 10 °C
Reaction time: 17 h

Procedure:
Into a three-necked flask having an inner volume of 2 L equipped with a stirrer, a thermometer and a dropping funnel, the whole amount of “Aqueous Solution B” obtained above was charged, and cooled down to 10° C. 99% Formic acid (93.27 g, 2.01 mol) was weighed and added dropwise to the reaction system so that the inner temperature of the reaction system was maintained in a range of 11 to 15° C. After that, the inner temperature was raised up to 50 to 53° C. by heating, and then 30% hydrogen peroxide aqueous solution (162.5 g, 1.43 mol) weighed and contained in another dropping funnel was added dropwise to the reaction system over 3 hours. After completion of the dropping, the inner temperature of the reaction system was also maintained at around 50° C. After 17 hours from completion of the dropping, the reaction liquid was analyzed by HPLC to confirm that conversion ratio of pyridinium 5-bornene-2-sulfonate was 99.0%. After cooling down the reaction liquid to 15° C., sodium sulfite was added slowly to the reaction system so that the inner temperature of the reaction system was maintained in a range of 15 to 18° C. until a starch paper did not detect hydrogen peroxide. Subsequently, sodium hydrogen carbonate was added slowly to adjust pH of the reaction liquid at 7.5 so that the inner temperature of the reaction system was maintained in a range of 17 to 20° C. The reaction liquid was extracted with ethyl acetate (900 g) twice, and the resultant organic layers were combined, washed with water (200 g), and then concentrated under the reduced pressure until the amount of the liquid became 226.9 g. Isopropyl ether (169.5 g) was added to the resultant concentrated liquid in a heated state at 50° C., then the mixture was cooled down to 5° C. at a rate of about 10° C./hour, to precipitate crystal of the product. After filtering the precipitated crystal, the filtered out crystal was washed with isopropyl ether (50 g) at 5° C., and dried at 40° C. for 2 hours under the reduced pressure, to obtain 2-hydroxy-4-oxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide (88.8 g, purity: 99.0%, 0.462 mol). It should be noted that, yield of the product from 5-norbornene-2-sulfonyl chloride was 61.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23]S[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:39][S:40]([O-:42])=O.[K+]>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:40](=[O:42])(=[O:39])[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Yield: 77.7 %

Procedure:
0.55 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-yl)-quinazoline-2,4(1H,3H)-dione and 0.196 g of Oxone® in 100 ml of an MeOH/water mixture (10/1) (v/v) is stirred at room temperature overnight. The resulting mixture is evaporated under reduced pressure. Water is added and the resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4. The resulting solution is filtered and the filtrate is then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture from (50/50, v/v) to (0/100, v/v) to give 0.454 g of the expected product.