Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:16]2[CH2:20][CH2:19][CH:18]([F:21])[CH2:17]2)=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH:5]=[N:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[SH:22][C@@H:23]([CH2:27][C:28]([OH:30])=[O:29])[C:24](O)=[O:25]>C1(C)C=CC=CC=1>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][N:6]1[C:24](=[O:25])[C@@H:23]([CH2:27][C:28]([OH:30])=[O:29])[S:22][CH:5]1[C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[C:3]=1[N:16]1[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]1
Reactant: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)C1
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@@H](CC(=O)O)SC1c1cccc(F)c1N1CC[C@H](F)C1

Procedure:
N-(3-Fluoro-2-(3-fluoropyrrolidin-1-yl)benzylidene)-3,3-dimethylbutan-1-amine (400 mg, 1.359 mmol) was taken in toluene and (S)-2-mercaptosuccinic acid (204.1 mg, 1.359 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. Then the reaction mixture was concentrated, triturated with ether and dried overnight to give crude 2-((5R)-3-(3,3-dimethylbutyl)-2-(3-fluoro-2-((S)-3-fluoropyrrolidin-1-yl)phenyl)-4-oxothiazolidin-5-yl)acetic acid which was used directly in the next step. The product was identified by HPLC and LC/MS. (LC/MS: m/z=427.2 M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:8]=1)=[O:6]
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2n[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ccccc32)n1
Yield: 68.2 %

Procedure:
Compound 9a was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 36 mg (0.13 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-cinnolin-4-one 8a, 7 mg (0.17 mmol) of 60% sodium hydride and 33 mg (0.17 mmol) of 2-bromomethyl-6-methyl-pyridine in 0.7 mL N,N-dimethylformamide at rt for 3 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. The HPLC fractions containing pure product were combined and lyophilized to give 34 mg of a pale yellow solid 9a as the trifluoroacetate salt: LC-MSD, m/z for C24H21N3O2 [M+H]+=384.5, HPLC retention time: 2.3 min; 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 2.85 (s, 3H), 6.1 (s, 2H), 7.15-7.2 (m, 1H), 7.25-7.3 (m, 1H), 7.45-7.55 (m, 2H), 7.6-7.7 (m, 3H), 7.7-7.8 (m, 1H), 8.0-8.1 (m, 1H), 8.3-8.4 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH:38]([N:41]([CH3:51])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:40])[CH3:39]>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:51])=[O:50])[CH2:49][CH2:48]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-isopropyl-N-methyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 737.4 [(M+H)+]
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1
Reactant: Cl
Reactant: OCCCCCCc1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCCCCc1ccncc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.03 ml) is added to 4-pyridinehexanol hydrochloride (2.42 g) and the mixture is stirred at 20° C. for 30 minutes. Excess saturated aqueous NaHCOs and CHCl3 (20 ml) is added. The organic phase is washed with saturated NaHCO3, brine and water, dried (MgSO4) and the solvent evaporated to give crude material which is purified by flash chromatography on silica gel (CH3OH:CHCl3 =1:49 by vol.) to give 4-(6-chlorohexyl)-pyridine as an oil.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][C:29](Cl)=[O:30]>N1C=CC=CC=1>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]([C:24]1[S:23][CH:27]=[CH:26][CH:25]=1)[C:29]([O:10][CH2:9]/[CH:8]=[C:7](\[CH3:11])/[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[O:30]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Reactant: O=C(Cl)Cc1cccs1
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/COC(=O)C(c1cccs1)c1cccs1)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol in 5 ml of anhydrous pyridine was added dropwise 2 ml of 2-thienylacetyl chloride under ice-cooling. After 1 hour, ice-water was added and extraction was done with ethyl ether. The ether layer was washed successively with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was distilled off to give an oily substance, which was then purified by a column chromatography with silica gel (15 g) to afford 1.1 g of the end product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:17].CN.C(O)(=O)C.[BH3-][C:25]#[N:26].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:17]
Reactant: O=C(CN1CCOCC1)c1ccc(Br)c(F)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCOCC1)c1ccc(Br)c(F)c1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To an ambient temperature solution containing 1.52 g of 1-(4-bromo-3-fluorophenyl)-2-(4-morpholinyl)ethanone (5.04 mmols) in 25 mL of THF was added 10.1 mL of MeNH2 (20.2 mmols, 2M solution in THF). After stirring for 15 min. 0.66 mL of acetic acid and 1.27 g of NaCNBH3 (20.2 mmols) were added to the reaction mixture. The reaction mixture was then warmed to 40° C. and stirred for 24 h. The reaction mixture was quenched with 10% aqueous Na2CO3 (10 mL). The reaction was diluted with 100 mL of EtOAc, and the layers were separated. The organic layer was washed with 10% aqueous Na2CO3 (1×10 mL) and saturated aqueous brine solution (1×10 mL). The organics were then dried over MgSO4, filtered through a frit, and concentrated. The crude title product was isolated as a brown solid (1.6 g, ˜100%) and used without further purification. MS (ES) m/e 317 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)(=[O:9])=[O:8]>[Ni].CO>[NH2:17][C:13]1[CH:12]=[C:11]([CH2:10][S:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=1
Reactant: COCCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COCCCNS(=O)(=O)Cc1cccc(N)c1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
N-(3-Methoxy-propyl)-C-(3-nitro-phenyl)-methanesulfonamide (0.31 g, 1.08 mmol) was hydrogenated over Raney nickel (0.05 g) in methanol at 50° C. and 70 psi for 4 h. Then, the catalyst was filtered off, washed with warm methanol, and the combined filtrates were evaporated to give 0.14 g (50%) of C-(3-amino-phenyl)-N-(3-methoxy-propyl)-methanesulfonamide
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCCCNc1ccnc2cc(Cl)ccc12
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCCNc3ccnc4cc(Cl)ccc34)CC2)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
The product of Preparation 2 (0.69 g, 0.00219 mol) and 1-(4-methoxyphenyl)piperazine (0.51 g, 0.00263 mol) were dissolved in THF (15 mL) and triethylamine (0.44 g, 0.00438 mol) was added. The reaction mixture was stirred and heated at reflux for 4 days. After cooling to room temperature, saturated NaHCO3 solution (30 mL) was added, and the mixture was extracted with chloroform (3×10 ml). The organic layer was dried over MgSO4 and evaporated. The resulting powder was dissolved in a mixture of methanol/ethyl acetate (1:3) (10 ml). After filtering, the solution was evaporated to give the title compound (0.09 g, 10%) as a solid.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH:28]([CH3:52])[CH:29]([OH:51])[CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][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][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][CH:28]([CH3:52])[CH:29]([O:51][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:30][OH:31])[CH2:12][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][CH3:26]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(C)C(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5.01 g of 50% sodium hydride in 100 ml of dimethylformamide containing 15.79 g of benzyl bromide at 0° C., was added 46 g of 3-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 50 ml of dimethylformamide. This mixture was stirred overnight at room temperature then poured into water and extracted with petroleum ether. The organic extract was dried and the solvent removed. The residue was dissolved in a mixture of 190 ml of methanol and 100 ml of tetrahydrofuran, then 400 mg of p-toluenesulfonic acid was added. This mixture was allowed to stand overnight, then the solvent was removed. The residue was dissolved in petroleum ether, washed wtih saturated aqueous sodium bicarbonate, dried and the solvent removed, giving and oil. This oil was purified by HPLC using the system hexane:ethyl acetate (9:1), giving 21.84 g of the desired compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([S:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Sc3ccc(Cl)cc3)c(=O)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of [8-chloro-3-(4-chlorophenylsulfanyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.26 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.25 g) and acetic acid chlorodifluoromethyl ester (0.13 mL) was stirred at 80° C. for 17 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (7:3 by volume) to afford title compound, 0.044 g.
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH3:15])=[O:13])[NH2:11])=[CH:7]1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[F:29][C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:2]([N:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH3:15])=[O:13])[NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]=2[F:29])=[CH:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCCCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Yield: 77.2 %

Procedure:
The same procedures as in Example 146 were carried out from the compound obtained in Example 145 (2.0 g), triethylamine (1.0 mL), 2-fluorocinnamic acid (1.2 g), WSC.HCl (1.4 g), and methylene chloride (60 mL), to give the captioned compound (2.1 g, 77%) as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1>CC#N>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:15]1[CH2:16][CH2:17][CH2:18][C:13](=[O:19])[CH2:14]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1C=CCCC1
Solvent: CC#N
Product: O=C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of 5-nitroindole (4.00 g, 25.61 mmol) in dry MeCN (5.00 mL) was added cyclohex-2-enone (7.40 mL, 76.83 mmol) and Bi(NO3)3 (0.12 g, 0.26 mmol) and the mixture stirred overnight at room temperature. The solvent then was evaporated and the crude was purified by column chromatography (50% Hexane:50% EtOAc) to obtain the title compound (2.70 g, 41%) as a yellow solid. 1H-NMR (CDCl3) δ 1.81-2.09 (m, 3H), 2.26-2.34 (m, 1H), 2.37-2.55 (m, 2H), 2.65 (dd, 1H, J=9.9, 12.9 Hz), 2.77-2.85 (m, 1H), 3.47-3.56 (m, 1H), 7.15 (d, 1H, J=2.1 Hz), 7.41 (d, 1H, J=9.0 Hz), 8.12 (dd, 1H, J=2.1, 9.0 Hz), 8.51 (s, 1H), 8.59 (d, 1H, J=2.1 Hz); EI-MS (m/z, %) 258 (M+, 100).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:12][CH2:13][CH:14]([CH2:16][OH:17])[OH:15]>N1C=CC=CC=1>[C:1]([O:12][CH2:13][CH:14]([OH:15])[CH2:16][O:17][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: OCC(O)CO
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
n-Nonanoyl chloride (23 g) was dropwise added to a stirred solution of glycerin (6.0 g) in dry pyridine (60 ml) at 0° to 5° C. over 30 minutes. The mixture was stirred at the same temperature for an hour, and then allowed to stand at room temperature overnight. The resultant mixture was poured into ice water (300 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with water (10 ml), 10% aqueous hydrochloric acid and a saturated aqueous solution of sodium chloride (40 ml) in turn, and then dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was subjected to column chromatography on silica gel (636 g) with a mixture of chloroform and acetone (30:1). The eluate was evaporated in vacuo to give 1,3-di-n-nonanoyloxy-2-propanol, mp 30°-31° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C=O.[C:14](O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCN(C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Piperidine-4-carboxylic acid ethyl ester (78 g) was dissolved in MeOH (1.2 L) at RT then formaldehyde (37%, 90 ml) and acetic acid (42 ml) were added and stirred for 2 h. The mixture was cooled to 0° C., NaCNBH3 (70 g) was added, and the mix was stirred for 20 min at 0° C., then overnight at RT. The mixture was cooled to 0° C. then quenched with 6N NaOH. The mixture was concentrated in vacuo to an aqueous layer, which was extracted with EtOAc (4×), brine-washed, dried over Na2SO4, and concentrated in vacuo to provide 1-methylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([OH:22])=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH:29]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(Cl)(Cl)Cl>[CH:29]1([O:22][C:17]2[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1cc2nccc(Oc3cccnc3O)c2cc1OC
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3cccnc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
6,7-Dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (21 mg) was dissolved in chloroform (7 ml) to prepare a solution. Potassium carbonate (300 mg) and cyclopentyl bromide (0.2 ml) were added to the solution. The mixture was stirred at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (14 mg, yield 55%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]\[C:51]2[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=2)=[CH:45][C:39]=1[O:40][CH2:41][C:42](O)=[O:43]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[C:46](/[CH:49]=[CH:50]\[C:51]4[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=4)[CH:47]=[CH:48][C:38]=3[O:37][CH3:36])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 783.2 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic ac id (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8i) (450 mg, 80% yield)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1C(C)=NOC=1C.Cl.ClCC[N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[H-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:11][N:12]=1
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)CCN(CCN2CCCCC2)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising 2-chloroethylpiperidine hydrochloride (Aldrich; 55 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (90 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:43])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:43])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCOCC4)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCOCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-morpholin-4-ylpropanamide, and the procedure described in General Procedure F. m/z (M+H)+ 585.4.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)([OH:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:14][C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[O:26][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OCC(O)(CCN(Cc2ccccc2)C(=O)CCl)c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CCN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of N-benzyl-2-chloro-N-[(3RS)-3-(3,4-dichlorophenyl)-3-hydroxy-4-(4-methoxyphenoxy)butyl]acetamide (7.41 g) in THF (741 mL) was added sodium tert-butoxide (1.37 g), and the mixture was stirred at 0° C. for 2 hr, and then stirred while warming to room temperature for 14 hr. To the reaction mixture was added water, and the mixture was concentrated. The concentrated residue was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.02 g).