Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[C:25]([CH3:37])[CH:24]=1)=[O:10])=[O:4].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:37][C:25]1[CH:24]=[C:23]([NH:22][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CCl)cc34)cc2C)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CN5CCOCC5)cc34)cc2C)cn1
Temperature: 100 °C
Yield: 38 %

Procedure:
0.07 g of the compound obtained in Example 108 dissolved in 5 ml of N,N′-dimethylformamide was reacted with 0.02 ml of morpholine and 0.04 g of potassium carbonate for 10 hours while heating to 100° C. The reacted solution was diluted with distilled water, extracted with ethylacetate, washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (0.03 g, 38%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:26]([O:25][CH2:24][C:10]1([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:39]([C:36]2[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=2)(=[O:41])=[O:40])[N:11]1[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C(CO)CCC1(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
To a mixture of tert-butyl 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(hydroxymethyl)pyrrolidine-1-carboxylate (400 mg, 0.82 mmol) and 4-dimethylaminopyridine (300 mg, 2.45 mmol) in DCM (20 mL) was added 4-toluenesulfonyl chloride (312 mg, 1.64 mmol) at 0° C. The mixture was stirred at 25° C. for 16 h. Then the mixture was diluted with DCM (50 mL) and washed with saturated NH4Cl (50 mL) three times, saturated NaHCO3 (50 mL) three times and water (50 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(p-tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate 81i (410 mg, 77%) which was used for next step without further purification. MS: calc'd (MH+) 644, measured (MH+) 644.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][Cl:19].CC(O)(C(Cl)(Cl)Cl)C>C(Cl)(Cl)Cl.O>[Cl:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1cccc2ccccc12
Agent: CC(C)(O)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: OC(CCCl)COc1cccc2ccccc12
Temperature: 65 °C

Procedure:
To a mixture of 1 mole (147 g.) of 1-naphthol, 350 ml. of water and 2 moles (112 g.) of potassium hydroxide was added at 54° C. 1 mole (143 g.) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was kept below 60° C. during the addition of the chlorobutanol. The reaction mixture was heated at 65° C. for 12 hr., then mixed with 500 ml. of water and 350 ml. of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated and the residual oil distilled under reduced pressure to give 128 g. of a crystalline solid which was distilled at 162°-165° C./0.01 mm. The solid was recrystallized with ether and pet. ether (30°-60°) to give material melting at 75°-77° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:12](/Cl)=[N:13]/[OH:14])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:20]=[C:19]([Cl:29])[CH:18]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([C:12]2[CH2:24][C:23]([C:21]3[CH:20]=[C:19]([Cl:29])[CH:18]=[C:17]([Cl:16])[CH:22]=3)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1nc2c(/C(Cl)=N/O)ccc(Br)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(Br)c2o1
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of 7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl chloride (Example 6.8) (3.63 g) in 2-propanol (100 ml) was added 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (3.43 g) and sodium hydrogen carbonate (1.44 g). The reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: 2-25% v/v ethyl acetate in heptane) to give 7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole (3.7 g). 1H-NMR (400 MHz, CDCl3): 7.71-7.42 (m, 5H), 4.50 (d, 1H), 4.06 (d, 1H), 2.73 (s, 3H) ppm.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[CH2:5][C@H:4]1[NH2:9].CC(N(C1C=CC=CC=1)CC(O)=O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>>[OH:1][CH2:2][C@H:3]1[C@H:6]([CH2:7][OH:8])[CH2:5][C@@H:4]1[NH2:9]
Reactant: N[C@@H]1C[C@H](CO)[C@H]1CO
Agent: CC(=O)N(CC(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: N[C@H]1C[C@@H](CO)[C@@H]1CO

Procedure:
To the (1R, 2R, 3S)-2,3-bis(hydroxymethyl)-1-cyclobutylamine/N-acetyl-L-phenylglycine salt thus isolated is added an alkaline aqueous solution of, for example, sodium hydrogencarbonate, sodium carbonate or sodium hydroxide. Then the mixture is extracted with an organic solvent such as t-butanol or secbutanol. Or a solution of the salt is treated with an ion exchange resin. Then the salt is separated into the aimed free base (1R, 2R, 3S)-2,3-bis(hydromethyl)-1-cyclobutylamine and N-acetyl-L-phenylglycine. On the other hand, (1S, 2S, 3R)-2,3-bis(hydroxymethyl)-1-cyclobutylamine may be produced by the same method as the one described above except that the N-acetyl-L-phenylglycine is replaced by N-acetyl-D-phenylglycine.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:18]([O:20][C:21]([C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([NH2:33])[S:25][C:24]=1[NH2:34])=[O:22])[CH3:19]>C(O)(C)C>[CH2:18]([O:20][C:21]([C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([N:33]=[CH:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:25][C:24]=1[NH2:34])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC

Procedure:
In a 50 mL round bottom flask, 30 mg of 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester was dissolved in 20 mL of isopropanol. To this solution, 5-nitro-2-thiophenecarboxaldehyde (91 mg) was added with vigorous stirring, followed by the addition of a catalytic amount of TFA. The reaction was refluxed for 30 minutes. The title compound was isolated as a dark black-purple powder (87%) by flash chromatography (SiO2). M.p.: 194°-196° C. 1H-NMR (300 MHz, [D] acetone): δ=8.21 (s, 1H), 8.00 (d, 1H, 3J=4.4 Hz), 7.74 (s, 2H), 7.50 (d, 1H, 3J=4.4 Hz), 4.37 (q, 2H, 3J=7.1 Hz), 4.22 (q, 2H, 3J=7.1 Hz), 1.40 (t, 3H, 3J=7.1 Hz), 1.27 (t, 3H, 3J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:29][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:22])[CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CCC3)cc2n1
Yield: 80 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using cyclobutylamine instead of aminomethylcyclopropane, to the title compound (89 mg, 80%) which was obtained as a light yellow foam. MS: m/e=373.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:39][NH2:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:39][NH:40][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(OC)c(Br)c1
Yield: 53.9 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol) and 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.581 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 ml, 5.6 mmol) was stirred in dichloromethane (45 mL) at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4 and then evaporated to dryness which gave, initially, a glassy gum, but which then appeared to crystallize. The residue was taken up in a small amount of MeOH and sonicated for a while. A crystalline white solid formed and was collected and dried to afforded N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (804 mg, 53.9%) as a white solid. LC-MS m/z 601.3 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.[C:33]1(OS(C(F)(F)F)(=O)=O)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:36][CH2:35][CH:34]=4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCc2ccccc21
Temperature: 60 °C
Yield: 90.9 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 4, Step B (0.760 g, 1.89 mmol), 3,4-dihydro-naphthalen-1-yltrifluoromethanesulfonate (0.579 g, 2.08 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.0460 g, 0.0567 mmol) were combined in N,N-dimethylformamide (9.5 mL). Aqueous sodium carbonate (2M, 4.73 mL, 9.45 mmol) was added and the was heated to 60° C. for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexane. Recrystallization from hexane afforded 0.740 g of the title compound as white crystals, m.p.108° C.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[C:24](F)=[CH:23][C:22]=1[F:31]>>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[F:31])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:17](=[O:19])[NH:27]2
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Product: O=C1Nc2cc(F)c(F)cc2N2CCNCC12
Yield: 16.7 %

Procedure:
By the same procedure described for example 2 method 2B, from 1.5 g of racemic 4-carbobenzyloxypiperazine-2-carboxylic acid and 1,2,4-trifluoro-5-nitrobenzene, there was obtained 0.4 g (16.7%) of title compound as an orange-red residue.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24].Cl>O.CCCCCC.O1CCCC1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([N:15]([CH2:16][CH3:17])[S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1cccc(SCc2ccccc2)n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(c1cccc(SCc2ccccc2)n1)S(=O)(=O)C(C)C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a mixture of 3.16 g of the 2-benzylthio-6-ethylaminopyridine obtained in 1) above and 30 ml of tetrahydrofuran was added dropwise 9.4 ml of a 1.65 mol/l hexane solution of n-butyl lithium at -10° to 0° C. in a nitrogen stream. To the reaction mixture was added 1.84 g of isopropylsulfonyl chloride at 0° to 15° C., followed by reacting for 0.5 hour. After completion of the reaction, the reaction mixture was poured into water, made weakly acidic with hydrochloric acid, and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/19 by volume) to obtain 0.77 g of N-(6-benzylthiopyridin-2-yl)-N-ethylisopropylsulfonamide as an oily substance.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Cl)(Cl)[Cl:25]>ClCCl>[Cl:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Reactant: ClP(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Cl)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.89 g) and phosphorous trichloride (0.57 g) in dichloromethane (50 ml) were stirred at 0° C. for 2 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to dryness. The crude product was purified by column chromatography on silica eluted with a mixture of petroleum ether/ethyl acetate to give 4-[chloro-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 298, 0.79 g) as a yellow oil: NMR: (CDCl3) 1.1 (4H, m) 1.9(1H, m) 6.9(1H, s) 7.9(1H, m) 8.0(1H, s) 8.25(2H, m).
Reaction SMILES: [I-:1].[I-].[I-].[CH2:4]([N:7]([C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[S+:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2)[CH2:8][CH2:9][CH3:10])[CH2:5][CH3:6].C(N([C:32]1[CH:33]=[CH:34][C:35]2C([CH:45]=1)=[S+]C1[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=1)[N:36]=2)CCC)CC.C(N(C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)CCC)CC.C(NCCCCC)CCCC>>[I-:1].[CH2:37]([N:36]([C:19]1[CH:18]=[CH:17][C:16]2[C:21]([CH:20]=1)=[S+:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([N:7]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6])[CH:24]=1)[N:15]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCN(CCC)c1ccc2nc3ccccc3[s+]c2c1
Agent: CCCCCNCCCCC
Agent: [I-]
Product: CCCCCN(CCCCC)c1ccc2nc3ccc(N(CCC)CCC)cc3[s+]c2c1

Procedure:
This compound was obtained following isolation of 3-(N,N-dipropylamino)-phenothiazin-5-ium triiodide and subsequent treatment with dipentylamine. Precipitation from dichloromethane by addition of diethyl ether yielded purple lustrous crystals. Mass spectrometry: C28H42N3OS requires m/z=452; found m/z 452 (I− not detected by mass spectrometry).
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+].Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:19][C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]#[N:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: N#Cc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A dimethoxyethane (5 ml) suspension of sodium 4-chlorobenzenesulfinate (218 mg, 1.10 mmol) and 2-bromomethylbenzonitrile (215 mg, 1.10 mmol) was stirred at 70° C. for 17 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a short silica gel column and the fraction obtained from the ether eluate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure to give a white solid. The resulting white solid was washed with ether, and collected by filtration, whereby the title compound (226 mg, 70%) was obtained as a white powder.
Reaction SMILES: C=C1OC(=O)C1.BrBr.[Br:9][CH2:10][C:11](=[O:16])[CH2:12][C:13](Br)=[O:14].[NH2:17][CH:18]1[C:44](=[O:45])[N:20]2[C:21]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:22]([CH2:25][S:26][CH3:27])[CH2:23][S:24][C@H:19]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:9][CH2:10][C:11](=[O:16])[CH2:12][C:13]([NH:17][CH:18]1[C:44](=[O:45])[N:20]2[C:21]([C:28]([O:30][CH:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:22]([CH2:25][S:26][CH3:27])[CH2:23][S:24][C@H:19]12)=[O:14]
Reactant: O=C(Br)CC(=O)CBr
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: BrBr
Agent: C=C1CC(=O)O1
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: O
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1

Procedure:
To a solution of diketene (1.3 ml) in methylene chloride (10 ml) was added dropwise a solution of bromine (1.24 g) in methylene chloride (10 ml) at -30° C. with stirring, and the stirring was continued at -20° C. for half an hour to prepare a solution of 4-bromoacetoacetyl bromide. This solution was added dropwise to a solution of benzhydryl 7-amino-3-methylthiomethyl-3-cephem-4-carboxylate (4.44 g) and trimethylsilylacetamide (5.46 g) in methylene chloride (100 ml) at -30° to -20° C. over a period of 5 minutes with stirring, and the stirring was continued at -10° C. for half an hour. After addition of water, the resultant mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate, followed by separating out the organic layer, which was washed with water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated to dryness to give benzhydryl 7-(4-bromoacetoacetamido)-3-methylthiomethyl-3-cephem-4-carboxylate (6.0 g).
Reaction SMILES: O=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].[ClH:31]>CO>[ClH:31].[NH2:28][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: N#Cc1ccc(N2C3CCC2CC(=O)C3)c2ccccc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Yield: 36 %

Procedure:
156AF03-217 (252 mg, 0.912 mmol) was dissolved in methanol (25 mL). Ammonium acetate (702 mg, 9.12 mmol) and sodium cyanoborohydride (57.3 mg, 0.912 mmol) were added together with some molecular sieves (3 Å). This mixture was allowed to react at rt for 60 hours. Hydrochloric acid (2 M) was added until pH<2 and the mixture was washed with ethyl acetate (2×25 mL). The aqueous layer was made alkaline with sodium hydroxide and extracted with ethyl acetate (3×30 mL). The combined organic layers were evaporated to dryness and purified by ion-exchange (SCX) to give 90 mg (36%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of methyl 4-hydroxybenzoate in DMF (5 ml) was treated with K2CO3 (2.76, 20 mmol) and 2-benzyloxy benzyl bromide (1.52 g, 10 mmol). The reaction was stirred at ambient temperature over night. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed well with water dried (MgSO4) and evaporated. The crude material was purified by chromatography [EtOAc:hexane] to give methyl 4-(2-(benzyloxy)benzyloxy)benzoate as a white solid (3.06 g, 88%).