Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CC#N>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:36])=[O:35]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(NS(=O)(=O)c2ccccc2Cl)cc2ccoc12

Procedure:
The title product was prepared according to the procedure of Example 121, Step 4, starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (obtained in Example 121, Step 3) and 2-chlorobenzenesulfonyl chloride (0.043 g, 0.2 mmol). Yield: 0.017 g (26%). HPLC 94% RT=2.01 min (System A; 10-97% MeCN over 3 min), 98% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 534.2 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)=[O:10])[CH2:3]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:7]2[CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)=[O:10])[CH2:3][C@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared from the product of step (i) (1.4 g) and 4-cyanobenzenesulphonyl chloride (1 g) by the method of Example 58 step (ii) as a white solid. Yield: 0.41 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH2:26][CH2:25][C:24]1=[O:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:23]([CH3:22])[C:24](=[O:42])[CH2:25][CH2:26]3)[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(OC[C@H]4CCCN4C(=O)OC(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, reaction of (R)-2-((5-bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate A-55) and 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as a colorless solid. MS: 438.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH2:14][O:15][CH3:16].[Li]CCCC.[I:22]I>C1COCC1.CC(OC)(C)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]([I:22])[C:3]=1[O:13][CH2:14][O:15][CH3:16]
Reactant: COCOc1cc2c(c(F)c1F)OCCC2
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCOc1c(F)c(F)c2c(c1I)CCCO2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
16.6 g (72.1 mmol) of 7,8-difluoro-6-methoxymethoxychroman are initially introduced in 350 ml of THF, and 54.3 ml (86.5 mmol) of n-BuLi (15% soln. in hexane) are added dropwise at −78° C. When the addition is complete, the mixture is stirred at this temperature for 30 min and subsequently at 20° C. for 1 h. The solution is re-cooled to −78° C., and a solution of 22.0 g (86.5 mol) of iodine in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 1.5 h and subsequently diluted with MTBE. The solution is washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The crude product remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 7,8-difluoro-5-iodo-6-methoxymethoxychroman as a brownish oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1.[CH3:18]I.O>CN(C=O)C>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH3:18])[C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1
Reactant: O=C1NCCc2[nH]c3ccc(F)cc3c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(F)ccc31)C(=O)NCC2
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DMF (20 ml) at 21° under nitrogen. After 15 min, the solution was cooled (0°) and a 10% (v/v) solution of methyl iodide in DMF (1.6 ml) was added dropwise. After 10 min, water (150 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×50 ml), then brine (100 ml) and evaporated to give a solid which was purified by FCC Eluting with dichloromethane:methanol (80:1) to give the title compound (240 mg), m.p. 200°-202°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cccc(O)c1C
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Yield: 86.9 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (20 mL) were added ethyl 3-(3-hydroxy-2-methylphenyl)propanoate (197 mg) and cesium carbonate (511 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:16])[CH2:17][N:27]([CH3:28])[CH3:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3cccnc3)CO2)CCN(C)C1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CN(C)C)c2cccnc2)CCN(C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2,8-Dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.6 mmol) was added to 2M dimethylamine solution in THF (5 mL) and the reaction mixture was allowed to stir at 40° C. overnight. The progress of reaction was monitored by LCMS. The solvent was removed under reduced pressure to obtain a crude oily product that was purified by reverse phase HPLC to afford 50 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(dimethylamino)-2-(pyridin-3-yl)propan-2-ol as the TFA salt. 1H NMR (CDCl3, Free base) δ (ppm): 8.74 (s, 1H), 8.50 (d, 1H), 7.79 (d, 1H), 7.25 (dd, 1H), 7.16 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.08 (m, 2H), 3.83 (dd, 2H), 2.98 (m, 4H), 2.74 (d, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.98 (s, 6H). Separation by chiral HPLC provided enantiomers II-265a-b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[F:21][CH:22]([F:24])Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:22]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[F:24]
Reactant: FC(F)Cl
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(c2nc(C)nc3ccccc23)C(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100 mg, 0.35 mmol) in 3 mL of dimethylformamide in a 15 mL high pressure reaction vessel was cooled to −78° C. Diflurochloromethane (about 0.8 mL) was condensed into the solution, then cesium carbonate (160 mg, 0.49 mmol) was added. The reaction vessel was capped and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and cooled to −78° C. and the seal tube was uncapped, warm to room temperature and allowed to stand for 2 h. The reaction mixture was diluted with 50 mL of ethyl acetate and the organic layer was washed with water (50 mL×3), followed by saturated aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexane, 6 drops triethylamine/500 mL of solvent) to give the title compound (35 mg, 0.111 mmol, 32%). 1H NMR (CDCl3): 8.35 (dd, J=1.8, 8.1, 1H), 7.35−(m, 3H), 7.25 (t, J=72.1, 1H), 7.21-7.25 (m, 2H), 6.86-6.91 (m, 2H), 3.82 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.Cl.Cl[CH2:30][CH2:31][N:32]([CH2:37][CH2:38]Cl)[C:33]([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C>[C:33]([N:32]1[CH2:37][CH2:38][N:1]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=5)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:30][CH2:31]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)N(CCCl)CCCl
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)CC1
Yield: 31.7 %

Procedure:
A mixture of 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (90 mg, 0.243 mmol), N,N-bis(2-chloroethyl)-2-methylpropan-2-amine hydrochloride (114 mg, 0.486 mmol) and Na2CO3 (129 mg, 1.22 mmol) in t-BuOH (2 mL) was heated at reflux overnight. Purification by HPLC gave 7-(4-tert-butylpiperazin-1-yl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (40 mg, 0.077 mmol, 32% yield). MS (ESI) m/z 496.2 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.30 (1H, s), 8.60 (2H, d, J=1.53 Hz), 8.56 (1H, br. s.), 8.40 (1H, s), 8.07 (1H, d, J=8.55 Hz), 7.85 (1H, br. s.), 7.74-7.78 (2H, m), 7.20 (1H, d, J=1.83 Hz), 7.00 (1H, dd, J=8.85, 2.14 Hz), 3.23-3.28 (4H, m), 2.71 (4H, d, J=4.27 Hz), 1.08 (9H, s).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]1[C:28]2[N:27]=[C:26]([CH3:29])[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.O.NN>C(O)C>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[C:26]([CH3:29])[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: Cc1ccc2c(n1)C(N(CCCCN1C(=O)c3ccccc3C1=O)Cc1nc3ccccc3n1C(=O)OC(C)(C)C)CCC2
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(n1)C(N(CCCCN)Cc1nc3ccccc3[nH]1)CCC2
Reaction time: 96 h
Yield: 58.7 %

Procedure:
To a solution of 2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (228 mg, 0.384 mmol) in ethanol (10 mL) at room temperature was added hydrazine hydrate (0.10 mL). The mixture was stirred for 4 days. The mixture was concentrated in vaccuo and the resultant material was purified by column chromatography on silica gel (1:1:10 MeOH: NH4OH: CH2Cl2) to provide the product as a colourless oil (82 mg, 59%): 1H NMR (CDCl3) δ 1.25-1.45 (m, 4H), 1.60-1.70 (m, 1H), 1.81-1.93 (m, 1H), 1.97-2.04 (m, 1H), 2.10-2.18 (m, 1H), 2.46-2.56 (m, 3H), 2.62-2.82 (m, 6H), 3.95-3.99 (m, 1H), 4.00 (d, 1H, J=17.1 Hz), 4.09 (d, 1H, J=17.1 Hz), 6.98 (d, 1H, J=7.8 Hz), 7.15-7.21 (m, 2H), 7.30 (d, 1H, J=7.8 Hz), 7.57-7.60 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:11]([N:14]1[C:18]([NH2:19])=[N:17][N:16]=[N:15]1)[CH2:12][CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:19][C:18]1[N:14]([CH2:11][CH2:12][CH3:13])[N:15]=[N:16][N:17]=1)=[O:7]
Reactant: CCCn1nnnc1N
Reactant: O=C(O)c1cccc(F)c1
Product: CCCn1nnnc1NC(=O)c1cccc(F)c1
Yield: 52 %

Procedure:
Employing 0.25 g (1.8 mmol) of 3-fluoro-benzoic acid and 0.23 g (1.8 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.8:0.1:0.1) gave the product in 52% yield.
Reaction SMILES: [OH-].[K+].[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([O:28]C)=[O:27])=[CH:23][C:22]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:21][CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[N:3]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([OH:28])=[O:27])=[CH:23][C:22]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:21][CH:20]=4)[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCCC4)CC3)c(C(=O)O)c2c1
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Potassium hydroxide (0.699 g, 12.46 mmol) in water (10 mL) was added to a solution of methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.47 g, 2.493 mmol) in methanol (30 mL). The mixture was heated to reflux for 5 h before the solvent was removed under reduced pressure. The residue was acidified to pH 5-6 with 2N HCl, and the mixture was allowed to stand overnight at room temperature. The solvent was collected by filtration, washed with water, and dried via azeotrope with benzene to give 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.69 g, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=1.51 Hz, 1H), 8.09-8.15 (m, 3H), 7.91 (d, J=7.53 Hz, 1H), 7.80 (d, J=7.78 Hz, 1H), 7.69 (t, J=7.65 Hz, 1H), 3.51 (s, 2H), 3.28 (s, 3H), 2.48 (br. s., 2H), 2.33 (br. s., 4H), 2.04 (br. s., 1H), 1.84 (t, J=11.29 Hz, 2H), 1.43 (br. s., 6H), 1.29-1.38 (m, 2H), 0.95-1.11 (m, 2H); MS (m/z) 576.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][C:30](O)=[O:31])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][C:48]([OH:50])=O>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][C:30]([CH:48]([OH:50])[CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][NH2:33])=[O:31])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: NCCOCCOCCOCCOCCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCC(=O)C(O)CCOCCOCCOCCOCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
The mixture of pentafluorophenyl ester of Cholest-5-en-3β-yloxyacetic acid (175 mg, 0.29 mmol) and 15-amino-4,7,10,13-tetraoxapentadecanoic acid (160 mg, 0.60 mmol) was dried in an apparatus equipped with septum for 4 h at room temperature and 0.1 Pa. The apparatus was flushed with argon (2×) and then dry N,N-dimethylformamide (6 ml) and N-ethyldiisopropylamine (2 ml) were added through the septum and the mixture was stirred at room temperature for 16 h. Flash chromatography of the crude reaction mixture on silica gel column (200 ml) in toluene-ethyl acetate (gradient: 0-80% ethyl acetate, 10 ml/min, 160 min) gave (cholest-5-en-3β-yloxy)acetyl-15-amino-4,7,10,13-tetraoxapentadecanol acid (general formula X, where n3=1 and n4=3; 167 mg, 84%). For C40H69NO8Na HR-MS, calculated: m/z: 714.4915. found: m/z: 714.4916; 1H NMR (400 MHz, CDCl3) δ ppm: 5.34-5.38 m, 1H (CH2-5′); 4.00 s, 2H (CH2COO); 3.78 t, J=6.06 Hz, 2H (CH2-3); 3.59-3.68 m, 14H (7×CH2O); 3.52 q, J=5.47 Hz, 2H (CH2-14); 3.23 tt, J=11.24, 4.36 Hz, 1H (CH-3′); 2.61 t, J=6.00 Hz, 2H (CH2-2); 2.36 ddd, J=13.20, 4.70 (CH-4′a); 2.19-2.29 m, 1H (CH-4′b); 1.77-2.06 m, 5H (cholesteryl); 1.00 s, 3H (CH3-19′); 1.29 d, J=3.66 Hz, 24H (cholesteryl); 0.92 d, J=6.57 Hz, 3H (CH3-21′); 0.88 d, J=1.89 Hz, 3H (CH3-26′); 0.86 d, J=1.77 Hz, 3H (CH3-27′); 0.68 s, 3H (CH3-18′).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:15]([C:31]3[C:32]4[CH:39]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:31]3[C:32]4[CH:39]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.00 g, 1.76 mmol) in DCM (8 mL) was treated with 4N HCl in dioxane (2 mL). The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure to yield (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine trihydrochloride. LCMS (APCI+) m/z 468.2 [M+H]+; Rt=3.42 min.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27](OC)=[O:28])[CH2:24][CH2:25]2.N12CCN(CC1)CC2.C1(C)C=CC=CC=1>CO>[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:28])[CH2:24][CH2:25]2
Reactant: COC(=O)C1CCC2OC2C1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: C1CN2CCN1CC2
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)C1CCC2OC2C1
Yield: 90.4 %

Procedure:
To a 3-neck 100 mL flask equipped with an argon inlet, stir bar and distillation apparatus was added 1-octadecanol (5.03 g, 19 mmol, obtained from Sigma-Aldrich), methyl 3,4-epoxycyclohexanecarboxylate (ERL-4140, 8.69 g, 56 mmol, obtained from Dow Chemical Company), 1,4-diazabicyclo[2.2.2]octane (DABCO™, 1.02 g, 9.1 mmol, obtained from Sigma-Aldrich) and toluene (15 mL). The reaction mixture was refluxed until methanol ceased collecting in the receiving flask and the completion of the reaction was confirmed by 1H NMR spectroscopy. The still pot from the distillation was diluted with toluene (15 mL) and washed with brine (3×15 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed in vacuo. The excess methyl 3,4-epoxycyclohexane carboxylate was removed via Kugelrohr distillation under reduced vacuum to give 6.78 g (87%) of a white solid (mp=32-34° C.) of octadecyl 3,4-epoxycyclohexanecarboxylate. 1H NMR (CDCl3, δ): 4.06 (td, J=6.7, 1.9 Hz, 2H), 3.25-3.14 (m, 2H), 2.55-2.45 (m, 1H), 2.31-1.26 (m, 38H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)c3ncco3)cc2)n1

Procedure:
The title compound was prepared from (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 496 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:16])[C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:36]=1)#[N:2].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])([O:16][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:12]([F:14])([F:13])[F:15])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: COC(=O)CBr
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2cc(C#N)ccc2o1)C(F)(F)F
Product: COC(=O)COC(c1nc2cc(C#N)ccc2o1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F

Procedure:
The title compound was synthesized from tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 128-A) and methyl 2-bromoacetate following Example 109-A. MS (ESI+) m/z 574.3 (M+H).