Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:12][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][OH:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1cn2ccccc2n1
Solvent: CN(C)C=O
Product: OCc1nc2ccccn2c1Cl
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-2-ylmethanol (1.0 g, 6.75 mmol) in anhydrous DMF was added 1-chloropyrrolidine-2,5-dione (0.898 g, 6.75 mmol) at room temperature. The reaction mixture was allowed to stir for 2 hours. The solvent was evaporated, and the residue was purified by CombiFlash using dichloromethane and methanol (0-10%) to provide {3-chloroimidazo[1,2-a]pyridin-2-yl}methanol as a grey solid (0.799 g, 65% yield); M+1 183.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (2.34 g, 8.58 mmol) and commercially available 4-iodo-imidazole (2.50 g, 12.9 mmol) according to the general procedure IVa. Obtained as a light brown solid (2.67 g, 72%). MS (ISP) 431.1 [(M+H)+]; mp 167° C.
Reaction SMILES: [CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of crude dihydrobromide salt of (1R,3R,4S)-N1-isopropyl-3-(methoxymethyl)-N1-methylcyclohexane-1,4-diamine prepared according to the procedure of Example 4b, Step 2 (423 mg) in acetonitrile (5 mL) was treated with 2-(benzyloxycarbonylamino)acetic acid (259 mg), diisopropylethylamine (0.80 ml) and HATU (516 mg). The mixture was stirred overnight at rt, then was concentrated under vacuum. The residue was purified by reverse phase HPLC followed by lyopholization to provide benzyl 2-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexylamino)-2-oxoethylcarbamate (192 mg) as a white powder. MS found: (M+H)+=406.3.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:50])[CH:7]([C:31]([CH:35]([NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH:36]([CH3:38])[CH3:37])([OH:34])[PH2:32]=[O:33])[CH2:8][C:9]1[CH:10]=[N:11][C:12]([N:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:13]([CH3:15])[CH:14]=1)C.CO>C(#N)C>[CH2:43]([O:42][C:40]([NH:39][CH:35]([C:31]([OH:34])([PH2:32]=[O:33])[CH:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[C:13]([CH3:15])[CH:14]=1)[C:6]([OH:50])=[O:5])[CH:36]([CH3:38])[CH3:37])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(O)([PH2]=O)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: Cc1cc(CC(C(=O)O)C(O)([PH2]=O)C(NC(=O)OCc2ccccc2)C(C)C)cnc1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
1 M LiOH (2 mL) was added dropwise to a solution of 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphinoylmethyl]-3-(6-bis(tert-butoxycarbonyl)amino-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (100 mg, 0.145 mmol) in acetonitrile (2 mL). The mixture was stirred overnight and concentrated under reduced pressure. The mixture was purified by column chromatography (isopropanol/concentrated aqueous NH3/water, 4:2:1) to give impure product. The impure product was stirred with MeOH, filtered and concentrated under reduced pressure. The crude product was stirred with EtOH, filtered and concentrated under reduced pressure. The crude product was stirred with ethylacetate/ethanol, filtered and concentrated under reduced pressure to give 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphinoylmethyl]-3-(6-tert-butoxycarbonylamino-5-methyl-pyridin-3-yl)-propionic acid (52 mg, 63.8%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
First, 20.0 g of methylmalonic acid diethyl ester was dissolved in a mixed solution of 30 g of water and 30 g of ethanol. To this solution was added dropwise 9.6 g of 48% aqueous NaOH solution, and the mixture was vigorously stirred at room temperature for 7 hours. After completion of the reaction, the reaction solution was adjusted to pH 3 by the addition of 35% hydrochloric acid and concentrated under reduced pressure. To the residue was added 80 g of water, and the mixture was extracted twice with 40 g of ethyl acetate. The organic layers were combined and concentrated under reduced pressure. To the residue was added 100 g of n-hexane, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure to give 16.1 g of methylmalonic acid monoethyl ester.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11]>ClC1C=CC=CC=1>[C:13]1([S:10]([N:9]([CH3:8])[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Clc1ccccc1
Product: CN(S(=O)(=O)N=C=O)S(=O)(=O)c1ccccc1
Temperature: 120 °C
Yield: 58.7 %

Procedure:
44 g (0.31 mole) of chlorosulfonyl-isocyanate are added to a solution of 50 g (0.29 mole) of benzenesulfonic acid methylamide in 150 ml of chlorobenzene, and the whole is heated at 120°C for 4 hours with agitation. The distillation yields 47 g (58 %) of phenylsulfonyl-methylaminosulfonylisocyanate having a boiling point of 125° -128°C/ 0.03 torr.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:26]5[S:25][CH:29]=[CH:28][CH:27]=5)[CH2:35]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1csc(C2CNCCN2)c1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5cccs5)C4)c(F)cc3cc2c1=O
Yield: 69.4 %

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (1.68 g) and (RS)-2-(2-thienyl)piperazine (1.01 g). (RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine (1.68 g) is thereby obtained in the form of a yellow solid, m.p. 220° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12](S(C2C=NC=CC=2)(=O)=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([F:36])[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][C:29]=2[F:36])[NH:12][CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1F
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: [Na+]
Product: CN(Cc1c[nH]c(-c2ccc(Cl)cc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-chloro-2-fluorophenyl)boronic acid (243 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 127 mg, 54%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([NH:27][C:28](=O)[CH2:29][O:30][CH2:31][CH3:32])=[C:20]2[NH:34][CH2:35][CH2:36][CH3:37])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[N:23]=[CH:22][C:21]3[N:27]=[C:28]([CH2:29][O:30][CH2:31][CH3:32])[N:34]([CH2:35][CH2:36][CH3:37])[C:20]=3[C:19]=2[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCNc1c(NC(=O)COCC)cnc2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCn1c(COCC)nc2cnc3ccc(OCc4ccccc4)cc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
Triethylamine (22.16 mL, 159.0 mmol) was added to a solution of N-(6-benzyloxy-4-propylaminoquinolin-3-yl)-2-ethoxyacetamide hydrochloride (16.1 g) in ethanol (265 mL), and the reaction mixture was heated at reflux and stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature. The ethanol was removed under reduced pressure and the residue dissolved in chloroform. The resulting solution was washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was dissolved in acetonitrile and concentrated under reduced pressure to yield 14.32 g of 8-benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline as a brown, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:21])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A solution of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 ml (0.013 mole) of 57% ammonium hydroxide. After stirring for 16 h the reaction mixture was diluted with 100 ml of water and the solid which precipitated was collected by filtration (2.4 g). Recrystallization from benzene/ligroin yielded 1.6 g (83.5%) of white crystals, mp. 156°-159° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[OH:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1ccc(F)cc1C1CCCC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(F)cc1C1CCCC1
Temperature: 25 °C

Procedure:
2-Cyclopentyl-4-fluorophenol (1.70 g, 9.43 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (2.6 mL, 18.85 mmol), cooled to 0° C., then treated with methyl chloroformate (1.09 mL, 14.14 mmol) and allowed to warm to room temperature over 16 h. The reaction was quenched with 3 mL saturated NaHCO3, washed with 50% saturated NaHCO3 (1×50 mL) and brine (1×50 mL), then dried over Na2SO4. Filtration followed by concentration yielded 2-cyclopentyl-4-fluorophenyl methyl carbonate as an oil which was used for the next step without purification. 1H NMR (400.0 MHz, CDCl3) δ 7.09-7.01 (m, 2H), 6.92-6.87 (m, 1H), 3.92 (s, 3H), 3.13 (dd, J=8.4, 17.2 Hz, 1H), 2.08-2.01 (m, 2H), 1.86-1.66 (m, 4H), 1.59-1.50 (m, 2H). MS (ESI) m/z (M+H+): 239.5.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O:9][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])=[O:8]
Reactant: CC(C)CC(N)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(N)CC(C)C
Yield: 102.2 %

Procedure:
To a stirred solution of DL-leucine 42 (20 g, 152 mmol) in toluene (400 mL) was added 1-dodecanol 2 (25.56 g, 137.2 mmol) in one lot, followed by pTSA (31.9 g, 167.7 mmol). After addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically, and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 43 (42 g, yield: 91.9%) as a liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]([CH:14]1[CH2:16][CH2:15]1)([CH3:13])[CH3:12])C(OCC)=O)[CH3:2].[Li+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:11]([CH:14]1[CH2:15][CH2:16]1)([CH3:12])[CH3:13])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC(C)(C)C1CC1
Temperature: 170 °C
Yield: 66 %

Procedure:
Step B To a solution of 2-(1-cyclopropyl-1-methyl-ethyl)-malonic acid diethyl ester (4.3 g, 17.8 mmol) in DMSO (30 mL) was added LiCl (1.5 g, 35.6 mmol) and H2O (0.3 mL, 17.8 mmol). The reaction mixture was heated at 170° C. for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-cyclopropyl-3-methyl-butyric acid ethyl ester as a colorless oil (2 g, 66%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]1[C:26]2[C:27](=[O:52])[N:28]3[CH2:43][C@H:42]([O:44][Si](C(C)(C)C)(C)C)[CH2:41][C@H:29]3[C:30](=[O:40])[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:53][CH3:54]>C1COCC1.C(Cl)Cl>[CH3:19][O:20][C:21]1[C:26]2[C:27](=[O:52])[N:28]3[CH2:43][C@H:42]([OH:44])[CH2:41][C@H:29]3[C:30](=[O:40])[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:53][CH3:54]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
A solution of 1 N TBAF in THF (19.58 mL, 19.58 mmol) was added to a stirred solution of 172 (7.0 g, 13.05 mmol) in THF (50 mL). The reaction mixture was allowed to stir at room temperature for 2 hours and diluted with DCM (200 mL), washed with water (2×200 mL), brine (2×200 mL) and dried over anhydrous MgSO4. Filtration and removal of excess solvent afforded the crude product, which was purified by flash column chromatography using 50:50 petroleum ether:EtOAc as eluent. Evaporation in vacuo of the pure fractions afforded the product (173) (5.9 g). 1H NMR (270 MHz, CDCl3) δ7.30 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.52 (d, 1H, J=9.9 Hz, SEM amino acetal CH2), 4.68-4.64 (m, 2H, SEM amino acetal CH2+2), 4.30 (dd, 1H, J=5.86, 8.24 Hz), 3.91 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.87-3.51 (m, 4H, SEM 1′ CH2+3), 2.95 (dt, 1H, J=5.31, 13.56 Hz, 1), 2.17-2.08 (m, 1H, 1), 1.02-0.93 (m, 2H, SEM 2′ CH2), 0.03 (s, 9H, 3× SiCH3); 13C NMR (67.8 MHz, CDCl3) δ169.7, 165.9, 151.9, 147.1, 134.0, 121.1, 111.2, 105.5, 78.2, 69.1, 67.1, 56.5, 56.1, 53.9, 34.9, 18.4, −1.3.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[Cl-].[NH4+:10].[OH-].[Na+]>CO.O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH2:10])=[CH:4][CH:5]=1
Reactant: [NH4+]
Reactant: C=Cc1ccncc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCc1ccncc1
Temperature: 0 °C
Yield: 29.5 %

Procedure:
4-Vinylpyridine (5.26 ml, 50 mmol) and ammonium chloride (5.35 g, 100 mmol, 2.0 eq) were dissolved in methanol (2.5 ml) and water (15 ml), and the mixture was stirred with reflux for 23 hours. This reaction mixture was poured into ice water, and a 15% aqueous sodium hydroxide solution was added to make the same strong alkaline. The mixture was extracted 3 times with chloroform (50 ml). The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was distilled under reduced pressure to give 2-(4-pyridyl)ethylamine (1) (1.80 g, 30%; 87° C./6 mmHg) as a colorless oil. The residue from the distillation was subjected to column chromatography (chloroform/methanol=30/1-9/1) to give bis[2-(4-pyridyl)ethyl]amine (2) (1.11 g, 20%) as a pale-yellow oil.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[N:32][C:33]#[N:34])SC)=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[N:32][C:33]#[N:34])[NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: NCc1ccc(F)cc1
Reactant: CSC(=NC#N)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Product: N#CN=C(NCc1ccc(F)cc1)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1

Procedure:
From the compound of Example 10 (400 mg, 0.79 mmol) and 4-fluorobenzylamine (1 ml, excess) as a white solid (300 mg). 1Hnmr (300 MHz, CDCl3) δ 3.29 (2H, d, J 8.0 Hz), 4.23 (1H, t, J 7.99 Hz), 4.43 (2H, d, J 5.67 Hz), 5.10 (1H, br), 6.44 (1H, t, J 73.57 Hz), 6.48 (1H, t, J 73.34 Hz), 6.90 (2H, d, J 5.89 Hz), 7.02-7.06 (2H, c), 7.10 (1H, br), 7.13-7.26 (8H, c) and 8.39 (2H, d, J 5.97 Hz). m/z (ESI, 60V) 582 (MH+, 100), 562 (21), 540 (39), 489 (15), 447 (12).
Reaction SMILES: Cl.[CH2:2]([N:4]([C:7]([O:9][CH2:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)=[O:8])[CH2:5][CH3:6])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:22]([N:12]1[CH2:13][CH2:14][N:15]([C:22](=[O:23])[C:21]2[CH:20]=[C:19]([O:18][CH3:17])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:16][CH:11]1[CH2:10][O:9][C:7]([N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])=[O:8])=[O:23]
Reactant: CCN(CC)C(=O)OCC1CNCCN1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Product: CCN(CC)C(=O)OCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Yield: 79.5 %

Procedure:
Working again according to a protocol identical to the one used in step 1.3 of Example 1, followed by treating, under the same conditions as those of step 1.4 of Example 1, 0.5 g (1.73 mmol) of 2-(N,N-diethylaminocarbonyloxymethyl)piperazine hydrochloride with 1 g of 3,4,5-trimethoxybenzoyl chloride, 0.83 g of 1,4-bis(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine is obtained. Yield: 80%. Melting point: 128.6° C. Rf=0.35 (3/97 v/v MeOH/CH2Cl2).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CC(O)=O.[BH4-].[Na+]>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C@@H:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-methyl 2-amino-2-phenylacetate (1.0 g, 6.06 mmol) in anhydrous MeOH (20 mL) was added 4-methoxy benzaldehyde (0.82 g, 6.06 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., NaBH4 (0.69 g, 12.12 mmol) was added and the contents were stirred at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), MeOH was removed under reduced pressure and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was taken directly for step 2. MS ES+APCI calc'd. for C17H19NO3 [M+H]+ 286. Found 286.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32]C)=[O:31])=[CH:20][CH:19]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([OH:32])=[O:31])=[CH:20][CH:19]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10]([CH3:11])=[O:42])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 259.4 %

Procedure:
The operation is carried out as in Example 15 starting with 1.55 g of the product obtained in Example 21 using 213 mg of metachloroperbenzoic acid. 1.8 g of crude product is obtained which is chromatographed on silica (eluant: methylene chloride - acetone (7-3)). 1.5 g of desired product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCBr)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 12.5 g (60.4 mmol) of 1,3-dibromopropane (purity: 99 wt. %), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. in an argon gas atmosphere for 8 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 15.1 g (isolated yield: 88.8%, purity: 98% in terms of area percentage by high performance liquid chromatography) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate as a white crystalline product.