Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:18]Cl>C(Cl)Cl>[Cl:18][C:6]1[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: ClCl
Reactant: COc1ccc(CCCCCCO)cc1OC
Solvent: ClCCl
Product: COc1cc(Cl)c(CCCCCCO)cc1OC
Reaction time: 16 h

Procedure:
To 1.40 g of 6-(3,4-dimethoxyphenyl)hexan-1-ol in 25 mL of methylene chloride cooled in a ethanol-dry ice bath was added 4.6 mL of 1.35M chlorine in methylene chloride. The reaction mixture was kept at -75° for 1.5 hours, at -18° for 16 hours and then at 0° for 24 hours. After concentration under reduced pressure, the crude product was purified by HPLC to give 6-(6-chloro-3,4-dimethoxyphenyl)hexan-1-ol as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave a molecular ion at m/z 272 (C14H21ClO3).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1)=O)(C)(C)C.C(OC(N1CCO[C@H](CO)C1)=O)(C)(C)C>>[CH3:6][N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Product: CN1CCO[C@@H](CO)C1

Procedure:
(R)-(4-Methylmorpholin-2-yl)-methanol was prepared similar to the procedure described for Intermediate 10, but using (R)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 9) instead of (S)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 8). The title compound was obtained as a colourless oil (560 mg, 77%).
Reaction SMILES: N1CCC[CH2:2]1.C([Li])CCC.[CH3:11][CH2:12][C@@H:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])[CH3:14].[C:40]1([B:46]([O-:48])[O-:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CI>C1COCC1>[CH3:11][CH2:12][C:13]([C:15]([O:17][C@@H:18]1[C@@H:23]2[C@@H:24]([CH2:29][CH2:30][C@H:31]3[O:37][C:35](=[O:36])[CH2:34][C@H:33]([OH:38])[CH2:32]3)[C@@H:25]([CH3:28])[CH:26]=[CH:27][C:22]2=[CH:21][C@H:20]([CH3:39])[CH2:19]1)=[O:16])([CH3:2])[CH3:14].[C:40]1([B:46]([O-:48])[O-:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: C1CCNC1
Agent: [Li]CCCC
Agent: [O-]B([O-])c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: -57.5 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
A 2L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyllithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at a temperature between −20 and −25° C. over a period of 1 hour. The solution was maintained at this temperature for 30 minutes and then cooled to −55 to −60° C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to a temperature of −50° C. and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between −50 and −55° C. during the addition. The reaction was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below −55°C. The reaction was stirred for 13 hours at −15 to −20° C. and then quenched with 500 mL of 2M HCl at a temperature below 0° C. After warming to 20° C., the layers were separated and the aqueuous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110° C. for 3 hours and then cooled to −5 to −10° C. for 1 hour. The product was filtered and washed with 25 mL of −5° C. acetonitrile and dried under vacuum to provide 43.7 g of simvastatin phenylboronate at >99% purity by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24]>C(OCC)C>[Cl:1][C:2]1[C:3]([O:13][C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)C(Cl)(Cl)Cl)c1Cl
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To a solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine and 2.0 g (0.02 mole) triethylamine in 100 ml diethyl ether was added 3.6 g (0.02 mole) trichloroacetyl chloride. After the exothermic reaction subsided, the reaction mixture was stirred an additional 10 minutes and filtered. The filtrate was concentrated in-vacuo and the residue recrystallized from ligroin to give 1.6 g starting material and 2.3 g product; m.p. 92° C. The corrected yield was 35%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].Cl>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][CH:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[C:37]2=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:22])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A portion (5.2 g; 20 mmol) of the methyl 4-Boc-piperazine-2-acetate product from the previous step was combined with 60 mL of THF and 60 mL of 1 N NaOH (aqueous) and stirred at room temperature for 6 hours to saponify the methyl ester. The reaction was cooled to 0° C., adjusted to pH 9-10 with 10% HCl(aqueous), and 5.2 g (20 mmol) of FMOC-Cl was added. The reaction was stirred at room temperature for 6 hours, (adding 1 N NaOH (aqueous) to maintain pH=9-10) 1 hour, then acidified with 10% HCl to pH=1. The reaction was extracted twice, the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 8.56 g of the desired 4-Boc-1-Fmoc-piperazine-2-acetic acid (the compound of formula (XXIV)); 1H NMR (CDCl3) δ1.4 (s, 9), 2.5-3.0 (m, 5), 3.9-4.2 (m, 6), 4.5 (m, 1), 7-25 (t, 4), 7.32 (t, 4), 7.48 (d, 4),7.75 (d, 4).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([O:27][CH3:28])[CH:11]=1>CO>[CH3:28][O:27][C:12]1[CH:11]=[C:10]([CH2:9][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(CBr)cc1OC
Reactant: Oc1ccccc1
Solvent: CO
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(COc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of phenol (130 mg, 138 mmol) and methyl 4-[4′-(bromomethyl)-2′-methoxy-5′-nitrophenoxy]butanoate (7) (500 mg, 138 mmol) in anhydrous methanol (5 cm3) was added KtOBu (186 mg, 166 mmol). The resulting green mixture was stirred at r.t. for 30 mins after which time a white precipitate had formed. The precipitate was filtered and recrystallised from methanol affording the desired compound 9 as a pure white solid (319 mg, 61%). m.p. 96-98° C. Found C, 61.0; H, 5.8; N, 4.0; C19H21NO7 requires C, 60.8; H, 5.6; N, 3.7%; Rf 0.64 (SiO2, hexane:EtOAc 2:1 v/v); νmax (KBr disc)/cm−1 3000-2800 (m), 1720 (s), 1610, 1580, 1520, 1280, 1220; δH (300 MHz, CDCl3) 2.21 (2H, q, J=6.7 Hz, CH2), 2.57 (2H, t, J=6.7 Hz, CH2), 3.71 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.14 (2H, t, J=6.7 Hz, CH2), 5.50 (2H, s, CH2), 6.98-7.02 (3H, m, ar), 7.29-7.34 (3H, m, ar), 7.77 (1H, s, ar) ppm; δC (100 MHz, CDCl3) 24.7 (CH2), 30.4 (CH2), 51.7 (OCH3), 56.3 (OCH3), 67.0 (CH2), 68.2 (CH2), 109.4 (CH), 109.6 (CH), 115.0 (CH), 121.5 (CH), 129.6 (CH), 129.7 (CH), 138.9, 147.0, 154.3, 158.1, 173.2 (COOCH3) ppm; m/z (FAB) 376 [(MH), 20%], 282 [(M-C6H5O), 80%].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][C:6](Cl)=[CH:5]2>[Pd]>[Cl:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(Cl)CC2
Agent: [Pd]
Product: COC(=O)c1c(Cl)c(-c2cccnc2)n2c1CCCC2
Yield: 71.5 %

Procedure:
Methyl 2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate is prepared as in Example 39, from 1.4 g of methyl 2,7-dichloro-3-(3-pyridyl)-5,6-dihydroindolizinecarboxylate and 0.28 g of 10% palladium on charcoal. 0.9 g of methyl 2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate are thus obtained in the form of beige powder melting at 111° C.
Reaction SMILES: [C:1](=[S:5])([S:3][CH3:4])[NH2:2].[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[CH:30](Br)[CH:31]=O)[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:24]2=[O:42])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(O)C.O.C(OCC)(=O)C>[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:5][C:1]([S:3][CH3:4])=[N:2][CH:31]=1)[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:24]2=[O:42])=[O:21])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSC(N)=S
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Temperature: 66 °C
Yield: 16.4 %

Procedure:
A solution of methyl dithiocarbamate (9 g) in tetrahydrofuran (250 cc) is heated to the reflux temperature, and a solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (44 g) in ethanol (100 cc) is then added. The reaction mixture is heated at 66° C. for 65 minutes and is then diluted with water (2 liters) and ethyl acetate (1 liter). The aqueous phase is decanted and washed with ethyl acetate (250 cc). The combined organic phases are washed with a half-saturated sodium chloride solution (1 liter), then dried over sodium sulphate, and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is chromatographed on a column (diameter: 8 cm) of silica gel (0.2-0.06 mm) (1 liter), 500 cc fractions being collected. Elution is carried out successively with methylene chloride (3.5 liters) and with a 90:10 (by volume) mixture of methylene chloride and ethyl acetate (8 liters). Fractions 14 to 16, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is triturated with isopropyl ether and is then filtered off and dried; 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methylthio-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (7.3 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH:19](=[N+:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: C(c1ccccc1)=[N+]1CCCC1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2)N2CCCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and 1-benzylidene-pyrrolidinium chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)OCc3ccccc3)C2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCNC2)C1
Yield: 98.8 %

Procedure:
A solution of compound 5b (1.3 g, 3.46 mmol), 10% Pd/C (200 mg) in EtOH (50 mL) was hydrogenated under 40 psi hydrogen pressure in a Parr apparatus for 4.5 h. The reaction was filtered through a pad of diatomaceous earth and the organic solution was concentrated and dried under vacuum to give compound 5c as a thick oil (0.825 g). 1H NMR (300 MHz, CDCl3): δ 4.10 (m, 2H), 3.64-3.55 (m, 3H), 3.23 (m, 1H), 3.05 (m, 1H), 2.97-2.85 (m, 2H), 2.68 (m, 1H), 1.97 (m, 1H), 1.51 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(C)(C)C)cc3)nn3ccnc23)n1
Yield: 38.4 %

Procedure:
To a solution of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (60 mg, 0.183 mmol) and 4-tert-butylphenylboronic acid (49 mg, 0.274 mmol) in dioxane/H2O (10 mL/1 mL) was added Na2CO3 (39 mg, 0.366 mmol) followed by Pd(dba)2 (21 mg) and X-Phos (9 mg) under nitrogen with stirring. The mixture was refluxed for 15 h under nitrogen. After cooling, the solvent was concentrated in vacuo. The residue was purified by chromatography (silica, dichloromethane:MeOH=100:1) to give 6-(4-tert-butylphenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyri-dazin-8-amine (30 mg, 38%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 8.30 (brs, 1H), 7.90 (d, 1H, J=7.5 Hz), 7.60 (s, 1H), 7.51-7.38 (m, 4 h), 6.31 (d, 1H, J=7.2 Hz), 6.03 (d, 1H, J=8.1 Hz), 4.24 (brs, 1H), 3.66 (brs, 1H), 3.49-3.47 (m, 1H), 2.15-2.09 (m, 3H), 1.75 (brs, 1H), 1.38 (s, 9H), 1.23 (d, 3H, J=6.3 Hz). LC/MS: 427 [M+H]+, tR=2.51 min. HPLC: 95.63% at 214 nm, 99.19% at 254 nm, tR=99.79% min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(N(CC)CC)C>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:32])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
4-Phenylbutyric acid (2.46 g, 15 mmol) was dissolved in distilled tetrahydrofuran (70 ml) in an argon atmosphere. After cooling in an ice bath, carbonyl diimidazole (2.43 g, 15 mmol) was added and the mixture was stirred cold 1 hour and at room temperature 1 hour. The mixture was then cooled and glycine ethyl ester.hydrochloride (2.09 g, 15 mmol) and distilled triethylamine (2.1 ml, 15 mmol) were added. The mixture was left stirring overnight at room temperature. After removal of the solvent in vacuo, ethyl ether (200 ml) was added. The solution was washed with 1 N hydrochloric acid (70 ml), 0.5 N sodium hydroxide (70 ml) and saturated sodium chloride solution (70 ml), dried over anhydrous magnesium sulfate and freed of solvent in vacuo leaving the title I compound (3.13 g) as white crystalline material.
Reaction SMILES: C[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=[O:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[OH:42][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C=O
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cccnc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 152 %

Procedure:
To a stirred solution of 2-methyl-pyridine-3-carbaldehyde (75 mg, 0.62 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (246 mg, 0.62 mmol) and AcOH (40 μL, 0.62 mmol) in THF (6.2 mL) was added NaBH(OAc)3 (394 mg, 1.86 mmol) and the mixture was stirred at room temperature overnight. Purification of the crude white foam (280 mg) by column chromatography on silica gel (200:3:1-CH2Cl2:MeOH:NH4OH) afforded the desired product (116 mg, 37%) as a colorless syrup.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[NH:15][C:14](=[O:16])[NH:13][C:10]3=2)[CH2:5][CH2:4]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:16]=[C:14]1[NH:13][C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[C:9]2[NH:15]1)[CH2:5][CH2:4][CH:3]([CH2:2][O:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[O:12]3
Reactant: O=c1[nH]c2ccc3c(c2[nH]1)OC(CO)CC3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Yield: 83 %

Procedure:
A solution of 8-hydroxymethyl-3,6,7,8-tetrahydro-1H-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-2-one (331 mg, 1.5 mmol) and p-toluenesulfonyl chloride (572 mg, 3 mmol) in anhydrous pyridine (50 mL) was stirred for 12 hours followed by removal of the solvent in vacuo to a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to a residue followed by chromatography (20% CH2Cl2-hexanes) to afford 466 mg (83%) of the title compound as a solid: mp 205° C.; 1H NMR (400 MHz, CDCl3): 1.87 (m, 1H), 2.02 (m, 1H), 2.48 (s, 3H), 2.81 (m, 2H), 4.22 (m, 2H), 4.31 (m, 1H), 6.56 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.58 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 8.18 (s, 1H); IR: 3280, 3000, 2950, 1700, 1510, 1350 cm−1; MS 375 [M+H]+.
Reaction SMILES: [P:1]([O-:15])([O:9]CC(C)(C)C)[O:2]C1C=CC=CC=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)([CH3:25])[CH3:24])=[CH:19][CH:18]=1.C[O-].[Na+]>>[CH2:20]([PH:1]([OH:15])([OH:9])[OH:2])[C:23]([CH3:26])([CH3:25])[CH3:24].[CH2:20]([PH:1]([OH:15])([OH:9])[OH:2])[C:23]([CH3:26])([CH3:25])[CH3:24].[OH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: CC(C)(C)COP([O-])Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)C[PH](O)(O)O
Temperature: 130 °C

Procedure:
A mixture of 272 g (1.2 mole) of phenyl neopentyl phosphite, 126 g (0.55 mole) of bisphenol-A (BPA) and 1 g of sodium methoxide were heated together in a round-bottom flask. The temperature of the reaction vessel was raised to 130° C. and a vacuum was applied. Phenol was distilled over at 90° C. head temperature at 35 mm. The temperature was raised slowly to 160° C. and the vacuum increased to 0.2 mm Hg to remove any remaining phenol and unreacted phenyl neopentyl phosphite. The proton NMR spectrum of the product recovered showed the methyl protons at 0.77, 1.30 and 1.65 δ (18.1 hydrogens), the methylene protons at 3.67 and 4.30 δ (7.2 hydrogens) and the aromatic protons from 6.7-7.3 δ (8.7 hydrogens). This bisphosphite had the following structure: ##STR3##
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7].O.Cl>[OH-].[Na+].CC(C)=O>[CH:6]([NH:9][C:10](=[O:11])[NH:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:8])[CH3:7]
Reactant: CC(C)N=C=O
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)NC(=O)NCC(=O)O
Temperature: 0 °C
Yield: 48.6 %

Procedure:
A solution of glycine (75.1 g.) in normal sodium hydroxide solution (one litre) is heated at 36° C. A solution of isopropyl isocyanate (76.5 g.) in acetone (100 cc.) is then added dropwise, whilst stirring. A rise in temperature from 36° to 50° C is observed in the course of the addition. The reaction mixture is stirred for a further 30 minutes after the end of the addition. Crushed ice (500 g.) and water (250 cc.) are then added and the mixture is acidified by adding 5 N hydrochloric acid (200 cc.), while stirring. The precipitate is then filtered off, and dried. 2-(3-Isopropylureido)-acetic acid (70 g.) melting at 178° C is thus obtained. A second crop (44 g.) of 2-(3-isopropylureido)-acetic acid, melting at 178° C, is obtained by concentrating the filtrate.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:4]2[N:11]=[N:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8].[Li][CH2:28]CCC.CI>C1COCC1.CCCCCC>[Br:1][C:2]1[C:3]([N:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:28])=[C:4]2[N:11]=[N:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: CCC(CC)Nc1c(Br)c(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCC(CC)N(C)c1c(Br)c(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [6-bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine (50 mg, 0.12 mmol) in dry THF )1.5 ml) was added 2.5 M n-BuLi in hexane (0.14 ml) at −78° C. After stirring at −78° C. for 10 min, 0.5 ml of methyl iodide was added at that temperature then allowed to warmed to room temperature and stirred for 15 min for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 46 mg of brown oil. The residue was purified through silica gel coliumn chromatography using 1:1 chloroform:hexane as eluent to give the title compound as a golden oil. 1H NMR (CDCl3) ä 7.04(s, 2H), 4.35(m, 1H), 3.32(s, 3H), 2.70(s, 3H), 2.38(s, 3H), 1.94(s, 6H), 1.7-2.0(m, 4H), 1.01(t, 6H)ppm.