Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.CC(O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[C:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:33]1[CH2:38][CH2:37][CH:36]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH2:14][CH2:15]2)[CH2:35][CH2:34]1
Reactant: COc1ccc2cc(N3CCNCC3)ccc2c1
Reactant: O=C1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2cc(N3CCN(C4CCC(c5c[nH]c6ccc(F)cc56)CC4)CC3)ccc2c1
Temperature: 23 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To 400 mg (1.66 mmol) of 1-(6-methoxy-naphthalen-2-yl)-piperazine in 40 mL of CH2Cl2 and 100 mg of glacial HOAc at 23° C. was added 384 mg (1.66 mmol) of 4-(5-fluoro-1H-indol-3-yl)-cyclohex-3-enone followed by 216 mg, (1.89 mmol) of Na(OAc)3BH. After stirring at 23° C. for 12 hours, the reaction mixture was transferred to a separatory funnel and partitioned between water and CH2Cl2. The organics were washed with brine, dried over MgSO4, and chromatographed on silica gel eluting with 20:1 EtOAc:2 M NH3 in MeOH. The product fractions were pooled, stripped, and treated with 115 mg (1.3 mmol) of (CO2H)2 in absolute EtOH to give 640 mg (1.40 mmol, an 84% yield) of the oxalate salt of the title compound as a white crystalline solid. mp: 200-203° C.; MS (ES) m/z 458 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(O)(CC)(C)C.C(O)(=O)C>[F:23][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COCCOc1ccc(N)cc1
Solvent: CCC(C)(C)O
Solvent: CC(=O)O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1

Procedure:
tert-Butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)carbamate (800 mg, 2.37 mmoL) and 4-(2-methoxyethoxy)aniline (576 mg, 2.84 mmoL) were suspended in tert-amyl alcohol (14 mL) and acetic acid (5 drops). Heated to reflux for 4 h. After cooling, solvent was removed via rotary evaporation. The dark oil was partitioned between water/brine and THF (10 mL each), agitated, and separated layers and dried organic phase over sodium sulfate. The solvent was removed via rotary evaporation to afford a purple solid, 0.55 g. LC/MS (RT=2.997/(M+1)) 470.2. Additional 150 mg of product minus the (BOC) protecting group crystallized from the aqueous layer
Reaction SMILES: N1C=CC=CC=1C=O.CC1N=C(CO)C=CC=1.[OH:18][CH:19]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=[O:21].[OH:36][CH:37]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=1)=[O:39]>>[CH3:35][C:31]1[N:30]=[C:29]([C:19](=[O:18])[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=2)=[O:21])[CH:34]=[CH:33][CH:32]=1.[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:37](=[O:36])[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=1)=[O:39]
Reactant: Cc1cccc(C(=O)C(O)c2ccccn2)n1
Reactant: Cc1cccc(C(=O)C(O)c2cccc(C)n2)n1
Agent: Cc1cccc(CO)n1
Agent: O=Cc1ccccn1
Product: Cc1cccc(C(=O)C(=O)c2cccc(C)n2)n1
Product: Cc1cccc(C(=O)C(=O)c2ccccn2)n1

Procedure:
In addition, in the reaction between 2-pyridinecarboxaldehyde with (6-methylpyridine-2-yl)methanol shown below as reaction 5, the main products obtained are keto-enol compounds: 2-hydroxy-1,2-bis(6-methyl-2-pyridyl)-1-ethanone and 2-hydroxy-1-(6-methyl-2-pyridyl)-2-(2-pyridyl)-1-ethanone. Subsequent treatment with solvent produces 1,2-bis(6-methylpyridine-2-yl)ethane-1,2-dione and 1-(pyridine-2-yl)-2-(6-methylpyridine-2-yl)ethane-1,2-dione and in a much lesser quantity 1,2-bis(6-methylpyridine-2-yl)ethene-1,2-diol (M. J. Percino, V. M. Chapela, O. Urzua, H. Toribio, C. Rodriguez-Barbarin Journal of Chemical Research, (2007), 187).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[C:13]([Cu])#[N:14].C(OCC)(=O)C.O>CN(C=O)C>[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([OH:12])[CH:5]=1)[C:13]#[N:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(O)cc(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(O)cc(C#N)c1
Temperature: 170 °C
Reaction time: 1.25 h
Yield: 68.2 %

Procedure:
A solution of 403 mg of 3-bromo-5-tert-butylphenol and 200 mg (1.28 mmol) of CuCN in 5 mL of DMF was stirred at 160° C. After 75 min. 365 mg of CuCN was added and stirring was continued at 160° C. After about 1 h, the temperature was increased to 170° C. and the mixture was refluxed for 19 h. Ethyl acetate and H2O were added, and the mixture was filtered through a Buchner funnel, and the layers were separated. The organic layer was washed with 10 mL of H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided 153 mg of 3-tert-butyl-5-hydroxybenzonitrile as an orange solid in 49% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[CH3:27])[N:6]=1)=[O:4]
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Product: COC(=O)c1nc(-c2ccc(Cl)cc2C)c(C(F)(F)F)cc1N

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 4-chloro-2-methylphenylboronic acid analogously to Intermediate H; LC-MS Rt=1.53 mins, [M+H]+ 331 (Method 2 min LC_v002).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: O=C1CCCCC1c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccccc1
Yield: 43.9 %

Procedure:
A solution of 15 g (86 mmole) of 2-phenylcyclohexanone in 60 mL of carbon tetrachloride at -5° C. was treated via rapid dropwise addition with a solution of 14.4 g (90 mmole) of bromine in 70 mL of carbon tetrachloride so as to maintain the reaction temperature below 5° C. The color disappeared rapidly. The mixture was concentrated in vacuo to a brown solid and the solid triturated with methanol. The resulting white solid was collected by filtration to provide 9.55 g of product. After cooling the mother liquor at -25° C., an additional 5.2 g of solid was obtained, for a total yield of 68%, a portion of which was carried on directly in Step B below.
Reaction SMILES: [CH2:1](O)[C:2]([NH2:7])(CO)CO.Cl.[3H]C(N1CCC(C(C2C=CC(F)=CC=2)=O)CC1)(C(N1[C:26](=O)[NH:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:17]1=O)([3H])[3H])[3H].CS(C)=[O:45]>>[CH:22]1[C:21]([OH:45])=[CH:20][C:19]2[C:17]([CH2:1][CH2:2][NH2:7])=[CH:26][NH:25][C:24]=2[CH:23]=1
Reactant: NC(CO)(CO)CO
Reactant: CS(C)=O
Reactant: [3H]C([3H])(N1CCC(C(=O)c2ccc(F)cc2)CC1)C([3H])([3H])n1c(=O)[nH]c2ccccc2c1=O
Agent: Cl
Product: NCCc1c[nH]c2ccc(O)cc12

Procedure:
5-HT2A receptor binding assay was performed in reference to a method described by Hirose et al. (Japan. J. Pharmacol., 53, 321-329, 1990). After a reaction in a total volume of 200 μL of 50 mM Tris-HCl (pH=7.6) buffer solution containing 50 μL of [3H]-ketanserin (final concentration 1 nM), 1 μL of test drug in DMSO, and 149 μL of human 5-HT2A receptor-expressing CHO cell membrane sample, human 5-HT2A receptor binding activity of [3H]-ketanserin was measured. The reaction solution let stand for 15 minutes at 37° C., and then it was quickly added on a glass fiber filter plate (Multiscreen FB, Millipore inc.) coated with 0.05% Brij 35 and filtered under reduced pressure. The glass fiber filter was washed with 200 μL of ice-cooled 50 mM Tris-HCl (pH=7.6) twice, repeatedly filtered under reduced pressure, and then transferred to a vial containing 4 mL of Ecoscint A (National Diagnostics inc.). The residual radioactivity on the glass fiber filter was measured by a liquid scintillation counter. Nonspecific binding was measured in the presence of 10 μM of MDL-100907, and [3H]-ketanserin binding inhibition rate in the presence of 1 nM or 10 nM of test drug was determined. The results are shown in Tables 8 to 13.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:57])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:29](=[O:48])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:36]([O:38]C)=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:57])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:29](=[O:48])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]([NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[C:36]([OH:38])=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
A solution of methyl ester 45 (2.00 g, 2.18 mmol) in MeOH/THF/H2O (60 mL/60 mL/20 mL) was charged with NaOH (436 mg, 10.9 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH of the solution was adjusted to 5 with 1 N HCl. The suspension was partitioned between CH2Cl2 (50 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 46 (1.90 g, 97%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.08-4.00 (m, 1H), 3.98-3.89 (m, 2H), 3.27-3.10 (m, 4H), 3.02 (t, J=6.6 Hz, 2H), 1.86-1.65 (m, 4H), 1.64-1.24 (m, 14H), 1.43 (s, 18H), 1.42 (s, 18H).
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[CH:13][C:12]=1[O:34][CH3:35].ClC(Cl)(Cl)C(=N)O[C@H:40]1[C@@H:45]2[O:46][C:47](=[O:49])[O:48][C@@H:44]2[C@@H:43]([O:50][CH3:51])[C:42]([CH3:53])([CH3:52])[O:41]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:35][O:34][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([CH3:21])[C:11]=1[O:10][C@H:40]1[C@@H:45]3[O:46][C:47](=[O:49])[O:48][C@@H:44]3[C@@H:43]([O:50][CH3:51])[C:42]([CH3:53])([CH3:52])[O:41]1)[O:18][C:17](=[O:22])[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:15]2
Reactant: COc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@H]2OC(=O)O[C@@H]12
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.1 %

Procedure:
Boron trifluoride etherate (5.30 μL, 0.042 mmol) was added to 23a (50.0 mg, 0.14 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (171 mg, 0.47 mmol) in anhydrous CH2Cl2 (3.00 mL). After stirring at room temperature for 14 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25a as a colorless foam (74.0 mg, 95%): 1H NMR (CD2Cl2, 400 MHz) 8.29 (s, 1H), 7.64 (s, 1H), 7.47-7.39 (m, 5H), 6.91 (s, 1H), 5.52 (d, J=3.4 Hz, 1H), 5.26 (s, 2H), 5.23 (dd, J=8.4, 3.5 Hz, 1H), 4.95 (t, J=8.2 Hz, 1H), 3.92 (s, 3H), 3.60 (s, 3H), 3.33 (d, J=8.0 Hz, 1H), 2.42 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.6, 152.7, 152.1, 148.1, 144.8, 141.8, 134.5, 127.8, 127.7, 127.5, 127.3, 122.3, 120.2, 119.8, 115.1. 109.6, 105.2, 98.3, 82.0, 77.1, 66.5, 65.5, 59.4, 57.4, 55.1, 26.0, 20.9, 8.9; IR (film) νmax 2957, 2928, 2854, 2359, 2341, 1817, 1709, 1522, 1464, 1389, 1371, 1205, 1174, 1111, 1072, 1034, 957, 800 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C28H29NO11, 556.1819. found, 556.1822.
Reaction SMILES: C[B-:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[N+](C)(C)C.C1(Br)C=CC=CC=1.[Mg].B(F)(F)F.CCOCC>C(OCC)C>[C:15]1([B:2]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)C
Agent: FB(F)F
Agent: [Mg]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: c1ccc(B(c2ccccc2)c2ccccc2)cc1

Procedure:
In the case of the tetramethylammonium methyl triphenyl borate, concretely, its production is performed by reacting phenyl bromide with magnesium in diethyl ether to prepare a Grignard reagent, dripping it in a solution of boron trifluoride diethyl etherate in diethyl ether, and then stirring for several hours to obtain triphenylborane, followed by addition of methyllithium without isolating triphenylborane to convert it to lithium methyl triphenyl borate and by addition of tetramethylammonium bromide to effect ion exchange to obtain tetramethylammonium methyl triphenyl borate.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](O)=[O:35])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34]([NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:35])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCCc1ccccc1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccccc1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 67 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-phenylethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-phenethylisonicotinamide was obtained as a colorless solid in 67% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.90-8.86 (m, 1H), 8.55-8.50 (m, 2H), 8.06-8.03 (m, 2H), 7.64-7.47 (m, 4H), 7.34-7.18 (m, 5H), 3.54-3.48 (m, 2H), 2.87 (t, J=7.4 Hz, 2H); MS (ES+) m/z 346.5 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][C@@H:8]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.CN(C)C(=O)CN([C@H](C1C=CC=CC=1)C)C(=O)C[C@@H](CC1N=C(N)SC=1)C(N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:42].[OH-].[Li+].OO>>[CH:29]1([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:32])[C:9]([OH:10])=[O:42])[CH2:31][CH2:30]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)N(CC(=O)N(C)C)[C@@H](C)c1ccccc1)Cc1csc(N)n1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)CC1CC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H](CC1CC1)C(=O)O

Procedure:
The protected amide, 3(R)-(cyclopropylmethyl)-4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxobutanoic acid tert-butyl ester: Following the procedure of section (g) of example 2, the product of section (b) of this example (10.2 g, 30 mmol) was reacted with lithium hydroxide-hydrogen peroxide to give the desired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of 2(R)-(cyclopropylmethyl)butanedioic acid, as a colorless oil (6.65 g, 97%); [α]D23 +16.1° (c 2.61, CHCl3).
Reaction SMILES: [F:1][C:2]([F:17])([CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28]([CH:40]=O)[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]>COC(C)(C)C.O>[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28](/[CH:40]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:17])[CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]
Reactant: CC[C@H](C)CC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC[C@H](C)CC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of dimethyl ((5S)-3,3-difluoro-5-methyl-2-oxoheptyl)phosphonate (A) (74.7 g, 274 mmol) in t-butyl methyl ether (1120 ml), lithium hydroxide monohydrate (11.5 g, 273 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (B) (64.02 g, 160.6=1) in t-butyl methyl ether (278 ml) and water (21.7 ml) were added thereto, and the mixed solution was heat refluxed for approximately 31 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (351 ml) was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (234 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (351 ml), and dried with anhydrous magnesium sulfate (55 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2110 g; ethyl acetate:hexane=1:4 to 1:2). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane=1:4 to 1:2) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (C) (75.03 g; 137.8 mmol; yield: 85.8%) as a pale yellow oil.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[OH2:16]>CN(C=O)C>[Cl:3][C:2]1[N:1]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:5]([N:10]2[CH2:15][CH2:14][O:16][CH2:12][CH2:11]2)[N:4]=1
Reactant: C1COCCN1
Reactant: O
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 56 %

Procedure:
Cyanuric chloride (1.00 g, 5.42 mmol, 1.0 eq.) was dissolved in DMF (5 ml) and morpholine (2.11 ml, 24.4 mmol, 4.5 eq.) was slowly added into reaction mixture at 0° C., stirred for 20 minutes at the same temperature, poured to water and colorless precipitate was filtered, washed with hexane and diethyl ether and dried to provide the title compound as a colorless solid (860 mg, 56%).
Reaction SMILES: [Cl: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.[CH3:18][C:19]1[C:27]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=2)=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1>>[Cl: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:23](=[O:24])[C:22]3[CH:26]=[C:27]([C:28]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=4)[C:19]([CH3:18])=[N:20][CH:21]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Reactant: Cc1ncc(C(=O)O)cc1-c1noc(C(F)(F)F)n1
Product: Cc1ncc(C(=O)NCC(C)(C)c2nc(-c3ccc(Cl)cc3)cs2)cc1-c1noc(C(F)(F)F)n1
Yield: 59 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 6-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (28 mg, yield 59%). 1H NMR (400 MHz, CDCl3) δ 9.11 (br s, 1H), 8.80 (br s, 1H), 8.07 (br s, 1H), 7.79-7.77 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.35-7.33 (d, J=8.8 Hz, 2H), 3.86-3.84 (d, J=5.5 Hz, 2H), 3.02 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C23H19ClF3N5O2S: 521.09. found: 522.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>O1CCOCC1.C(Cl)Cl>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:11][NH2:12])[C:7]=1[I:8]
Reactant: Clc1ccnc(Cl)c1I
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: NNc1nccc(Cl)c1I
Temperature: 80 °C

Procedure:
To a solution of 2,4-dichloro-3-iodopyridine [CAS 343781-36-3] (4.7 g, 17.16 mmol) in 1,4-dioxane (240 ml), was added hydrazine monohydrate (5.096 ml, 102.962 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 16 h. After cooling, the solvent was concentrated in vacuo. The white solid residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous saturated solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was washed with diethylether. The solid thus obtained was discarded. The mothe liquours were concentrated in vacuo to yield intermediate compound D45 (2.31 g, 49%)
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[F:27][C:23]1[CH:22]=[C:21]([CH:11]2[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-3) (18.1 g, 38.2 mmol) in THF (76 mL) at room temperature was added TBAF (50 mL of a 1.0 M solution in THF, 49.7 mmol). The mixture was stirred at room temperature for 2 hours then poured into water. The mixture was extracted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The mixture was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (1-4). 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 1 H), 7.07 (bd, J=7.6 Hz, 1 H), 7.01 (bd, J=7.5 Hz, 1 H), 6.92 (dt, J=8.4 Hz, 1 H), 4.83 (bs, 1 H), 4.50 (q, J=5.2 Hz, 1 H), 3.89 (bs, 1 H), 3.58 (ddd, J=1.2, 3.6, 12.0 Hz, 1 H), 2.62 (bs, 1 H), 2.0 (dt, J=4.4, 17.6 Hz, 1 H), 1.23 (s, 6 H). MS m/z 304.1 (M+23)+.