Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:1].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(CCCn1ccnc1)c1ccc(Cl)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of 1-(4-chlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (2.20 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.58 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.3 g (39%) of product, mp 205°-207° C. (dec).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[NH:19][N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([C:41](=O)[CH2:42][CH2:43][CH3:44])[C:36](OCC)=[O:37])=[CH:30][CH:29]=1)#[N:21]>ClC1C=CC(Cl)=CC=1Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:36](=[O:37])[C:35]([CH2:34][C:31]3[CH:32]=[CH:33][C:28]([C:23]4[C:22]([C:20]#[N:21])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:29][CH:30]=3)=[C:41]([CH2:42][CH2:43][CH3:44])[N:19]3[N:18]=[CH:17][N:16]=[C:15]23)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1ccc(CN2CCC(Nc3ncn[nH]3)CC2)cc1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of 1-benzyl-N-(1H-1,2,4-triazol-5-yl)-piperidine-4-amine (7.53 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (14.41 g) in 1,2,4-trichlorobenzene (20 mL) was stirred at 195° C. for 2 days. The reaction mixture was cooled to room temperature and purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→50/50 (volume ratio)] to give the title compound (4.82 g, 30%) as a brown amorphous compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.Cl.[NH2:17]O.O>N1C=CC=CC=1>[C:10]1([CH2:9][CH:7]([NH2:17])[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)c1ccncc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NC(Cc1ccccc1)c1ccncc1
Reaction time: 4 h

Procedure:
5.34 g of benzyl 4-pyridyl ketone and 3.75 g of hydroxylamine hydrochloride in 50 ml of pyridine are heated to boiling for 4 hours. After cooling, the mixture is stirred into 600 ml of water, and the oxime (5.6 g) of melting point 194°-196° C. is filtered off. The oxime is hydrogenated with hydrogen in isopropanol with Raney nickel at 50° C. and under normal pressure. After the customary working up, the amine is obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10](S(C)=O)SC)=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:17]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:17])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CC(SC)S(C)=O)cc1
Solvent: CO
Product: COc1ccc(CC=O)cc1
Yield: 53 %

Procedure:
2.65 g of methyl 2-(p-methoxyphenyl)-1-methylthioethyl sulfoxide was dissolved in 50 ml. of methanol, and with the addition of 20 ml. of 1N sulfuric acid, the solution was heated for 6 hours at 50°C. The reaction mixture was concentrated at reduced pressure to 20 ml., and extracted with ether (150 ml., 2 times). The extracted layer was washed with water and then with an aqueous solution of sodium hydrogencarbonate, and dried with anhydrous sodium sulfate. It was then concentrated at reduced pressure, and the residue was subjected to column chromatography (silica gel, benzene and methylene chloride) to give 774 mg of p-methoxyphenylacetaldehyde as a colorless liquid. The yield was 53%, b.p. 61°-63°C/2.5 mmHg.
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:55].Cl.[NH2:57][C@@H:58]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:59]([OH:72])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH:69]([CH3:71])[CH3:70])[CH:64]=1>C(OCC)(=O)C.O1CCCC1.CO.O>[ClH:55].[ClH:55].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([NH:57][C@@H:58]([CH2:73][C:74]1[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=1)[C@H:59]([OH:72])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH:69]([CH3:71])[CH3:70])[CH:64]=1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCN(C)Cc1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(C)C)c2)c1
Reaction time: 16 h

Procedure:
Analogous to the method in Example SP-188, methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (50 mg, 0.2 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (17 mg, 0.4 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (2 mL), and diisopropylethylamine (140 μL, 0.8 mmol), HATU (95 mg, 0.25 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in Example SP-170, Step 4 (85 mg, 0.2 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 566.3 [M+H]+.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH2:18][C@@H:19]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cn1cc(C[C@@H](N)C(=O)OCc2ccccc2)c2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)OCc1ccccc1
Yield: 84.6 %

Procedure:
Boc-L-Leu-OH (1.30 g), HCl.H-D-Trp(CH3)-OBzl (1.76 g), WSCD (950 mg) and HOBT (827 mg) in DMF (30 ml) was reacted at 5° C. overnight in a similar manner to that of Preparation 1-1) to give Boc-L-Leu-D-Trp(CH3)-OBzl (2.48 g).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[C:29]([CH3:30])=[CH:28][C:27](N)=[CH:26][N:25]=2)[C:5]1=[O:32])[CH:2]=[CH2:3].Cl.OO.N([O-])=O.[Na+]>O1CCOCC1.C(O)(=O)C>[CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc(N)cc2C)C1=O
Agent: Cl
Agent: O=N[O-]
Agent: OO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncccc2C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-1-(5-amino-3-methylpyridin-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 113, Step B) (89 mg, 0.185 mmol) in 1,4-dioxane (4.0 mL) and acetic acid (0.50 mL) was added 3.0M HCl (730 μL, 2.2 mmol) at 0° C. After the reaction was stirred for 5 minutes, hydrogen peroxide (6% wt aq., 95 μL, 0.185 mmol) was added dropwise, followed by sodium nitrite (46 mg, 0.74 mmol). The reaction mixture was stirred for 2 hours at 0° C. The reaction mixture was warmed to room temperature, quenched with 1M NaOH and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 55% EtOAc/Hex, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: C(OC(N1CC(=C)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)C.[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78](Br)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57].[CH3:84][O:85][C:86](=[O:121])[NH:87][CH:88]([C:92]([N:94]1[CH2:98][CH2:97][CH2:96][CH:95]1[C:99]1[NH:103][C:102]2[C:104]3[C:109]([CH2:110][CH2:111][C:101]=2[N:100]=1)=[CH:108][C:107](B1OC(C)(C)C(C)(C)O1)=[CH:106][CH:105]=3)=[O:93])[CH:89]([CH3:91])[CH3:90]>>[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78]([C:107]4[CH:108]=[C:109]5[C:104](=[CH:105][CH:106]=4)[C:102]4[NH:103][C:99]([CH:95]6[CH2:96][CH2:97][CH2:98][N:94]6[C:92](=[O:93])[CH:88]([NH:87][C:86]([O:85][CH3:84])=[O:121])[CH:89]([CH3:91])[CH3:90])=[N:100][C:101]=4[CH2:111][CH2:110]5)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc1CC2)C(C)C
Yield: 73.9 %

Procedure:
This compound was synthesized using the procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.641 g, 1.449 mmol) and (2-Methyl-1-{2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (1.06 g, 2.029 mmol) to give 2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.812 g, 74% yield) as a solid. LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.75 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.30 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.17 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 0.5 hour at −78° C. and to the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4→1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 131) (204 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17](O)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([O:29][Si](C)(C)C)=[C:26]([CH3:28])[CH3:27]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:26]([CH3:28])([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol (0.41 mmol) in 20 mL of CH2Cl2 at 0° C. was added 1M TiCl4 in CH2Cl2 (0.5 mmol) all at once. After 30 min, (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.24 mL, 1.2 mmol) was added and the reaction was warmed to rt and stirred overnight. The reaction was quenched with water and extracted with CH2Cl2. The CH2Cl2 extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoate. MS found: (M+H)+=383.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[CH3:33][C:34](OC(C)=O)=[O:35]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:34](=[O:35])[CH3:33])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)[C@H]2CCCc3cccnc32)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCN(Cc1ncc(C)cc1C)[C@H]1CCCc2cccnc21
Yield: 41.7 %

Procedure:
To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (56 mg, 0.17 mmol) in CH2Cl2 (3 mL) was added Et3N (70 μL, 0.50 mmol) followed by Ac2O (30 μL, 0.32 mmol). The resultant solution was stirred at room temperature for 70 minutes. The mixture was diluted with CH2Cl2 (20 mL), washed with brine (3×5 mL), dried (Na2SO4), and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 40:1:1 CH2Cl2-MeOH—NH4OH) provided 27 mg (43%) of the free base of the title compound as a colorless oil. Using General Procedure D: Conversion of the oil to the HBr salt gave COMPOUND 365 as a white solid. 1H NMR (D2O) δ 1.11-1.39 (m, 4H), 1.82-1.85 (m, 4H), 1.97-2.27 (m, 2H), 2.41-2.49 (m, 8H), 2.65-2.72 (m, 1H), 2.98 (br s, 4H), 4.17 (d, 1H, J=17.7 Hz), 4.36 (d, 1H, J=17.7 Hz), 4.48 (dd, 1H, J=5.4, 10.2 Hz), 7.86 (dd, 1H, J=7.8, 5.7 Hz), 8.22 (s, 1H), 8.34 (d, 1H, J=7.8 Hz), 8.44 (s, 1H), 8.59 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 16.95, 17.50, 20.48, 20.60, 22.17, 25.55, 26.51, 27.82, 38.95, 52.01, 52.43, 61.54, 125.80, 136.33, 137.29, 137.53, 139.25, 140.56, 148.02, 149.11, 151.32, 174.09; ES-MS m/z 381 (M+H). Anal. Calcd. For C23H32N4O.3.0HBr.3.0H2O: C, 40.79; H, 6.10; N, 8.27; Br, 35.39. Found: C, 40.73; H, 6.04; N, 8.02; Br, 35.61.
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.CN(C=O)C.[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>CCOCC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:20][C:17](=[O:19])[CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCBr)cc2)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCOC(C)=O)cc2)cc1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
60 m moles(10.9 g) of tetramethylammonium hydroxide pentahydrate was added into a DMF solution of 60 m moles(3.6 g) of acetic acid, stirred for one hour, then 50 m moles(27.3 g) of the above 4'-(16-bromohexadecyloxy)biphenyl-4-carboxylic acid ethyl ester was added, and stirred for 12 hours. The reaction solution was ether extracted and concentrated, then purified by column chromatography to obtain 18.1 g of 4'-(16-acetyloxyhexadecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 69%)
Reaction SMILES: C([O:4][CH2:5][CH:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.C[O-].[Na+].CO.Cl>CO>[C:19]([O:18][C:16]([NH:15][C@@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@H:6]([OH:23])[CH2:5][OH:4])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(=O)OCC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suitable reactor was added 4a (52.3 g, 162 mmol), MeOH (810 mL), and 25% NaOMe/MeOH (8.1 mmol) at 20-30° C. under N2. The mixture was stirred at 20-30° C. for 2 hr, and 1 N HCl aqueous solution (16.2 mmol) was added at this temperature. The separated organic portion was concentrated at 40-50° C. under reduced pressure. Toluene (1100 mL) was added and the mixture was heated to 108-110° C. for dissolution. The mixture was cooled to 45-50° C. and stirred for 30 min. The mixture was further cooled to 20-30° C. and stirred for 1 hr. The mixture was filtered, and the filtered cake was washed with toluene (220 mL). The wet cake was dried at 40-50° C. under reduced pressure to give diol 7 as an off-white to white powder (39.5 g, 87% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[NH2:20][CH2:21][CH2:22][OH:23].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:20][CH2:21][CH2:22][OH:23])[N:14]=1)=[O:8]
Reactant: NCCO
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCCO)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate 7) was taken up in tetrahydrofuran and an excess of the 2-amino-ethanol (20 equiv.) was added. The reaction was allowed to stir overnight at room temperature. The reaction was poured into water and extracted with EtOAc, partitioned with brine, dried over Na2SO4, filtered, and volatiles were removed in vacuo. The resulting solid was triturated with EtOAc, followed by diethyl ether to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21]1(/[CH:27]=[CH:28]/[CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:30][CH:29](/[CH:28]=[CH:27]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=C/C=C/c1ccccc1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: CN1OC(/C=C/c2ccccc2)CC1(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
A mixture of compound 2 (11.02 g, 0.042 mol) and trans-1-phenyl-1,3-butadiene (8.0 g, 0.062 mol) in 500 ml of toluene is heated to 85° C. and held there for 72 hours, cooled and evaporated to dryness. The oil that remained is purified by flash chromatography on silica gel (eluent comprised of 98% CHCl3 and 2% MeOH by volume). The resulting semisolid is dissolved in chloroform, decolorized with carbon, and filtered through a bed of celite. The solvent is evaporated and the resulting tan solid recrystallized from ethyl acetate/hexane, m.p. 166°-169° C. (Found: C, 78.68; H, 6.39; N, 10.60. C26H25N3O requires: C, 78.96; H, 6.37; N, 10.62).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][S:19](O)(=[O:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][S:19]([Cl:27])(=[O:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: O=S(=O)(Cl)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
(1-(3-(Trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methanesulfonic acid was dissolved in benzene (3 ml), thionyl chloride (0.034 ml) was added and the mixture was refluxed for 4 h. After cooling, the reaction mixture was concentrated in vacuo and the crude product was employed in the next stage without purification.