Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Br[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)CCc1ccc(O)c(Br)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: COC(=O)CCc1ccc(OC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Intermediate 5 (4.50 g) in DMF (20 ml) was added with 60% sodium hydride (440 mg, KANTO) under ice cooling. The reaction mixture was stirred for 10 minutes, then added with bromocyclopentane (1.61 ml, TCI), warmed to room temperature, stirred for 1.5 hours, then warmed to 60° C., and further stirred for 16 hours. The reaction mixture was added with water (50 ml) and isopropyl ether (300 ml)) for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:isopropyl ether=7:1) to obtain the title compound (Compound No. A-5, 2.50 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: CCc1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCc1ccc(O)c(Br)c1
Reaction time: 1 h

Procedure:
A solution was prepared by dissolving 105 g of 4-ethylphenol into 500 ml of chloroform. The solution was cooled by ice water bath, followed by dropwise addition of 45 ml of bromine while stirring. The addition was took 1 hour. Then, the reaction mixture was cooled by an ice water bath while stirring for 4 hours, moved into a separatory funnel to wash with water, an aqueous solution saturated with NaCl, 10% water solution of sodium hydrogencarbonate and an aqueous solution saturated with NaCl in turn, and dried with magnesium sulfate anhydride. The solvent in the reactant was distilled off under reduced pressure to yield 173 g of light brown and oily 2-bromo-4-ethylphenol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].C[O-].[Na+].C(O)(C)C>O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[N:16]=1
Reactant: N#Cc1ccco1
Reactant: N#Cc1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(-c2ccco2)nc2ccccc12

Procedure:
5.4 g. (0.05 mol) of o-aminobenzonitrile, 4.7 g. (0.05 mol) of 2-furonitrile and 5.4 g. (0.1 mol) of sodium methoxide in 150 ml. of isopropanol are refluxed for 48 hours under a nitrogen atmosphere. The reaction mixture is then decomposed with water and the isopropanol is distilled off. 80 ml. of diethyl ether and 80 ml. of water are added and the precipitate is filtered off. The ethereal layer is separated and the ether is distilled off. The residue is identical to the solid already filtered off. The product is crystallized from a mixture of ethanol and petroleum ether (boiling range 40°-60°C.) to give 4-amino2-(2-furyl)quinazoline, m.p. 219°-221°C. The base is converted into the monohydrochloride, and the salt after crystallization from ethanol melts above 300°C.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].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.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]3)[CH:42]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
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: O
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Yield: 93.1 %

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step 2, chiral intermediate), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.030 g, 0.080 mmol, from Combi-Blocks), sodium carbonate (0.014 g, 0.13 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol). The mixture was degassed with N2 for 5 minutes, and then heated at 120° C. overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to give the crude product (0.040 g) which was used in the next step directly. LCMS calculated for C33H44ClN8O4 (M+H)+: m/z=651.3. found: 651.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:29]>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:4]=[CH:9][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([NH2:29])=[O:28])=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:7][C:6]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 58 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid and ammonia (7 mol/L in methanol) following a procedure analogous to that described in Example 1. Yield: 58% of theory; TLC: rf=0.24 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[C:6](OCC)(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]>CCOCC>[CH2:3]=[C:2]=[CH:1][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CC[Mg]Br
Reactant: CCCCC(=O)OCC
Solvent: CCOCC
Product: C=C=CC(=O)CCCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.50 moles of propargylmagnesium bromide in 340 ml. of ether at -78° C. is added a solution of 65.2 g. (0.50 moles) of ethyl valerate in 100 ml. of ether during 60 minutes. The solution is stirred at -78° C. for 30 minutes and then hydrolyzed by pouring onto a mixture of ice and ether. The ether layer is washed with brine, treated with hydroquinone, dried over magnesium sulfate, and concentrated.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])(C)C)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O=C1CCC(=O)N1OC(=O)OC[C:33]1[CH:38]=[CH:37]C=[CH:35][CH:34]=1>Cl>[CH2:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([CH3:19])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)=[O:13])[C:18]1[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Methyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.71 g, 10 mmol) is heated with 6M aq. HCl (20 mL) at 95° C. for 2 days. The mixture is cooled, basified with 33% aq. NaOH (ice bath cooling) and extracted with ether (2×50 mL). A spatula of NaH2PO4 is added, then the pH adjusted to 7 with conc. aq. HCl, CH2Cl2 (50 Vol %) is added and the mixture cooled at 0° C. Carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (1.508 g, 5 mmol) is added to the strongly stirred biphasic system and the mixture is stirred for 2 h. The pH is adjusted to 14 with aq. NaOH (1M) and the phases are separated. The aq. phase is extracted with CH2Cl2 (2×50 mL), the organic extracts are discarded. The pH is adjusted to 2 and the mixture is extracted with CHCl3 (4×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (80 mg, 0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in 2 ml of dry THF was added potassium tert-butoxide (35 mg, 0.31 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 91 mg (83%) of the title compound as yellow solid, mp 160-162° C. 1H NMR (CDCl3) δ 7.62 (d, 1H), 6.87 (s, 2H), 6.18 (s, 1H), 3.40 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]([OH:8])[CH2:6][CH:7]=1.C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Cl:22][CH2:2][C:3]1[CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]([OH:8])[CH2:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)CC1C(CO)=CCC1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CC1C(CCl)=CCC1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-hydroxymethyl-1-hydroxycyclopent-3-en-2-yl]acetic acid, Ʊ-lactone, the compound of formula (1), (188 mg, 1.22 mmol) in 10 ml of methylene chloride was added 4-dimethylaminopyridine (119 mg, 0.97 mmol), followed by p-toluenesulfonyl chloride (280 mg, 1.46 mmol) and triethylamine (123 mg, 1.22 mmol). After stirring for 2 hours at room temperature, the mixture was diluted with diethyl ether (80 ml), filtered and the filtrate washed successively with aqueous 10% copper sulfate (50 ml), 10% aqueous sodium bicarbonate (50 ml) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 70/30) to give 165 mg of [3-chloromethyl-1-hydroxycyclopent-3-en-2-yl]acetic acid, Ʊ-lactone, m.p. 33°-34° C., the compound of formula (2).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5](C)=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Reactant: COCOc1nn(-c2ccccc2C)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3C)nc2OCOC)cs1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (1.26 g) in tetrahydrofuran (40 mL) was added sodium hydride (60% in oil, 0.192 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carbaldehyde (0.99 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20-1:3, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (0.81 g, yield 57%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([CH:15]1[CH2:25][CH2:24][C:18]2([O:22][CH2:21][C:20](=O)[CH2:19]2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>O.O1CCCC1>[C:11]([CH:15]1[CH2:25][CH2:24][C:18]2([O:22][CH2:21][C:20](=[N:2][OH:3])[CH2:19]2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NO
Reactant: CC(C)(C)C1CCC2(CC1)CC(=O)CO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC2(CC1)CC(=NO)CO2
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (6.9 g, 0.1 mol) and triethylamine (10.0 g, 0.1 mol) in 10 ml of water was added 8-t-butyl-1-oxaspiro(4,5)decane-3-one (16.0 g, 0.076 mol) in 30 ml tetrahydrofuran. The mixture was stirred at room temperature for 3 hours and at 60° C. for 1 hour. The solvent was then evaporated in vacuo and the residue was partitioned between toluene and brine (100 ml each). The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo to yield a colourless oil (17.0 g) which crystallised on standing. Recrystallisation from light petroleum gave two fractions of colourless crystals (6.6 g and 5.3 g) mp.: 118°-120 and 105-108° C. 1H-NMR indicated mixtures of geometric isomers (E/Z) in ratios of 1:1 and 2:1 respectively.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])=[O:14].FC(F)(F)C(O)=O>ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([OH:29])=[O:28])=[O:21])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCCCCN1C(=O)C=CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCCCCN1C(=O)C=CC1=O
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a mixture of the tert-butyl ester 77 in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL). After 40 min the reaction was determined to be complete by HPLC analysis. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane and concentrated a second time to give 37 mg (100%) of 78 as a white solid: 1H-NMR (400 MHz, CDCl3) δ 6.68 (s, 2H), 4.62 (m, 2H), 3.81 (m, 1H), 3.70 (m, 1H), 3.57 (m, 2H), 3.45 (m, 2H), 2.40-1.91 (m, 10H), 1.70-1.45 (m, 4H), 1.33 (m, 2H); MS (ES+) m/z 406.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:3]=1.[CH3:20][O:21][C:22]([C@H:24]1[CH2:28][C@H:27]([NH2:29])[CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23].C(N(CC)CC)C>O1CCOCC1.ClCCl>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([NH:29][C@@H:27]2[CH2:26][N:25]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C@@H:24]([C:22]([O:21][CH3:20])=[O:23])[CH2:28]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: COC(=O)[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@H]1C[C@H](Nc2nc(-c3ccccc3OC)nc3ccccc23)CN1C(=O)OC(C)(C)C
Yield: 51.7 %

Procedure:
4-Chloro-2-(2-methoxyphenyl)quinazoline (0.463 g, 1.709 mmol), (2R,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.480 g, 1.709 mmol) and triethylamine (0.715 mL, 5.127 mmol) in dioxane (9 mL) were heated at reflux for 3 days. The mixture was cooled, diluted with dichloromethane (50 mL), and washed with water (50 mL). The organic extracts were dried (MgSO4) and concentrated. Purification by silica gel chromatography (10% methanol in dichloromethane) gave the title compound as a solid (0.423 g, 52%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][C@@H:12]([CH:14]([CH3:16])[CH3:15])[N:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:25].C(N(CC)CC)C.[F:33][C:34]([F:52])([F:51])[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>ClCCl>[CH2:18]([O:17][N:11]1[C@H:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][C@@H:9]([NH:8][S:47]([C:44]2[CH:43]=[CH:42][C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:51])[F:52])=[CH:36][CH:37]=3)=[CH:46][CH:45]=2)(=[O:49])=[O:48])[C:10]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)[C@@H]1C[C@@H](N)C(=O)N1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of (3R,5S)-3-amino-1-(Benzyloxy)-5-isopropyl-2-pyrrolidinone trifluoroacetate (0.072 g, 0.19 mmoles), triethylamine (0.13 mL, 0.93 mmoles) and dry dichloromethane (1.0 mL) was added in small portions 4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonyl chloride (0.063 g, 0.20 mmoles) during two minutes. The mixture was stirred under dry nitrogen at 22° C. for 45 minutes, concentrated by rotary evaporation, re-dissolved in dichloromethane (2 mL), mixed with a silica (1 g), concentrated again and then applied on a silica column. Elution with ethyl acetate/n-heptane (1:4 through 1:1) and concentration of pure fractions gave 0.082 g (83% yield) of the title compound as a white solid. LC-MS (APCI) m/z 533 (M+1). 1H NMR (CDCl3) δ 8.01 (d, J=8 Hz, 2H), 7.72 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H) 7.70 (d, J=8 Hz, 2H), 7.41–7.33 (m, 5H), 5.55 (d, J=4 Hz, 1H), 5.00 (d, J=11 Hz, 1H), 4.93 (d, J=11 Hz, 1H), 3.79 (dt, J1=4 Hz, J2=9 Hz; 1H), 3.37–3.31 (m, 1H), 2.29 (ddd, J1=2 Hz, J2=9 Hz, J3=11 Hz; 1H), 2.09–1.98 (m, 2H), 0.85 (d, J=7 Hz, 3H) and 0.76 (d, J=7 Hz, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine (140 mg, 0.56 mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (144.37 mg, 0.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (214.42 mg, 1.12 mmol), and 1-hydroxybenzotriazole (HOBt) (120.91 mg, 0.89 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Diisopropylethylamine (DIEA) (0.39 mL, 2.24 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (60 mL) and washed with water (1×20 mL) and brine (1×20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was then purified on Combiflash ISCO (0-30% Ethyl Acetate:Hexanes) to give the desired product (164 mg, 60% yield). 1H NMR (CDCl3) δ 8.52 (1H, t), 8.22 (1H, dt), 8.12 (1H, t), 8.03 (1H, dt), 7.85-7.81 (2H, m), 7.57 (1H, d), 7.35 (1H, s), 7.05-7.00 (2H, m), 3.80 (2H, d, J=4 Hz), 1.55 (6H, s); MS (ESI) m/z: Calculated for C23H18F4N4O2S: 490.11. found: 491.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[OH-:10].[Na+].[K].[OH2:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])=[O:10])=[CH:4][C:3]=1[F:9]
Reactant: O
Reactant: [OH-]
Reactant: Cc1ccc(Br)c(F)c1
Agent: [K]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Br)c(F)c1
Yield: 86.3 %

Procedure:
A mixture of 4-bromo-3-fluorotoluene (15.0 g, 79.35 mmol) and sodium hydroxide (3.3 g, 82.53 mmol) in pyridine (80 ml) and water (160 ml) was stirred at reflux. Potassium permanganese (52.7 g, 333.28 mmol) was added to the mixture over 30 min. The resulting suspension was heated at reflux for 3 h. The mixture was filtered through celite. The celite was washed with hot water, followed by ethyl acetate. The cooled aqueous layer was acidified to pH 1 with conc.HCl and extracted with ethyl acetate. The extracts was dried (MgSO4) and concentrated to afford 15.0 g (86.3%) of the titled compound as a white crystal. The compound was used for the next reaction directly.