Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1.[CH:48]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH2:49]>CCO>[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:37][CH2:38][N:39]([CH2:49][CH2:48][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:40][CH2:41]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Temperature: 90 °C

Procedure:
A mixture of the TFA salt of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.061 mmol) and methyl vinyl sulfone (318.4 mg, 3.0 mmol) in EtOH (2.0 mL) was heated at 90° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (125:10:1) afforded a fluorescent product which was subjected to HPLC purification to afford the title compound in TFA salt form. 1H NMR (DMSO-d6) δ 2.01-2.17 (4H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 3.15 (s, 3H, CH3), 3.23 (m, 2H), 3.51-3.75 (8H), 4.01 (m, 2H), 4.15 (m, 1H), 4.34 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.36 (dd, J=7 Hz and 6 Hz, 1H), 7.59 (br s, 1H), 7.83 (br s, 1H), 11.14 (br s, 1H, NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 649.5 (MH+).
Reaction SMILES: C([O:9][C:10]1([CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38](=[O:40])[NH2:39])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:41])=[CH:20][CH:21]=[N:22]3)=[CH:17][C:16]=2[O:42][CH3:43])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[F:41][C:27]1[CH:28]=[C:29]([N:32]([C:30]2[CH:29]=[CH:28][C:27]([F:41])=[CH:26][CH:31]=2)[C:33]([C:35]2([C:38]([NH2:39])=[O:40])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:19]1[C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][C:10]3([OH:9])[CH2:12][CH2:11]3)=[C:16]([O:42][CH3:43])[CH:17]=2)[N:22]=[CH:21][CH:20]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(N)=O)CC4)cc3F)ccnc2cc1OCC1(OC(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.4 %

Procedure:
To a solution of 1-((4-(4-(1-(carbamoyl)cyclopropanecarboxamido)-2-fluorophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl benzoate (800 mg, 1.178 mmol) in CH3OH (10 mL) was added aqueous NaOH (94 mg, 2.356 mmol) solution (5 mL). The reaction was stirred at rt overnight. The suspension was concentrated, and the residual was purified by a silica gel column chromatography (EtOAc to 100:1 (v/v) EtOAc/CH3OH) to give the title product as a white solid (520 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19](OC3C=CC([N+]([O-])=O)=CC=3)=[O:20])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)=[O:20])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:10])([F:12])[F:11]
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
A solution of 5.85 g (9.54 mmol, purity 80%) of the compound from Example 77A in 1-methyl-2-pyrrolidone (50 ml) was admixed with 5.43 ml (5.91 g, 57.2 mmol) of thiomorpholine and 4.99 ml (3.70 g, 28.6 mmol) of N,N-diisopropylethylamine and then heated in 4 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 45 min. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 4.29 g (93% of theory)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([CH:11]([N:14]1[C:22]2[N:21]3[N:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[N:19]=[C:18]([CH3:27])[C:17]=2[CH2:16][CH2:15]1)[CH2:12][CH3:13])[CH3:10].O>CN(C)C=O.C(OCC)(=O)C>[CH2:9]([CH:11]([N:14]1[C:22]2[N:21]3[N:23]=[C:24]([CH3:26])[C:25]([I:1])=[C:20]3[N:19]=[C:18]([CH3:27])[C:17]=2[CH2:16][CH2:15]1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCC(CC)N1CCc2c(C)nc3cc(C)nn3c21
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)N1CCc2c(C)nc3c(I)c(C)nn3c21
Reaction time: 1 h
Yield: 75.8 %

Procedure:
N-Iodosuccinimide (3.5 g, 15 mmol) was added to a solution of 8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (3.7 g 15 mmol) in N,N-dimethylformamide (40 mL) at room temperature, followed by stirring for one hour. Hypo water was added, and the mixture was diluted with ethyl acetate, washed with an aqueous saturated solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatgraphy (20-40% ethyl acetate/hexane), to give the title compound (4.37 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:26]([OH:33])[C@@H:27]([C@@H:29](CO)[OH:30])[OH:28].C(=O)([O-])[O-].[K+].[K+].C(O)=O>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C@@H:26]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:33])=[O:7]
Reactant: OC[C@@H](O)[C@@H](O)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OC[C@H](O)[C@H](O)CO)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 10 h

Procedure:
Under reduced pressure of 60-70 mmHg and nitrogen gas stream, 199 g (0.564 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 191 g (1.56 mol) of erythritol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL) at 78-83° C. After the reaction mixture was stirred at the same temperature for 10 hours, formic acid was added at 75° C. to adjust the pH to 4. After the resulting solution was subjected to vacuum concentration, the residue was diluted with t-butylmethylether (1.5 L), and the insoluble matter generated was separated by filtration. The filtrate was washed with 10% sodium bicarbonate aqueous solution twice, and decolorized with activated carbon (8 g). After filtration, the filtrate was concentrated, and the residue was dissolved in ethanol, followed by filtration through cellulose powder. After the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate mixture) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](=O)[CH3:33])[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:32]([CH3:33])[CH2:31][C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC(C)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-(3,5-difluoro-phenyl)-propan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 14.1, 19.2, 19.5, 20.1, 21.1, 24.3, 26.6, 36.1, 36.6, 43.6, 44.1, 54.4, 54.9, 56.0, 59.1, 59.1, 60.9, 61.1, 67.3, 101.8, 101.9, 102.0, 102.2, 102.3, 102.4, 104.7, 104.7, 112.0, 112.1, 112.2, 112.3, 112.3, 112.4, 112.5, 131.1, 137.2, 137.3, 143.1, 143.1, 161.8, 162.0, 164.3, 164.4, 172.1, 172.4; MS m/z 462.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:10][N:11]2[CH2:15][CH2:14][N:13]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:12]2=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1NCCN1N=Cc1ccc(O)c(O)c1
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(C=NN2CCN([Si](C)(C)C)C2=O)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a mixture of 5.0 g (22.6 mmol) of 1-[[(3,4-dihydroxyphenyl)methylene]amino]-2-imidazolidinone and 8.1 g (74.6 mmol) of chlorotrimethylsilane in 200 ml of ethyl acetate was added 7.5 g (74.6 mmol) of triethylamine. After stirring overnight at ambient temperature, the precipitate was filtered off and the filtrate evaporated in vacuo to afford 8.8 g of 1-[[[3,4-bis[(trimethylsilyl)oxy]phenyl]methylene]amino]-3-(trimethylsilyl)-2-imidazolidinone.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C@H:9]1[C@H:37]([CH3:38])[C@@H:36]2[C@@:12]([C:40]([OH:42])=[O:41])([CH2:13][CH2:14][C@@:15]3([CH3:39])[C@:20]4([CH3:35])[CH2:21][CH2:22][C@H:23]5[C@@:28]([CH2:30][OH:31])([CH3:29])[C@@H:27]([OH:32])[C@H:26]([OH:33])[CH2:25][C@:24]5([CH3:34])[C@H:19]4[CH2:18][CH:17]=[C:16]32)[CH2:11][CH2:10]1>N1C=CC=CC=1>[CH3:8][C@H:9]1[C@H:37]([CH3:38])[C@@H:36]2[C@@:12]([C:40]([OH:42])=[O:41])([CH2:13][CH2:14][C@@:15]3([CH3:39])[C@:20]4([CH3:35])[CH2:21][CH2:22][C@H:23]5[C@@:28]([CH2:30][O:31][C:30]([CH3:28])=[O:31])([CH3:29])[C@@H:27]([O:32][C:27]([CH3:26])=[O:32])[C@H:26]([O:33][C:5]([CH3:6])=[O:7])[CH2:25][C@:24]5([CH3:34])[C@H:19]4[CH2:18][CH:17]=[C:16]32)[CH2:11][CH2:10]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@]1(C)[C@@H]2CC[C@]3(C)[C@H](CC=C4[C@@H]5[C@@H](C)[C@H](C)CC[C@]5(C(=O)O)CC[C@]43C)[C@@]2(C)C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 10 °C

Procedure:
With reference to the first step in scheme 7 above, asiatic acid (5 g) was dissolved in pyridine (10 ml) with stirring. The solution was cooled down to 10° C., and 15 ml of acetic anhydride were added. The resultant solution was stirred at room temperature for 20 hours, and then 200 ml of ice water were added. A precipitate formed, was filtered out and washed with water, and then was dried under 50° C. to yield 6.28 g of asiatic acid triacetate as a white powder.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([N+:26]([O-])=O)=[C:19]([O:24][CH3:25])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:6][CH2:5]1)[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([NH2:26])=[C:19]([O:24][CH3:25])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:8][CH2:9]1)[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCN(C(C)C)CC1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)CN(C(=O)CCN1CCN(C(C)C)CC1)CC2
Yield: 98.5 %

Procedure:
A solution of 2-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (285 g, 0.731 mmol) in ethanol (10 mL) was treated with 10% palladium on carbon (30 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (0.26 g, 0.72 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers δ ppm 0.92-0.98 (m, 6 H), 2.30-2.71 (m, some signals underneath DMSO, 15 H), 3.56-3.63 (m, 2 H), 3.72 (s, 3 H), 4.37-4.47 (two singlets at 4.38 and 4.45, 2 H), 4.53-4.59 (two broad singlets at 4.55 and 4.58, 2 H), 6.38-6.42 (two singlets at 6.39 and 6.41, 1 H), 6.55-6.58 (two singlets at 6.56 and 6.57, 1 H); ESIMS (M+H)+=361.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Cc1cccc(C=O)c1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methylbenzaldehyde (0.5 g, 4.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.092, 73%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[NH2:11][C:12]1[C:21](Cl)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[NH2:11][C:12]1[C:21]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: OCc1cccnc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2nc1OCc1cccnc1
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
3-Pyridinemethanol (487 μL, 5.01 mmol) was dissolved in tetrahydrofuran (6.0 mL). To this, 60% sodium hydride (in oil) (200 mg, 5.01 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at the same temperature for 15 minutes. To this, 2-amino-3-chloroquinoxaline (300 mg, 1.67 mmol) was added and the mixture was stirred at room temperature for 14 hours. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1). Further, slurry purification was performed using diisopropyl ether, to give 2-amino-3-[(pyridin-3-yl)methoxy]quinoxaline (Compound BA) (383 mg, yield: 91%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH3:19]
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(O)ccc1N
Reaction time: 8 h

Procedure:
1-Benzyloxy-3-methoxy-4-nitrobenzene (11.0 g) was dissolved in tetrahydrofuran (100 ml)-methanol (100 ml), and then 10% palladium carbon (5.0 g) was added thereto, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with tetrahydrofuran, ethyl acetate and methanol in this order. The filtrate was concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (5.88 g, quantitatively) as brown powder.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([NH:18][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCC1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: O[C@@H](CNC1CCCC1)c1ccc2nnnn2c1
Yield: 75.4 %

Procedure:
A solution of 250 mg (1.54 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 0.751 ml (7.61 mmol) of cyclopentyl amine in 0.6 ml of absolute ethanol was heated at 100° C. for 3 hours in a sealed reaction tube. The reaction mixture was concentrated to dryness and the residue (375 mg) purified by preparative Tlc on silica gel (90:10:2 ethyl acetate: methanol:triethylamine) to give 287 mg of pure product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[C:13]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)CCCC>[C:13]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:4]3[N:3]=[C:2]([NH2:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: Nc1nc(Cl)nc2ccccc12
Solvent: CCCCCO
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(c3nc(N)c4ccccc4n3)CC2)cc1
Temperature: 120 °C
Yield: 73.3 %

Procedure:
4-amino-2-chloro-quinazoline (0.070 g, 0.39 mmol) was added to a solution of (49) (0.13 g, 0.47 mmol) in n-pentanol (5 mL) at 25° C. The mixture was heated to 120° C. and was maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and concentrated to a brown yellow oily residue. Purification of the residue by flash column chromatography (gradient elution 0 to 5% MeOH in CH2Cl2) provided the title compound (0.12 g, 73%): TLC (Rf =0.33; 5% MeOH/CH2Cl2); 1H NMR (CDCl3) δ 7.83 (d, 2H, J=8.7), 7.51 (m, 3H), 7.10 (t, 1H, J=6.6), 6.57 (d, 2H, J=8.8), 5.35 (br s, 2H), 4.81 (d, 2H, J=13.6), 4.00 (br s, 1H), 3.60 (m, 1H), 3.14 (t, 2H, J=14.0), 2.13 (d, 2H, J=13.2), 1.57 (s, 9H), 1.47 (m, 2H); 13C NMR (CDCl3) δ 166.1, 161.6, 158.8, 152.0, 150.4, 133.2, 131.5, 125.9, 121.8, 121.3, 120.3, 111.8, 109.7, 79.9, 50.3, 42.8, 32.3, 28.3; Anal. (C24H29N5O2 ·1/4HCl)·C, H, N.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:24](Cl)(=[O:26])[CH3:25].[NH4+].[Cl-]>C1COCC1>[C:24]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:26])[CH3:25]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a stirred suspension of 5.000 g (4R)-(−)-4-phenyl-2-oxazolidinone (30.03 mmol) in 100 mL THF, were added 21.0 mL n-butyllithium in hexane (1.5 M, 31.53 mmol, 1.05 eq) at 0° C. within 10 min. The resulting colorless solution was stirred for additional 50 min at 0° C. 2.57 mL acetyl chloride (36.04 mmol, 1.2 eq) were then added within 1 min. After 3.5 h the reaction was stopped by addition of 25 mL saturated aqueous NH4Cl and the mixture was extracted with 75 mL ethyl acetate. The organic phase was washed with 50 mL saturated aqueous NaHCO3 and with 50 mL brine. The solution was dried for 30 minutes over 5 g Na2SO4 and filtered. The filter cake was washed with 10 mL ethyl acetate. After removal of solvent in a rotary evaporator (40° C., 18 mbar), the crude product was obtained as white crystals (6.13 g, 100% w/w; HPLC purity 88.3% area). Further purification was achieved by dissolving in 10.6 mL ethyl acetate at reflux temperature and subsequent dropwise addition of 26.6 mL heptane. The resulting suspension was allowed to slowly cool down to 5° C. and after standing overnight, the precipitate was collected by filtration. After washing with 3 mL heptane, the title compound was obtained as white crystals (5.26 g, 25.6 mmol, 85% by weight) and in high purity (HPLC purity 96.6% area).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4](I)[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CNc1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CNc1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 83.9 %

Procedure:
A mixture of 6.05 g (19.3 mmol) (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine, 23.6 g (23.6 mmol) 2-chlorophenylboronic acid, 441 mg (1.96 mmol) palladium(II) acetate, 1.03 g (3.93 mmol) triphenylphosphine, 47.1 ml 2 N sodium carbonate solution and 50 ml 1,2-dimethoxyethane was heated at 80° C. for 90 min. The reaction mixture was cooled to room temperature and diluted with 100 ml ethyl acetate. The aqueous layer was separated and extracted with 100 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 4.1 g (83%) of the title compound as a light brown solid.
Reaction SMILES: CI.[Cl:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([O:11][CH3:12])=[CH:6][N:5]=1.[C:13]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:3][C:4]1[N:9]([CH3:13])[C:8](=[O:10])[C:7]([O:11][CH3:12])=[CH:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(Cl)[nH]c1=O
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
128 g (0.9 mol) of MeI was added dropwise to the suspension of 2-chloro-5-methoxypyrimidin-4(3H)-one (74 g, crude, about 0.3 mol) and Cs2CO3 (195 g, 0.6 mol) in 600 mL of DMF at 0° C. and the reaction mixture was stirred at this temperature for 1 h, then warmed to r.t., and stirred another 1 h. The mixture was poured into water and extracted with EtOAc several times. The extract was washed with water, brine and dried over Na2SO4 before being filtered and concentrated to give a crude product, which was purified by silica gel chromatography to give 31.2 g (71.2%) of 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one. 1H-NMR (CDCl3, 400 MHz) δ 7.37 (s, 1H), 3.80 (s, 3H), 3.61 (s, 3H). MS (ESI) m/z (M+H)+ 175.0/176.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:15]3[CH:14]4[CH2:16][CH:13]4[CH2:12][C:11]=3[C:10]([C:17]([O:19]CC)=[O:18])=[N:9]2)[CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nn(CC2CCOCC2)c2c1CC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nn(CC2CCOCC2)c2c1C[C@H]1C[C@@H]21
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
Ethyl 2-((tetrahydro-2H-pyran-4-yl)methyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylate (127 mg, 0.437 mmol) was dissolved in THF (4.00 mL) and H2O (4.00 mL). Lithium hydroxide hydrate (55.1 mg, 1.312 mmol) was added and the reaction was stirred at 45° C. for 1.5 h. The organic solvent was removed under reduced pressure to give the title compound (115 mg) as a brown solid. LCMS m/z=263.2 [M+H]+.