Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([C:34](O)=[O:35])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:70]1([CH2:75][CH2:76][NH2:77])[CH2:74][CH2:73][CH2:72][CH2:71]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([C:34]([NH:77][CH2:76][CH2:75][N:70]2[CH2:74][CH2:73][CH2:72][CH2:71]2)=[O:35])=[CH:4]1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 44f) (7 g, 14.30 mmol) in N,N-Dimethylformamide (DMF) (50 mL) was added HATU (8.16 g, 21.45 mmol) and DIPEA (7.49 mL, 42.9 mmol), the resulting mixture was stirred at r.t. for 30 min. 2-(Pyrrolidin-1-yl)ethanamine (2.70 mL, 21.45 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with MeOH/DCM (0-30%) to afford 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (6.6 g, 11.27 mmol, 79% yield) as a pale yellow solid. LCMS: (M+H)+: 586.5.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: OB(O)c1ccccc1F
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 2-fluorobenzeneboronic acid. Light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.I.CS[C:27]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)=[NH:28]>C(O)C>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27](=[NH:28])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 99.1 %

Procedure:
A solution of compound 86 (0.45 g, 1.426 mmol) in dry ethanol (25 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.81 g, 2.853 mmol) at room temperature and resulting solution was stirred for 24 h. The solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and CH2Cl2 (50 mL). The organic layer was separated and aqueous layer was extracted into CH2Cl2 (2×25 mL). The combined organic layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 3:97) to obtain compound 87 (0.6 g, quantitative) as a foam. 1H NMR (DMSO-d6) δ 1.40-1.56 (m, 11H), 1.90-1.94 (m, 2H), 2.86-2.94 (m, 3H), 4.02-4.06 (m, 2H), 6.26 (s, 1H), 6.64 (dd, 1H, J=1.2, 8.4 Hz), 6.99 (s, 1H), 7.05 (d, 1H, J=1.8 Hz), 7.09 (dd, 1H, J=3.6, 4.9 Hz), 7.27 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.63 (s, 1H); ESI-MS m/z (%): 425 (MH+, 100).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].[CH2:20](I)[CH3:21].O>C1COCC1>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH2:20][CH3:21]
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Reactant: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Temperature: -78 °C
Yield: 70 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)-2-phenylethene (0.53 g, 1.7 mmol) in THF (10 mL) was added t-Butyl Li (1.1 mL, 1M in THF) at −78° C. After the addition complete, the solution was slowly heated to reflux for 30 min and then cooled down to −78° C. Ethyl iodide (1.2 eq, 0.27 mL) was added to the solution. Water (10 mL) was added after the completion of the reaction. THF was evaporated and the mixture was extracted with CH2Cl2 (3×5 mL). The extract was combined and dried over anhydrous magnesium sulfate. Evaporation of the solution followed by flash chromatography using 20% ether in hexane gave 1,3-dimethoxy-2-ethyl-5-(2-phenylethenyl)benzene in 70% yield. 1HNMR (CDCl3, ppm): δ 1.12 (t, J=7.2 Hz, 6H), 2.70 (q, J=7.2 Hz, 2H), 3.91 (s, 6H), 6.74 (s, 2H), 7.07 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]#[N:22]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[NH:22])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N#Cc1cccs1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10.4 g, 61.1 mmol) in toluene (400 ml) at 0° C., trimethylaluminum (2M solution in toluene, 46.8 ml, 91.6 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 2-thiophenecarbonitrile (10.0 g, 91.6 mmol) in toluene (200 ml) was added over 10 minutes and the mixture was heated to 80-850° C. After 16 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellow solid was stirred with ethyl acetate and filtered. The pale yellow solid (9.8 g, 57%) was used in the next reaction without: further purification: m.p. (DSC) 182° C. Anal. Calc'd. for C12H12N2S2O2: C, 51.41, H, 4.31, N, 9.99, S, 22.87. Found: C, 51.02, H, 4.37, N, 9.80, S, 22.93.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[CH:15]([O-])([O-])[O:16]CC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][OH:16]
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: CCOC([O-])[O-]
Product: COc1cc2c(cc1OC)C(=CO)C(=O)N2

Procedure:
As illustrated above in Scheme (A), the intermediate, 5,6-dimethoxy oxindole (I) is reacted with ethyl ortho formate (II) to provide 5,6-dimethoxy-3-hydroxymethylene oxindole (III). This oxindole (III) is then reacted with primary or secondary amines in refluxing benzene in the presence of acetic acid or toluene sulfonic acid to yield 5,6-dimethoxy-3-(substituted amino methylene) oxindoles (IV) or (V), respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.[CH2:14](OC(OCC)OCC)[CH3:15].[OH-].[Na+]>C(O)C.CCOCC>[CH3:13][C:8]1[CH2:7][C:6]2[C:10]([C:9]=1[O:12][CH2:14][CH3:15])=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOC1=C(C)Cc2ccc(OC)cc21
Reaction time: 72 h

Procedure:
6-Methoxy-2-methylindanone [1.76 g (0.01 mole)] is dissolved in 6.5 ml of absolute ethanol (containing 20% anhydrous ether). This solution is stirred with 2.4 g (0.016 mole) of triethylorthoformate and a drop of redistilled BF3C2H5O C2H5 for about 72 hours. The reaction mixture is diluted with ether, poured slowly into 8.1 ml of 5.0% sodium hydroxide solution with crushed ice with stirring. Two layers separate and the organic layer is washed with cold water until neutral followed by saturated sodium chloride solution and dried over sodium sulfate. This is then filtered and the solvent removed and the residue distilled with 1 ml of benzene solution which contains about 47.5 mg of anhydrous p-toluene sulfonic acid to obtain 2-methyl-3-ethoxy-5-methoxyindene.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Na].[CH2:23]([SH:29])[CH2:24][CH:25]=[CH:26][CH2:27][CH3:28]>>[CH2:23]([S:29][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH2:24][CH:25]=[CH:26][CH2:27][CH3:28]
Reactant: CCC=CCCS
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Agent: [Na]
Product: CCC=CCCSc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the sodium salt of 3-hexene-1-thiol to obtain 4-(3-hexenylthio)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, m.w., 413.4.
Reaction SMILES: OS(O)(=O)=O.[OH:6][CH2:7][C:8]([CH2:13][OH:14])([CH3:12])[C:9]([OH:11])=[O:10].[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[C:8]([CH2:13][OH:14])([CH3:12])[CH2:7][OH:6]
Reactant: CC(CO)(CO)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Add H2SO4 (4.5 g) to a suspension of 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid (100 g) in MeOH (1 L, HPLC grade solvent) and stir at room temperature through the week-end (ca. 70 h). Remove the solvent and partition the residue between EtOAc (1 L) and H2O (100 mL). Re-extract the aqueous layer with EtOAc, and dry the combined organic layers over MgSO4. Filter and concentrate under reduced pressure to yield 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid methyl ester. 1H NMR (CDCl3, 300 MHz): δ ppm 3.9 (d, 2H, J=11.1. Hz), 3.76 (s, 3H), 3.71 (d, 2H, J=1-1. Hz), 2.8 (bs, 2H), 1.1 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].OCC[CH2:18][CH2:19][NH:20][C:21](=[O:56])[C@H:22]([CH3:55])[CH2:23][C@H:24]([OH:54])[C@@H:25]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:26][C@@H:27]([CH:43]([CH3:45])[CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1>CN(C1C=CN=CC=1)C.O1CCCC1>[C:12]([O:11][CH2:8][CH2:9][CH2:18][CH2:19][NH:20][C:21](=[O:56])[C@H:22]([CH3:55])[CH2:23][C@H:24]([OH:54])[C@@H:25]([NH:46][C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:26][C@@H:27]([CH:43]([CH3:45])[CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCCO)C(C)C)ccc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCCOC(C)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30 ml of triethylamine, 2 mg of 4-(N,N'-dimethylamino)pyridine (DMAP) and 20 ml of acetic anhydride are added at 0° C. to 116 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid [N-(4-hydroxybutyl)]amide (Example 93) in 5 ml of tetrahydrofuran. The reaction solution is stirred for 18 hours at room temperature. The reaction mixture is partitioned between diethyl ether and water/saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by FC (40 g of silica gel, eluant: dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.60.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)[CH:16]=[O:17]>C1COCC1>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:16]=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
A solution of 3-bromobiphenyl (Aldrich; 1 molar eq.) in dry THF was cooled to −78° C. and treated with tert-butyl]ithium (Aldrich; 1.7 M in hexanes, 2 molar eq.) in a dropwise manner. The reaction was allowed to stir at −78° C. for 40 minutes. Dimethylformamide (Aldrich; 2.5 molar eq.) was added and stirring continued an additional 20 minutes. The mixture was partitioned in a separatory funnel between methylene chloride and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 5% ethyl acetate/hexanes. The desired aldehyde was obtained in 71% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[K+].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21]>C(OCC)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:20]=[O:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=Cc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-bromoindole (5.0 g) was added to a stirred suspension of potassium hydride (2.92 g) in diethyl ether (100 ml) at 0° C. The reaction mixture was stirred for 15 mins, cooled to −78° C. before tert-butyl lithium (31.5 ml) was added, and after 30 minutes dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 18 hrs and then poured into ice-cold 1N HCl the layers were separated and the aqueous was extracted with ethyl acetate (×3). The combined organic layers were washed with saturated sodium bicarbonate solution, brine, dried MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with Dichloromethane/Methanol (97/3, v/v) to afford a white solid (1.8 g).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]2[S:8](=[O:22])(=[O:21])[C:9]3[CH:16]=[C:15]([C:17](OC)=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:25][N:26]([Al](C)C)[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:27])[C:17]([C:15]1[CH:14]=[CH:13][C:10]2[CH2:11][CH2:12][C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:24]=[CH:23][C:7]=3[S:8](=[O:22])(=[O:21])[C:9]=2[CH:16]=1)=[O:18]
Reactant: CN(C)[Al](C)C
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(C)=O)cc1CC2
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)N(C)C)cc1S2(=O)=O
Temperature: 70 °C

Procedure:
To a solution of the ester from Step 1 (440 mg, 1.28 mmol) in dry toluene (5 mL) was added dropwise at room temperature a solution of N,N-dimethylamino dimethyl aluminum 0.8M in toluene (16 mL, 12.8 mmol). The resulting solution was heated to 70° C. for 2 hours. The reaction mixture was then cooled to 0° C. and quenched with excess ethyl acetate followed by addition of lN aqueous HCl. The solvents were removed under reduced pressure and the resulting solid was filtered, washed with ethyl acetate to afford the title product which was used as such for the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl.CO>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:9]3[C:4]4[O:3][CH2:2][O:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: c1cc2c(c(C3CCNCC3)c1)OCO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Benzo[1,3]dioxol-4-yl-piperidine (0.680 g, 3.31 mmol,) in dichloromethane (35 ml) and methanol (1 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.04 g, 4.31 mmol) and the solution was allowed to stir for 120 min. Sodium triacetoxyboron hydride (1.26 g, 5.96 mmol) was added portion wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude material was purified by flash chromatography on silica gel The crude material was purified by flash chromatography (methanol in dichloromethane 0-10%) to yield trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.43 g, 74%), MS (ISP) m/z=431.5 [(M+H)+].
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([CH:25]=[CH2:26])=[CH:20][N:19]=1>COCCOC.O.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>[Cl:24][C:23]1[C:18]([C:11]2[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[N:19][CH:20]=[C:21]([CH:25]=[CH2:26])[CH:22]=1
Reactant: C=Cc1cnc(Cl)c(Cl)c1
Reactant: Cc1ccc(B(O)O)cn1
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: COCCOC
Product: C=Cc1cnc(-c2ccc(C)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
8.1 g of Na2CO3 (76 mmol), 3.5 g of 6-methylpyridin-3-ylboronic acid (11) (25 mmol), and 0.97 g of Pd(PPh3)4 were added to 4.9 g of compound (8) (28 mmol) prepared in Example 5 dissolved in 100 mL of 1,2-dimethoxyethane and 100 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to obtain 5.2 g of 3-chloro-6′-methyl-5-vinyl-2,3′-bipyridine (yield 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C.C(OCC)(=O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[C:10]([C:21]([F:24])([F:23])[F:22])=[N:9][N:5]2[C:6]([OH:8])=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][C:4]=12
Reactant: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc(N2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12

Procedure:
To a solution of 5-chloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol (79 mg, 0.2 mmol) in ethanol (2 mL) was added morpholine (87 mg, 0.99 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 150° C. for three hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% HCl solution (5 mL). Organic layer was dried, filtered, and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (28 mg, 31%); LC/MS: MS (ES+) m/e 447 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.35 (br. s., 4H) 3.65-3.75 (m, 4H) 4.19 (s, 2H) 5.22 (s, 1H) 6.84 (s, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.52 (s, 1H) 11.28 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(CC([NH:23][CH:24](C#N)[C:25]([O-:27])=[O:26])=O)C.Cl>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][C@@H:24]([C:25]([OH:27])=[O:26])[NH2:23])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(CCl)cc1
Reactant: CCCC(=O)NC(C#N)C(=O)[O-]
Agent: Cl
Product: N[C@@H](Cc1ccc(C(=O)c2ccc(O)cc2)cc1)C(=O)O

Procedure:
FIG. 1 is a schematic showing the synthesis of HBPA. 4-(Chloromethyl)benzoyl chloride (II) is made by refluxing 4-(chloromethyl)benzoic acid with oxalyl chloride in benzene. Mixing this compound with pyridine with gentle heating using a steam bath followed by ice quench gave 4-chloro-methylbenzoic anhydride (III). 4-Chloromethylbenzoic anhydride (III) is reacted with phenol in polyphosphoric acid to give the 4-chloromethylbenzoyl ester of 4-chloromethyl-4'-hydroxybenzophenone (IV). Reacting IV with ethylacetamidocyanoacetate and subsequent hydrolysis with concentrated HCl gives racemic p-(4-hydroxybenzoyl)phenylalanine (HBPA, VI). D,L-HBPA is derivatized using standard Fmoc chemistry for incorporation into the peptide (e.g., at position 8 of substance P) by solid-phase synthesis. Radioiodination of L-HBPA8 -SP is accomplished using Chloramine-T. See "Experimental Procedures" for details. HBPA can also be prepared by procedures disclosed in Horner and Medem., Chem. Ber., 85:520 (1952), the teachings of which are incorporated herein by reference.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([O:48]CC5C=CC=CC=5)=[CH:44][CH:43]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[H][H]>[Pd].C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(O)cc2)c1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 4C (0.05 g) and 5% palladium on carbon (0.1 g) in ethanol (5 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight. The solid was removed by filtration, and filtrate was concentrated to provide the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:12]([N:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCCCN
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCCCC)C(=O)c1ccccc1C(=O)O

Procedure:
Reaction of phthalic anhydride and arachidyl amine to form N,N-diarachidyl phthalamic acid.