Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH2:18]C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCC(C(O)C)CC1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:40])[CH3:41])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH3:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCN(C(=O)OCc5ccccc5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (400 mg, 1.23 mmol), 4-(1-hydroxyethyl)piperidine-1-carboxylic acid benzyl ester (487 mg, 1.85 mmol) and triphenylphosphine (548 mg, 2.09 mmol) in dioxane (7 mL) was added dropwise DIAD (410 ul, 2.09 mmol) and the reaction mixture was stirred at RT for 18 h. The mixture was then diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were then washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc), then suspended in DCM and filtered. The filtrate was concentrated in vacuo and purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) affording 4-{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester (140 mg, 20%). LCMS: RT 3.90 min [M+H]+ 571.0
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[Br:7][C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][CH:9]=1>ClCCl>[Br:7][C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH2:21][CH2:22]3)[CH:15]=[CH:16][C:11]2=[N:10][CH:9]=1
Reactant: CC(C)N=C=O
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 17 h
Yield: 109.3 %

Procedure:
2-Isocyanatopropane [1795-48-8] (120 μL, 1.2 mmol) was added, via syringe, to a stirred, ambient temperature, clear, colorless solution of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (334.6 mg, 1.2 mmol) in dichloromethane (20 mL). The solution was allowed to proceed for 17 h then evaporated to dryness to afford 481.5 mg of light yellow solid foam. LRMS (ESI) m/z 367.0/369.0 [(M+H)]+, calc'd for C14H19BrN6O: 367.25.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[CH:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=1)=[O:4].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[N:10][C:9]=2[CH:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=1)=[O:4]
Reactant: CCN=C=O
Reactant: COC(=O)c1cc(-c2cccnc2)cc2nc(N)sc12
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)c2s1
Temperature: 100 °C

Procedure:
A stirred mixture of 2-Amino-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (125 mg, 0.439 mmol), ethyl isocyanate (0.21 ml, 2.187 mmol) and dibutyltindiacetate (12 drops) in anhydrous 1,4-dioxane (10 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the solvent was removed in vacuo to give 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester which was used without further purification. A stirred mixture of 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (78 mg, 0.22 mmol) and aqueous ethylamine solution (70% w/v, 3 ml) was heated by microwave irradiation in a CEM Discover reactor at 100° C. for 1 h. The reaction mixture was purified by Preparative HPLC to provide the 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid ethylamide as a white solid (8.7 mg, 5%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:11]O>C(O)CCC>[N+:1]1([O-:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: OO
Solvent: CCCCO
Product: [O-][n+]1cccc2ccccc21

Procedure:
A quantity of 40 ml n-butanol, 25 ml 96% quinoline i.e. 203 mmoles and 250 mg SeO2 is introduced successively into a reactor with a capacity of 125 ml. 6 ml of 85% H2O2 are then added in 10 minutes (i.e. 200 mmoles), and the mixture is allowed to react for 2 hours at 343 K. whilst removing the water formed by azeotropic distillation. 140 mmoles of quinoline oxide are obtained in this way. The results are as follows:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1.ClC(Cl)(Cl)[C:14]([N:16]=C=O)=[O:15].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.O1CCCC1.O>[NH2:16][C:14]([O:1][CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1)=[O:15]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(=O)S[C@@H]1CO[C@@H](CO)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1CO[C@@H](COC(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a -20° C. solution, under argon, of 0.406 g of product from Example 6 in 30 ml of methylene chloride is added 0.3 ml of trichloroacetyl isocyanate. The reaction is followed by thin layer chromatography (tlc). When reaction is complete, 1.16 ml of acetic acid, 0.54 ml of water and 9.84 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran is added. The mixture is stirred at room temperature overnight followed by concentration in vacuo. The residue is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 0.430 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:33])([CH3:34])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CN(CCC#N)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
Title compound was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound isolated as a white lyophilate (40 mg, 33%). 99% purity, LCMS (510.19 M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.00 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.42-7.37 (m, 3H), 7.02-6.97 (m, 2H), 6.66 (d, J=9.0 Hz, 1H), 3.28 (t, J=6.4 Hz, 2H), 2.73 (s, 3H), 2.53 (t, J=6.6 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.06 (t, J=6.9 Hz, 2H), 1.27 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@:9]3([CH3:49])[O:12][CH:13]=[CH:14][C@H:15]([O:47][CH3:48])[C@@H:16]([CH3:46])[C@@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:18]([CH3:41])[C@H:19]([OH:40])[C@H:20]([CH3:39])[C@@H:21]([OH:38])[C@@H:22]([CH3:37])[CH:23]=[CH:24][CH:25]=[C:26]([CH3:36])[C:27]([NH:29][C:30]4[C:34](=[O:35])[C:4](=[C:5]([C:32](=[O:33])[CH:31]=4)[C:6]=2[C:10]3=[O:11])[C:3]=1[OH:50])=[O:28]>CC1C2OC3(C)C(C=2C2C(OCC(NC4C=CC(I)=CC=4)=O)=CC(NC(C(C)=CC=CC(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)C=CO3)=O)=C(O)C=2C=1O)=O>[CH3:1][C:2]1[C:7]2[O:8][C@@:9]3([CH3:49])[C:10]([C:6]=2[C:5]2[C:32]([OH:33])=[CH:31][C:30]([NH:29][C:27]([C:26]([CH3:36])=[CH:25][CH:24]=[CH:23][C@H:22]([CH3:37])[C@H:21]([OH:38])[C@@H:20]([CH3:39])[C@@H:19]([OH:40])[C@@H:18]([CH3:41])[C@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:16]([CH3:46])[C@@H:15]([O:47][CH3:48])[CH:14]=[CH:13][O:12]3)=[O:28])=[C:34]([OH:35])[C:4]=2[C:3]=1[OH:50])=[O:11]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: COC1/C=C/OC2(C)Oc3c(C)c(O)c4c(O)c(cc(OCC(=O)Nc5ccc(I)cc5)c4c3C2=O)NC(=O)/C(C)=C\C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C1C
Agent: COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(cc(OCC(=O)Nc5ccc(I)cc5)c4c3C2=O)NC(=O)C(C)=CC=CC(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(cc(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(cc(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Temperature: 50 °C

Procedure:
Reaction--Ten grams of the enzyme adsorbed on celite were added to 300 ml of 1% rifamycin B solution (10 mM phosphate buffer, pH 8.5). The conversion to rifamycin S was completed in 7 hours of reaction at 40° C. with aeration and agitation. The celite filter cake recovered by filtration on a sintered glass was washed with 200 ml of methanol. The final methanolic aqueous solution of rifamycin S was warmed to 50° C. in order to solubilize completely the residual rifamycin S precipitate. 30 ml of 5% ascorbic acid solution in water was added thereto dropwisely while continuous stirring. The purpose color of rifamycin S was gradually changed to the deep red color of rifamycin SV. After adjusting the final pH to 4.0, the methanol was completely evaporated using suction evaporator at 40° C. Afte chilling the final solution at 4° C. for 2 days, the rifamycin SV crystals were recovered by filtration. 2.4 gr of deep yellowish rifamycin SV crystals were obtained after drying over sodium sulfate (yield=87%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:29][C:12]1[C:10]2[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:7]=[CH:8][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCNc1ncc2c(ccn2-c2ccc(F)cc2)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1ncc2c(n1)c(Br)cn2-c1ccc(F)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of N-butyl-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (1.03 g, 3.61 mmol) in DMF (10 mL) was added NBS (0.71 g, 3.97 mmol) at room temperature. The resulting solution was stirred for 1 h and diluted with EtOAc. The resulting solution was washed with a sat. aq. solution of NaHCO3, H2O and brine. The EtOAc layer was dried (Na2SO4), concentrated and purified by ISCO to provide the desired product (1.05 g, 80%). 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.68 (s, 1H), 7.52-7.42 (m, 2H), 7.32-7.21 (m, 2H), 3.44 (t, J=7.1 Hz, 2H), 1.68-1.54 (m, 2H), 1.49-1.36 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 363.1 [M+H]+.
Reaction SMILES: BrC[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[C:18]2[C:35](=[CH:36][CH:37]=1)[O:34][C:21]1([CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]1)[CH2:20][C:19]2=[O:38]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[C:18]2[C:35](=[CH:36][CH:37]=1)[O:34][C:21]1([CH2:26][CH2:25][N:24]([CH2:27][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:23][CH2:22]1)[CH2:20][C:19]2=[O:38]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and (3-bromopropyl)benzene (0.134 ml, 0.88 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (3 ml), and the mixture was stirred at RT for 24 h and then under reflux for 18 h. The solvent was removed and the crude mixture was purified by column chromatography (eluent:DCM/MeOH 97:3) to give (E)-3-{1′-(3-phenyl-propyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (173 mg) as a yellow oil.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:43])[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])=[CH:11][CH:10]=1>C1COCC1.C(OCCCC)CCC.[Cl-].[Zn+2].[Cl-].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]>[C:9]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=[CH:11][C:12]([C:15]2([CH3:43])[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:25][CH2:26][OH:27])=[N:17][S:16]2(=[O:41])=[O:42])=[CH:13][CH:14]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1(C)c1ccc(Br)cc1
Reactant: [Li]c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(C)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Under inert gas, 5.52 ml of a 0.5 N zinc chloride solution in THF were cooled to −75° C., and 1.02 ml of a 1.8 N phenyllithium solution in dibutyl ether was added dropwise. The reaction solution was allowed to come to room temperature and stirred for 30 minutes. Then this solution was added to a solution of 110 mg of [5-(4-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine and 8 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium in 3 ml of THF. After stirring at 60° C. for 75 minutes, the reaction solution was concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 2 ml of methanol, 0.2 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated by rotary evaporation and the residue was extracted with 20 ml of dichloromethane and 10 ml of water, and the aqueous phase was washed once again with 10 ml of dichloromethane. The combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation, and the crude product was purified further in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (39.7 mg) with a molecular weight of 478.6 g/mol (C27H30N2O4S); MS (ESI): m/e=479 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([C:4]1[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCOc1ccc(C(C)=O)cc1OC
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-acetyl-2-methoxyphenoxy)butyrate (10 g) was added to cold 70% nitric acid (140 cm3) and the resulting orange solution was stirred for 2 h and then poured into a beaker containing ice-water (1 dm3). The slurry warmed with stirring overnight to give a yellow solid which was collected and recrystallised from methanol to give methyl 4-(4-acetyl-2-methoxy-5-nitrophenoxy)butyrate as a pale yellow solid (8.5 g). 1H NMR (CDCl3) δ2.21 (2H, m, J=6.6 Hz, CCH2C), 2.50 (3H, s, MeCO), 2.57 (2H, t, J=7.1 Hz, CH2CO), 3.7 (3H, s, OMe), 3.99 (3H, s, OMe), 4.16 (2H, t, J=6.2 Hz, CH2O), 6.75 (1H, s, aromatic) and 7.62 (1H, s, aromatic).
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN>CCOCC.CO>[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1[NH:1][CH3:3])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Agent: CN
Solvent: CO
Solvent: CCOCC
Product: CNC1=C([N+](=O)[O-])C(=O)NC1=Cc1ccccc1
Yield: 45 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of methylamine solution for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 5-Benzylidene-4-methylamino-3-nitro-1,5-dihydropyrrol-2-one was obtained with a melting point of 238° C. in a yield of 45%.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC.Cl>C(Cl)Cl>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][CH2:5][O:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OCCOC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclopropoxyethanol (400 mg, 3.92 mmol) in DCM (10 mL) were added TsCl (821 mg, 4.31 mmol) and Et3N (0.6 mL, 4.31 mmol). The reaction was stirred at room temperature overnight. Then, 1N HCl was added, and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow oil. The oil was purified by preparative TLC to obtain intermediate BP (50 mg) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([NH:35][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCNCc2ccccc2)c2ccccc21

Procedure:
6.0 gm of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido [2,3-b]-[1,4]benzodiazepin-6-one, 2.3 gm of sodium carbonate and 4.4 gm of benzylamine were refluxed in 80 ml of ethanol for 4 hours. Then the hot mixture was suction-filtered, the alcohol was distilled off, and the residue was purified on a silica gel column. The evaporation residue of the eluate was recrystallized twice from n-propanol.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1>C(O)C>[F:18][CH:2]([F:1])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:7]([NH:11][CH3:10])=[N:6][C:5]#[N:4])[N:11]=1
Reactant: NCCSCc1csc(NC(N)=NCC(F)F)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1csc(NC(N)=NCC(F)F)n1
Reaction time: 16 h
Yield: 115.1 %

Procedure:
Dimethyl (cyanoimido)dithiocarbonate (0.07 g.) and 2-[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole (0.15 g.) were dissolved in ethanol (3 ml.) and heated under reflux for 20 minutes. The solvent was evaporated and the residual gum was dissolved in ethanolic methylamine (33% w/v, 3 ml.) and allowed to stand at room temperature for 16 hours. The solvent was evaporated and the residual gum purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. The appropriate zone of the chromatogram was isolated and extracted with methanol/ammonia 10:1 v/v. The solvent was evaporated and the residue was dissolved in ethyl acetate, filtered and added to a solution of maleic acid (0.1 g.) in ethyl acetate. The precipitate was filtered to give 2-[2-(2,2-difluoroethyl)guanidino]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (0.11 g.), m.p. 108°-112° (decomp.) containing 1.25 molar equivalents of maleic acid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]1[CH:21]([CH3:22])[C:20](=O)[CH2:19][CH2:18][NH:17]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]1[CH:21]([CH3:22])[C:20](=[CH2:1])[CH2:19][CH2:18][NH:17]1
Reactant: COc1ccccc1CC1NCCC(=O)C1C
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCNC(Cc2ccccc2OC)C1C

Procedure:
20.1 g (56 mmol) of methyl-triphenylphosphonium bromide, 6.3 g (56 mmol) of potassium tert-butoxide and 11 g (47 mmol) of 2-(2-methoxyphenyl)methyl-3-methyl-4-piperidone 15 in 200 mL of abs. THF are used. The product is crystallized from acetone as the oxalate. Yield: 13.1 g (87%); melting point: 145° C.
Reaction SMILES: Cl.[O:2]=[C:3]([NH:18][C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)[CH2:4][NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[OH:24][C:25]1([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH:29]2[CH2:31][CH2:32][CH:26]1[CH2:27][C:28]2=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[OH:24][C:25]1([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH:29]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]2[N:21]1[CH2:22][CH2:23][C@@H:19]([NH:18][C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:17])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=2)[CH2:20]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: O=C1CC2CCC1CC2(O)c1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CC3CCC2CC3(O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{2-Oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide hydrochloride (100 mg, 0.284 mmol) and 5-hydroxy-5-pyridin-3-ylbicyclo[2.2.2]octan-2-one (62.0 mg, 0.284 mmol) were dissolved in dry THF (10 mL). Triethylamine (80 uL, 0.57 mmol) and sodium triacetoxyborohydride (120 mg, 0.57 mmol) were added and the mixture was stirred at room temperature overnight. TLC indicated conversion to desired products in about a 1:1 ratio of isomers. Adsorbed reaction mixture onto silica gel and chromatographed eluting with dichloromethane to 10% methanol/dichloromethane/0.5% ammonium hydroxide. Fractions were combined to give pure higher Rf isomer and pure lower Rf isomer: Higher Rf product: LC/MS (positive ion) m/z=517.1 (M+H)+; Lower Rf product: LC/MS (positive ion) m/z=517.2 (M+H)+.