Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])[C:4]=2[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:41]1[C:49]2[N:48]=N[NH:46][C:45]=2[CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:46][C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:49]=3[NH2:48])=[O:26])=[O:18])[C:4]=2[CH:3]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
6-(2-(2,7-dibromo-9H-fluoren-9-ylidene)acetamido)hexanoic acid (493 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (437 mg, 76% yield) as a brown solid. LC-MS (m/z) 584 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(N(CC)CC)C.[CH3:14][C:15]1[CH:51]=[CH:50][CH:49]=[CH:48][C:16]=1[CH2:17][NH:18][C:19]([C@@H:21]1[C:25]([CH3:27])([CH3:26])[S:24][CH2:23][N:22]1[C:28](=[O:47])[C@@H:29]([OH:46])[C@@H:30]([NH:38][C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:20]>C(OCC)(=O)C>[CH3:14][C:15]1[CH:51]=[CH:50][CH:49]=[CH:48][C:16]=1[CH2:17][NH:18][C:19]([C@@H:21]1[C:25]([CH3:27])([CH3:26])[S:24][CH2:23][N:22]1[C:28](=[O:47])[C@@H:29]([OH:46])[C@@H:30]([NH:38][C:39](=[O:45])[C@@H:40]([NH:41][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:42]([CH3:44])[CH3:43])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:20]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (32 μel), triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in ethyl acetate (3 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (149 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][NH2:12].O1CCCC1>O1CCCC1.O>[CH3:11][NH:12][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Br)s1
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonyl chloride (602 mg) in tetrahydrofuran (5 mL) was added dropwise a solution of 2.0M methylamine-tetrahydrofuran (3.5 mL) on an ice bath. After stirring for 15 minutes on an ice bath, the solution was diluted with water and extracted with ethyl acetate. After washing with an aqueous solution of saturated sodium bicarbonate and saturated sodium chloride water, the solution was dried with anhydrous sodium sulfate. After filtration through silica gel, the solvent was removed by evaporation to provide the title compound (608 mg) as a colorless oily matter.
Reaction SMILES: N1C=C[CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[NH:8][N:7]=1.[N:17]1[CH:22]=C(B(O)O)C=[N:19][CH:18]=1>>[N:19]1[CH:3]=[C:2]([C:6]2[C:14]3[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH:22]=[N:17][CH:18]=1
Reactant: O=Cc1ccc2c(-c3ccc[nH]3)n[nH]c2c1
Reactant: OB(O)c1cncnc1
Product: O=Cc1ccc2c(-c3cncnc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-(1H-pyrrol-2yl)-1H-indazole-6-carbaldehyde, except substituting pyrimidin-5-ylboronic acid (34 mg, 0.15 mmol), the title compound was obtained as a beige solid (8.1 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 10.15 (s, 1H), 9.44 (s, 2H), 9.21 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.23 (t, J=1.3 Hz, 1H), 7.84 (dd, J=8.5, 1.3 Hz, 1H); MS ESI 225.0 (100) [M+H]+, calcd for [C12H8N4O+H]+ 225.07.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[F:13]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)n1
Yield: 92.5 %

Procedure:
Under an argon atmosphere, to a solution of methyl 5-bromo-6-chloropicolinate (12.0 g) in toluene (300 mL) were added 2-fluoro-5-methoxyphenylboronic acid (9.83 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.00 g) and a solution of sodium carbonate (14.8 g) in water (60 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and diluted with water. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound (13.1 g) as pale-yellow crystals.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[NH:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:5])C.C[O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1>>[C:13]12([CH2:12][CH2:11][C:10]3[NH:9][C:8]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[N:7][C:6]=3[C:4]([NH:40][C:36]3[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=3)[C:33]([OH:41])=[O:32])=[O:5])[CH2:22][CH:17]3[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]3)[CH2:20]1)[CH2:14]2
Reactant: COC(=O)c1cccc(N)c1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1cccc(NC(=O)c2nc(-c3ccc(Cl)c(Cl)c3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-Adamantan-1-yl-2,3-dioxo-pentanoic acid ethyl ester monohydrate (Example 44) was reacted with 3,4-dichlorobenzaldehyde according to the procedure of Example 20, step b to produce 5-(2-adamantan-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester. The ester was hydrolyzed according to the procedure of Example 20, step c and the resulting 5-(2-adamantan-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-1-H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester using essentially the same procedure as in Example 52, step a. Deprotection was carried out following essentially the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.89 (2H, br s), 9.90 (1H, s), 8.50 (1H, s), 8.32 (1H, s), 8.03 (2H, m), 7.76 (1H, d), 7.63 (1H, d), 7.43 (1H, t), 2.98 (2H, m), 1.97 (3H, s), 1.70-1.39 (14H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 56.90; H, 6.44; N, 7.08%; C36H46Cl2N4O8.1.6 H2O requires: C, 56.72; H, 6.50; N, 7.35%.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:22][CH3:23])=[C:19]([O:20][CH3:21])[C:12]=2[N:11]=1)(C(C)(C)C)(C)C.[Si](OCC1N(C)C2C(OC)=C(OC)C(OC)=CC=2N=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C1COCC1.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:22][CH3:23])=[C:19]([O:20][CH3:21])[C:12]=2[N:11]=1
Reactant: COc1cc2c(nc(CO[Si](C)(C)C(C)(C)C)n2C)c(OC)c1OC
Agent: COc1cc2nc(CO[Si](C)(C)C(C)(C)C)n(C)c2c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(nc(CO)n2C)c(OC)c1OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture (471 mg) of 2-tert-butyldimethylsilyloxymethyl-1-methyl-4,5,6-trimethoxybenzimidazole and 2-tert-butyldimethylsilyloxymethyl-1-methyl-5,6,7-trimethoxy-benzimidazole was dissolved in a mixed solvent of acetic acid (5 mL), water (2.5 mL) and THF (2.5 mL), and the solution was stirred at 90° C. for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was alkalified with an aqueous solution of potassium carbonate and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (chloroform:methanol=13:1) to obtain a mixture of the title compounds.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.ClCCCC.N1C=CC=NC=1>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:11]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:17])=[O:21])[N:3]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: Cc1cc(C)nc(N)n1
Solvent: CCCCCl
Solvent: c1cncnc1
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a suspension of 1.2 g of 2-amino-4,6-dimethylpyrimidine in 25 ml of acetonitrile was added 2.6 g of 1,1'-biphenyl-2-sulfonyl isocyanate with stirring at ambient temperature. After stirring for 2 hours, the mixture was filtered and the filtrate concentrated in vacuum. The residue thus obtained, after trituration with chlorobutane, melted at 78° with gas evolution. It showed peaks in the nuclear magnetic resonance spectrum (60 MHz) at δ 2.2, (singlet, CH3); δ 6.56, (singlet, CH of pyrimidine) and at δ 6.8-7.9, (multiplet, phenyl hydrogens) in a ratio of 6:1:9, consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.C[CH2:18][N:19](C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:18]#[N:19])[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Cl)cc(CC#N)c21

Procedure:
To a solution of compound 17 (1 g, 4.2 mmol), at room temperature and under nitrogen atmosphere, in dry dichloromethane (10 mL) were added DIPEA (0.8 mL, 4.62 mmol) and methane sulfonic anhydride. (0.8 g, 4.62 mmol) The resulting mixture was stirred for 2 h. Then, the reaction mixture was quenched with water and the mixture was extracted with more dichloromethane. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent evaporated to give the desired product as yellow oil.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCCC1>[O:20]1[CH2:21][CH2:22][N:17]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:18][CH2:19]1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCOCC1)c1ccccc1-2
Reaction time: 20 h
Yield: 42.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (0.50 g, 2.13 mmol) was suspended in 5 ml of dry tetrahydrofuran, while cooling in an ice bath. Morpholine(0.37 ml, 4.27 mmol) dissolved in 2 ml of dry tetrahydrofuran was added over 2 min. After 1 hour the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran, 10% acetic acid, water and dried to give 0.365 g of the crude product. Recrystallization from ethanol afforded 0.257 g (42%) of the title compound. M.p. 265°-267° C. 1H-NMR (DMSO-d6, δ): 2.47 (m, 2H), 2.61 (m, 2H), 3.56 (m, 4H), 4.54 (s, 1H), 7.13 (t, 1H), 7.3 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 11.8 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Br:42][C:43]1[C:44](=[O:54])[NH:45][C:46]2[C:51]([C:52]=1O)=[CH:50][CH:49]=[CH:48][CH:47]=2>C1COCC1>[CH2:34]([O:41][C:52]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][C:44](=[O:54])[C:43]=1[Br:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(O)c1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(OCc2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of PPh3 (1.64 g) in THF (42 mL) was added diisopropylazodicarboxylate (1.21 mL) dropwise. The mixture was stirred at 0° C. for 15 minutes before the addition of benzyl alcohol (0.52 mL) followed by quinoline alcohol from Step 1 (1.0 g). The mixture was stirred 15 minutes at 0° C. then 5 hours at room temperature. A suspension had formed at that point. The solid was filtered and washed with cold isopropanol to afford the desired product (0.78 g). LRMS (ES+) m/z 352.1 (M+Na)+.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]S(C)(=O)=O)[CH2:4][CH2:3]2.[CH3:47][CH:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:50]([CH:48]([CH3:49])[CH3:47])(=[O:52])=[O:51])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)S(=O)(=O)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(=O)(=O)C(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using propane-2-sulfonyl chloride as the reagent in Step 1. The product was isolated as a colorless oil (3.5 mg, 34%). LCMS: m/e 679.55 (M+H)+, 2.36 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.56 (br. s., 1H), 7.98 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.91 (t, J=6.3 Hz, 1H), 5.94 (br. s., 1H), 5.18 (d, J=4.5 Hz, 1H), 4.87 (s, 1H), 4.71 (s, 1H), 3.88-3.69 (m, 1H), 3.63-3.49 (m, 1H), 3.37-3.16 (m, 3H), 2.90-2.68 (m, 1H), 2.26-1.07 (m, 22H), 1.70 (s, 3H), 1.44 (dd, J=8.8, 6.8 Hz, 6H), 1.20 (s, 3H), 1.02 (s, 3H), 0.96 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]1([CH2:37][CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[N:4]([CH2:39][CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: BrCCCc1ccccc1
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C(C)N1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.7 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (4.0 g, 12.0 mmol) in dry dimethylformamide (10 ml) under argon was treated with finely ground potassium carbonate (4.97 g, 36.0 mmoles), 3-phenylpropyl bromide (2.19 ml, 14.4 mmoles) and a catalytic amount of 18-crown-6. The resulting suspension was allowed to stir at room temperature for 72 hours, diluted with ether, filtered and the filtrate washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (10-15% ethyl acetate in hexanes) to provide the desired product (3.29 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]\[C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]2[CH:7]=[C:6](/[CH:18]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]\[C:14]([CH3:15])([CH3:16])[CH3:17])[C:8]2[CH:7]=[C:6](/[CH:18]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(/C=C\C(C)(C)C)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)/C=C\C1=CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)O)cc3)cc21
Reaction time: 30 h
Yield: 84.8 %

Procedure:
A solution of methyl 4-[(E)-(5,6-dihydro-5,5-dimethyl-8-((Z)-3,3-dimethyl-1-buten-1-yl)-2-naphthalenyl)ethenyl]benzoate (3.0 g, 7.49 mmol) in tetrahydrofuran (60 mL) and ethanol (30 mL) was treated with 4N sodium hydroxide (9.36 mL, 37.6 mmol) and stirred for 30 hours. The reaction mixture was diluted with water and acidified to pH 2 with concentrated hydrochloric acid. The acid precipitated and was extracted into ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude residue was dissolved in dichloromethane (75 mL) and ethanol (50 mL), filtered through a sintered glass and the filtrate was concentrated. The title material precipitated and was collected and dried to give a white solid (2.455 g, 85%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:35](Cl)=[O:36]>O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[C:26]=2[C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH3:41])[CH:40]=[C:32]([CH3:31])[CH:33]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1
Reaction time: 0.2 h

Procedure:
To a cooled (0°) solution of 14.0 g. (0.105 mol.) of aluminum chloride in 100 ml. of nitrobenzene was added 11.2 g. (0.05 mol.) of 2-p-methoxyphenylbenzofuran followed immediately by 10.0 g. (0.06 mol.) of 3,5-dimethylbenzoyl chloride. The reaction mixture was stirred at 0° for 12 minutes (until the red color began to turn reddish-brown) then poured into water. The aqueous mixture was steam distilled to remove nitrobenzene and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with aqueous sodium carbonate and saturated sodium chloride solution, dried (MgSO4) and concentrated at reduced pressure to give a residue which was purified by column chromatography to give 2-p-methoxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran which was then crystallized from ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@:32]12([CH2:42][S:43](O)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]>CC(C)=O.CO>[C@@:32]12([CH2:42][S:43]([O:22][C@@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([C@H:14]([C:11]3[S:12][CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=3)[CH3:31])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC(C)=O
Solvent: CO
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OS(=O)(=O)C[C@@]12CCC(CC1=O)C2(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee); m.p. 164-166° C.; [α]=−30° (c=1, methanol, 25° C.); NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz). The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).