Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5](C1C=C(Br)C=CC=1OCC1C=CC=CC=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[C:6]1([CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccccc1

Procedure:
A solution of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenyl-propionic acid methyl ester (0.391 g, 0.92 mmol) in ethanol (5 ml) was treated at 50° C. with excess aqueous sodium hydroxide solution until the milky emulsion became clear. The reaction mixture was then acidified (pH 3), evaporated and extracted with dichloromethane. The organic extract was evaporated and the remaining oil was redissolved in a minimum of boiling ethanol. The precipitation formed after 18 hrs at 4° C. was filtered off and dried in vacuo to yield 0.27 g (71.4%) of (±)-3-(2-Benzyloxy)-5-bromophenyl)-3-phenylpropionic acid, colourless crystals, m.p. 124.9° C.; tlc: (1) 0.15 (starting material methyl ester 0.75); NMR (CDCl3): 39.15, 40.26, 70.25, 113.21, 113.90, 126.62, 127.27, 127.98, 128.17, 128.47, 128.54, 130.46, 130.68, 134.34, 136.45, 142.16, 154.95, 177.65. LC-MS: 412/410 (14/11%, M+·), 394/392 (15/13%), 321/319 (17/22%), 304/302 (17/21%), 259 (24%), 194 (22%), 178 (21%), 167 (65%), 152 (49%), 92 (100%). IR (KBr): 3434, 3030, 1708, 1485, 1452, 1403, 1289, 1243, 1126, 1018, 804, 735, 698, 649. Calculated for C22H19BrO3 (mol-wgt. 411.30): C 64.25%, H 4.66%, Br 19.43%, O 11.67%; found: C 63.72%, H 4.70%, Br 19.75%, O 11.80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ncccn2)cn1
Yield: 58 %

Procedure:
As described for Example 46, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (97 mg, 0.4 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (75 mg, 58%) as a light yellow solid. MS: m/e=322.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[CH:13]1([C:19]([C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
To a solution of methyl pyrrole-3-carboxylate (1.25 g., 10 mmoles) in 25 ml. of methylene chloride under nitrogen, was added cyclohexanecarbonyl chloride (1.46 g., 1.33 ml., 10 mmoles) and then stannic chloride (3.13 g., 1.4 ml., 14 mmoles). The resulting solution was stirred 3 hours at room temperature, then 15 ml. of water added slowly and finally 50 ml. of ether. The organic phase was separated, washed with 20 ml. of water, filtered and evaporated to yield methyl 5-cyclohexylcarbonylpyrrole-3-carboxylate (Rf 0.25 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant). The entire batch was used, without weight determination, in the next step.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[SH:50][C@@H:51]1[CH2:55][N:54](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:53]([CH:69]2[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]2)[CH2:52]1>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:50][C@@H:51]3[CH2:55][NH:54][C@H:53]([CH:69]4[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]4)[CH2:52]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: CN1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C4CCN(C)CC4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.50 g, 4.2 mmol) in acetonitrile (60ml), N,N-diisopropylethylamine was dropwise added in a nitrogen stream under cooling with ice, followed by dropwise adding a solution of (2S,4S)-4-mercapto-2-(N-methylpiperidin-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine trifluoroacetic acid salt (2.30 g, 4.6 mmol, compound of Reference Example 37 in acetonitrile (60 ml). After the mixture was stirred at 0° C. for 15 hours, the precipitate was collected by filtration, washed with acetonitrile and dried to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2 -[(2S,4S)-2-(N-methylpiperidin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (2.12 g, yield: 69.7%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][CH2:18][C:19](Br)=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([C:19](=[O:20])[CH2:18][Br:17])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccc(Cl)cc1Cc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1Cc1ccccc1
Reaction time: 1 h

Procedure:
The N-methyl 2-benzyl-4-chloroaniline (10.8 g) in solution in ethyl acetate is treated at 5° C. with 4.9 ml of bromoacetyl bromide. After 1 hour at room temperature, decantation and washing with water, the solution is concentrated. Upon crystallization, N-methyl 2'-benzyl-4'-chloro-bromoacetanilide is obtained (12.21 g). MP = 78° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:12])[CH:5]=1.CS(O[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)(=O)=O.O>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH:18]2[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]2)=[CH:5][C:6]=1[CH3:12])=[O:9]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1C=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A slurry of sodium hydride (60%, 0.12 g, 3.10 mmol) in DMF (4 ml) was cooled by an ice-bath. Under nitrogen, 4-hydroxy-2-methylbenzaldehyde in DMF (2 ml) was added. The mixture was stirred for 30 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate in DMF (4 ml) was added. The mixture was heated to 100° C. using an oil bath for 3 days and then cooled to RT. Water (100 ml) was added while stirring. The mixture was extracted trice with EtOAc. The combined organic solutions were dried (MgSO4) and then evaporated. The residue was purified by silica gel chromatography eluting with EtOAc/heptane (10:90). There was obtained 120 mg (20%) of partly purified 69A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.46 (s, 9H), 2.64 (s, 3H), 4.01 (m, 2H), 4.33 (m, 2H), 4.94 (m, 1H), 6.60 (d, 1H), 6.66 (dd, 1H), 7.76 (d, 1H), 10.13 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:10][CH:9]=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=CCCc1cccc(Cl)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 1-chloro-3-iodobenzene (9.63 g, 40.38 mmol), allyl alcohol (5.86 g, 100.96 mmol), sodium bicarbonate (8.48 g, 100.96 mmol), tetrabutylammonium chloride (11.22 g, 40.38 mmol), and Pd(OAc)2 (317 mg, 1.413 mmol) in 25 mL DMF was stirred at 50° C. for 18 h. The mixture was cooled to room temperature, diluted with water, and the aqueous solution was washed with EtOAc. The organic solution was washed with water followed by brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified via flash chromatography on silica gel (9:1 hexanes:EtOAc) to afford the title compound as an oil (5.04 g).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[O-]S([O-])(=O)=O.[Mg+2].[CH3:15][NH:16][NH2:17]>C(Cl)(Cl)Cl>[CH3:15][NH:16][N:17]=[C:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CNN
Reactant: CCOC(=O)C(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)=NNC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
To a suspension of ethyl pyruvate (37.8 mL, 338 mmol) and MgSO4 (40.8 g, 339 mmol) in CHCl3 (500 mL) was added a solution of methylhydrazine (18.0 mL, 332 mmol) in CHCl3 (100 mL) at 0° C. The reaction mixture was warmed to room temperature. After stirring for 24 hours at room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 44 g (94%) of the desired product that was used directly without further purification.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][SH:11])=[CH:6][CH:5]=1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13]>C(O)C>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][S:11][CH2:10][C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)[CH3:13]
Reactant: SCc1ccncc1
Reactant: CCOC(CBr)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSCc1ccncc1)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (0.60 g., 11 moles) is dissolved in approximately 15 ml. of stirring ethanol and cooled in an ice bath. 4-Picolyl mercaptan (1.4 g., 11 mmoles) in approximately 3 ml. of absolute ethanol is added over 5 minutes and the mixture stirred for 15 minutes. Bromoacetaldehyde diethylacetal (2.4 g., 11 mmoles) in approximately 15 ml. of absolute ethanol is then added over 5 minutes. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture is filtered and the filtrate evaporated to yield title product, which if desired, can be further purified by chromatography on silica gel.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[C:20]([O:21][CH3:22])=[CH:19][C:18]2[CH2:17][CH:16]([NH:23][C:24](=O)[CH3:25])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.C(OC(=O)C(SC1C=CC2CC(NCC)CCC=2C=1)(C)C)(C)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[C:20]([O:21][CH3:22])=[CH:19][C:18]2[CH2:17][CH:16]([NH:23][CH2:24][CH3:25])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(cc1SC(C)(C)C(=O)OC(C)(C)C)CCC(NC(C)=O)C2
Agent: B
Agent: CCNC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Solvent: C1CCOC1
Product: CCNC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(OC)cc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.68 g; 1.74 mmol) in THF (15 mL) was added a solution of 1.0 M borane-THF (15 mL), dropwise at room temperature. The reaction mixture was allowed to stir for 18 h at room temperature, then carefully quenched with MeOH (10 mL) and the solvent evaporated under reduced pressure. The residual oil was further azeotroped with MeOH (3×) to yield a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and it's borane complex as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16]([O:18]CC)=[O:17].O.[OH-].[Li+].CO.Cl>O1CCCC1.O.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C1CC1c1nc(-c2ccccc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2ccccc2)nc1C1CC1C(=O)O

Procedure:
To a solution of ethyl 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylate (746 mg, 2.76 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide monohydrate (232 mg, 5.52 mmol) in water (5.00 mL) at rt. Added methanol (5.00 mL) and stirred for 15 h at rt. Removed solvent. Obtained a white solid. Redissolved in water (15 mL) and neutralized with 5.5 mL of 1.0 M HCl. Removed solvent and azetroped with toluene (2×10 mL). Dried for 20 h and obtained 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid as a white powder. MS (ESI) 243 (M+H); Rf=1.35 (Condition A).
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(O)(=O)C.O>[CH3:13][C:14]1[N:15]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[CH:16]=[CH:17][N:18]=1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: Cc1ncc[nH]1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nccn1-c1nccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 8 g of 2-methyl-1H-imidazole, 25 ml of N-methylpyrrolidinone, 3.4 g of anhydrous potassium carbonate and 50 mg of copper powder was refluxed for 6 hours, allowed to cool to room temperature and then poured into 100 ml of water. The resulting solution was neutralized by adding acetic acid and the resulting solution was allowed to stand overnight at room temperature. The solid that separated was collected, recrystallized from dimethylformamide and dried in a vacuum oven at 90°-95° C. to yield 2.4 g of 5-(2-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >310° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[CH:26]=[CH:25][C:23](N)=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Br)cc4F)c3c2s1
Yield: 30 %

Procedure:
Prepared from VII and 4-bromo-2-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 30%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3325, 3053, 2230, 1649, 1614, 1582, 1556, 1499, 1462, 1380, 1351, 1250, 1154, 1132, 1052, 969, 904, 875, 817; 19F NMR (282 MHz, DMSO-d6) δ −119.9; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=9.0 Hz), 8.26 (d, 1H, J=9.0 Hz), 7.78 (m, 1H), 7.55-7.52 (m, 1H), 7.38-7.25 (m, 2H); HRMS calcd for C16H8N5SBrF (M+H+): 399.9668, found 399.9662.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][C:4]([Br:14])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Brc1ccc(Nc2ccccc2)cc1
Reaction time: 300 h

Procedure:
In a 1-L conical flask, 51 g (0.3 mol) of diphenylamine was dissolved in 700 mL of ethyl acetate, and then 54 g (0.3 mol) of N-bromosuccinimide (abbreviation: NBS) was added to this solution. About 300 hours later, this mixture solution was washed with water, and then magnesium sulfate was added thereto to remove moisture. This mixture solution was filtered, and the filtrate was concentrated and collected. The object of the synthesis was obtained as 70 g of a dark brown oily substance in 94% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[O:33][C:32]1=[O:43].[Cl:44]C1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O=P(Cl)(Cl)Cl>[Cl:44][C:39]1[CH:38]=[C:37]([C@H:34]2[O:33][C:32](=[O:43])[N:31]([CH2:30][C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[C:4]3[CH:5]=[C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=4[CH3:19])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C@H:35]2[CH3:36])[CH:42]=[CH:41][N:40]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccncc4)[C@@H]3C)c2)c(C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-2-oxo-5-pyridin-4-yl-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (175 mg, 0.296 mmol) in CH2Cl2 (15 mL) at 0° C. under N2, was added 3-chloroperbenzoic acid (146 mg, 0.593 mmol) as a powder. The mixture was stirred at 0° C. for 15 min. Then it was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with satd Na2SO3 (1×) followed by satd K2CO3 (2×). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue obtained was dissolved in POCl3 (10 mL). The resulting solution was heated at 110° C. under N2 for 2 h. Then it was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and water (10 mL) and washed with satd NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 2″-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=625.2; found=625.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.40 (s, 0.5H); 8.39 (s, 0.5H); 7.97 (s, 1H); 7.90 (t, J=5.8 Hz, 1H); 7.72 (s, 0.5H); 7.69-7.63 (m, 1.5H); 7.48 (d, J=11.8 Hz, 0.5H); 7.44 (s, 0.5H); 7.43-7.37 (m, 1H); 7.32-7.26 (m, 1H); 7.24 (s, 0.5H); 7.20 (s, 0.5H); 7.16 (d, J=2.2 Hz, 0.5H); 7.14 (d, J=2.2 Hz, 0.5H); 7.12-7.06 (m, 1.5H); 7.05 (d, J=5.1 Hz, 0.5H); 5.42 (d, J=8.1 Hz, 0.5H); 5.18 (d, J=8.1 Hz, 0.5H); 4.92 (dd, J=15.9, 18.5 Hz, 1H); 4.19 (d, J=15.8 Hz, 0.5H); 3.99 (d, J=15.8 Hz, 0.5H); 3.95 (s, 3H); 3.88 (s, 3H); 3.81-3.75 (m, 1H); 2.39 (s, 1.5H); 2.35 (s, 1.5H); 0.60 (d, J=6.5 Hz, 1.5H); 0.49 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](OC(C)(C)C)=[O:17])[CH2:11]1)=[O:9])C.CS(O)(=O)=O.[C:39]([C:41]1[CH:49]=[CH:48][C:44](C(O)=O)=[CH:43][CH:42]=1)#[N:40].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C.O.C(N(CC)CC)C.CN(C=O)C>[C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([C:8]([NH:7][CH2:6][C@H:5]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:4]([OH:3])=[O:33])=[O:9])[CH2:11]2)=[O:17])=[CH:43][CH:42]=1)#[N:40]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](CNC(=O)C1CCCN(C(=O)OC(C)(C)C)C1)NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(C(=O)N2CCCC(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound (373 mg) obtained in the above (1) in acetonitrile (1.5 ml) is added dropwise a solution of methanesulfonic acid (380 mg) in acetonitrile (1.5 ml), and the mixture is stirred at room temperature for 30 minutes. To the mixture are added dropwise DMF (4 ml) and triethylamine (400 mg) at 5°-10° C. under ice-cooling, and further thereto am added 4-cyanobenzoic acid (129 mg), HOBT.H2O (146 mg) and then further WSC.HCl (183 mg). The mixture is stirred at 5°-10° C. for 30 minutes, and further stirred at room temperature for 12 hours. The reaction mixture is poured into water, and extracted with ethyl acetate. The combined organic layers are washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine (each twice), and dried over magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (390 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>C1(C)C=CC=CC=1.O.Cl.C(O)(=O)C.[Zn].[Hg](Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1c(CCCC(=O)O)ccc2c1CCCC2
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1c(CCCC(=O)O)ccc2ccccc12
Reaction time: 0.08 h

Procedure:
155.4 g of zinc turnings, 18.6 g of mercury(II) chloride, 231.2 ml of water and 7.7 ml of concentrated hydrochloric acid are combined and shaken well for 5 minutes. The aqueous phase is decanted off from the zinc amalgam and the latter is added to a solution of 78.45 g (0.31 mol) of the compound from Example 1 in 140 ml of toluene, 175 ml of water, 310 ml of concentrated hydrochloric acid and 15 ml of glacial acetic acid. The mixture is heated to reflux for 18 h, 81 ml of concentrated hydrochloric acid being added every 6 h. The solution is filtered, shaken 3 times with 300 ml of ethyl acetate each time and the combined ethyl acetate phases are washed with 500 ml of saturated sodium chloride solution. After drying over sodium sulphate, the solution is evaporated and the residue is flash chromatographed on silica gel using CH2Cl2 /acetone as the eluent.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[OH-].[K+].FC(F)(F)C(O)=O>CO>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:9]2[CH:8]=[N:7][C:6]3[C:10]2=[N:11][C:12]([C:14]([F:17])([F:15])[F:16])=[N:13][C:5]=3[NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:23][CH:22]=1)([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(-n2cnc3c(NC4CC4)nc(C(F)(F)F)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)c1ccc(-n2cnc3c(NC4CC4)nc(C(F)(F)F)nc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.7 %

Procedure:
6-Cyclopropylamino-9-(4-methoxycarbonylphenyl)-2-trifluoromethylpurine (20 mg, 0.053 mmol) was treated with 0.53 mmol of 1-2 M KOH in methanol (containing 5% water) and stirred for 14 hours at room temperature. The reaction mixture was acidified with trifluoroacetic acid (30% in dichloromethane) to pH=2 and concentrated under vacuum. The residue was extracted with 20% methanol in dichloromethane. The extraction was loaded on a silica gel column and eluted with 20% methanol in dichloromethane to give 9-(4-carboxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine (14 mg, 70% yield). 1H NMR (300 MHz, DMSO) δ 8.85 (s, 1H), 8.70 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 3.07 (b, 1H), 0.78 (b, 2H), 0.68 (b, 2H). [ESMS m/z (363.9 (M+1)+)]