Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:26]([O:28]C)=[O:27])([CH3:25])[NH:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[C:7]([C:15]3[NH:23][C:22]4[CH2:21][CH2:20][NH:19][C:18](=[O:24])[C:17]=4[CH:16]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Li+].[OH-].CO.Cl>[NH4+].[Cl-]>[CH3:25][C:2]([NH:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[C:7]([C:15]3[NH:23][C:22]4[CH2:21][CH2:20][NH:19][C:18](=[O:24])[C:17]=4[CH:16]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:1])[C:26]([OH:28])=[O:27]
Reactant: COC(=O)C(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 2-methyl-N-(3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)alaninate (Ex. 57, 160 mg, 0.407 mmol), LiOH (51.2 mg, 1.220 mmol), and MeOH (2 mL) was stirred at 25° C. for 16 h. The reaction was then diluted with saturated aq. NH4Cl (10 mL) and neutralized to ˜pH 6 with 5 N HCl (aq). The resulting solution was extracted with 15% IPA:CHCl3 (3×30 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 2-methyl-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propanoic acid ((145 mg, 94%). 1H NMR (MeOH-d4) δ: 7.93-7.98 (m, 1H), 7.58-7.62 (m, 1H), 7.32-7.38 (m, 1H), 6.95 (s, 1H), 3.57-3.62 (m, 2H), 3.17-3.22 (m, 2H), 2.63-2.67 (m, 3H), 1.73-1.76 (m, 6H). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20].N1C=CC=CC=1>ClCCl>[CH3:1][CH:2]([CH3:6])[C:3]([O:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])=[O:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)(C)O2
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1OC(=O)C(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of 2-methylpropionylchloride (isobutyryl-chloride, 8.05 g, 75.55 mmol) in dichloromethane (10 mL) is added dropwise at 0° C. and under nitrogen to a solution of 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (12.8 g, 58.11 mmol) and pyridine (5.97 g, 61 mmol) in dichloromethane (58 mL). The ice bath is removed and the mixture is stirred for 2 hrs at room temperature. Water (10 mL) is added and the organic phase is washed with 2N hydrochloric acid (100 mL), water (100 mL), 10% sodium bicarbonate (100 mL) and brine. The solution is dried (magnesium sulfate) and evaporated to dryness to give 17 g (100%) of 5-(2-methylpropionoxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one as an oil which is used without purification for the next step. Rf=0.5 (heptane/ethyl acetate 90:10)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CO>[C:33]([NH:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1)(=[O:35])[CH3:34]
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C)Cc1ccccc1

Procedure:
A solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (25 mg, 0.058 mmol) and acetic anhydride (200 ml)-in methanol (2 ml) was kept at room temperature for 1 h. Evaporation followed by chromatography of the resultant product on a column of silica gel (10% methanol/dichloromethane) provided the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:11]2([C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19]C3CCCCO3)[C:13](=[O:26])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29].C(OCC)(=O)C>C(OCC)(=O)C.CCO>[ClH:29].[OH:19][CH2:18][CH2:17][N:14]1[C:13](=[O:26])[CH2:12][C:11]2([CH2:27][CH2:28][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(CCOC1CCCCO1)C2=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC2(CCNCC2)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 1,3-dioxo-2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.6 g) in ethyl acetate (1 ml), EtOH (1.0 ml) and 4N HCl/ethyl acetate (4 ml) are added at room temperature. The reaction mixture is stirred for overnight at room temperature. The solvent is removed by evaporation to give 1.06 g of crude 2-(2-hydroxy-ethyl)-2,8-diaza-spiro[4.5]decane-1,3-dione. hydrochloride.
Reaction SMILES: [CH2:1]([O:3][O:4][P:5]([CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH2:20][CH3:21])([CH3:19])[NH:15][C:14]1=[O:22])([O:7][O:8][CH2:9][CH3:10])=[O:6])[CH3:2].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.[OH-].[Na+].ClCl.[P]>[Cl-].C[N+](C)(C)C.O>[CH2:23]([N:15]1[C:16]([CH2:20][CH3:21])([CH3:19])[C:17](=[O:18])[N:13]([CH2:12][CH2:11][P:5]([O:7][O:8][CH2:9][CH3:10])([O:4][O:3][CH2:1][CH3:2])=[O:6])[C:14]1=[O:22])[CH:25]1[O:27][CH2:26]1
Reactant: ClCC1CO1
Reactant: CCOOP(=O)(CCN1C(=O)NC(C)(CC)C1=O)OOCC
Agent: C[N+](C)(C)C
Agent: ClCl
Agent: [Cl-]
Solvent: O
Product: CCOOP(=O)(CCN1C(=O)N(CC2CO2)C(C)(CC)C1=O)OOCC
Temperature: 60 °C

Procedure:
61.2 g of 3-(diethoxyphosphonoethyl)-5-ethyl-5-methyl-hydantoin (0.2 mol), 277.5 g of epichlorohydrin (3.0 mols) and 0.2 g of tetramethylammonium chloride are stirred for 90 minutes at 115° - 119° C. The mixture is then cooled to 60° C and 17.6 g of 50% strength aqueous sodium hydroxide solution are added dropwise over the course of 4 hours whilst stirring, under a waterpump vacuum. The water present in the mixture is removed by azeotropic circulatory distillation analogously to Example 1 (c). The mixture is worked up analogously to Example 1 (c) and 65.7 g of a yellow, clear, viscous resin (90.6% of theory) having an epoxide content of 2.71 epoxide equivalents/kg (96.7% of theory) are obtained. The product contains 0.65% of chlorine and 6.72% of phosphorus.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19][C@H:18]1[CH2:30]OS(C)(=O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O.C(OCC)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH2:19][C@H:18]1[CH2:30][O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 300 mg, 7.50 mmol) was added to a solution of phenol (710 mg, 7.54 mmol) in N,N-dimethylformamide (10 ml). The resulting reaction solution was stirred at room temperature for 30 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(mesyloxymethyl)pyrrolidine (2.05 g, 5.00 mmol) in N,N-dimethylformamide (5 ml) was added thereto. The resulting liquid mixture was stirred at 70° C. overnight. The reaction solution was poured into a liquid mixture of water with ethyl acetate. The organic layer was washed with 1N aqueous potassium hydrogensulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated in Vacuo. The resulting residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1→1:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(phenoxymethyl)pyrrolidine (1.23 g, yield 60%) as a pale yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:18][OH:19])[CH2:17][CH:6]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:5]2[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2([CH2:18][O:19][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:17][CH:6]3[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:9][CH:5]3[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)(CO)CC2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CC3CN(C(=O)OC(C)(C)C)CC3C2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
The diol compound prepared in Example K is dissolved in pyridine and treated with p-toluenesulfonyl chloride at -10° C., warmed to room temperature over two hours, diluted with aqueous sodium bicarbonate and extracted into chloroform to afford the title compound in 93% yield. This material is used without further purification. 1HNMR (400 MHz, CDCl3): β=1.26 ppm (m, 2H); 1.45 (s, 9H); 1.80 (m, 2H); 2.47 (s, 6H); 2.59 (m, 2H); 3.10 (d, 2H); 3.39 (dd, 2H); 3.78 (s, 2H); 3.85 (s, 2H); 7.36 (m, 4H); 7.72 (m, 4H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:16][CH:15]2[CH:11]1[CH:12]=[C:13]([CH2:17][CH3:18])[CH2:14]2)=O)(C)(C)C.C1(SC)C=CC=CC=1.O.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>C1C=CC=CC=1>[C:36]1([CH3:46])[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:43])=[O:44])=[CH:40][CH:41]=1.[NH2:8][CH2:9][C:10]1([CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH:15]2[CH:11]1[CH:12]=[C:13]([CH2:17][CH3:18])[CH2:14]2
Reactant: CCC1=CC2C(C1)CC2(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CSc1ccccc1
Product: CCC1=CC2C(C1)CC2(CN)CC(=O)O
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Tert-butyl [6-(tert-butoxycarbonylamino)methyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate (1152.23 g, 391.6 mmol) was dissolved in benzene (1.2 L). To the solution, thioanisole (145.57 g, 1173 mmol) and p-toluenesulfonic acid monohydrate (89.39 g) were then added, and the mixture was stirred for 2 hours under reflux. The mixture was left standing overnight at room temperature, and the resulting powder was collected by filtration. The obtained powder was washed with ethyl acetate and then dried to obtain the compound of interest as a white powder (88.29 g, 59%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:36])[C:8]1=[O:37])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[CH2:29]([C:14]1[C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:37])[N:9]([CH3:36])[C:10]=2[CH:17]=[N:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of 3-(5-benzyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydro pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.097 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (8.18 mg, 0.194 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (26.4 mg, 56% yield) as a white solid. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 7.45-7.37 (m, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.24 (s, 2H), 7.22-7.11 (m, 3H), 6.86 (d, J=7.1 Hz, 2H), 4.71 (s, 2H), 4.18 (t, J=6.1 Hz, 2H), 3.73 (d, J=13.2 Hz, 3H), 3.42 (t, J=5.6 Hz, 2H), 1.88-1.76 (m, 2H). LCMS: MH+ 486 and TR=2.808 min
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]([N:7]([CH3:24])[C:8]2[CH:9]=[C:10]3[C:19](=[CH:20][CH:21]=2)[O:18][CH2:17][C:16]2[N:11]3[C@H:12]([CH3:23])[C:13](=[O:22])[NH:14][N:15]=2)([CH3:6])[CH2:3]1.[Br-:25].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[O-]S([O-])(=S)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[Br:25][C:21]1[CH:20]=[C:19]2[C:10]([N:11]3[C:16]([CH2:17][O:18]2)=[N:15][NH:14][C:13](=[O:22])[C@H:12]3[CH3:23])=[CH:9][C:8]=1[N:7]([C:4]1([CH3:6])[CH2:5][N:2]([CH3:1])[CH2:3]1)[CH3:24]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(N(C)C4(C)CN(C)C4)cc3N21
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(N(C)C4(C)CN(C)C4)cc3N21
Temperature: 20 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a mixture of (R)-6-[(1,3-dimethyl-azetidin-3-yl)-methyl-amino]-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (3 g, 9.11 mmol) in DCM (40 mL) and MeOH (20 mL) was added tetra-n-butylammonium tribromide (6.59 g, 13.66 mmol) in portions and the reaction mixture was stirred at 20° C. for 16 h. Saturated aqueous Na2S2O3 (10 mL) was added and saturated aqueous sodium bicarbonate (5 mL) was added to neutralize the mixture. The organic phase was separated, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in DCM) to give (R)-7-bromo-6-[(1,3-dimethyl-azetidin-3-yl)-methyl-amino]-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (3 g, 81%) as a brown solid. LC/MS (Table 1, Method 3), Rt=1.060 min.; MS m/z: 410 [M+H+2]+& 408 [M+H]+. SFC (Table 1, Method 49), Rt=5.174 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20]2[O:21][C:22]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.CN(C1C=CC=CN=1)C.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(Cl)(Cl)Cl>ClCCl>[C:45]([N:26]([CH2:25][C:22]1[O:21][C:20]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)(=[O:47])[CH3:46]
Reactant: COCOc1cc(CC(=O)OC)c(-c2ccc(CNCCCN3CCOCC3)o2)c(OCOC)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCOc1cc(CC(=O)OC)c(-c2ccc(CN(CCCN3CCOCC3)C(C)=O)o2)c(OCOC)c1
Reaction time: 20 h
Yield: 89.5 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-{5-[N-(3-morpholinopropyl)aminomethyl]furan-2-yl}phenylacetate (46 mg, 0.094 mmol) obtained in Example 247 was dissolved in dichloromethane (1.0 mL), and dimethylaminopyridine (20 mg, 0.16 mmol) and acetic anhydride (0.1 mL, 1.1 mmol) were added thereto and stirred for 20 hours. Chloroform was added to the reaction solution for liquid-liquid separation. The organic layer was washed with 2 mol/L hydrochloric acid, aqueous saturated carbonic acid solution and aqueous saturated sodium chloride solution in order, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (methanol/chloroform=1/9) to obtain methyl 2-{5-[N-acetyl-N-(3-morpholinopropyl)aminomethyl]furan-2-yl}-3,5-bis(methoxymethoxy)phenylacetate (45 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc23)CC1
Yield: 57.8 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 29.0 mg (0.15 mMol) 4-trifluoromethylbenzoic acid, 11.6 mg (58%) of the title compound were recovered.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: C1CCNC1
Product: CC(C)(C)c1nc(N2CCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidine and isolated as white solid (12.4 mg, 71%). MS (m/e): 371.4 (MH+).
Reaction SMILES: Br.Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[O:12]=[C:13]([CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[C:20]([C@H:29]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[O:30]2)[CH:21]=[C:22]([OH:28])[C:23]=1[O:24][CH2:25][CH2:26][CH3:27])(=[O:17])=[O:16].C(=O)([O-])[O-]>CN(C=O)C>[O:12]=[C:13]([CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[C:20]([C@H:29]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=3)[O:30]2)[CH:21]=[C:22]([O:28][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:23]=1[O:24][CH2:25][CH2:26][CH3:27])(=[O:16])=[O:17]
Reactant: BrCCCc1cccnc1
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCc2cccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 70 °C

Procedure:
3-(3-Bromopropyl)pyridine hydrobromide (51 mg, 0.18 mmol) was added to a solution of trans-2-[3-(2-oxopropylsulfonyl)-4-n-propoxy-5-(2-hydroxy)phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (50.8 mg, 0.1 mmol) [Example 1, Step L] in DMF (2 mL) containing postassium carbonate (28 mg, 0.2 mmol), and the reaction mixture was heated at 70° C. for 1 h. The product was extracted with ethyl ether in the usualy way and purified by preparative TLC (hexane-ethyl acetate; 1.2, v/v) Rf 0.15; MS, m/z 628 (M+1)+. ; NMR (CDCl3)δ d 1.09 (t, J=7.5 Hz, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 2.18 (m, CH2CH2CH2Pyr), 2.37 (s, CH2COCH3), 2.87 (T, CH2CH2CH2Pyr), 3.83 (s, OCH3), 3.88 (s, 2 OCH3), 4.08 (t, CH2CH2CH2Pyr), 4.18 (t, CH2CH2CH3), 4.48 (s, CH2CO), 5.13-5.27 (m, H-2 & H-5), 6.61 (s, 2 H, C5ArH).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CN(C)[C:18](=[O:21])[CH:19]=[CH2:20].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>ClC(Cl)C>[CH2:25]1[C:26]2=[C:31]3[C:30](=[CH:29][CH:28]=[CH:27]2)[C:18](=[O:21])[CH2:19][CH2:20][N:23]3[CH2:24]1
Reactant: C=CC(=O)N(C)C
Reactant: c1ccc2c(c1)CCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C1CCN2CCc3cccc1c32
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
Add trifluoromethanesulfonic anhydride (10.5 mL, 63 mmol) in dichloroethane (30 mL) to N,N-dimethylacrylamide (6.4 mL, 63 mmol) in dichloroethane (100 mL) at 0° C. dropwise with vigorous stirring over 5 minutes. Add indoline (5.6 mL, 50 mmol) in dichloroethane (30 mL) dropwise over 5 minutes. Remove from cooling bath and heat at reflux for 3.5 hours. Cool to room temperature. Dilute with diethyl ether (600 mL). Wash with aqueous potassium carbonate (400 mL), dilute aqueous sodium bicarbonate (2×300 mL) and saturated aqueous sodium chloride (300 mL). Dry over sodium sulfate and concentrate under reduced pressure. Subject the residue to chromatography (pre-packed silica gel), eluting with 19:1 dichloromethane/ethyl acetate to provide the desired compound (2.65 g, 31%).
Reaction SMILES: Cl.[O:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].CCO>CS(C)=O>[Cl:10][CH2:11][C:12]([NH:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:13]
Reactant: NOc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCO
Solvent: CS(C)=O
Product: O=C(CCl)NOc1ccccc1
Yield: 67 %

Procedure:
This compound was prepared from phenoxyamine hydrochloride and chloroacetyl chloride by the method described in Preparation 1, m.p. 126°-128° (decomp.), λmax (EtOH) 266.5 nm (ε15,400), νmax (Nujol) 3340, 3260, 3140 (--NH--), 1720, 1710, 1690 cm-1 (--CONH--), τ(DMSO d6) 5.79 (ClCH2CO--), -2.2 (--NH--), 2.3-3.2 (phenyl). Yield 67%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br.BrC[C:38]1[CH:43]=[CH:42]C=C[N:39]=1.[ClH:44]>>[ClH:44].[ClH:44].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][C:24]2[CH:25]=[CH:42][CH:43]=[CH:38][N:39]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: Cl
Product: Cc1csc(Nc2ncc(SCc3ccccn3)cc2OCc2ccccc2)n1
Yield: 62.1 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 2-(bromomethyl)pyridine hydrobromide (42.6 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-2-ylmethylthio)pyridin-2-amine dihydrochloride (51.6 mg, 62.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 10.80 (bs, 1H), 8.63 (d, 1H), 8.04 (t, 1H), 7.81 (d, 1H), 7.60-7.53 (m, 4H), 7.49-7.34 (m, 4H), 6.76 (s, 1H), 5.30 (s, 2H), 4.42 (s, 2H), 2.28 (d, 3H); Mass spectrum (apci) m/z=330.0 (100), 421.0 (95), 238.0 (50).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.[C:30]([N:38]=[C:39]=[S:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C1COCC1>[CH2:13]([O:12][C:11](=[O:20])[NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:39]([NH:38][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[S:40])[CH2:5][CH2:6]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCC1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.9 %

Procedure:
A solution of benzyl N-[4-(aminomethyl)cyclohexyl]carbamate HCl (3.46 g, 11.58 mmol) and diisopropylethylamine (6.0 ml) in anhydrous THF (90 ml) was stirred at room temperature for 20 minutes. To this solution was added benzoylisothiocyanate (2.00 g, 12.3 mmol). The solution was stirred at room temperature for 14 hours, poured into water (200 ml) and then extracted with Et2O (2×150 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield a solid. The solid was triturated with hexane and filtered to yield 99% (5.023 g) of the desired product.