Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(C)C=CC(S(O[CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.Cl>O.C(OCC)C>[CH3:28][O:27][CH2:26][CH2:25][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COCCc1ccc(-c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
Metallic magnesium (14.6 g, 0.6 mol) was placed in a completely dried 2 l three-neck flask and dry nitrogen gas was passed through the inside of the vessel to completely dry it, followed by adding anhydrous ethyl ether (45 ml) and a trace of iodine. A dry ethyl ether solution (500 ml) of p-bromobiphenyl (140 g, 0.6 mol) was gradually added with stirring while maintaining the reaction temperature at 30° to 35° C., and after the addition, the reaction was further carried out at the same temperature for 3 hours. At an inner temperature of 35° C., an anhydrous ethyl ether solution (300 ml) of β-methyloxyethyl p-toluenesulfonate (276 g, 1.2 mol) obtained in step A was gradually added. During the addition, reflux began to occur due to the reaction heat. After the addition, the mixture was placed under reflux for 2 hours while maintaining it on a water bath at an inner temperature of 35° C. After completion of the reaction, the reaction liquid was cooled and 500 ml of water was added and then 6 N--HCl (1.5 l) was added. The reaction liquid was transferred into a separating funnel and subjected to extraction with toluene (500 ml). The resulting toluene layer was separated from the resulting aqueous layer, and this aqueous layer was further subjected to extraction with toluene (100 ml). The toluene layers were combined together, and insoluble matters therein were removed by suction filtration. The resulting toluene layer was washed once with 2 N--NaOH aqueous solution (200 ml) and filtered through a pleated filter paper, followed by distilling off toluene under reduced pressure. To the residue were added NaOH (10 g), water (20 ml) and ethanol (500 ml), and the mixture was placed under reflux on a water bath for 30 minutes. The mixture liquid was cooled and poured in 1 l of water, and toluene (300 ml) was added, followed by transferring the mixture into a separating funnel, washing the upper toluene layer 3 times with 300 ml of water and distilling off toluene under reduced pressure. The residue was then distilled under reduced pressure and fractions of b.p. 137°~140° C./1.5 mmHg were collected to obtain 4-(β-methyloxyethyl)-biphenyl (IV) (34 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][C:20]([CH3:31])([CH2:25][C:26](=O)[CH2:27][S:28][CH3:29])[C:21]([O:23]C)=[O:22]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:27]([S:28][CH3:29])=[C:26]2[CH2:25][C:20]([CH3:31])([CH3:19])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)CC(=O)CSC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Product: CSc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-5-methylthio -4-oxopentanoate as starting materials and hydrolysis at reflux, the title compound was prepared, mp 161°-163°.
Reaction SMILES: [CH:1]1([Ti:6]([Cl:9])(Cl)Cl)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:10]1([N:16]=[CH:17][C:18]([CH3:26])=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Mg]>C1COCC1>[Cl:9][Ti:6]1([CH:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]([CH3:26])=[CH:17][N:16]1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cl[Ti](Cl)(Cl)C1C=CC=C1
Reactant: CC(C=NC1CCCCC1)=Cc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=CN(C2CCCCC2)[Ti](Cl)(C2C=CC=C2)C1c1ccccc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a solution of 5 g (22.79 mmol) cyclopentadienyltitanium(IV) chloride in 100 ml THF were added 5.18 g (22.79 mmol) 1-cyclohexyl-3-methyl-4-phenyl-1-aza-buta-1,3-diene and 0.55 g magnesium and the mixture was stirred at room temperature until the metal was fully reacted. The solvent was then removed to dryness in vacuo and the residue was extracted with 50 ml diethyl ether. 4.36 g 2-chloro-2-cyclopentadienyl-1-cyclohexyl-4-methyl-3-phenyl-1-aza-2-titana-cyclopent-4-ene were isolated from the diethyl ether extract as dark brown crystals. (51% yield, characterised by 1H-NMR, 13C-NMR and elemental analysis).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[SH:17])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[SH:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCn2ccnc2S)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(CCCn2ccnc2S)cc1

Procedure:
A solution of 1.75 g (0.007 mole) of 1-[3-(4methoxyphenyl)propyl]-2-mercaptoimidazole in 60 ml of CH2Cl2 was deprotected by treatment with a solution of 7.0 g (0.028 mole) of BBr3 in 10 ml of CH2Cl2. After 1 5 hr, the reaction mixture was cooled to 0° , and methanol was cautiously added. After a vigorous reaction subsided, the solvents were evaporated. The residue was recrystallized from ethanol to give 1-[3-(4-hydroxyphenyl)-propyl]-2-mercaptoimidazole, 1.02 g (67%), mp 185° .
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[O-:36][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: CCCCCCC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCCCC(=O)CCCn1c(CCC)nc2c[n+]([O-])c3ccccc3c21

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one (6.10 g, 17.2 mmol) by reaction with m-CPBA (8.50 g) to provide 1-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one followed by reaction with p-toluenesulfonyl chloride (4.90 g, 25.8 mmol) and ammonium hydroxide solution (100 mL) to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one) as a white solid after recrystallization from aqueous methanol, mp 111-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H][H]>N.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(Cl)cc1
Agent: N
Solvent: CO
Product: NCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Sponge nickel from Comparative Example 1 (12 mg, 20 mol % Ni on substrate) was washed with MeOH three times to remove water and added to 4-chlorobenzonitrile (0.137 g, 1 mmol) dissolved in 7 N ammonia in MeOH (4 ml) in a pressure vessel. The vessel was sealed and purged twice with hydrogen then pressurised to 5-6 bar with hydrogen and the contents magnetically stirred at room temperature. Progress of reaction was carried out by GCMS analysis. After 24 h the hydrogen was vented and the Ni catalyst removed by filtration. The filtrate was concentrated on a rotary evaporator to give 4-chlorobenzylamine (0.14 g, 99%). GCMS purity 78%.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:12]>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([Br:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(O)CC1
Reactant: BrP(Br)Br
Product: CCCC1CCC(Br)CC1
Temperature: 25 °C
Yield: 176 %

Procedure:
142 g (1.0 mol) of 4-propylcyclohexanol (trans-cis form mixture) was given drop addition of 136 g (0.5 mol) of PBr3 while stirring at room temperature, and heated to about 80° C. The reactant was stirred for 1 hour on a 70° C. hot water bath, then cooled to room temperature and poured into ice water to decompose the excess PBr3. The oily layer was taken off, and the water layer was extracted with chloroform, combined with the oily layer and washed with water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 97° C./14 mmHg) to obtain 180 g (0.88 mol) of 4-propylbromocyclohexane (trans-cis form mixture).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7]/[C:6]/2=[CH:16]\[C:17]([NH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24]C)=[O:23])=[O:18].[Li+].[OH-]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7]/[C:6]/2=[CH:16]\[C:17]([NH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23])=[O:18]
Reactant: COC(=O)c1ccccc1NC(=O)/C=C1\CNC(=O)c2cc(OC)c(OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)/C(=C/C(=O)Nc1ccccc1C(=O)O)CNC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirred solution of (Z)-methyl 2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoate (140 mg, 0.35 mmol) in MeOH (4 mL) and THF (8 mL) was added 2N LiOH (0.7 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight then the reaction was quenched by addition of 1N HCl and the solvent was removed under reduced pressure. The mixture was diluted with water, cooled and the precipitate collected by filtration to afford (Z)-2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoic acid (125 mg, 93%). 1H-NMR (400 MHz, DMSO-d6) δ 3.80, (s, 3H), 3.84 (s, 2H), 3.85 (s, 3H), 7.00 (s, 1H), 7.10 (m, 1H), 7.22 (d, J=6.0 Hz, 1H), 7.56 (m, 1H), 7.61 (s, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H), 8.57 (dd, J=8.4, 0.8 Hz, 1H), 11.38 (d, J=5.6 Hz, 1H), 13.54 (br s, 1H); LC-MS (ES-API); rt 8.27 min; m/z calculated for C20H18N2O6[M+H]+ 383.1, found 383.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[C:28]([CH3:30])[N:29]=[C:2]([N:34]4[CH2:35][CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(Cl)n1
Reactant: CC1CCCNC1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(N2CCCC(C)C2)n1

Procedure:
Compound is formed by reacting 2-chloro-6-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide with 3-methylpiperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.22 (d, 1H), 7.85 (m, 1H), 7.57 (m, 2H), 7.43 (d, 1H), 7.17 (s, 1H), 7.04 (d, 1H), 6.99 (s, 1H), 4.31 (m, 2H), 3.60 (t, 4H), 2.88 (t, 2H), 2.79 (t, 2H), 2.56 (t, 4H), 2.39 (s, 3H), 1.85-1.20 (m, 6H), 1.15 (m, 1H), 0.94 (d, 3H). MS: 489.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:13])[C:11]=1[OH:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:13])[C:11]=1[O:12][CH2:18][CH2:19][CH2:20][Cl:21])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(O)c(Br)c2N1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCc2cc(Cl)c(OCCCCl)c(Br)c2N1
Reaction time: 1 h

Procedure:
5 Grams of 6-chloro-8-bromo-7-hydroxy-3,4-dihydrocarbostyril and 3 g of sodium hydroxide are mixed with 120 ml of isopropanol and stirred at 50°-60° C. for 1 hour. Then 10 ml of 3-bromo-1-chloropropane are added thereto and stirred at 70°-80° C. for 6 hours. The reaction mixture is concentrated under reduced pressure to dryness and the residue thus obtained is extracted with chloroform. The chloroform layer is washed with water and dried. Then chloroform is removed by distillation and the residue thus formed is recrystallized from ethanol to obtain 6.2 g of 6-chloro-8-bromo-7-(3-chloropropoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8][C:9]([NH:11][C:12]2[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=2[CH3:17])=[S:10])[CH:7]=1.[CH3:21]I>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8]/[C:9](=[N:11]\[C:12]2[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=2[CH3:17])/[S:10][CH3:21])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1NC(=S)Nc1c(C)nn(C)c1C
Reactant: CI
Solvent: CC(C)=O
Product: CS/C(=N/c1c(C)nn(C)c1C)Nc1cc(Cl)ccc1C
Yield: 73.5 %

Procedure:
Under anhydrous conditions, a solution of 1-(5-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea (2.3 g, 7.5 mmol) produced in example 8 and methyl iodide (0.94 mL, 15 mmol) in 70 mL of acetone was stirred at ambient temperature for 64 hours. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The organic phase was washed with dilute Na2S2O3 and dried (Na2SO4). Removal of solvent and crystallization of the residue from Et2O provided 1.78 g of title compound as a white solid (74% of theory, m.p. 134-135° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-fluorobenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C)nc1OS(=O)(=O)c1ccc(C)cc1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(C)nc1NCc1ccccc1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
To a solution of 2-methyl-4-(toluene-4-sulfonyloxy)-thiazole-5-carboxylic acid ethyl ester (2.0 g, 5.865 mmol) in 1,4-dioxane (50 mL) was added benzylamine (1.92 mL, 17.6 mmol) and the mixture was heated at 120° C. for 6 h. The reaction mixture was cooled to RT and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (0.80 g, 49%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:10])[NH2:9])[CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: N=C(N)c1cccnc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2cccnc2)ns1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
To a solution of pyridine-3-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 110 mg (4.38%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>CC(O)C>[C:14]([NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (30 g, 97 mmol) in IPA (400 ml) was added TEA (27 ml, 195 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (25 g, 107 mmol; see P. H. Carter, et al. PCT application WO 2005/021500). The mixture was stirred at room temperature overnight and then stirred at 70° C. for 1 h. The resulted solution was concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (1 L) and extracted with acetic acid solution I (prepared by combining 700 mL of water and 22.6 mL of glacial acetic acid) twice (500 ml, 200 ml). The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 ml). The dichloromethane layer was extracted with acetic acid solution II (300 ml; prepared by combining 300 mL water with 4 mL of glacial acetic acid). The combined acetic acid layers were basified with 1 M NaOH to pH>12 and extracted with dichloromethane (3×700 ml). The combined organic layers were dried and concentrated to give the crude product as a solid (45.6 g, 93% yield). The crude product was purified by recrystallization from EtOAc (400 ml)/Hexane (900 ml) to give 42.86 g (88%) N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide with 99.7% purity. 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.71 (1H, br. s.), 9.02 (1H, s), 8.71 (1H, d, J=7.97 Hz), 8.59 (1H, s), 8.04 (1H, dd, J=8.66, 1.79 Hz), 7.88 (1H, d, J=8.52 Hz), 4.91-5.13 (1H, m), 4.30-4.57 (1H, m), 3.86 (1H, dt, J=11.89, 3.71, 3.64 Hz), 3.43-3.57 (1H, m), 3.35-3.45 (1H, m), 3.04 (1H, t, J=3.85 Hz), 2.23-2.40 (1H, m), 2.05-2.22 (1H, m), 1.90-1.98 (1H, m), 1.86-1.93 (3H, m), 1.50-1.78 (5H, m), 0.98-1.15 (9H, m). 13C-NMR (126 MHz, DMSO-d6) δ ppm 171.23, 169.35, 159.54, 156.87, 151.17, 128.97, 128.20, 125.76 (1 C, q, J=30.52 Hz), 121.55 (1 C, br. s.), 124.04 (1 C, q, J=272.11 Hz), 114.31, 53.26, 52.39, 50.81, 47.56, 45.70, 42.77, 34.52, 32.17, 29.14 (3 C, s), 26.49, 23.29, 20.30. 19F-NMR (471 MHz, DMSO-d6) δ ppm −60.34 (s). m/z: 507.0 [M+H]. Anal. Calcd for C25H33N6O2F3: C, 59.27;H, 6.56; N, 16.59; F, 11.25 Found: C, 59.44;H, 6.64; N, 16.74; F, 10.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]
Reactant: Nc1cnccn1
Reactant: COc1ccc([N+](=O)[O-])cc1N=C=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)Nc1cnccn1

Procedure:
A mixture of 2-methoxy-5-nitrophenyl isocyanate (5.0 g, 25 mmol) and aminopyrazine (2.5 g, 26 mmol) in tetrahydrofuran (THF, 250 mL) was stirred at reflux for 24 hours. The product was precipitated from the cooled reaction mixture and was collected by filtration, washed with ethyl acetate, and dried in vacuo (4.3 g, 57%). 1H NMR (300 MHz, d6-DMSO) (mixture of rotamers) δ: 10.38 (br, s, 1H), 10.27 (s, 1H), 9.39, 8.88 (2 singlets, 1H), 9.10 (d, 1H), 8.33 (s, 1H), 8.26 (d, 1H), 7.98-8.25 (m, 1H), 7.97-7.84 (m, 1H), 4.05, 4.03 (2 singlets, 77:28 ratio, 3H).
Reaction SMILES: B(Br)(Br)Br.ClCCl.C[O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18](=[O:27])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1>CO>[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18](=[O:27])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2cc(=O)n(C)c3ncccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)cc(-c2cccc(O)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A 1 M-dichloromethane solution of boron tribromide (25 ml, 25 mmol) was added to a dichloromethane solution (30 ml) of 4-(3-methoxyphenyl)-1-methyl-1,8-naphthyridin-2(1H)-one (1.3 g, 4.9 mmol) at -35° C., and the mixture was gradually warmed up to room temperature and then stirred at room temperature for 2 hours. Methanol (10 ml) was added to the reaction solution at -60° C., and the mixture was warmed up to room temperature and then stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, methanol (30 ml) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (benzene-ethyl acetate) to give 4-(3-hydroxyphenyl)-1-methyl-1,8-naphthyridin-2(1H)-one (0.29 g, 23%).