Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O)(C)(C)C.[ClH:20].C(OCC)C.N>C(O)C.O>[ClH:20].[ClH:20].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccnc1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To an ice cooled solution of the compound of step 9a (286 mg, 1.08 mmol) in absolute ethanol (4 mL), was added a hydrogen chloride saturated ethanol solution (4 mL), under nitrogen. The reaction mixture was stirred 18 hours while gradually warming to room temperature. The reaction mixture was then concentrated in vacuo, the product dissolved in absolute ethanol and triturated with diethyl ether. Two recrystallizations from ethanol and diethyl ether yielded pure product in 81% yield as a white powder (174 mg, 87 mmol). MS (DCI/NH3) m/e 165 (M+H)+, 182 (M+NH4)+. 1NMR (D2O, 300 MHz) δ: 8.60-8.59 (d, J=2.9 Hz, 1H), 8.48-8.46 (d, J=5.8 Hz, 1H), 8.25-8.21 (ddd, J=9.0 Hz, J=2.6 Hz, J=1.1 Hz, 1H), 5.05-4.97 (m, 1H), 4.59-4.57 (d, J=4.0 Hz, 2H), 4.22-4.05 (m, 2H), 2.77-2.67 (dd, J=16.9 Hz, J=8.45 Hz, 2H). Anal. calcd. for C9H12N2O.2.7 HCl.0.2 H2O: C, 40.60; H, 5.71; N, 10.52. Found: C, 40.75; H, 5.76; N, 10.51.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.OC1C=CC=CN=1.[C:14]([O:18][C:19](=[O:48])[NH:20][C@H:21]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:38])[CH3:37])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19](=[O:48])[NH:20][C@@H:21]([CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:37])[CH3:38])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:44]([CH3:46])[CH3:45])([CH3:15])([CH3:16])[CH3:17]
Reactant: NC1CCCC1
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: CC(C)[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
0.17 g of cyclopentylamine (2.0 mmol) and 37 mg of 2-hydroxypyridine (0.39 mmol) were added to 200 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.39 mmol), and the mixture was stirred at 80° C. for six hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 193 mg of the title compound (yield: 83%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:44](=[O:45])[N:6]2[C:7]([C:31]([O:33]CC3C=CC([N+]([O-])=O)=CC=3)=[O:32])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][C:24]6[C:29]([CH:30]=5)=[CH:28][CH:27]=[CH:26][CH:25]=6)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].CI.[CH2:48](OCC)C>C(#N)C.C(Cl)(Cl)Cl>[OH:1][C@@H:2]([C@H:4]1[C:44](=[O:45])[N:6]2[C:7]([C:31]([O-:33])=[O:32])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N+:23]([CH3:48])[C:28]6[C:29]([CH:30]=5)=[CH:24][CH:25]=[CH:26][CH:27]=6)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cnc6ccccc6c5)c4s3)[C@H](C)[C@H]12
Reactant: CCOCC
Solvent: CI
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc6ccccc6[n+](C)c5)c4s3)[C@H](C)[C@H]12
Temperature: 40 °C
Reaction time: 72 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinolin-3-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (93 mg) was dissolved in acetonitrile (2.25 ml)/chloroform (0.75 ml) to prepare a solution. Methyl iodide (0.063 ml) was added to the solution at room temperature, and the mixture was stirred at 40° C. for 3 days. The reaction solution was poured into diethyl ether to produce a powder which was filtered to give an N-quaternarized compound. The title compound (7.7 mg) was prepared in substantially the same manner as in step b) of Example 1, except that this compound was used as the starting compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cccc(NC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 21 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, 3-methoxyphenyl isocyanate (0.36 ml) was added, and the admixture was refluxed with heat for 40 minutes. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) and then with chloroform/acetone (5/1) to obtain 31 mg of the title compound (yield: 21%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].C([O:14][C:15]([CH:17]1[C:21](=O)[CH2:20][CH2:19][O:18]1)=O)C>CCO>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]2[N:6]=[C:15]([OH:14])[C:17]3[O:18][CH2:19][CH2:20][C:21]=3[N:5]=2)[CH:7]=1
Reactant: CCOC(=O)C1OCCC1=O
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CCO
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 80 °C
Yield: 48.2 %

Procedure:
To a solution of 2-fluoro-5-chlorobenzamidine (1.05 g, 6.08 mmol, 1.2 eq) in EtOH (20 ml) was added 3-oxo-tetrahydrofuran-2-carboxylic acid ethyl ester (prepared according to Moyer, M. P; Feldman, P. L.; Rapoport, H. J. Org. Chem, 1985, 50, 5223-5230; 800 mg, 5.06 mmol, 1 eq) in ethanol (5 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to afford a white solid 2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ol (650 mg, 53%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:30].O1CCOCC1>CCOC(C)=O>[ClH:30].[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:15])[O:16][CH3:17])=[CH:9][C:8]=2[C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To 85I (1.63 g, 3.84 mmol) in EtOAc (15.0 mL) at rt was added 4.0 N HCl in dioxane (30 mL, 120 mmol). The mixture was stirred at rt for 4.0 h. TLC and LC-MS indicated a clean formation of the product. After evaporation of solvent, 85J (1.31 g, 95% yield) was obtained as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 0.98-1.10 (m, 3H) 1.21-1.33 (m, 1H) 2.10-2.20 (m, 1H) 2.24-2.34 (m, 2 H) 2.41-2.50 (m, 1H) 2.80-2.89 (m, 1H) 3.31-3.41 (m, 2H) 3.70 (s, 3H) 5.45 (t, J=7.69 Hz, 1H) 7.54 (dd, J=8.79, 2.20 Hz, 1H) 7.85 (d, J=8.79 Hz, 1H) 7.99 (d, J=2.20 Hz, 1H), LC-MS 325 (M+H).
Reaction SMILES: O[C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].[CH:14]1[C:19](=[O:20])[C:18]([OH:21])=[CH:17][O:16][C:15]=1[CH2:22]Cl>>[OH:12][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][C:9]=1[OH:11])[C:4]([O:6][CH2:22][C:15]1[O:16][CH:17]=[C:18]([OH:21])[C:19](=[O:20])[CH:14]=1)=[O:5]
Reactant: [OH-]
Reactant: O=c1cc(CCl)occ1O
Reactant: O=C(O)c1ccc(O)cc1O
Agent: [Na+]
Product: O=C(OCc1cc(=O)c(O)co1)c1ccc(O)c(O)c1
Yield: 82.3 %

Procedure:
By following the procedure of Example 1 by employing 4.22 g(27.4 mmole) of 2,4-dihydroxybenzoic acid, 1.1 g (27.5 mmole) of sodium hydroxide and 4 g(24.9 mmole) of chlorokojic acid, there was obtained 5.7 g(85.3%) of 2-(3,4-dihydroxybenzoyl)oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](Cl)(C)C.[CH2:21](N(CC)CC)C.[C:28]([O-:32])(=[O:31])[CH:29]=[CH2:30]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(/[CH:30]=[CH:29]/[C:28]([O:32][CH3:21])=[O:31])=[O:15])[CH3:14]
Reactant: C=CC(=O)[O-]
Reactant: CCO[PH](=O)CCCCc1ccccc1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOP(=O)(/C=C/C(=O)OC)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of (4-phenylbutyl)-phosphinic acid, ethyl ester (8.0 g, 35.4 mmols) in chloroform (40 ml) were added trimethylsilyl chloride (13.5 ml, 106 mmols) and triethylamine (19.7 ml, 142 mmols). The resulting mixture was stirred at 25° C. for 2.5 hours, after which it was concentrated in vacuo. To the residue were added methyl α-chloro=acrylate (20 g, 0.16 mole, prepared as described by C. S. Marvel and J. C. Cowan, J. Amer. Chem. Soc. 61, 3156 (1939)) and triethylamine (9.0 ml, 64 mmol). The resulting yellow mixture was stirred overnight at 65° C., resulting in an orange semisolid. The mixture was diluted with ethyl acetate and washed sequentially with 1N hydrochloric acid and saturated sodium bicarbonate solution, dried (MgSO4), and concentrated to an orange oil. The oil was chromotographed on LPS-1 silica gel, eluting with a gradient from 1:1 hexane:ethyl acetate to ethyl acetate, to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][NH:3]1.[N:7]([O-])=O.[Na+].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1C=O>[Zn]>[O:11]1[CH:15]=[CH:14][CH2:13][C:12]1=[N:7][N:3]1[CH2:4][CH2:5][NH:6][C:2]1=[O:1]
Reactant: O=Cc1ccco1
Reactant: O=C1NCCN1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Product: O=C1NCCN1N=C1CC=CO1

Procedure:
15.8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. by wt. of sodium nitrite and 27.5 pts. by wt. of zinc dust, and 15.8 pts. by wt. of furan-2-aldehyde, are reacted as in Example 1.1. 17.5 pts. by wt. of 1-furylideneamino-2-oxo-imidazolidine of melting point 218°-220° C. are obtained.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:16])[CH:10]=[CH:11]2)=[N:6]1.CC(O)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41][OH:42])[CH2:36]1>CO>[OH:42][CH2:41][CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)=[O:16])[CH:10]=[CH:11]3)=[N:6]2)[CH2:36]1
Reactant: O=CCCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1
Reactant: OCC1CCCNC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2cn(CCCN3CCCC(CO)C3)nc2c1
Reaction time: 18 h

Procedure:
To a solution of 1-[2-(3-oxopropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea (20 mg, 0.05 mmol) in Methanol containing 2% v/v AcOH (1 mL) was added 3-piperidinemethanol (10 mg, 0.10 mmol) and MS-CNBH3 (52 mg, 0.065 mmol). The reaction was shaken vigorously at 40 C for 18h. The reaction was filtered, eluting with additional Methanol (3×0.5 mL). The sample was directly purified by RP-HPLC to afford the titled product. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.15 (m, 1 H), 1.65 (m, 2 H), 1.83 (m, 2 H), 2.30 (m, 2 H), 2.63 (m, 1 H), 2.77 (m, 1 H), 3.10 (m, 2 H), 3.24 (dd, J=10.68, 6.61 Hz, 1 H), 3.36 (m, 1 H), 3.44 (m, 2 H), 4.47 (t, J=6.27 Hz, 2 H), 6.97 (m, 5 H), 7.09 (m, 1 H), 7.36 (m, 2 H), 7.49 (m, 2 H), 7.62 (m, 1 H), 7.90 (s, 1 H), 8.29 (s, 1 H), 8.76 (m, 2 H) and 9.16 (s, 1 H); MS (ESI) 500 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]1([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=2)=[C:31]([Cl:44])[CH:30]=1)OC)(=O)[CH3:2].C1(C)C=CC=CC=1.B(F)(F)F.O(CC)CC.[OH2:61]>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]21[C:34]1[C:29](=[CH:30][C:31]([Cl:44])=[C:32]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=3)[CH:33]=1)[O:28][CH2:27][CH2:26]2)(=[O:61])[CH3:2]
Reactant: O
Reactant: CCc1ccc(Cc2ccc(OCC[C@]3(OC)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2Cl)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OCC[C@]32O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(2S,3R,4S,5R,6R)-6-(Acetoxymethyl)-2-(2-(3-chloro-4-(4-ethylbenzyl)phenoxy)ethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (18) (19 mg, 0.03 mmol) was azeotropically dried (3×) with toluene, then dissolved in CH2Cl2 (0.4 mL), cooled to 0° C., and treated with BF3—OEt2 (approx 8 drops of a 48% solution). After 24 h, the reaction was concentrated onto celite and chromatographed over SiO2 (ISCO system, 0-40% EtOAc/hexanes) to provide a film (9.6 mg, 53%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.35 (s, 1H), 7.09 (s, 4H), 6.83 (s, 1H), 5.63 (d, J=9.9 Hz, 1H), 5.40 (t, J=9.6 Hz, 1H), 5.18 (t, J=10.2 Hz, 1H), 4.26-4.33 (m, 1H), 4.05-4.20 (m, 4H), 3.95 (s, 2H), 3.93 (m, 2H), 2.60 (q, J=15, 7.5 Hz, 2H), 2.04 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.83 (s, 3H), 1.21 (t, J=7.8 Hz, 3H). LC/MS 99.7% (ELSD) tR=2.93 min, calcd for C31H35ClO10: 602.19, found 620.4 (M+H2O)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[K+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([N:8]2[C:9]([C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=3)=[N:10][NH:11][C:28]2=[O:29])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n[nH]c1=O
Temperature: 24 °C
Reaction time: 18 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl) benzene carbohydrazonamide (4 g, 9.7 mmol) was taken up in THF (600 ml) under N2, and 1,1'-carbonyldiimidazole (1.9 g, 11.72 mmol) added. The solution was stirred for 18 h at 24° C. before solvent was removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 2.92 g (68.6%) mp 205.5°-207° C. IR(KBr, ν=cm-1) 3170, 3057, 1726,1504, 1277, 1128; 1H NMR (300 MHz, DMSO-d6) δ3.48 (3H, s), 7.15 (1H, d, J=9.0 Hz), 7.55 (1H, dd, J=8.9 Hz, 2.6 Hz), 7.69 (1H, d, J=2.6 Hz), 7.87 (2H, br.s), 8.17 (1H, br.s), 12.50 (1H, br.s); MS(DCl)m/z: 438(MH+). Anal. calcd. for C17H10ClF6N3O2 : C, 46.65; H, 2.30; N, 9.60. Found: C, 46.71; H, 2.20; N, 9.60.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[C:20](C)([C:24]([O-:26])=[O:25])[C:21]([O-:23])=O.[CH:28](Cl)(Cl)Cl>CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21](=[O:23])[CH2:20][C:24]([O:26][CH3:28])=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
2.47 g of [3-[3-(piperidinomethyl)phenoxy]propylamine was dissolved n 40 ml of dimethylmalonate and stirred at external temperature of 130° C. for 2 hours. Then, an excessive quantity of dimethylmalonate was distilled of under reduced pressure. Light brown oily substance was obtained. The obtained substance was subjected to silica gel column chromatography (solvent; chloroform:methanol=6:1). As a result, 3.06 g of oily N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-methoxycarbonylacetamide was obtained.
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[C:11]([CH3:14])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].C(#N)C.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O>[Br:18][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:14])=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2nc(C(C)Br)cc(=O)n12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
Under nitrogen, a suspension of 7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(13.2 g, 48.3 mmol) in acetonitrile (100 mL, 2000 mmol) was stirred until a clear solution was obtained. N-Bromosuccinimide (9.891 g, 55.57 mmol) was then added and the reaction mixture was stirred at 50° C. After 20 minutes, HPLC indicated that the reaction was complete. A solution of sodium sulfite (3.046 g, 24.16 mmol) in water (50 mL) was added and the mixture was stirred at room temperature for 20 minutes. Water (200 mL) was added slowly and the mixture stirred at room temperature for 30 minutes and then filtered. The solid was washed with water (100 mL×3) and dried to give 6-bromo-7-(1-bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as an off-white solid (15.61 g, 91%). LCMS calculated for C9H9Br2N2OS (M+H)+: m/z 352.87, 354.87; Found: 352.65, 354.60. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (q, J=1.3 Hz, 1H), 5.51 (q, J=6.7 Hz, 1H), 2.66 (d, J=1.2 Hz, 3H), 1.90 (d, J=6.7 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1([CH3:13])[CH2:10][C:9]([F:12])([F:11])[CH2:8]1)(=O)=O.[C-:14]#[N:15].[Na+]>CS(C)=O.O>[F:11][C:9]1([F:12])[CH2:10][C:7]([CH2:6][C:14]#[N:15])([CH3:13])[CH2:8]1
Reactant: [C-]#N
Reactant: CC1(COS(C)(=O)=O)CC(F)(F)C1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(CC#N)CC(F)(F)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of Intermediate 229B (200 mg, 0.934 mmol) in DMSO (3 mL) was added NaCN (114 mg, 2.334 mmol) at RT and the reaction mixture was heated to 80° C. and stirred for 12 h. The reaction mixture was cooled to RT, was diluted with water and was extracted with EtOAc (3×10 mL) To the combined organic layer was washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford Intermediate 229C as a brown oil (100 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.56-2.42 (m, 6H), 1.17 (s, 3H).
Reaction SMILES: [NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=[O:13])[C:9](=[O:14])[NH:8]3)[N:3]=[N:2]1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=[O:13])[C:9](=[O:14])[NH:8]3)[N:3]=[N:2]1.[O:14]=[C:9]1[C:10](=[N:22][NH:21][C:20]2[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=2)[C:11]2[C:7](=[CH:6][CH:5]=[C:4]3[C:12]=2[N:1]=[N:2][NH:3]3)[NH:8]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C1Nc2ccc3nn[nH]c3c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]nnc4c32)cc1

Procedure:
1,6-Dihydro-1,2,3,6-tetraaza-as-indacene-7,8-dione was prepared according to Procedure A in 56% yield: 1H NMR (DMSO-d6): δ 6.93 (d, J=8.6 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 11.14 (s, 1H); APCI-MS m/z 189 (M+1)+. Condensation of 1,6-dihydro-1,2,3,6-tetraaza-as-indacene-7,8-dione with 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 15% yield: 1H NMR (DMSO-d6): δ 7.06 Z (d, J=8.4 Hz, 1H), 7.24 E (d, J=8.4 Hz, 1H), 7.30 Z (s, 2H), 7.30 E (s, 2H), 7.55 E (d, J=8.5 Hz, 2H), 7.82 Z (d, J=8.5 Hz, 2H), 7.82 E (d, J=8.5 Hz, 1H), 7.90 E (d, J=8.7 Hz, 2H), 7.90 Z (d, J=8.8 Hz, 2H), 7.98 Z (d, J=8.4 Hz, 1H), 10.86 E (s, 1H), 11.35 Z (s, 1H), 12.87 Z (s, 1H), 12.95 E (s, 1H), 16.00 Z (s, 1H), 16.25 E (s, 1H); APCI-MS m/z 356 (M−H)−. Anal. Calcd for C14H11N7O3S.H2O: C, 44.80, H, 3.49; N, 26.12; S, 8.54. Found C, 44.72, H, 3.46; N, 26.05; S, 8.48.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][Cl:38]>CN(C=O)C.O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([Cl:38])[CH3:2])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCCCBr
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC(C)Cl)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt (3 g, 8.54 mmol) in DMF (30 ml) was added potassium carbonate (2.95 g, 21.35 mmol) and the mixture stirred at 60° C. for 1 hour under an atmosphere of nitrogen. The mixture was then cooled to room temperature and 1-bromo-6-chlorohexane (1.27 ml, 8.54 mmol) was added and the reaction heated to 50° C. and stirred overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water (ca. 50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic extracts were dried (MgSO4), filtered and the filtrate concentrated to give an orange oil (ca. 3.5 g). This material was dissolved in dichloromethane and purified on a Flashmaster II (70 g aminopropyl cartridge) using a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil which solidified to a pale yellow solid (1.2 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([Cl:7])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cccc(Cl)c1
Temperature: 60 °C

Procedure:
Methyl bromoacetate (8.3 g, 54.3 mmol), 3-chloroaniline (8.31 g, 65.1 mmol) and diisopropylethylamine (7.01 g, 54.3 mmol) were dissolved in N,N-dimethylformamide (20 mL) to give a light yellow solution and the reaction mixture heated at 60° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give (3-chloro-phenylamino)-acetic acid methyl ester as a solid which was washed with hexanes, filtered and dried (10.2 g, 96%).