Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:22]=2[O:34][CH3:35])=[C:7]([O:36][CH3:37])[CH:6]=1)=[O:4].C([O-])(O)=O.[Na+].[O:43](C(OC(C)(C)C)=O)[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=O>C1COCC1>[C:47]([O:46][C:44]([N:17]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:22]=1[O:34][CH3:35])[CH2:16][CH2:15][O:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[O:36][CH3:37])=[O:43])([CH3:50])([CH3:49])[CH3:48]
Reactant: COC(=O)c1cc(OC)c(OCCNCCOc2cc([N+](=O)[O-])c(C(=O)OC)cc2OC)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(OCCN(CCOc2cc([N+](=O)[O-])c(C(=O)OC)cc2OC)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
N,N-di[2-(4-methoxycarbonyl-2-methoxy-5-nitrophenyl-oxy)ethyl]amine, compound 9, (crude, 4.16 mmol) and NaHCO3 (210 mg, 2.50 mmol) was suspended in THF, and treated with (BOC)2O (999 mg, 4.58 mmol) at 0° C. and stirring was continued at rt for 3 h. After removal of THF, the residue was partitioned between H2O and EtOAc (100/100 mL). Aqueous layer was further extracted with EtOAc (2×50 mL). The combined EtOAc layers were washed with brine (80 mL), dried (MgSO4), and concentrated. Purification of the residue by flash chromatography (silica gel, 6:4 hexanes/EtOAc) yielded N-tert-butoxycarbonyl-N,N-d i[2-(4-methoxycarbonyl-2-methoxy-5-nitro-phenyloxy)ethyl]amine, compound 10, as light yellow solid: 1HNMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 3.77 (m, 4H), 3.83, 3.86 and 3.87 (3×s, 12H), 4.20 and 4.26 (2×t, J=3.9 Hz, 4H), 6.97 and 6.99 (2×s, 2H), 7.36 and 7.40 (2×s, 2H); EIMS m/z 646 ([M]++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:41]([O:40][C:38](=[O:39])[C:30]1[CH:31]=[C:32]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:33]=[CH:34][C:29]=1[Cl:28])[CH3:42]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)ccc1Cl

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=564.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](=[NH:18])(OCC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.CO>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[NH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)O
Reactant: CCOC(=N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(NCC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A white suspension of glycine (3.81 g, 50 mmol) in water (0.9 g) and methanol (16 ml) was stirred at room temperature, adjusted to pH 9.6 by the addition of sodium hydroxide solution and admixed with ethyl benzimidate (7.69 g, 50 mmol). The mixture was heated for 1 hour at 50° C. and allowed to cool at room temperature. The solid was filtered off, washed with toluene and dried at room temperature/30 mbar. The yield of the title compound was 6.81 g (approximately 95 percent pure by H-NMR), 74 percent based on glycine. Other data concerning the title compound was:
Reaction SMILES: Cl[P:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1.[OH2:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:34]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1
Reactant: O
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To a solution of 8.9 g (0.019 mol) of the compound of Example 4 in 150 mL of toluene at ambient temperature is added dropwise a solution of 0.34 mL (0.019 mol) of distilled water in 4.0 mL (0.029 mol) of triethylamine. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 minutes. The reaction solvent is removed under vacuum and the residue is recrystallized twice with 50 mL of acetonitrile. The acetonitrile is then removed in vacuo and the residue is dried under vacuum to give 2.4 g (79.5% yield) of the title compound as an off-white solid melting at 164° C.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][C@@H:21]2[C@@H:28]([CH2:29][O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:27][C@H:24]([O:25][CH3:26])[C@H:23]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:22]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:39]([O:38][C@@H:23]1[C@@H:22]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:21]([O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:28]([CH2:29][O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:27][C@@H:24]1[O:25][CH3:26])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.543 g, 2.71 mmol) is dissolved in hot toluene (2 0 ml) and methanol (80 ml) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D -glucopyranoside as an amorphous solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CC1(C)[O:14][C:13](=O)[CH:12]=[C:11]([CH3:16])[O:10]1>CC(C)=O>[C:13]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])(=[O:14])[CH2:12][C:11]([CH3:16])=[O:10]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: C[Si](C)(C)CCO
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCC[Si](C)(C)C

Procedure:
A mixture of 6.70 g of 2-trimethylsilylethanol (56.7 mmol) and 8.05 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (56.7 mmol) was placed in a round bottom flask equipped with a short distillation apparatus and heated to to drive off acetone. The calculated amount of acetone was collected, and the residue was distilled under reduced pressure. The fraction boiling at 106-110° C. (5-10 mmHg) was collected (8.52 g, 74%). The product was used in the next step after spectral characterization.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][C:6]=1[CH:16]=C.[BH4-].[Na+]>ClCCl.CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][C:6]=1[CH2:16][OH:1]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(O[C@H](C)CC)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)Oc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ozone was bubbled through a −78° C. solution of 1-fluoro-4-{[(1R)-1-methylpropyl]oxy}-2-vinylbenzene (0.81 g, 4.17 mmol) in dichloromethane (27.8 ml) and MeOH (13.90 ml) until the reaction color remained blue. The reaction stirred 10 min, and then was purged with N2 for 10 min. MeOH (25 mL) was added, followed by sodium borohydride (0.237 g, 6.25 mmol). The reaction warmed to rt. After 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on a silica gel cartridge (12% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[N:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH:25]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][C:35]2[CH:51]=[CH:50][N:38]3[C:39](=[O:49])[CH:40]=[C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:42]=[C:37]3[CH:36]=2)[S:31][CH:32]=1)([CH3:27])[CH3:26]>C(Cl)Cl>[CH:25]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][C:35]2[CH:51]=[CH:50][N:38]3[C:39](=[O:49])[C:40]([C:14](=[O:15])[CH2:13][C:10]4[N:11]=[N:12][N:8]([CH2:7][C:6]5[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:9]=4)=[C:41]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[N:42]=[C:37]3[CH:36]=2)[S:31][CH:32]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Reactant: COc1ccc(Cn2nnc(CC(=O)Cl)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnc(CC(=O)c3c(N4CCOCC4)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 7.8 %

Procedure:
The 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]ethanoyl chloride (0.27 g, 1.05 mmol) obtained in (C) was dissolved in methylene chloride (3 ml), added dropwise with pyridine (170.2 μl, 2.10 mmol) under ice cooling, and added dropwise with a solution of 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4 H-pyrido-[1,2-a]pyrimidin-4-one (80.9 mg, 0.21 mmol) in methylene chloride (3 ml). The reaction solution was stirred at room temperature for 23 hours, then further added with a solution of 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]ethanoyl chloride (0.27 g, 1.05 mmol) in methylene chloride (2 ml) and pyridine (170.2 μl, 2.10 mmol) under ice cooling. Further, the reaction solution was added with the same amounts of the acid chloride and pyridine twice every 24 hours, and stirred at room temperature. The solvent was evaporated, and the residue was added with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by preparative TLC (hexane:ethyl acetate=1:1, v/v and chloroform:methanol=30:1, v/v) to obtain the title compound (10.1 mg, 7.8%) as yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I.IC(I)(C(F)(F)F)C(F)(F)F.C([O-])(=O)C>CS(C)=O.[Cu]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[C:13]([F:22])([F:21])[I:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Reactant: CC(=O)Oc1ccc(I)cc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: FC(F)(F)C(I)(I)C(F)(F)F
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(C(F)(F)C(F)(F)C(F)(F)I)cc1
Reaction time: 3.5 h

Procedure:
The first stage of the process (equation A) involves reacting p-iodophenyl acetate (II) with 1,3-diiodohexafluoropropane (III). The reaction is conducted in anhydrous dimethyl sulfoxide (DMSO) in the presence of copper powder. Equimolar amounts of the reactants can be used, but it is usually preferred to employ an excess of the diiodohexafluoropropane e.g., 1 to 1.5 moles per mole of the acetate. For every mole of acetate, at least 2, e.g., about 2 to 10, gram atoms of copper are utilized. The reaction is carried out in an inert atmosphere at a temperature ranging from about 110° to 130° C. Examples of gases suitable for providing an inert atmosphere include nitrogen, helium and argon. The reaction period usually ranges from about 2 to 5 hours. At the end of the reaction period, the reaction product is recovered from the reaction mixture. In a preferred procedure, the reaction mixture is allowed to cool after which saturated aqueous ammonium chloride and methylene chloride are added. The excess copper and cuprous salts are then filtered off, and the organic layer is separated. After extracting the aqueous layer with additional methylene chloride, the organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and finally reduced in volume to a light yellow oil. The oil is refluxed in acetic anhydride for about 30 minutes to one hour followed by removal of excess acetic anhydride and acetic acid by vacuum distillation. Distillation of the residual oil yields crude 4-(perfluoro-3-iodopropyl)phenyl acetate (IV) which is then purified by recrystallization from hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=[O:23])[CH2:4][CH2:3]1.[C:25]([Si:27](C)([CH3:29])[CH3:28])#N>C1COCC1.[I-].[Zn+2].[I-]>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)=[CH:7][C:6]=2[C:5]([O:23][Si:27]([CH3:29])([CH3:28])[CH3:25])=[CH:4][CH2:3]1
Reactant: C[Si](C)(C)C#N
Reactant: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1(C)CC=C(O[Si](C)(C)C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cold solution (0° C.) of 50 mg (0.07 mmol) of zinc iodide (dried in vacuo over P2O5 for several hours) in 2 ml of dry THF (flushed with argon) was added a solution of 0.110 g (0.34 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) in 2 ml of THF followed by 0.14 ml (1.03 mmol) of cyanotrimethylsilane. The resulting mixture was stirred at 25° C. for 12 hours and purified by flash chromatography (silica, 50% EtOAc-hexane) to yield the title compound as a white solid.
Reaction SMILES: NC[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.N1CCC([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)CC1>>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:11]3[N:10]=[C:9]([N:6]4[CH2:7][CH2:8][CH:3]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:4][CH2:5]4)[C:14]([F:15])=[CH:13][N:12]=3)=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)OCc5ccccc5)CC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using benzyl piperidin-4-ylcarbamate. MS 548.4 (M+H); UV 215.8, 258.8, 279.8 nm.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[N:19][C:18](Br)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[CH:6]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[CH:20]=[N:19][C:18]([C:27]4[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:17][N:16]=3)[CH2:12][CH2:13]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cnc(Br)cn2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)cn2)cc1

Procedure:
According to the same method as in Example 1-2), 3), 4) but using 2-(1-t-butoxycabonylpiperidin-4-yloxy)-5-bromopyrazine and 4-cyanophenylboronic acid, the entitled compound was obtained.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][C:23]3([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][C:23]3([OH:28])[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:15][CH:16]=2)[C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccc(C#CC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(CCC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-(1-hydroxycyclopentyl)ethyl)-3-methylnaphthalen-2-yl)acetic acid (91) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.58 (s, 1H), 7.51 (m, 2H), 7.29 (m, 2H), 7.07 (s, 1H), 5.05 (s, 1H), 2.70 (m, 2H), 2.62 (s, 3H), 1.75 (m, 4H), 1.61 (m, 6H), 0.94 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.69.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[CH3:8][N:9]1[C@H:13]2[C:14]([C:17](OC)=O)=[CH:15][CH2:16][C@@H:10]1[CH2:11][CH2:12]2>C1COCC1>[CH3:2][C:1]1[N:3]=[C:17]([C:14]2[CH:13]3[N:9]([CH3:8])[CH:10]([CH2:16][CH:15]=2)[CH2:11][CH2:12]3)[O:5][N:4]=1
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2=CCC3CCC2N3C)n1

Procedure:
Acetamide oxime (500 mg, 6.75 mol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with NaH (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 ml) and 4 A° molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[N:13]1([CH2:12][C:11]2[CH:10]=[C:9]([CH:28]=[CH:27][CH:26]=2)[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[C:2]([F:29])([F:1])[F:30])=[O:8])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 99.7 %

Procedure:
tert-Butyl 4-(3-(1,1,1-trifluoro-2-methylpropan-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (0.792 mmol, 340 mg) wsa dissolved in dichloromethane (3 mL) and trifluoroacetic acid (7.92 mmol, 0.588 ml, 903 mg) added. After 2 hours stirring, the mixture was taken up in dichloromethane, loaded on to a strong cation exchange column (5 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (260 mg). MS (ESI) m/z 330.3 [M+H]+
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:2][CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:40]([S:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:22]2[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=[C:19]([C:13]4[S:14][C:10]([CH2:9][NH:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:11][CH:12]=4)[CH:20]=3)[NH:24][CH:23]=2)[CH2:36][CH2:35]1)(=[O:39])=[O:38])[CH3:41]
Reactant: CCCOCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 2 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexaness/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.44 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 109° C., (yield 0.645 gm, 89.3%).