Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN[C@@H:3]([C:11]1C=CC=C[CH:12]=1)[CH2:4]N1CCCCC1.C([Li])CCC.[C:22]1([CH:28]=[CH:29][C:30](=[O:32])[CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.[Cu]I>[C:22]1([CH:28]([CH2:4][CH2:3][CH2:11][CH3:12])[CH2:29][C:30](=[O:32])[CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: CN[C@H](CN1CCCCC1)c1ccccc1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(CC(C)=O)c1ccccc1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (361.1 mg, 1.66 mmol) was dissolved in ether (12 mL) and n-butyllithium (2.5M in hexanes, 0.66 mL, 1.65 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (263 mg, 1.38 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.55 mL, 1.38 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 30 min, the ether (1 mL) solution of 4-phenyl-3-buten-2-one (201.5 mg, 1.38 mmol) was added slowly at -78° C. The reaction mixture was stirred for 1 hr at -78° C. and warmed to -20° C. The reaction was quenched by adding 4N NH4Cl (15 mL) at -20° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (8:1=hexanes/ethyl acetate) to afford (+)-4-phenyl-2-octanone (95.6 mg, 34% chemical yield, 2% ee, [α]D =0.06 (c=5.00, chloroform)).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH:15]3[CH:10]([CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14]3)[CH2:9]2)=[O:7])=[C:4]([N:25]2[CH:29]=[CH:28][N:27]=[N:26]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:15]12[N:8]([C:6]([C:5]3[C:4]([N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[N:3][C:2]([CH3:1])=[CH:24][CH:23]=3)=[O:7])[CH2:9][C@H:10]1[CH2:11][CH2:12][NH:13][CH2:14]2
Reactant: Cc1ccc(C(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(-n2ccnn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2C[C@H]3CCNC[C@H]32)c(-n2ccnn2)n1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To 1S,6R)-tert-butyl 8-(6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.05 g, 2.64 mmol) in DCM (15 mL) was added TFA (3 mL). The resulting mixture was allowed to stir at ambient temperature. After 16 h the mixture was concentrated under reduced pressure and the crude residue was purified by FCC (SiO2, gradient DCM to 15% MeOH/10% NH3/DCM) to yield the title compound (790 mg, 71%). MS (ESI) mass calcd. for C15H18N6O, 298.2; m/z found, 299.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[S:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:15]=[C:16]=[O:17]>CN(C)C(=O)C>[S:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[NH:15][C:16]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:17]
Reactant: O=C=NC1CCCS1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Product: O=C(NC1CCCS1)n1cc(F)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of 5-fluorouracil (2.6 g.) in N,N-dimethylacetoamide (10 ml.) was added to oily 2-tetrahydrothiophenyl isocyanate (3.1 g.). The mixture was stirred at 50° C. for 8 hours and concentrated in vacuo. The residue was treated with water (80 ml.) to give crystalline precipitates, which were collected by filtration and dried over phosphoric anhydride to give 1-[N-(2-tetrahydrothienyl)carbamoyl]-5-fluorouracil (3.68 g.); pale yellow crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.I[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: ICC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2=C(N(CC3CCOCC3)NC2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 140 °C

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.155 mmol), 4-(iodomethyl)-tetrahydro-2H-pyran (70 mg, 0.310 mmol), and Cs2CO3 (101 mg, 0.310 mmol) in DMF (1 mL) is heated in microwave at 140° C. for 30 min. After cooling, the mixture is filtered through a 0.45 μm microfilter, and the filtrate is purified by a semi-preparative HPLC to give pure product as white powder. MS (ESI) m/z 421.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCNCc1ccccc1F
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and ethyl-(2-fluoro-benzyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H24FNO5 [M+H]+:390.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.CCN(CC)CC>C(Cl)Cl>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([C:23]2[C:18]3[N:17]=[N:16][NH:15][C:19]=3[CH:20]=[CH:21][CH:22]=2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1cccc2[nH]nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
p-Nitrobenzyl chloroformate (0.5 mmol) was dissolved in 5 mL of CH2Cl2 and treated with benzotriazole (0.5 mmol) using Et3N (2 mmol) as base. The mixture was stirred overnight at room temperature, diluted with CH2Cl2 (20 mL) and washed with 3×5 mL of 1N HCl, 2×5 mL of 1N NaOH and 1×5 mL of brine. The organic phase was dried and filtered. The volatiles were removed and the product was triturated with diethyl ether to provide a pale yellow solid (59% yield). mp 160-162° C. 1H NMR (CDCl3) δ 8.27 (d, 1H, J=8.9 Hz), 8.17 (m, 3H), 7.72 (d, 1H, J=8.9 Hz), 7.65 (td, 1H, J=8.3 Hz, 1.1 Hz), 7.53 (m, 2H), 5.26 (s, 2H). 13C NMR (CDCl3) δ 154.84, 146.17, 142.27, 141.30, 132.01, 130.82, 128.78, 126.37, 124.16, 120.86, 113.58, 68.66. HRMS (FAB) calcd for C14H11N4O4 ([M+H]+): 299.0775. found 297.0775.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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.C(OCC)(=O)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc(F)c2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 17 h
Yield: 71.6 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol), 3-fluorophenylboronic acid (380 mg, 2.71 mmol) and tripotassium phosphate (288 mg, 1.36 mmol) were dissolved in 1,4-dioxane (8 ml), then at room temperature, tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) was added. The solution was stirred under nitrogen atmosphere at 95° C. for 17 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and aqueous saturated ammonium chloride solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=8:1) to obtain the entitled compound (151 mg, 72%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=O.[NH3:33].[Cl-].[Na+]>C(O)CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:2])[NH:33][C:6](=[O:8])[C:5]3=[CH:10][C:11]=2[NH:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2)c(Nc2ccc(OC)cc2)cc1C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: COc1ccc(Nc2cc3c(cc2Nc2ccc(OC)cc2)C(=O)NC3=O)cc1
Reaction time: 18 h

Procedure:
Analogously to Example 1, 393 mg (0.9 mmol) of 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester in 25 ml of ethyleneglycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 18 hours. The reaction mixture is cooled, saturated with sodium chloride and extracted with ethyl acetate. The ethylacetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with ethyl acetate/hexane 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, m.p. 191°-193° C., FAB-MS: 390 [M+ +H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:11][C@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:10])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: COc1cccc([C@H](C)N)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc([C@H](C)Nc2nc(Cl)ncc2Cl)c1
Yield: 91.6 %

Procedure:
To a solution of (1S)-1-(3-methoxyphenyl)ethanamine (1.50 g, 9.92 mol) (S-isomer, >99% ee purity) and 2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.1 g, 30 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. Then EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered, and concentrated to give the desired product as a light yellow thick oil (2.84 g, 96%). LCMS for C13H14Cl2N3O (M+H)+: m/z=298.0, 300.0, 302.0 (9:6:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:23])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.51 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot methanol, filtered while hot, and cooled to room temperature. The resulting solid was collected by filtration and dried under high vacuum at room temperature to give 3.00 g (54%) of title compound, mp >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:28][CH2:29][C:30](Br)=[O:31]>C(Cl)Cl>[Br:28][CH2:29][C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:20][CH:21]=1)=[O:31]
Reactant: COP(=O)(OC)C(Cc1ccc(N)cc1)P(=O)(OC)OC
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: COP(=O)(OC)C(Cc1ccc(NC(=O)CBr)cc1)P(=O)(OC)OC
Yield: 68.2 %

Procedure:
A solution of 13 (0.959 g, 2.87 mmol) and pyridine (349 μL, 4.31 mmol) in CH2Cl2 was cooled in an ice-bath while stirring. A solution of bromoacetylbromide (250 μL, 2.87 mmol) in CH2Cl2 (5 mL) was added drop-wise and the resulting mixture was stirred for 4 h at that temperature. The reaction was quenched by the addition of water and the product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow solid was purified by silica gel chromatography resulting in 14 as a colorless solid (0.897 g, 67%). 1H NMR (400 MHz, CDCl3) δ 2.65 (tt, J=6.2, 24.4, 1H), 3.22 (dt, J=6.2, 17.4, 2H), 3.72 (d, J=3.7, 6H), 3.75 (d, J=3.7, 6H), 4.01 (s, 2H), 7.26 (d, J=8.6, 2H), 7.47 (d, J=8.6, 2H), 8.15 (bs, 1H): 31P (162 MHz, CDCl3) δ 26.33 (s, 2P).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([O-])=O.CO>C(O)(=O)C.CCOC(C)=O.[Zn]>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:1]
Reactant: Cc1ccccc1-c1ccncc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1-c1ccncc1N
Temperature: 70 °C

Procedure:
Zinc dust (3.0 g, 46 mmol) was added to 3-nitro-4-o-tolyl-pyridine (1.35 g, 6.3 mmol) in acetic acid (32 mL). The reaction mixture was heated to 70° C. for 90 min. After cooling to room temperature, solids were removed from the reaction mixture by filtration. Evaporation of volatiles in vacuo gave a solid that was triturated with toluene. Removal of solids by filtration followed by evaporation of volatiles in vacuo gave a heavy oil. The product 4-o-tolyl-pyridin-3-ylamine was isolated by flash chromatography on silica gel eluting with EtOAc to 5% CH3OH in EtOAc (1.0 g, 86%).
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:25][C@@H:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.N#N.[Br:49]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO.O>[Br:49][C@H:22]1[C@H:23]2[C@H:24]([C:26](=[O:28])[O:27]2)[CH2:25][C@H:21]1[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=C(O)[C@H]1C=C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C1O[C@H]2[C@H](Br)[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To (1R,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylic acid (0.9 g, 0.0024360 mol) dissolved in methylene chloride (20 mL), was added 31% tetrabutylammonium hydroxide in MeOH (2.579 mL), and the mixture was stirred for 30 minutes at ambient temperature. The mixture was concentrated under reduced pressure. The resultant residue was then dissolved in methylene chloride (20 mL, 0.3 mol) and cooled to −70° C. under a blanket of N2. Bromine (251 uL, 0.00487 mol) in 5 ml of methylene chloride was then added dropwise and the mixture was stirred at −70° C. for 1 hour, then warmed to 0° C. Upon reaching 0° C., 20 mL of 5% w/v Na2SO3 in water was added dropwise and mixture was allowed to warm to ambient temperature. The reaction mixture was extracted with methylene chloride (3×10 mL), organic layers were combined and dried over Na2SO4, filtered and concentrated to give a red residue. The residue was filtered through a silica gel plug, eluting with 0 to 30% EtOAc/Hexane to remove inorganics and impurities to afford the title compound (0.73 g) as a white solid. 1H NMR (300 MHz, DMSO, δ): 7.49 (m, 6H), 7.24 (m, 9H), 4.95 (d, 1H), 3.91 (m, 1H), 3.65 (m, 1H), 2.97 (m, 1H), 2.66 (m, 1H), 1.62 (m, 1H) and 1.20 (m, 1H). LCMS: Rf=14.40 mins, ES+Na=470 (AA).
Reaction SMILES: [C:1]1([NH:7][C:8]2[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Br:17]Br>C(Cl)(Cl)Cl.O>[Br:17][C:11]1[C:12](=[O:14])[NH:13][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][CH:10]=1
Reactant: O=c1ccnc(Nc2ccccc2)[nH]1
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1[nH]c(Nc2ccccc2)ncc1Br
Reaction time: 0.67 h

Procedure:
To a suspension of 2-(phenylamino)pyrimidin-4(3H)-one (0.200 g, 1.07 mmol) in CHCl3 (5 mL) and a small amount of MeOH at 0° C. was added bromine (0.0547 ml, 1.07 mmol). The reaction was stirred for 40 minutes, diluted with H2O, and then quenched with 10% sodium bisulfite solution. The reaction mixture was diluted with EtOAc, the layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The product was obtained (0.284 g; 100%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.32 (br s, 1H), 8.89 (br s, 1H), 8.04 (s, 1H), 7.55 (d, 2H), 7.33 (m, 2H), 7.06 (t, 1H). LRMS (ESI pos) m/e 266, 268 (M+, Br pattern).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C[C:46](O)=[O:47]>O>[CH:46]([C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:47]
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)c1
Reactant: CC(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: 70 °C
Yield: 99 %

Procedure:
To a stirred solution of diethyl 5-hydroxyisophthalate (4.0 g, 15.9 mmol) in HOAc (40 mL) was added a solution of CAN (19 g, 34.9 mmol) in H2O (40 mL) dropwise. The reaction mixture was heated at 70° C. for 6 h during which time the color of the solution turned from red to colorless. The reaction mixture was cooled to room temperature and dilute with H2O and was extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaHCO3, brine, dried with Na2SO4 and concentrated under reduced pressure to provide diethyl 5-formylisophthalate (3.93 g, 99%) as a white solid. 1H NMR (CDCl3): d 10.17 (s, 1H), 8.95-8.96 (m, 1H), 8.74-8.75 (m, 2H), 4.50 (q, J=7.2 Hz, 4H), 1.47 (t, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[BH4-].[Na+].Cl>C(O)C>[OH:10][C:11]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: COc1cccc(C=O)c1O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN[C@H](C)c2ccccc2)c1O
Yield: 98.4 %

Procedure:
15.0 g (0.124 mole) of (R)-(+)-1-phenylethylamine and 19.8 g (0.13 mole) of 2-hydroxy-3-methoxybenzaldehyde were dissolved in 300 ml of ethyl alcohol, and the resultant solution was stirred at room temperature for 3 hours, and then stirred under reflux for 2 hours. After that, 2.35 g (0.062 mole) of sodium borohydride were added at room temperature to the reaction mixture, which was then stirred at a temperature of from 30° to 35° C. for 1 hour, and thereafter stirred at a temperature of from 55° to 60° C. for 1.5 hours. After the completion of the reaction, 50 ml of a 10% hydrochloric acid were added at room temperature. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in 150 ml of water. The aqueous solution thus formed was washed with 150 ml of toluene, and the aqueous layer was neutralized or weakly alkalized with a 23% aqueous sodium hydroxide solution. The toluene layer was washed with water, and concentrated under reduced pressure to give 31.41 g of (R)-(+)-N-(2-hydroxy-3-methoxybenzyl)-1-phenylethylamine as oily substance. Yield: 98.6%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
In a 100 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 20.0 g (73.5 mmol) of 6-iodoquinazolin-4-one, 13.5 g (88.2 mmol) of phosphorus oxychloride, and 60 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 8.92 g (88.2 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and the reaction was carried out for 2 hours. After the reaction was complete, the reaction mixture was cooled to 0° C. and stirred for one hour. Thus precipitated pale yellow crystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in 100 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed with 120 mL of water, and dried under reduced pressure, to give 19.3 g (isolated yield: 90%, purity 99.3% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.