Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:29]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=4[O:27][CH3:26])(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(OC)c(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,5-dimethoxybenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:30][C:31]([OH:33])=O)[C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1.ON1C2N=CC=CC=2N=N1.[C:44]([O:48][C:49]([NH:51][C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][C:31]([N:54]2[CH2:55][CH2:56][C@H:52]([NH:51][C:49](=[O:50])[O:48][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:53]2)=[O:33])=[CH:17][CH:18]=1
Reactant: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.36 g, 1.87 mmol) was added to a solution of {(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 13 (0.37 g, 1.24 mmol), 1-hydroxy-7-azabenzotriazole (0.25 g, 1.87 mmol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (0.35 g, 1.87 mmol) and N-methyl-morpholine (0.27 mL, 2.5 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 3 days and then diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, NaHCO3 (×2) and brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/petrol (4:1)→ethyl acetate, to give the title compound as a white powder (0.419 g, 72%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (9H, s), 1.8-2.25 (2H, m), 3.4-3.8 (4H, m), 4.15 (1H, m), 4.6 (1H, m), 5.3 (1H, m), 6.43 (1H, d, J=16), 6.87 (2H, d), 7.2-7.32 (7H, m) and 7.65 (1H, d, J=16 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]=[C:7]([Br:11])[C:6]1=[O:12].[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]([Br:11])[C:6]1=[O:12]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCC1(CC(=O)OC)CCC=C(Br)C1=O
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(Cc2ccccc2)C(Br)C1=O
Reaction time: 0.08 h

Procedure:
A solution of 3-bromo-1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (10 g, 36.3 mmol, as prepared in Example 1) and copper (I) bromide-dimethyl sulfide complex (3.63 mmol, 746 mg) in 107 mL of dry tetrahydrofuran was stirred at 0° C. under nitrogen and treated with anhydrous zinc bromide (36.3 mmol, 8.17 g). After 5 minutes, the mixture was treated dropwise with 36.3 mmol of benzylmagnesium chloride (18.2 mL of 2M in THF). After 45 minutes, another 8 mmol of benzylmagnesium chloride were added followed by 350 mg of copper (I) bromide-dimethyl sulfide complex and then another 16 mmol of benzylmagnesium chloride. The reaction was quenched with 150 mL of 1M HCl and extracted with 4×50 mL of ether. The extracts were combined, dried over magnesium sulfate, and concentrated affording 3-bromo-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester. This was then stirred in a solution of 74 mL of N,N-dimethylformamide and 35 mL of water and treated with 109 mmol (18.96 g) of sodium dithionite. The mixture was heated at 55° C. under nitrogen for 20 minutes, poured into 200 mL of water and extracted with 4×100 mL of 1:1 ether-petroleum ether. The extracts were combined, washed with 100 mL of water and 100 mL of saturated sodium bicarbonate (aq), dried over magnesium sulfate, and concentrated affording 10.48 g (36.3 mmol, 100% crude yield) of product as a pale yellow oil. Analysis by capillary GC demonstrated a 4.41:1 ratio of diastereomers, with the cis isomer predominating. The reduction of the intermediate 3-bromo-1-ethyl- 2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester to the title compound can also be carried out as described in Example 3.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]([CH3:31])[CH:28]([CH3:30])[CH3:29])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:32]([O:34][CH3:35])=[O:33])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]([CH3:31])[CH:28]([CH3:30])[CH3:29])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:32]([O:34][CH3:35])=[O:33])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N(C)C(C)C)nc2c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1

Procedure:
A solution of methyl 2-[1-[(tert-butoxy)carbonyl]-1H-indazol-5-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (624 mg, 1.31 mmol) and trifluoroacetic acid (4 ml) in dichloromethane (20 ml) was stirred for 1 h at room temperature. The resulting solution was added water (200 ml) and adjusted to pH 8, extracted with dichloromethane (5×50 ml), dried over anhydrous magnesium and concentrated in vacuo to afford methyl 2-(1H-indazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (442 mg, crude).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60](=[O:84])[NH:61][CH:62]2[CH2:67][CH2:66][N:65]([C:68](=[NH:83])[NH:69]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:64][CH2:63]2)[CH2:43]1>>[C:68]([N:65]1[CH2:66][CH2:67][CH:62]([NH:61][C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:84])[CH2:63][CH2:64]1)(=[NH:69])[NH2:83]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NC4CCN(C(=N)N)CC4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 32) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonylamidino)piperidin-4-ylcarbamoyl]pyrrolidine (prepared as described in Preparation 110) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][NH:12]1)=O)C1C=CC=CC=1.[NH3:17]>>[OH:16][C@H:14]1[CH2:13][NH:12][C@H:11]([C:9]([NH2:17])=[O:8])[CH2:15]1
Reactant: N
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Product: NC(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
A solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid benzyl ester (1 g) in 880 ammonia (5 ml) is stirred for 18 hours then evaporated and triturated with diethyl ether to give the title compound as a white solid. 1H nmr (d6-DMSO, 400 MHz) 9.15 (s, br, 1H), 8.04 (s, 1H), 7.63 (s, 1H), 5.56 (s, 1H), 4.40 (s, 1H), 4.27-4.16 (m, 1H), 3.27 (d, J=7 Hz, 1H), 3.02 (d, J=7 Hz, 1H), 2.33-2.19 (m, 1H), 1.89-1.76 (m, 1H).
Reaction SMILES: C([Li])CCC.C([Si](C)(C)[O:11][CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(C)(C)C.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[OH:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Reactant: CC(C)OC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of n-butyllithium (37 mL of a 1.6 M solution in hexanes, 59.2 mmol) was added slowly to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane (see U.S. Pat. No. 5,739,141; 9.5 g, 39.0 mmol) in THF (100 mL) at −78° C. After 1 h at −78° C., isopropyl chloroformate (60 mL of a 1.0 M solution in toluene, 60 mmol) was added slowly. After 1 h at −78° C., the reaction was quenched by addition of saturated aqueous NH4Cl (150 mL) and was allowed to warm to room temperature. The phases were separated and the organic phase was dried (Na2SO4), filtered (washing with excess THF) and concentrated in vacuo. The crude residue was dissolved in THF (100 mL), cooled to 0° C. and treated with tetrabutylammonium fluoride (43 mL of a 1.0 M solution in THF, 43 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo, saturated aqueous NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 330 g silica (40% EtOAc/hexanes→60% EtOAc/hexanes, gradient) to afford 6.6 g (71%) of isopropyl 5-(2-hydroxyethyl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](Cl)=[O:8].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([NH2:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:28][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:3][C:2]=2[CH3:1])=[O:8])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
2-Methyl-5-phenyl-furan-3-carbonyl chloride (0.025 g) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.024 g) and N,N-diisopropylethyl-amine (0.018 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×5 mL) and basic (dilute NaHCO3, 2×5 mL) workup followed by washing with brine (saturated NaCl, 2×5 mL), drying over MgSO4, and concentration. The crude compound was purified by passing through a silica gel plug eluting with hexanes/ethyl acetate (2:1) to afford the title compound (0.035 g, 82% yield). ES-MS negative Q1 (m/z) 412.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]([O:14][CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[C:11]([O:12][CH3:13])=[N:10][C:9]([O:14][CH3:15])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(OC)nc(OC)c1N
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)nc(OC)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of the product of Example 29 (0.278 g, 1.31 mmol) in pyridine (2 mL) was added p-methoxybenzenesulfonyl chloride (0.28 g, 1.38 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with H2O. The mixture was extracted 3 times with ether. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo to provide 0.444 g (89%) of methyl 3-(4-methoxy-benzenesulfonylamino)-2,6-dimethoxy-isonicotinate as a solid. Electrospray Mass Spec: 382.8 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH3:22])[C:19]([NH2:21])=O)[C:11]3=[O:23])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH3:22])[C:19]([NH2:21])=[S:35])[C:11]3=[O:23])=[CH:4][CH:3]=1
Reactant: C[C@@H](C(N)=O)N1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: C[C@@H](C(N)=S)N1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Reaction time: 72 h
Yield: 36.3 %

Procedure:
A mixture of (S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide (171 mg, 0.5 mmol) and Lawesson's reagent (243 mg, 0.6 mmol) in tetrahydrofuran (20 mL) was stirrred at room temperature for 72 h. Then the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 99:1 to 19:1) to afford the title compound (65 mg, 36%) as an off-white solid after recrystallisation from MeOH. MS: m/e=359.2 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[CH:24][CH:23]=3)[C:18]2=[O:37])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:36][O:35][C:33]([CH2:32][CH2:31][NH:30][C:28]([C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][N:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[C:18]2=[O:37])=[CH:27][CH:26]=1)=[O:29])=[O:34]
Reactant: COC(=O)CCNC(=O)c1ccc(N2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
Prepared by treating 1-(1-benzyloxycarbonyl-4-piperidinyl)-3-[4-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-phenyl]-imidazolidin-2-one with hydrogen at 3 bars in the presence of 5% palladium/charcoal in methanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:14](=[O:16])[NH:13][CH:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]=3[CH:23]=2)=[C:5]([CH3:24])[O:4][N:3]=1.[H-].[Na+].Br[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:14](=[O:16])[N:13]([CH2:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]=3[CH:23]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)NC(=O)O2
Reactant: BrCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(CC1CCOCC1)C(=O)O2
Temperature: 25 °C

Procedure:
6-(3,5-Dimethyl-isoxazol-4-yl)-4-phenyl-3,4-dihydro-benzo[e][1,3]oxazin-2-one (20 mg, 0.06 mmol) is dissolved in DMF 0.5 mL. Sodium hydride (60% w/w, 2.6 mg, 0.065 mmol) is added. The mixture is cooled in an ice bath. 4-bromomethyltetrahydropyran (14 mg, 0.074 mmol) is added and the mixture stirred and allowed to warm to room temperature over night. Sodium hydride (0.5 mg, 0.013 mmol) is added and the mixture stirred at room temperature for a further 3 hours. The mixture is quenched by the addition of water (1 mL). The solvent is removed in vacuo and the residue is purified by preparative HPLC. The product fraction is lyophilized to produce the desired product as a yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([Cl:25])=[CH:18][N:17]=1>C(#N)C>[Cl:25][C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 36 h
Yield: 61.9 %

Procedure:
A mixture of 85.9 g (0.78 mole) of hydroquinone, 1200 ml of acetonitrile and 53.9 g (0.39 mole) of potassium carbonate is heated to 60° C., then a solution of 115.8 g (0.60 mole) of 2,5-dichloro-3-nitropyridine in 500 ml of acetonitrile is added dropwise over 6 hours and the mixture is stirred for 36 hours. The solvent is removed by distillation and the residue is poured into a mixture of ice-water and hydrochloric acid. After extraction with methylene chloride, the combined organic phases are dried over magnesium sulfate, treated with activated carbon, filtered and concentrated. The residue is purified by crystallisation in a mixture of hexane and ethyl acetate, affording 99 g (62% of theory) of 4-(5-chloro-3-nitropyridin-2-yloxy)phenol with a melting point of 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=O)[CH3:10].CC([O-])=O.[Na+]>CC(OC(C)=O)=O.[OH-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([CH:7]=[C:13]2[C:14](=[O:15])[O:16][C:9]([CH3:10])=[N:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(Cl)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC1=NC(=Cc2ccc(Cl)s2)C(=O)O1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture consisting of 5-chlorothiophene-2-carboxaldehyde (1.00 g, 6.82 mmol), N-acetylglycine (0.96 g, 8.18 mmol), NaOAc (0.67 g, 8.18 mmol) in Ac2O (5 mL) is warmed at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with dilute aqueous NaOH (0.5 M, 100 mL) and CH2Cl2 (100 mL). The layers are separated and the organic phase is washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 1.5 g (100%) of the title compound as a colorless oil which is used without further purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ2.39 (s, 3H), 6.94 (d, J=4.0 Hz, 1H), 7.21 (s, 1H), 7.26 (d, J=4.0 Hz, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[N:34]1([CH2:40][C:41]2[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=2)[O:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(OCC)(=O)C.CO>[C:16]1([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:7][N:2]([CH2:3][CH2:4][CH2:5][NH:6][C:22]([NH:48][CH2:47][CH2:46][CH2:45][O:44][C:43]2[CH:49]=[CH:50][CH:51]=[C:41]([CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:42]=2)=[O:23])[CH3:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN(CCCN)CCC(c1ccccc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.74 g (2.6 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.65 g (2.6 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=558 ([M+H]+, 11), 196 (100); IR (KBr): 1639 cm-1 (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: from 70° C. with decomposition.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1sc(N)nc1C
Product: CCCc1ccc(S(=O)(=O)Nc2nc(C)c(C(C)=O)s2)cc1

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (11.6 mg) with purity >90%: MS (pos) m/z 339.2; HEMS m/z 338.0748 (calc. of monoisotopic mass for C15H18N2O3S2 gives 338.0759).
Reaction SMILES: [CH:1]1(Br)[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[C:9]([OH:23])=[C:10]([C:15]([N+:20]([O-:22])=[O:21])=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH:1]1([O:23][C:9]2[C:8]([O:7][CH3:6])=[C:17]([O:18][CH3:19])[CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC1CCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
Cyclobutyl bromide (0.44 ml, 0.0047 mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1 g, 0.0039 mol) and potassium carbonate (1.2 g, 0.0086 mol) in dimethylformamide (10 ml) and the reaction stirred at 100° C. for 4 hours. On cooling, aqueous sodium carbonate solution was added and the mixture extracted with ethyl acetate (2×40 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with diethyl ether to give the subtitle compound as a colourless oil (511 mg, 42%). Rf 0.89 (diethyl ether). MS m/z 312 (MH)+. 1H-NMR (CDCl3): δ=1.48 (1H, m), 1.76 (1H, m), 2.27 (4H, m), 2.94 (9H, m), 4.70 (1H, m), 7.51 (1H, s)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O.C1CCN2C(=NCCC2)CC1>COCCOC>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN(C)CCO
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)CCOc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, 2-dimethylaminoethanol and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).