Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[S:14][C:13]([CH2:15][CH2:16][CH3:17])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[S:14][C:13]([CH2:15][CH2:16][CH3:17])=[N:12][C:7]=4[CH:8]=[N:9][C:10]=3[CH:11]=2)=[CH:27][CH:26]=1
Reactant: CCCc1nc2cnc3cc(O)ccc3c2s1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1nc2cnc3cc(OCc4ccc(F)cc4)ccc3c2s1
Reaction time: 0.5 h

Procedure:
A mixture of 7-hydroxy-2-propylthiazolo[4,5-c]quinoline (0.88 g, 3.6 mmol) and cesium carbonate (2.35 g, 7.20 mmol) in DMF (50 mL) was stirred for 30 min, then 4-fluorobenzylbromide (0.50 mL, 4.0 mmol) was added. After 2 h, the mixture was concentrated in vacuo to remove the DMF. The resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated to a light yellow solid. The solid was recrystallized from heptane and pure 7-(4-fluorobenzyloxy)-2-propylthiazolo[4,5-c]quinoline was isolated as a tan solid (0.86 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Br:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Br:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:31]([C:30]1[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Br)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of N-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (582 mg, 1.50 mmol) in N-methylpyrrolidone (5 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (310 mg, 1.95 mmol), and the mixture was stirred at room temperature for 18 hr. A 5% aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the mixture was stirred with heating under reflux for 15 min. After allowing the reaction mixture to cool to room temperature, the precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (658 mg, yield 86%) as a cream solid.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>O>[Cl:15][CH2:16][CH2:17][C:18]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][C:2]([C:18](=[O:19])[CH2:17][CH2:16][Cl:15])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:19]
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=C(Cl)CCCl
Solvent: O
Product: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2

Procedure:
Prepared from xanthene 16 and 3-chloropropionyl chloride as described in Scheme 5 to give a solid. Mp 179-181° C. 1H NMR (CDCl3, 400 MHz) δ7.86-7.84 (m, 4H), 7.13 (d, J=10 Hz, 2H), 4.18 (s, 2H), 3.94 (t, J=8 Hz, 4H), 3.44 (t, J=8 Hz, 4H). Anal. (C19H16Cl2O3. 0.1 H2O).
Reaction SMILES: O[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1O
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Reaction time: 5 h

Procedure:
13.4 g. of 6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester (0.05 mol.) and 100 ml. of phosphorous oxychloride are refluxed with stirring for 5 hours. The excess of chlorinating agent is distilled off and the dark residue is poured into ice-water. 6-Chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester precipitates, yield 6.4 g. (42%), m.p. 143°-145° (ethyl acetate).
Reaction SMILES: [N+](=[C:3]([C:10](=[O:21])[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-]>ClCCl.C(#N)C.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:19][C@@H:17]([C@H:16]1[C:15](=[O:20])[N:14]2[C@@H:13]1[C@@H:11]([CH3:12])[C:10](=[O:21])[CH:3]2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH3:18]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Product: C=CCOC(=O)C1C(=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.36 g) in dichloromethane (2.25 ml) was added rhodium(II) octanoate (6 mg) under reflux. After refluxing for 20 minutes, to the solution was added rhodium(II) octanoate (6 mg). The mixture was refluxed for 40 minutes. The reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous acetonitrile (4.5 ml) and then evaporated. This operation was repeated once again and the resulting residue was dried in vacuo to give allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The residue containing the compound obtained above was dissolved in anhydrous acetonitrile (4.5 ml) and cooled to 0°-5° C. under an atmosphere of nitrogen. To this solution were added diphenyl phosphorochloridate (0.35 ml) and N,N-diisopropyl-N-ethylamine (0.32 ml) successively and the solution was stirred at 0°-5° C. for 1 hour. To the resulting solution were added dropwise a solution of (2S,4S)-1-allyloxycarbonyl-4-mercapto-2-[(ureidocarbonylxethyl)oxymethyl]pyrrolidine (0.35 g) in a mixture of dimethylformamide (1 ml) and acetonitrile (3 ml), and N,N-diisopropyl-N-ethylamine (0.35 ml) successively with stirring at 0°-5° C., and the stirring was continued at the same temperature for 3 hours. To a reaction mixture was added ethyl acetate (50 ml) and water (50 ml) with stirring, and the organic layer was separated.
Reaction SMILES: [CH2:1]1[CH2:8][C:7]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:6]=2[C:4](=[O:5])[CH2:3][CH2:2]1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:3]1[CH2:2][CH2:1][CH2:8][C:7]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:6]=2[C:4]1=[O:5]
Reactant: O=C1CCCCc2ccc(F)cc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2CCCC1Br
Yield: 100.2 %

Procedure:
To a stirred solution of 8-fluoro-1-benzosuberone (20.00 g, 112.2 mmol) in glacial acetic acid (125 ml) was added bromine (5.8 ml, 112.6 mmol) dropwise. Once the addition was complete, the solution was poured into water (400 ml) and extracted with EtOAc (500 ml). The extract was separated and washed with water (500 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield 100% (28.9 g) of the desired product as a viscous oil: 1H-NMR (CDCl3) δ 2.00 (2H, m), 2.33 (2H, m), 2.84 (1H, m), 3.00 (1H, m), 4.83 (1H, m), 7.13 (2H, m), 7.29 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=1[CH:28]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:28][C:23]4[NH:24][C:25]([CH3:27])=[CH:26][C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 37 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (50 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) at 80° C. for 2 hours to give 50 mg (37%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.07 (br s, 1H, NH), 9.18 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.35 (s, 1H), 7.30-7.40 (m, 2H), 6.05 (s, 1H), 3.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.16 (s, 3H, CH3). MS 398 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[C:3]=1[N+:9]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:9][C:3]1[C:4]([OH:8])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ccnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
4-chloro-3-nitro-pyridin-2-ol (1.69 g, 9.72 mmol) and tin tetrachloride dihydrate (SnCl2.2H2O) (10.97 g, 48.62 mmol) was dissolved in ethanol (32 ml), heated to 70□ and stirred for 2 hours. The reaction mixture was cooled to room temperature and the ethanol was evaporated under reduced pressure. The residue was neutralized with saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain pale-yellow solid (650 mg, 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:12][C:10]([CH3:13])([CH3:11])[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][C:26]([C@@H:24]([N:20]3[CH2:19][CH2:18][C@:17]([CH2:16][C:15]([OH:14])([CH3:47])[CH3:48])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[O:22][C:21]3=[O:23])[CH3:25])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1
Reactant: CC(C)(O)COc1ccc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(OCC(C)(C)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yloxy)-2-methylpropan-2-ol (30 mg, 0.122 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg) under nitrogen. The mixture was stirred for 1 h at rt. A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (58.4 mg, 0.122 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated, and purified by preparative TLC (1:1 PE/EtOAc) and HPLC to afford the title compound (7.6 mg, 12.1%). 1H NMR (CDCl3): δ 8.23 (d, 1H), 7.72 (q, 1H), 7.74-6.68 (m, 10H), 5.70 (m, 1H), 4.24 (s, 2H), 3.43 (s, 1H), 2.85 (m, 1H), 2.40 (m, 1H), 2.27-2.14 (m, 5H), 1.54 (d, 3H), 1.33-1.29 (d, 3H), 1.18-1.12 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[OH:32])=[O:14])=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cn1ccnc1COc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Product: Cn1ccnc1COc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-chloro-phenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinic acid and (1R,2R)-2-amino-1-cyclohexanol as starting materials to yield 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinamide, MS (ISP) 441.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH:11]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)C=Cc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(CC)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-ethylphenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(4-ethylphenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OCC)(=O)[CH2:27][OH:28].[O-]CC.[Na+]>C(O)C.O>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]2[S:9][C:5]([C:3]3[N:4]=[C:26]([CH2:27][OH:28])[O:1][N:2]=3)=[CH:6][N:7]=2)[CH2:11]1
Reactant: NC(=NO)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Reactant: CCOC(=O)CO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1nc(-c2cnc(N3CC[C@H](Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 25 °C

Procedure:
A mixture of N′-hydroxy-2-{(3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (373 mg, 1 mmol), ethyl glycolate (380 μL, 4 mmol) and sodium ethoxide, (21 wt. % solution in ethyl alcohol, 1.6 mL, 4.2 mmol) in ethanol (10 mL) was refluxed for 30 min. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to give the title compound as a pale yellow powder. 1H NMR (500 MHz, acetone-d6): δ 7.83 (s, 1 H), 7.69-7.65 (m, 2 H), 7.41 (d, 1 H), 7.16 (t, 1 H), 5.52 (m, 1 H), 5.05 (s, 1 H), 4.87 (s, 2 H), 3.98 (m, 1 H), 3.85-3.69 (m, 3 H), 2.60-2.44 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].I[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[CH:34][CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[CH:33][CH:34]=1)(=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC(=O)c1ccc(OCCOCCOCCI)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
Di-tert-butyliminodicarboxylate (3.05 g, 14.07 mmol) and potassium tert-butoxide (1.58 g, 14.07 mmol) were stirred in DMF (50 mL) for 15 minutes followed by the addition of 1-(4-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)phenyl)butan-1-one (43; 3.81 g, 9.38 mmol). The resulting mixture was stirred under nitrogen for 18 hours, and then poured into 200 mL of ethyl acetate. This solution was washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to afford a liquid that was purified by flash silica gel column chromatography, eluting with 3:1 hexanes/ethyl acetate to afford 44 (2.27 g, 49%) as a clear oil: MS (ES+) m/z 496.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:21][NH:22][C:23](=[S:24])[N:25]=2)=[CH:5][CH:4]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2n[nH]c(=S)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of 4,4′-dimethoxybenzil (13.6 g, 50 mmol) and 6.06 g of thiosemicarbazide (66.5 mmol) in 50 mL of glacial acetic acid were stirred at room temperature then refluxed overnight. The cooled reaction mixture was diluted with 150 mL of water and filtered. The solids were washed with water and dried. The crude product was heated with 55 mL of ethyl acetate, cooled, filtered and dried to give 10.1 g of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-thione, mp 228–232° C.
Reaction SMILES: [ClH:1].CC(C1C=CC=CC=1[N:11]=[C:12]([C:14]1[S:15][C:16]([S:25][CH3:26])=[C:17](N)[C:18]=1C1N=CSC=1)[NH2:13])C.Br.[CH3:28][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]1[S:39][CH:40]=[C:41](C2C=C(C(OC)=S)SC=2C)[N:42]=1)[CH3:30]>>[ClH:1].[CH3:30][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]1[S:39][CH:40]=[C:41]([C:17]2[CH:18]=[C:14]([C:12]([NH2:13])=[NH:11])[S:15][C:16]=2[S:25][CH3:26])[N:42]=1)[CH3:28]
Reactant: CSc1sc(C(N)=Nc2ccccc2C(C)C)c(-c2cscn2)c1N
Reactant: COC(=S)c1cc(-c2csc(Nc3ccccc3C(C)C)n2)c(C)s1
Agent: Br
Agent: Cl
Product: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccccc2C(C)C)n1
Yield: 88 %

Procedure:
4-(2-{[2-(Methylethyl)phenyl]amino{(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (33.1 mg, 0.06 mmol) was treated as described in Example 154, step (b) to give 22.4 mg (88%) of 4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) δ 1.19 (d, 6H, J=6.8 Hz), 2.70 (s, 3H), 3.32 (m, 1H), 7.04 (s, 1H), 7.14-7.25 (m, 2H), 7.35 (dd, 1H, J=1.4, 7.5 Hz), 7.86 (dd, 1H, J=1.4, 7.9 Hz), 8.37 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C18H20N4S3, 388.58 (M+H), found 389.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]2[C:29]([O:31][C:32](=O)[C:20]=12)=[O:30]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:32](=[O:31])[C:20]3[CH:19]=[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[CH:22][C:21]=3[C:29]2=[O:30])=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3cc4ccccc4cc3C2=O)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A pressure tube was charged with N1-(4-methoxybenzoyl)-1,2-benzenediamine (1.00 g, 4.13 mmol), 2,3-napthalenedicarboxylic anhydride (820 mg, 4.13 mmol), and tetrahydrofuran (16 mL). The resultant slurry was then placed in a bath heated to 110° C. for 16 h. After cooling to ambient temperature and standing for 3 h, the mixture was further cooled to −10° C. for 20 h. The resulting solid was collected by filtration and washed with cold ethyl acetate. The solid was then pulverized and dried under vacuum at 50° C. for 20 h to yield 1.45 g (83%) of the title compound.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[CH2:8]([O:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[Cl:1][CH:2]([CH3:6])[C:3]([NH:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Cl)C(=O)NOCc1ccccc1
Yield: 48 %

Procedure:
Prepared in 48% yield (0.97 g, 3.9 mmol) from the reaction of 2-chloropropanoyl chloride (1.03 g, 8.2 mmol) with O-benzylhydroxylamine, hydrochloride (1.03 g, 8.2 mmol) via general procedure A. Rf=0.43 (3:1, hexanes:EtOAc); mp=70.1-72.8° C.; 1H-NMR (500 MHz, CDCl3): δ 9.09 (br s, 1H), 7.44-7.35 (m, 5H), 4.93 (s, 4H), 4.33 (q, J=7.1 Hz, 1H), and 1.69 (d, J=6.8 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ 167.1, 134.8, 129.5, 129.1, 128.8, 78.5, 53.2, and 22.3; FT-IR: (neat): 3112 (br), 2931, 1678 (s), 1494, 1454, 1364, 1222, 1204, 1074 cm-1. HRMS ESI-MS: calculated for C10H12ClNNaO2 (M+Na)+, 236.0449; found 236.0445.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:16][C:17]([OH:19])=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(C1NC=CN=1)(C1NC=CN=1)=O.[C:33]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[CH2:34]C([O-])=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH2:16][C:17](=[O:19])[CH2:34][C:33]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of N-CBZ L-aspartic acid 1-methyl ester (1.00 g, 3.55 mmol) in dry tetrahydrofuran (17 mL) is added carbonyl diimidazole (634.1 mg, 3.91 mmol). The mixture is stirred at room temperature for 6 hr then the magnesium salt of mono-tert butyl malonate (1.339 g, 3.91 mmol) (prepared according to Angew. Chem. Int. Ed. Engl. 1979, 18(1), 72-74) is added. The mixture is stirred at room temperature for another 20 h, then concentrated in vacuum. The residue is partitioned between ether (60 mL) and 0.5 N HCl (60 mL). The organic layer is washed with saturated NaHCO3 solution (50 mL) then dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 35 g of silica gel, eluted with EtOAc:Heptane (1:1) to afford (S)-2-Benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-tert-butyl ester 1-methyl ester (1.17 g, 87%).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(OCC)C>[N:12]1[N:13]=[N:14][N:7]2[CH:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][C:3]=12
Reactant: COC(=O)C1CCC(OC)=N1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C1CCc2nnnn21
Temperature: 60 °C
Reaction time: 48 h
Yield: 30.3 %

Procedure:
To a solution of starting methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (900 mg, 6.04 mmol) in 4 mL of acetic acid was added sodium azide (975 mg, 12.08 mmol) and the resulting suspension heat to 60° C. and stirred vigorously for 48 h. The solution was cooled to room temperature and diluted with 35 mL of ethyl ether. Solid potassium carbonate was added to the solution which was stirred at room temperature for 20 min. The solids were filtered off via fritted funnel, washed with cool ethyl ether and concentrated under vacuum. Solid precipitated during concentration and was filtered off after concentrating to one-fifth volume. The solids were washed once with cold ether (3 mL) and dried under high vacuum overnight to afford the title compound (308 mg, 31%). LC-MS: m/z (ES)=169 (MH)+.