Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]([CH3:28])=[CH2:27].C(N)CN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:28][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Reactant: C=C(C)Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: C=CCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-1H-imidazole (1.000 g), 2-bromo-1-propene (1.04 mL), ethylenediamine (0.40 mL), copper iodide (0.28 g) and tripotassium phosphate (1.30 g) were suspended in dioxane (10 mL), and reacted in a microwave reactor (product name: Initiator, manufactured by Biotage, Ltd.) at 140° C. for 5 hours. The reaction solution was filtered using Celite to filter off the insolubles, followed by concentration of the mother liquor. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→100%) using silica gel column (product name: Hi-Flash column 3 L, manufactured by Yamazen Corporation) to afford the title compound (0.350 g).
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].CCN(CC)CC>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[CH:7][CH:6]=1
Reactant: C#CCCO
Reactant: CC(Br)COc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)COc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-(2-Bromopropoxy)-1-iodobenzene (10 g, 29 mmol), 3-butyn-1-ol (26 mL, 37 mmol), Cul (980 mg, 5.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.6 g, 5.2 mmol) in dichloromethane (40 mL) was added Et3N (6.0 mL, 44 mmol) dropwise. The reaction was stirred overnight at room temperature under Ar. The solvent was evaporated under reduced pressure and ethyl acetate was added to dissolve the compound, the solution was filtered over celite to remove most of the Pd. The crude product was purified by silica gel chromatography, eluted with hexane/ethyl acetate (2:1). 2.6 g of the title compound were obtained as a light brown solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([NH:22][C:23](=O)[CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=O)[CH2:2]CC.[CH2:28](Cl)[CH3:29]>>[CH2:1]([O:6][CH2:7][CH:8]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH3:29])[CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCCl
Reactant: CCCC(=O)NC(CCOc1cccc2ccccc12)COC(=O)CCC
Product: CCCCN(CC)C(CCOc1cccc2ccccc12)COCC

Procedure:
2-(butanoylamino)-4-(1-naphthyloxy)butanol butyrate, described in Example 5, with ethyl chloride, followed by reduction, gives 1-ethoxy-N-butyl-N-ethyl-4-(1-naphthyloxy)-2-butanamine.
Reaction SMILES: [CH:1](Cl)(Cl)Cl.C=CC[CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]1[O:26][C@H:25]([C@@H:27]2[O:32][O:31][C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]2)[CH2:24][CH2:23]1>CO>[CH3:1][O:36][C:34]([CH2:33][C@H:30]1[O:31][O:32][C@H:27]([C@H:25]2[O:26][C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]/[CH:15]=[CH:14]\[CH:13]=[CH:12]/[CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:23][CH2:24]2)[CH2:28][CH2:29]1)=[O:35]
Reactant: ClC(Cl)Cl
Reactant: C=CCCC/C=C/C=C\CCCCCCCC[C@H]1CC[C@@H]([C@H]2CC[C@@H](CC(=O)O)OO2)O1
Solvent: CO
Product: C=CCC/C=C\C=C/CCCCCC[C@@H]1CC[C@@H]([C@@H]2CC[C@@H](CC(=O)OC)OO2)O1

Procedure:
colorless oil; [α]D25 −50.8° (c 0.39, CHCl3); IR (film) 1745, 1640, 1200, 1060 cm−1; UV (MeOH) λmax235 (ε=22000) nm- 1H NMR (CDCl3) 6.25 (m, 2H, H-18 and H-19), 5.82 (ddt, J=16.9, 10.3, 6.6 Hz, 1H, H-23), 5.44 (m, 2H, H-17 and H-20), 5.03 (ddd, J=16.9, 1.7, 1.6 Hz, 1H, H-24), 4.97 (bd, J=10.3 Hz, 1H, H-24), 4.54 (dddd, J=11.1, 7.7, 5.9, 2.2 Hz, 1H, H-3), 4.06 (ddd, J=11.1, 5.4, 2.4 Hz, 1H, H-6), 3.87 (m, 2H, H-7 and H-10), 3.69 (s, 3H, CH30-), 2.47 (dd, J=15.6, 7.7 Hz, 1H, H-2), 2.36 (dd, J=15.6, 5.9 Hz, 1H, H-2), 2.28 (bdd, J=14.7, 7.4, 2H, H-21), 2.15 (m, 2H, H-16), 2.13 (m, 2H, H-22), 1.99 (m, 1H, H-9), 1.95 (m, 1H, H-8), 1.92 (m, 1H, H-4eq), 1.77 (m, 2H, H-5ax and H-8), 1.70 (m, 1H, H-5eq), 1.58 (m, 1H, H-11),1.54 (m, 1H, H-4ax), 1.42 (m, 1H, H-9), 1.34 (m, 1H, H-11), 1.33 (m, 1H, H-12), 1.30 (m, 6H, H-13, H-14 and H-15), 1.28 (in, 1H, H-12); 13C NMR (CDCl3) 170.4 (s, C-1), 138.2 (d, C-23), 132.4 (d, C-17), 130.8 (d, C-20), 124.0 (d, C-19), 123.4 (d, C-18), 114.7 (t, C-24), 83.8 (d, C-6), 79.9 (d, C-10), 78.5 (d, C-7), 77.6 (d, C-3), 51.9 (q, CH3O—), 38.4 (t, C-2), 35.6 (t, C-11), 33.7 (t, C-22), 31.7 (t, C-9), 29.6 (t, C-13)*, 29.5 (t, C-14)*, 29.2 (t, C-15)*, 29.1 (t, C-4), 27.7 (t, C-8), 27.5 (t, C-16), 26.8 (t, C-21), 26.0 (t, C-12), 25.2 (t, C-5); EIMS (70 eV) m/z (rel. int.) 420 (2), 402 (18), 261 (25), 219 (7), 159 (15), 143 (36), 135 (29), 121 (41), 67 (100); HREIMS m/z 420.2865, C25H4005 requires m/z 420.2876.
Reaction SMILES: [Na].C(O[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:16]#[N:17].Cl>CCO>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[O:11])[CH2:12][C:13]1[CH:14]=[C:15]([C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[CH3:10]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(C#N)ccc1[N+](=O)[O-]

Procedure:
Dissolve sodium metal (0.345 g) in absolute EtOH (25 mL), add diethyloxalate (10 mL) and then add 3-methyl-4-nitrobenzonitrile (1a, m=0, 1.6 g, Aldrich) as an EtOH solution (25 mL). Stir reaction mixture at rt for 16 h, neutralize the reaction by addition of 5N HCl (3 mL) and remove the EtOH under reduced pressure. Partition the residue between CH2Cl2 (100 mL) and H2O (50 mL). Wash the organic layer successively with H2O (50 mL) and brine (50 mL), dry (MgSO4) and concentrate to give a crude oil. Purify the oil by chromatography on SiO2 (cyclohexane-EtOAc, 70-30 v/v) to give after drying (40° C., house vacuum), the title compound (1.2 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([F:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)ccn1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl [4-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate (88 mg, 0.20 mmol) in 1,4-dioxane (0.50 mL) was added 4 M hydrogen chloride in 1,4-dioxane (2.0 mL). The resultant reaction mixture was stirred at 40° C. for 1 hour. The reaction mixture was concentrated under vacuum to give the desired product as a very hygroscopic white powder (83 mg, 100%). LCMS for C17H16ClFN5 (M+H)+: m/z=344.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>O1CCCC1>[CH2:7]([N:14]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
In a nitrogen atmosphere, 1.44 g of lithium aluminum hydride was added to 100 ml of tetrahydrofuran, and a solution of 7.39 g of methyl 1-benzyl-1H-pyrazole-4-carboxylate in 50 ml of tetrahydrofuran was added dropwise at 0° C. over 30 minutes. Thereafter, the mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0° C., and 15 ml of a 1 mol/L aqueous potassium hydroxide solution was added dropwise. Precipitates were filtered, washed with tetrahydrofuran and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.32 g of (1-benzyl-1H-pyrazol-4-yl)methanol.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])([O:3][CH3:4])=[O:2].[CH3:16][O:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH2:26])[N:19]=1>C(#N)C>[CH3:25][O:24][C:22]1[N:23]=[C:18]([O:17][CH3:16])[N:19]=[C:20]([NH:26][C:14]([NH:13][S:10]([C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:11])=[O:12])=[O:15])[N:21]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1
Solvent: CC#N
Product: COC(=O)C1=C(S(=O)(=O)NC(=O)Nc2nc(OC)nc(OC)n2)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The sulfonyl isocyanate product of Example 3 (5 g) was diluted to a concentration of 1.5M with dry acetonitrile and 2.0 ml of this solution was added to a stirred suspension of 0.27 g 4,6-dimethoxy-1,3,5-triazine-2-amine in 4.0 ml dry acetonitrile under a nitrogen atmosphere. The mixture was heated briefly on the steam bath until a homogeneous solution resulted, then stirred at ambient temperature for 24 hours. Dilution of the mixture with ether precipitated the product which was collected by filtration and dried to 0.54 g of white crystalline solid; m.p. 168°-169°. An infrared spectrum (nujol) exhibited absorptions at 1730 and 1700 cm-1 and an NMR (60 MHz) spectrum in CDCl3 /DMSO-d6 solution exhibited absorptions at 2.1 (CH2), 3.0 (CH2 ×2), 3.75 (CH3O), 4.0 (CH3O×2), 9.9 (NH), 12.3 (NH) ppm indicating the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:10][C:11]1[C:14](=O)[C:13](=[O:16])[C:12]=1[O:17]CCCC)[CH2:7][CH2:8][CH3:9]>CO>[CH2:6]([O:10][C:11]1[C:12](=[O:17])[C:13](=[O:16])[C:14]=1[NH:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: NCCCBr
Solvent: CO
Product: CCCCOc1c(NCCCBr)c(=O)c1=O
Temperature: 22 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
Solid 3-bromopropylamine hydrobromide (41.52 g, 0.1897 mole) was added with stirring to a solution of sodium hydroxide (7.73 g, contains 0.187 mole) in methanol (150 mL) at 22° C., stirred for 15 minutes, then cooled to 0° C. to give a hazy solution of bromopropylamine base. The solution of bromopropylamine base was added slowly (over 20 minutes) with vigorous stirring to the product of Step A in methanol at 0° C. The mixture was stirred at 22° C. for 1.5 hours, polish filtered through diatomaceous earth (washed through with 50 mL of methanol) and added with vigorous stirring to water (1060 mL). The stirred mixture was cooled to -10° C. over several hours. The solid was collected by filtration, washed well with water (0° C., 440 mL) and dried in vacuo to give 50.0 g (91.8% yield) of the title compound as an off-white solid; m.p.=66°-68° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35](C(Cl)(Cl)Cl)[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1.O>CN(C=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35]([N:2]([CH3:3])[CH3:1])[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(C(Cl)(Cl)Cl)n2)c1Cl
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(N(C)C)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dimethylamine (40% aqueous, 0.51 mL, 4.1 mmol) was dissolved in DMF (2 mL) under nitrogen, and N-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.151 g, 0.23 mmol) was added. The reaction mixture was stirred for 40 minutes at ambient temperature, then poured into water (40 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×25 mL), brine (25 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum. The crude product was purified by flash chromatography on silica gel, eluting with 75% ethyl acetate/hexanes to afford N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6) 10.9 (br, 1), 9.4 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.8 (s, 2), 3.0 (s, 6) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14]C)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][OH:25]>C[O-].[Na+].CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1nc2c(N)nc(OCCO)nc2n1Cc1ccccc1
Reaction time: 10 h
Yield: 69 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-methoxyethoxyl)purine (130 mg, 0.36 mmol) in methanol (50 ml) was dissolved in 28% sodium methoxide/methanol (3 ml) and the solution was refluxed on heating under stirring for 10 hours. The reaction mixture was concentrated in vacuo to dryness, and to the residue was added saturated brine. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate, followed by removal of the solvent. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (78 mg, yield 69%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[S:10](Cl)(=[O:13])(=[O:12])[NH2:11].C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][O:9][S:10](=[O:13])(=[O:12])[NH2:11]
Reactant: Cc1ncsc1CCO
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncsc1CCOS(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
4-Methyl-5-thiazoleethanol (10.0 g, 0.0698 mole) was dissolved in acetonitrile, chilled, and sulfamoyl chloride (10.44 g, 0.091 mole) was added to the stirred solution. Triethylamine (9.19 g, 0.091 mole) was added dropwise while maintaining the temperature between 20°-25° C. A yellow solid precipitated after the addition was completed. The reaction was stirred at room temperature overnight, evaporated to a residue, and the residue partitioned between ethyl acetate/acetonitrile (1:1) and sodium bicarbonate/sodium chloride (1:1). The organic phase was treated with charcoal, dried (magnesium sulfate), filtered, and evaporated to a residue (9.29 g). The residue was dissolved in a small amount of methanol and isopropanol was added. The first crop (2.0 g) crystallized out of isopropanol as the methanol was evaporated. The crystals were collected and dried to yield 2.0 g (13%) of solid, mp 80°-83° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1>>[OH:23][C:18]1[CH:17]=[CH:16][C:15]([I:14])=[CH:22][C:19]=1[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(I)ccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(I)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-5-iodo-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-iodosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 2.42-2.47 (m, 4H), 3.28-3.55 (m, 6H), 5.26 (s, 1H), 6.61-6.63 (m, 1H), 7.38-7.46 (m, 2H), 7.84 (s, 1H), 10.30 (br s, 1H), 11.63 (br s, 1H). Mass spectrum (ES) MH+=413.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[OH:16][N:17]1C(=O)C2=CC=CC=C2C1=O.[OH-].[K+].C(O)(C)C.O.NN>C(Cl)Cl.CN(C)C=O>[O:16]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)[NH2:17]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(CON)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
15.0 Grams (0.049 mole) of tert-butyl 4-bromomethylbenzoate, 8.2 g (0.05 mole) of N-hydroxyphthalimide and 3.0 (0.054 mole) of potassium hydroxide were added to 200 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes and then an 50° C. for 30 minutes. The reaction solution was cooled with ice water and filtered to obtain crystals. The crystals were dissolved in 50 ml of methylene chloride, and to this solution was slowly added dropwise 3 ml of isopropanol containing 0.5 g (0.05 mole) of hydrazine hydrate at room temperature. After completion of the addition, the reaction solution was heated under reflux for 2 hours. The reaction solution was cooled and filtered, and the filtrate was concentrated to obtain 11.0 g of tert-butyl 4-(aminoxymethyl)benzoate.
Reaction SMILES: C(NCC(O)=O)C1C=CC=CC=1.NCCNCCCN.[NH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[CH2:34][NH2:35])=[O:24].C(NCC([N:48]([CH2:63][CH2:64][CH2:65][NH:66][C:67](=[O:77])[CH2:68][NH:69]CC1C=CC=CC=1)[CH2:49][CH2:50][NH:51][C:52](=[O:62])[CH2:53][NH:54]CC1C=CC=CC=1)=O)C1C=CC=CC=1>CN(C)C=O>[NH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[CH2:34][NH2:35])=[O:24].[NH2:21][CH2:22][C:23]([NH:25][N:48]([CH2:63][CH2:64][CH2:65][NH:66][C:67](=[O:77])[CH2:68][NH2:69])[CH2:49][CH2:50][NH:51][C:52](=[O:62])[CH2:53][NH2:54])=[O:24]
Reactant: O=C(CNCc1ccccc1)NCCCN(CCNC(=O)CNCc1ccccc1)C(=O)CNCc1ccccc1
Agent: NCC(=O)NCCCNCCNC(=O)CN
Agent: NCCCNCCN
Agent: O=C(O)CNCc1ccccc1
Solvent: CN(C)C=O
Product: NCC(=O)NCCCN(CCNC(=O)CN)NC(=O)CN

Procedure:
The p-nitrophenyl ester of N-benzylglycine and N-(2-aminoethyl)-1,3-propane diamine are reacted in the same proportions as in (A) above but in dimethyl formamide as the solvent to yield, after working up in a similar manner, N-(N-benzylglycyl)-N-[2-(benzylaminoacetamido)-ethyl]-3-(benzylaminoacetamido)-propylamine in 65% yield, δ(d6DMSO) 1.6 (m, 2H), 3.2 (m, 6H), 3.5 (d, 4H), 3.8 (d, 2H), 5.0 (s, 6H), 7.3 (s, 15H), 7.4 (m, 3H), 7.8 (m, 3H). Hydrogenation as in (A) above yields the title compound in 75% yield as an oil.
Reaction SMILES: CC([O-])(C)C.[K+].C(OC([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=O)(C)(C)C.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:34][CH2:33]1.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl.CO>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:26]2[CH:25]=[C:24]3[C:29]([C:20]([CH:17]4[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]4)=[N:21][CH:22]=[N:23]3)=[CH:28][CH:27]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: CN1CCN(CCCO)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCN(CCCOc2ccc3c(C4CCNCC4)ncnc3c2)CC1
Reaction time: 0.25 h
Yield: 108 %

Procedure:
Solid KOtBu (1.36 g, 12.1 mmol) was added in one portion under air to a homogeneous solution of 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.33 g, 10.1 mmol), as prepared in the preceding step, and commercial 3-(4-methyl-piperazin-1-yl)-propan-1-ol (1.50 g, 9.50 mmol) in dry THF (10 mL), while stirring on an ice bath. Following KOtBu addition, the ice bath was immediately removed, and the resulting homogeneous amber solution was stirred for 6 hr. 6 M aqueous HCl (10 mL, 60 mmol) was then added in one portion, and the reaction was stirred overnight (mild bubbles were seen following HCl addition, but these subsided after 15 min). The reaction was then partitioned with 9:1 DCM/MeOH (50 mL) and 2.5 M NaOH (28 mL, 70 mmol), and the aqueous layer was extracted with 9:1 DCM/MeOH (1×50 mL). The combined organic layers were dried (Na2SO4) and concentrated by rotary evaporation at 90° C. to provide the crude title compound as a clear yellow oil (3.79 g, “102%” crude yield). LC/MS (ESI): calcd mass 369.3, found 370.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([CH3:18])[CH:3]=1>CC(O)=O.[Fe]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([CH3:18])=[C:5]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1
Reactant: CCOC(=O)C(=O)c1cc([N+](=O)[O-])c(F)cc1C
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)c1cc(N)c(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)-2-oxoacetate (15 g, 59 mmol) and Fe (46 g, 828 mmol) in AcOH (200 mL) was stirred at RT overnight. The solid was removed by filtration, and the solvent was removed under reduced pressure. The residue was partitioned with water and EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give ethyl 2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9.0 g, 70% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.16 (d, J=6.9 Hz, 1 H), 6.91 (d, J=8.7 Hz, 1 H), 4.41 (q, J=7.2 Hz, 2 H), 2.50 (s, 3 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:10])[C:8]=1[OH:9])[CH3:2].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O.C(OCC)C>[CH2:13]([O:9][C:8]1[C:7](=[O:10])[CH:6]=[CH:5][O:4][C:3]=1[CH2:1][CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1occc(=O)c1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCc1occc(=O)c1OCc1ccccc1
Yield: 65.1 %

Procedure:
To a stirred mixture of 2-ethyl-3-hydroxy-4-pyrone (49 g, 0.35 mol) in methanol (600 ml) and sodium hydroxide (16 g, 0.4 mol) dissolved in water (50 ml) was added benzyl chloride (47.2 ml, 0.41 mol) dropwise at room temperature. After heating under reflux for 48 hours the reaction mixture was cooled, filtered and the filtrate rotary evaporated to provide an oil. The oil was extracted with dichloromethane (300 ml), the solution washed with 5% w/v sodium hydroxide solution (3×250 ml) and water (3×250 ml), then dried over anhydrous sodium sulphate, filtered and rotary evaporated to provide an oil which was dissolved in diethyl ether and crystallized by coating with liquid nitrogen. Recrystallization from diethyl ether gave the title compound as colourless crystals (52.5 g, 65%), m.p. 33°-34° C.