Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:25][C@@H:26]2[O:31][C@@H:30]([CH2:32]O)[C@H:29](O)[C@@H:28](O)[C@@H:27]2[NH:36]C)[C@@]1(O)C=O.CC(N)C([NH2:52])CCCCCC(O)=O.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>CC(=O)OCC>[NH2:36][C@H:27]([C:26]([OH:31])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:32][NH2:52]
Reactant: CC(N)C(N)CCCCCC(=O)O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 37 °C
Reaction time: 8 h

Procedure:
First, the pAET7 plasmid described in Example 1 was introduced into a wild-type strain of M. methylotrophus AS1 (NCIMB10515), and a transformant was selected in an SEII agar medium containing 50 mg/L streptomycin. The pMIV-FRTKmFRT-EA plasmid was introduced into the strain by electroporation in accordance with the method described in Example 2, and strains to which the mini-Mu cassette (EA unit) including the lysE24+dapA* genes was transferred to the chromosome were selected in an SEII agar medium containing 50 mg/L streptomycin and 20 mg/L kanamycin. From the strains, 200 strains were selected randomly and inoculated on SEII plates containing 50 mg/L streptomycin and 20 mg/L kanamycin, followed by culturing at 37° C. overnight. Then, bacterial cells present on the medium surface of about 0.3 square centimeters were scraped off and inoculated into an SEII production medium (5 ml) containing 50 mg/l streptomycin and 20 mg/L kanamycin, and the cells were cultured with shaking at 37° C. for 34 hours. After completion of culture, the bacterial cells were removed by centrifugation, and the concentration of L-lysine in each culture supernatant was measured using a Biotech-analyzer AS-210 (manufactured by Sakura Seiki Co., Ltd.) to select the strain having the highest concentration of L-lysine. The strain was designated as V1. Transfer was repeated 12 times in the same way as Example 3 to obtain the V12 strain. The amount of Lys produced by V1 was defined as 100, and the relative value of the amount of Lys produced by the V12 strain was calculated and shown in Table 9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[N-:12]=[N+:13]=[N-:14].[Na+]>>[N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCBr
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCCCC(=O)O

Procedure:
Reaction of 8-bromooctanoic acid and NaN3, as described for the synthesis of 6, gave 8-azidooctanoic acid 11. Saponification was not necessary. Used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33]I>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:33][CH2:32][O:31][CH3:30])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: COCCI
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a solution of 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (17 g) in dimethylformamide (50 ml) is added gradually sodium hydride (60% dispersion-type) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is cooled with ice, and thereto is added 2-methoxyethyl iodide (10.3 g). The mixture is stirred at room temperature for 2 hours, and heated to 80° C. One hour thereafter, the reaction solution is allowed to cool, and concentrated. The resulting residue is dissolved in ethyl acetate, washed with water, dried, and concentrated. The precipitated crystal is washed with diethyl ether to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-(2-methoxyethyloxy)-7-methoxynaphthalene (8.5 g).
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@@H:4]([NH2:18])[CH2:3][C@@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C[C@@H](F)C1

Procedure:
Following the procedure for Example 101, starting with Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 126 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.80 (s, 1H), 7.37-7.28 (m, 2H), 7.08-6.98 (m, 3H), 6.13 (s, 2H), 4.83-4.78 and 4.72-4.68 (2 m, 1H), 3.79-3.72 (m, 3H), 3.54-3.30 (m, 3H), 3.24-3.12 (m, 2H), 2.31-2.22 (m, 1H), 2.18-2.07 (m, 1H), 1.93-1.76 (m, 2H). LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])OC2=O)[NH:3]1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][NH:29][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:8][CH2:7][C:4]1[NH:3][C:2](=[O:1])[NH:6][N:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]nc(Cn2c(=O)oc(=O)c3ccccc32)[nH]1
Reactant: NOCc1ccccc1
Agent: Cl
Product: O=C(NOCc1ccccc1)c1ccccc1NCc1n[nH]c(=O)[nH]1

Procedure:
Starting materials: 1-(5-Oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (see preparation 7E) and O-benzyl-hydroxylamine hydrochloride (Aldrich).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[C:45](=[O:46])[C:44]3[S:43][C:42]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=4[C:36]=3[CH:35]=[N:34]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:30]=[C:22]3[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:27]([N:24]1[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:33]5[C:45](=[O:46])[C:44]6[S:43][C:42]7[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=7[C:36]=6[CH:35]=[N:34]5)[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:30]=[C:22]2[CH2:23]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)cc2C1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
A mixture of {4-[5-({5-acetyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridin-3-yl}methyl acetate 247a (100 mg, 0.16 mmol) and lithium hydroxide (96 mg, 4.0 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at 35° C. for 30 min. The mixture was concentrated under reduced pressure. To the residue was added water (5 mL) and the resulting mixture was extracted with dichloromethane three times. The combined organic layer was then concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 247 (51 mg, 53%). MS-ESI: [M+H]+ 599.3. 1H NMR (500 MHz, DMSO-d6, T=80° C.) δ 8.54-8.51 (m, 1H), 8.38 (d, J=3.0 Hz, 1H), 7.93-7.91 (m, 2H), 7.48 (d, J=8.5 Hz, 1H), 7.35 (d, J=3.0 Hz, 1H), 6.00 (s, 1H), 4.64-4.62 (m, 2H), 4.39 (s, 2H), 3.98-3.95 (m, 2H), 3.89-3.86 (m, 2H), 3.58 (s, 3H), 2.95-2.93 (m, 2H), 2.87-2.84 (m, 2H), 2.08 (s, 3H), 1.89-1.87 (m, 4H).
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH:11]=2)[CH:6]=[N:5]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.[BH3-]C#N.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:30]1([NH:35][CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:20][CH:21]=4)[CH:11]=3)[CH:6]=[N:5]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCC1
Reactant: O=CCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1ccc2cnn(CCNC3CCCC3)c2c1
Reaction time: 18 h

Procedure:
A mixture of N-[1-(2-oxoethyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide (20 mg, 0.05 mmol) and cyclopentylamine (10 μL, 0.10 mmol) in THF (1 mL) was stirred at room temperature for 0.5 hours after which NaCNBH3 (0.104 mL, 0.010 mmol, 1 M in THF) was added and the mixture was stirred for an additional 18 hours. The mixture was diluted with ethyl acetate (2 mL), washed with H2O (1 mL), concentrated under reduced pressure and purified by reverse phase-HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.5 (m, 6 H), 1.9 (m, 2 H), 2.9 (m, 1 H), 3.4 (m, 2 H), 3.8 (m, 2 H), 4.6 (t, 2 H), 7.0 (m, 4 H), 7.1 (m, 2 H), 7.4 (m, 4 H), 7.7 (m, 1 H), 8.05 (s, 1 H), 8.3 (s, 1 H), 8.6 (m, 1 H), and 10.4 (s, 1 H); MS (ESI) 455.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[C:24](Br)[CH:23]=[N:22][CH:21]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[C:24]([N:13]2[CH2:14][CH2:15][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:12]2=[O:16])[CH:23]=[N:22][CH:21]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: O=C1NCCN1c1ccc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cncc(N2CCN(c3ccc4ccccc4c3)C2=O)c1
Yield: 26.9 %

Procedure:
Using the same reaction conditions as in Example 79, 1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 100 mg, 0.4711 mmol) was reacted with 5-bromo-nicotinic acid methyl ester (112 mg, 0.5182 mmol), 1,4-dioxane (10 mL), copper iodide (11 mg), trans-1,2-diamino cyclohexane (22 mg) and potassium phosphate (200 mg, 0.9422 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% EtOAc in hexane) afforded 44 mg of the product (26.99% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[C:4](S)[N:3]=1>OO>[OH:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1
Reactant: Cc1nc(S)nc(O)c1C(C)C
Agent: OO
Product: Cc1ncnc(O)c1C(C)C
Temperature: 72.5 °C
Yield: 38 %

Procedure:
550 ml of 12 percent hydrogen peroxide solution was heated to 60° C. 4-Hydroxy-5-isopropyl-6-methylpyrimidine-2-thiol (50 g, 0.27 mole) was added in portions. The temperature was maintained at 70-75° C. by rate of addition and application of external heat. 20 min. after completion of the addition approx. 150 ml of distillate was removed under vacuum. The pH was adjusted to 7-8 by addition of 50 percent NaOH solution and the solution of was saturated with solid NaCl. The precipitated product was taken up in 150 ml dichloromethane. The inorganic solids were removed from the aqueous phase by filtration and the filtrate was extracted with dichloromethane (4×50 mL). The combined extracts were dried over sodium sulfate and evaporated to yield 15.6 g (38 percent yield).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[C:19]([NH2:26])=[C:20]([NH2:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1>>[Cl:17][C:18]1[C:19]2[NH:26][C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)=[N:25][C:20]=2[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1cc(Cl)cc(Cl)c1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4cc(Cl)cc(Cl)c4[nH]3)cc2)S1

Procedure:
4,6-Dichloro-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 3,5-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36](F)=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2].C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C(N3CC[C:80]([F:84])([F:83])[CH2:79]3)=O)C=C(Br)C=2)C=1CCC(OCC)=O)C.FC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([C:28]([N:29]3[CH2:31][CH2:79][C:80]([F:84])([F:83])[CH2:30]3)=[O:32])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N3CCC(F)(F)C3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Yield: 97 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (112 mg, 0.16 mmol), 3-fluorophenylboronic acid (45.23 mg, 0.32 mmol), PdCl2(dppf) (17.63 mg, 0.024 mmol) and cesium carbonate (105.6 mg, 0.32 mmol) in 1,2-dimethoxyethane (5.0 mL) to obtain 4-[3-{6-[5-(3,3-difluoro-pyrrolidine-1-carbonyl)-3′-fluoro-biphenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (111 mg, 97%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>C(O)C.O>[O:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCCCCCCOc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCOc2ccccc2)cc1

Procedure:
A mixture of 16.5 g of ethyl p-aminobenzoate, 10.3 g of 11-phenoxy-1-undecanol O-methanesulfonate and 50 ml of hexamethylphosphoramide is heated at 100°-110° C. for 20 hours, chilled, and diluted with 30 ml of ethanol and 10 ml of water. Chilling and filtering gives a solid which is washed with ethanol-water (1:1) and with water to give yellow crystals, mp 83°-87° C. Recrystallization from ethanol gives yellow needles, mp 89°-90° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1)(=[O:3])[CH3:2].B.CSC.[OH2:36].[Na]>C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([C@@H:8]([OH:36])[CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:13][CH2:12]4)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CCC3=C2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]32)C1
Reactant: O
Agent: B
Agent: [Na]
Solvent: CSC
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@]2(C)C3=C(C[C@H](O)[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Temperature: 0 °C

Procedure:
Cholesta-5,8-diene-3β-yl acetate (1.0 g) is dissolved in 250 ml diethylether. The reaction mixture is cooled to 0° C. and 2.35 ml of borane-dimethylsulphide-complex (2 M solution in tetrahydrofuran) is added. The reaction mixture is warmed to room temperature within 2 hours. Then, 26 ml water, 26 ml sodium hydroxyde solution (10 % aqueous) and 3.65 ml hydrogen-peroxyde (30%) are added at 0° C. After aqueous work-up and column chromatography 3β-(acetyloxy)-5α-cholest-8-ene-6α-ol (140 mg) is isolated.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][CH2:32][CH3:33].C(OCC)(=O)C.CCCCCC>CC(C)=O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4O)c3c2CC1
Reactant: CCCI
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)c1ccccc1)CC3

Procedure:
A slurry of 2-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenol (357 mg, 0.93 mmol), CS2CO3 (1.24 g, 3.82 mmol) and 1-iodopropane (195 mg, 1.15 mmol) in acetone (10 mL) was stirred at room temperature under nitrogen for 15 hours. The reaction was filtered and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow oil which was passed through a column of silica gel with 50% ethyl acetate/hexane to give 276 mg (70%) of a white foam as the title compound: MS m/z 425.3 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>>[CH3:27][CH:28]([CH3:32])[C:29]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:30]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C)C(=O)Cl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C(C)C)c4)CC3)cccc2n1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-methylpropanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:13][C:12]([CH:14]([OH:45])[CH:15]([NH:24][C:25]([CH:27]2[N:32]3[C:33](=[O:44])[CH:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:35][CH2:36][C:37](=[O:38])[N:31]3[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:11][CH:10]=1.C(NC1C(=O)N2C(C(NC(C(=O)COC(=O)C3C(Cl)=CC=CC=3Cl)CC(OC(C)(C)C)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1.[K+].[Br-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:13][C:12]([C:14](=[O:45])[CH:15]([NH:24][C:25]([CH:27]2[N:32]3[C:33](=[O:44])[CH:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:35][CH2:36][C:37](=[O:38])[N:31]3[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NS(C)(=O)=O)C(=O)N12)C(O)c1ncc(-c2c(Cl)cccc2Cl)o1
Agent: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NS(C)(=O)=O)C(=O)N12)C(=O)c1ncc(-c2c(Cl)cccc2Cl)o1

Procedure:
was prepared from 218b in an analogous way to compound 216e as an off-white powder (675 mg, 81%) mp 100-200° C.; [α]D24 −84.9 (c 1.01, CH2Cl2); IR (KBr) 3336, 2978, 2936, 1719, 1674, 1510, 1433, 1421, 1369, 1329, 1274, 1257, 1155, 991, 789; 1H NMR (CDCl3) δ7.47-7.38 (4H, m), 7.24 (1H, d), 5.61-5.53 (1H, m), 5.48 (1H, d), 5.38-5.30 (1H, m), 4.67-4.45 (2H, m), 3.48-3.18 (2H, m), 3.04-2.90 (2H, m), 2.97 (3H, s), 2.69-2.54 (1H, m), 2.42-2.32 (1H, m), 2.22-2.15 (1H, m), 2.07-1.93 (3H, m), 1.71-1.65 (2H, m), 1.38 (9H, s); Anal. Calcd for C28H33N3Cl2O9S: C, 48.98; H, 4.84; N, 10.20; S, 4.67. Found: C, 48.73; H, 4.95; N, 9.65; S, 4.54. MS (ES+) 692/90/88 (M+ +1, 100%), 636/4/2 . (71). Accurate mass calculated for C28H34N5Cl2O9S (MH+): 686.1454. Found: 686.1474.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=[O:19])=[CH:7]2.[CH2:20]([Li])[CH3:21]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:18]([OH:19])[CH2:20][CH3:21])=[CH:7]2
Reactant: [Li]CC
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Product: CCC(O)c1cc2cccc(C)c2nc1-c1ccccc1

Procedure:
The title compound was prepared in a similar manner to Intermediate 55, using 8-methyl-2-phenylquinoline-3-carboxaldehyde and ethyllithium (0.5N solution in ether, 4.6 mL, 2.3 mmol) and was obtained as a white solid (85 mg, 33%) after purification by column chromatography (SiO2, 10-50% EtOAc in heptane). δH (CDCl3) 8.35 (s, 1H), 7.66-7.72 (m, 1H), 7.40-7.62 (m, 7H), 4.96-5.04 (m, 1H), 2.80 (s, 3H), 1.97 (d, J 3.8 Hz, 1H), 1.60-1.70 (m, 2H), 0.84 (t, J 7.3 Hz, 3H). LCMS (ES+) 278 (M+H)+, RT 3.91 minutes (Method 3).