Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([O-])=O.[K+].IC1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:18][C:17]=2[CH:31]=1>C1(C)C=CC=CC=1.CN(C=O)C.[Cu]I>[F:7][C:3]([F:8])([C:4]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:23])[F:24])[C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:18][C:17]=2[CH:31]=1)[C:2]([F:10])([F:9])[F:1]
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2OC1C(F)(F)F
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Temperature: 120 °C

Procedure:
Potassium pentafluoropropionate (0.476 g, 2.35 mmol) was dissolved in toluene (6 mL) and DMF (6 mL). The vessel was fitted with a distilling head, and CuI (0.471 g, 2.474 mmol) was added with stirring. The reaction was heated to 120° C., removing the toluene by distillation. Ethyl 6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72, Step 3) (0.469 g, 1.178 mmol) was added and the reaction was heated to 150° C. for 2 hours. The reaction was allowed to cool to room temperature and was partitioned between diethyl ether and H2O. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel 60, eluant:hexanes-ethyl acetate, 8:1) yielding, upon concentration of the solution, the desired ester (0.096 g, 21%) as a tan solid mass of suitable purity to use without further purification: 1H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.91 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H, J=8.7, 2.2 Hz), 6.00 (q, 1H, J=7.1 Hz), 4.42–4.24 (m, 2H), 1.34 (t, 3H, J=7.3 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]([O:17]CC)=O)[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][NH2:22].CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]([NH:22][CH3:21])=[O:17])[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Reactant: CN
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 42.3 %

Procedure:
In 1.5 ml of methylene chloride were dissolved 0.5 g of ethyl (3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazin-4-yl)acetate and 0.16 g of 40% methylamine-methanol and the mixture was allowed to stand at room temperature for 3 days. The solvent was then distilled off and the residue was recrystallized from methylene chloride-hexane to give 0.2 g of 2-(3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazin-4-yl)-N-methylacetamide. This compound has the following physicochemical properties.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:10]([NH:12][C@@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[S:15][CH2:16][C:17](/[CH:25]=[C:26]1\[CH2:27][CH2:28][N:29]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:30]\1=[O:31])=[C:18]2[C:22]([OH:24])=[O:23])=[O:11])=O)(C)(C)C.C(OCC)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:8][C@H:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:10]([NH:12][C@@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[S:15][CH2:16][C:17](/[CH:25]=[C:26]1\[CH2:27][CH2:28][N:29]([CH2:32][C:33]([F:34])([F:36])[F:35])[C:30]\1=[O:31])=[C:18]2[C:22]([OH:24])=[O:23])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC(F)(F)F)C3=O)CS[C@H]12)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC(F)(F)F)C3=O)CS[C@H]12)c1ccccc1
Reaction time: 0.5 h

Procedure:
1.0 g (1.64 mmol) (6R,7R)-7-[(R)-2-t-butoxycarbonylamino-2-phenyl-acetylamino]-8-oxo-3-[(E)-5-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-4-ylidenemethyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 5 ml trifluoroacetic acid and stirred for 30 min at 0°-5° C. The solution was then poured on 100 ml diethyl ether and the separated material was filtered off. It was then stirred for 2 hours in 25 ml ethyl acetate; the crystals separated were filtered off and dried.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[C:1]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: O=C1CCCCCCCCCCC1
Agent: C1=C(/N2CCOCC2)CCCCCCCCCC/1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCCCCCCCCC1

Procedure:
A 100 mL three neck round bottom flask, equipped with a stir bar, thermometer and a Dean-Stark trap, was charged with 10 g (55 mmoles) of cyclododecanone, 6.7 g (77 mmoles) of morpholine, 40 mL of anhydrous toluene and a catalytic amount of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed for 48-77 hours. The toluene was removed under vacuum, and the reaction mixture was vacuum distilled to give 5.7 g of N-morpholino-1-cyclododecene (at 160°-168° C./0.5mm) as a 95% pure clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:46][C:47]1[C:51](B(O)O)=[C:50]([CH3:55])[O:49][N:48]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:51]2[C:47]([CH3:46])=[N:48][O:49][C:50]=2[CH3:55])=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1noc(C)c1B(O)O
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2c(C)noc2C)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (95.1 mg, 0.139 mmol), 3,5-dimethylisoxazole-4-boronic acid (98.5 mg, 0.699 mmol), Pd(PPh)3Cl2 (4.84 mg, 0.0069 mmol), 2 M Na2CO3 (aq., 0.210 mL, 0.419 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-90% CH3CN in 0.05% aqueous formic acid) afforded the product (30.2 mg, 31%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:20])[F:19])=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=O)=[O:7])=[C:4]([NH2:24])[CH:3]=1.OC1C=CC=CN=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:7])[C:8]3[C:9]([C:18]([F:19])([F:20])[F:21])=[N:10][NH:11][C:12]=3[C:13](=[O:15])[NH:24][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1N
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2c(C(F)(F)F)n[nH]c12
Temperature: 170 °C
Yield: 39.4 %

Procedure:
To a solution of ethyl 4-(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate (360 mg, 0.997 mmol) in toluene (50 mL) was added 2-hydroxypyridine (93.9 mg, 0.988 mmol). Toluene was removed by distillation and the residue was heated at 170° C. for 2 days. The flask was cooled to room temperature and dichloromethane (20 mL) was added. The insoluble material was filtered to give crude solid (284 mg). The crude material was continuously chromatographed eluting with dichloromethane (100 mL) and dichloromethane:2-propanol (98:2, 200 mL). The fractions were concentrated bv rotary evaporation and were found to contain a contaminant from tygon tubing. The fractions were combined and flash chromatographed through a plug of silica gel to remove the contaminant, eluting with hexanes, hexanes:ethyl acetate (95:5, 90:10), dichloromethane, and dichloromethane:2-propanol (95:5, 90:10). The product fractions were concentrated by rotary evaporation to give the title compound as a white solid (124 mg, 37%. m.p. 337-339° C.).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:38][CH2:37][CH3:41])[C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Yield: 29.8 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate (0.270 g; 0.73 mmol), LHMDS 1N in THF (0.8 mL; 0.8 mmol), 1-iodopropane (0.122 mL; 1.09 mmol) in DMF (3 mL) for 19 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.089 g (30%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:26]3[CH2:27][N:28](C(OCC)=O)[CH2:29][CH2:30][CH:25]3[N:13]3[CH2:14][CH:15]([CH3:24])[N:16](C(OCC)=O)[C:17]([CH:18]=1)=[C:12]23.[OH-].[K+]>CCCCO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:26]3[CH2:27][NH:28][CH2:29][CH2:30][CH:25]3[N:13]3[CH2:14][CH:15]([CH3:24])[NH:16][C:17]([CH:18]=1)=[C:12]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC(C)N3C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC1CN2c3c(cc(-c4ccc(Cl)cc4Cl)cc3C3CNCCC32)N1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a solution of diethyl 5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (30 mg, 0.06 mmol) in 10 mL of n-BuOH was added KOH (33 mg, 0.6 mmol) and stirred at 120° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with water (10 mL). The organic layer was collected and washed with 1N HCl (10 mL) and water (10 mL). This time the aqueous layer was collected and neutralized with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated to afford 5-(2,4-dichlorophenyl)-2-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (10 mg, 45%) as a solid. MS [M+H]+ 374.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].CN(C)P(N(C)C)(N(C)C)=O>O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O:28][CH3:29])=[O:27]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C#N)cc1

Procedure:
A solution of 12 g. of 4-aminobenzonitrile and 15 g. of methyl 16-bromohexadecanoate in 200 ml. of hexamethylphosphoramide is heated at 120° for 22 hours, allowed to cool, and diluted with water. The mixture is chilled and the precipitate which forms is collected, dried, and recrystallized from etherhexane to yield 4-(15-carbomethoxypentadecylamino)benzonitrile as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:22][CH3:23])[CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:31])=O>>[Cl:31][C:15]1[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:12]([O:22][CH3:23])[CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCC1CCN(C)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCC1CCN(C)CC1
Yield: 54 %

Procedure:
A solution of 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (3.1 g, 9.8 mmol) in thionyl chloride (40 ml) containing DMF (400 μl) was refluxed for 4 hours. After cooling, the volatiles were removed under vacuum. The residue was partitioned between methylene chloride and water and the pH of the aqueous layer was adjusted to 11 with solid sodium hydrogen carbonate and aqueous ammonia. The organic layer was separated, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.83 g, 54%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:17])[CH2:11][N:12]1[N:16]=[CH:15][CH:14]=[N:13]1)[CH3:8].Br[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30].Cl>C1COCC1.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:17])[CH:11]([N:12]1[N:13]=[CH:14][CH:15]=[N:16]1)[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:28][C:29]=1[CH3:30])[CH3:8]
Reactant: CCOC(=O)Cn1nccn1
Reactant: Cc1oc(-c2ccccc2)nc1CCCC#CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#CCCCc1nc(-c2ccccc2)oc1C)n1nccn1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Potassium t-butoxide (2.6 mL, 2.6 mmol) was added to a to a solution of [1,2,3]triazol-2-yl-acetic acid ethyl ester (355 mg, 2.3 mmol) in THF (30 mL) at −78° C. under N2 atmosphere and stirred for 1 hour. A solution of bromide 1-9 (1.5 g, 4.5 mmol) in THF (30 mL) was then added and the solution allowed to equilibrate to 0° C. for 1 hour. Reaction was then poured into dilute aqueous HCl and diluted with EtOAc. The organic layer was washed with water, brine, and dried over MgSO4. Chromatography with 20% EtOAc/Hex gave 550 mg of a mixture of mono-1-4 and bis-alkylated products. The mixture was not separated, and was taken on to hydrolysis step.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:8]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5.0 g (16.3 mmoles) of 2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro [5H]-pyrrolo[1,2 a]imidazole of Example 3 dissolved in 75 ml of chloroform, chilled in an ice bath, was added dropwise a solution of 3.30 g (16.3 mmoles) of 85% 3-chloroperbenzoic acid in chloroform. After stirring at 25° C. overnight, the reaction mixture was washed with 5% sodium carbonate, dried over anhydrous potassium carbonate, and stripped in vacuo. The residue was flash chromatographed on silica eluting with 5 to 10% methanol in methylene chloride: 2-propanol (9:1). The solvent was removed in vacuo and the residue recrystallized from ethyl acetate to give the desired titled compound, mp 163.5-165.5° C. 1H NMR (360 MHz, CDCl3) δ8.62 (2H,d), 7.68 (2H,d), 7.57 (2H,d), 7 25 (2H,d), 4.05 (2H,t), 3.02 (2H,t), 2.72 (s) superimposed upon 2.69 (m) (5H total). Mass Spec. (CI) (M+H) 324 (MW=323).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)=[C:4]([F:21])[CH:3]=1.[H][H]>[Pt]=O.C(O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:21])=[C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)[CH:6]=1
Reactant: [H][H]
Reactant: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Yield: 246.6 %

Procedure:
To a 500 ml Parr hydrogenation bottle was added 0.2 g of platinum oxide, 200 ml of ethanol, then 14.0 g (0.014 mole) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The bottle was placed in a Parr hydrogenator and the reaction mixture hydrogenated until the theoretical amount of hydrogen was taken up. The bottle was removed from the hydrogenator and the reaction mixture filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and subjected to column chromatography on silica gel. The appropriate fractions were combined and concentrated under reduced pressure to yield 10.0 g of 1-(5-amino-4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 84°-°86° C. The reaction was repeated several times.
Reaction SMILES: CN=C=S.[S:5]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][CH2:13][NH2:14])=[N:6]1.[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][N:19]=[C:20]=[S:21]>>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][NH:19][C:20]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:7]1[CH:8]=[CH:9][S:5][N:6]=1)=[S:21]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1ccsn1
Agent: CN=C=S
Product: CN(C)CCNC(=S)NCCNCc1ccsn1

Procedure:
By the procedure of Example 40(a) (ii), N-(3-isothiazolylmethyl)ethylenediamine is reacted with 2-dimethylaminoethyl isothiocyanate to give N-(2-dimethylaminoethyl)-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea. Reacting with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH:5]1[O:7][CH2:6]1)[CH3:2].[Na].[N:11]#[C:12][NH2:13]>CO>[NH2:11][C:12]1[O:7][CH:5]([CH2:4][N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])[CH2:6][N:13]=1
Reactant: CCN(CC)CC1CO1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: CCN(CC)CC1CN=C(N)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
0.2 Mole of the 1-diethylamino-2,3-epoxypropane thus prepared is added, drop by drop, to 12.8 g of the cyanamide monosodium derivative dissolved in 200 cc of anhydrous methanol with vigorous stirring. After 15 hours of stirring at ambient temperature, the methanol is evaporated and the residue picked up with 300 cc of ether. The precipitate is eliminated by filtering. The ether phase is washed twice with 2 cc of water then dried on Na2SO4 after decanting. The ether is evaporated under low pressure. The resulting oily phase crystallizes after washing with boiling heptane. 2-Amino-5-diethylaminomethyl-2-oxazoline is thus obtained with a yield of 68%. It is purified by recrystallization in heptane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1conc1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2nocc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution (120 ml) of 3-(4-hydroxyphenyl)isoxazole-4-carboxylic acid (1.39 g, 6.77 mmol) in dichloromethane were added acetic anhydride (2.07 g, 20.28 mmol), triethylamine (3.43 g, 33.90 mmol), and 4-N,N-dimethylaminopyridine (84 mg, 0.676 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.50 g, 78%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:38]O>C(O)(=O)C>[ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][S:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[O:38])=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CSc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CS(=O)c3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of 0.15 g (0.27 mMol) of 2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride in 10 ml of acetic acid was mixed with 0.09 ml (about 0.81 mMol) of 30% hydrogen peroxide solution and stirred at room temperature. After 4 days a further 0.18 ml of hydrogen peroxide solution was added and the resulting mixture was stirred for a further two days. After removal of the solvent in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=10:1 to 4:1). Yield: 58% of theory, C27H26N4O4S2 (534.66) Rf value: 0.24 (silica gel; methylene chloride/ethanol =4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =535
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1nccnc1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (100 mg, 0.37 mmol), 2-methoxy-phenol (47 mg, 0.37 mmol) and Cs2CO3 (242 mg, 0.74 mmol) in DMSO (10 mL) was stirred at 90° C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude compound, which was purified by column chromatography to afford pure product (13) (80 mg, 0.22 mmol, yield 61%) as solid. ESI-MS (M+1): 358 calc. for C19H23N3O4 357.