Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=O.O1CCCCC1[O:14][N:15]=[C:16]([C:52]1[N:53]=[C:54]([NH:57]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:55][CH:56]=1)[C:17]([NH:19][CH:20]1[C:50](=[O:51])[N:22]2[C:23]([C:34]([O:36]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:35])=[C:24]([CH2:27][N+:28]3([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:25][S:26][C@H:21]12)=[O:18].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[NH2:57][C:54]1[S:55][CH:56]=[C:52]([C:16](=[N:15][OH:14])[C:17]([NH:19][CH:20]2[C:50](=[O:51])[N:22]3[C:23]([C:34]([O-:36])=[O:35])=[C:24]([CH2:27][N+:28]4([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:53]=1
Reactant: C[N+]1(CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CCCC1
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NO)c4csc(N)n4)[C@H]3SC2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (0.9 g) in dichloromethane (2.7 ml) were added anisole (0.9 ml) and trifluoroacetic acid (1.8 ml) under ice-cooling. After stirring for 1 hour at room temperature, the mixture was poured into diisopropyl ether (50 ml). The resulting precipitate was collected by filtration, washed with diisopropyl ether, and dissolved in 5% sodium bicarbonate solution. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloricacid, and subjected to column chromatography on non-ionic adsorption resin "HP-20". The desired product was eluted with 5% diisopropyl ether and the eluate was concentrated and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate (syn isomer) (0.25 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([OH:9])=[C:5]([CH:7]=[O:8])[CH:6]=1.[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:9][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8])(=[O:12])[CH3:11]
Reactant: O=Cc1ccccc1O
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCCCOc1ccccc1C=O
Yield: 43549.4 %

Procedure:
A mixture of 12.2 g (0.1 mmol) of salicyladehyde, 23 g (0.11 mol) of 5-bromopentyl acetate, 44.2 g (0.3 mol) of anhydrous, granular potassium carbonate, and 700 mL of acetonitrile was stirred and refluxed for 20 hr. After being cooled, the resulting mixture was filtered with suction and the solids were washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving a yellow oil which was purified by flash chromatography on silica gel, eluting with 4:1 hexane-ether. There was obtained 10.9 g (43.6%) of 2-[[5-(acetyloxy)pentyl]oxy]benzaldehyde as an oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 10 °C
Reaction time: 16 h

Procedure:
A suspension of compound of Example 1a (1.0 eq) in DCM (approx 4.5 vol) is treated with thionyl chloride (1.0-1.2 eq, for example 1.1 eq) and catalytic amount (0.0055 eq) of DMF and the mixture is stirred for 16 h at reflux. Unreacted thionylchloride is distilled off with DCM and the residue after distillation is diluted with THF (approx 1.8 vol) and cooled to 10° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]12[O:20][C:17]([CH3:21])([CH:18]=[CH:19]1)[CH2:16][CH:15]([OH:22])[CH2:14]2.Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:22][CH:15]2[CH2:16][C:17]3([CH3:21])[O:20][C:13]([CH3:12])([CH:19]=[CH:18]3)[CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC12C=CC(C)(CC(O)C1)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CC3(C)C=CC(C)(C2)O3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
para-Toluenesulfonyl chloride (15.5 g,) was added portionwise over 20 minutes to an ice-cold stirred solution of 1,5-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-ol (10.0 g,) in dry pyridine (75 ml). The reaction mixture was stirred at 0° C. for 0.5 hour, allowed to stand in a refrigerator (0° C.) for 72 hours, and poured into a mixture of 80 ml concentrated hydrochloric acid and 100 g of ice. After stirring for 10 minutes, the precipitated solid was filtered. The collected solid dissolved methylene chloride was dried (MgSO4), filtered and concentrated to give 17.6 g (88%) of the desired product, m.p. 75°-77° C., as a 70:30 mixture of epimers.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:34])[N:19]([CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:20]2=[O:25])=[O:13])=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:34])[N:19]([CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:20]2=[O:25])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 17 h
Yield: 79 %

Procedure:
A 4N HCl solution in dioxane (1 ml) was added to a stirred solution of 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.5 g, 1.09 mmol) in CH2Cl2 (15 ml) and stirred for 17 hours. The resulting suspension was filtered to give 3-amino-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide hydrochloride (0.34 g, 79%) as a white solid: mp 161-163° C.; 1H NMR (DMSO-d6) δ d 11.15 (s, 1H), 8.88 (t, J=5.8, Hz, 1H), 8.06 (b, 3H), 7.87-7.79 (m, 3H), 5.19-5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.76 (d, J=5.8 Hz, 2H), 3.03-2.84 (m, 3H), 2.67-2.47 (m, 4H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ d 172.74, 169.88, 169.80, 167.45, 166.92, 138.92, 134.74, 133.46, 131.48, 127.09, 121.92, 48.86, 37.69, 35.11, 32.03, 30.92, 21.97; Anal. Calcd. For C17H19N4O5Cl+0.13 CH2Cl2+0.57 H2O: C, 49.44; H, 4.94; N, 13.46; Cl, 10.73. Found: C, 49.22; H, 4.88; N, 13.08; Cl, 10.95.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.C(Cl)(=O)CCCC>O>[CH2:11]([C:10]1[NH:1][C:2]2[C:3]([CH:8]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccccc1N
Reactant: c1ccncc1
Agent: CCCCC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 84 %

Procedure:
o-Toluidine (55 g) was mixed with 100 ml dry pyridine and 200 ml dry tetrahydrofuran in a 1-L 3-necked round bottom flask fitted with a Trubore stirrer, thermometer and a dropping funnel, under nitrogen. Then, with cooling in a refrigerated bath, valeryl chloride (60.3 g) was added dropwise over 1 hour. The mixture was stirred for another hour at room temperature and then poured onto 500 g ice and water. The precipitate was washed repeatedly with water on a Buchner funnel. The precipitate (88.9 g, 93%) was cyclized according to Verley and Bedure, 1925, Bull. Soc. Chim. Fr. (37): 190 to afford 2-n-butyl indole (67.4 g, 84%) as a very slightly yellow oil.
Reaction SMILES: N1C=CC(=O)NC1=O.[I:9][C:10]1[C:11](=[O:21])[NH:12][C:13](=[O:20])[N:14](CC(O)=O)[CH:15]=1.C(C(N)CNCC(OCC)=O)(OC(C)(C)C)=O>>[I:9][C:10]1[C:11](=[O:21])[NH:12][C:13](=[O:20])[NH:14][CH:15]=1
Reactant: O=C(O)Cn1cc(I)c(=O)[nH]c1=O
Agent: CCOC(=O)CNCC(N)C(=O)OC(C)(C)C
Agent: O=c1cc[nH]c(=O)[nH]1
Product: O=c1[nH]cc(I)c(=O)[nH]1

Procedure:
The PNA trimer can be synthesized manually or in an automated peptide synthesizer. The synthesis of universal base PNA monomer has been reported in the literature129,130 The modified uracil PNA monomer may be synthesized starting from 5-iodouracil-1-acetic acid.131 The starting material reacts with ethyl N-[2-Boc-aminoethyl]glycinate, providing a 5-iodouracil PNA monomer that can be converted into the desired product through the Sonogashira coupling132 with 3-benzoylthio-1-propyne followed by treating with di-tbutyl-1-(tbutylthio)hydrazine-1,2-dicarboxylate.34
Reaction SMILES: C[O:2][C:3](=[O:35])/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][C@@H:26]2[O:29]C=O)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([O:32]C=O)[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9].C>[OH-].[Na+]>[OH:32][C@@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][C@H:26]([OH:29])[C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH2:7][CH2:6]/[CH:5]=[CH:4]/[C:3]([OH:35])=[O:2])[CH3:9])[CH2:18]1
Reactant: COC(=O)/C=C/CCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Agent: [Na+]
Agent: [OH-]
Product: CC(CC/C=C/C(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 67.3 %

Procedure:
A mixture of 5.2 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)-trans-2-pentenoic acid methyl ester and 30 ml of 5 N aqueous sodium hydroxide was added and the mixture heated to reflux. The solution was then cooled, treated with charcoal and filtered with suction through a bed of diatomaceous earth. The filtrate was then cooled to 0° and with stirring was acidified to a pH3 by the dropwise addition of concentrated hydrochloric acid. The resulting precipitate was filtered and air dried overnight under house vacuum. Crystallization from methyl ethyl ketone gave 3 g of 5-(3α,12α-dihydroxy-5β-pregnane-20-yl)-trans-2-pentenoic acid, mp 204°-208°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[CH2:8][CH3:9].[C:11](=O)([O:13]CC)[NH2:12]>[Cl-].[Zn+2].[Cl-].O>[CH2:8]([C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:1][C:11](=[O:13])[N:12]=1)[CH3:9]
Reactant: CCC(=O)c1ccsc1N
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CCc1nc(=O)[nH]c2sccc12
Temperature: 200 °C

Procedure:
A mixture of 4.0 g of 2-amino-3-propionylthiophene, 8.9 g of ethyl carbamate and 0.53 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the resulting material is treated with hot water and then filtered. The filtrate is extracted with chloroform and the insoluble matter is washed with hot chloroform. The chloroform extracts were combined and washed with water. After removing the chloroform by distillation under reduced pressure, the resulting residue is crystallized from ethanol to give 4-ethyl-1,2-dihydrothieno[2,3-d]pyrimidine-2-one. Recrystallized from a mixture of ethanol and chloroform, there are obtained crystals having a melting point of 217° - 220°C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([CH2:44][CH2:45][OH:46])[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([CH2:44][CH2:45][OH:46])[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 110b (115 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC, using a gradient of 0-10% MeOH in DCM, to afford the title compound (94 mg, 48%). A sample of this (40.0 mg) was further purified by MDAP (Method 7) purification to afford the title compound (20 mg) as a white solid. LCMS (Method 5): Rt 3.64 min, m/z 589 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.83 (3H, d, J=5.6 Hz), 1.16 (9H, s), 1.83-1.96 (2H, m), 1.97-2.07 (1H, m), 2.08-2.17 (1H, m), 2.95 (1H, ddd, J=12.0, 7.2, 4.9 Hz), 3.17 (1H, dt, J=12.2, 3.3 Hz), 3.36-3.44 (2H, m), 3.62 (2H, q, J=5.5 Hz), 3.72-3.80 (2H, m), 3.81-3.88 (1H, m), 3.88-3.92 (2H, t, J=6.0 Hz), 4.81 (1H, td, J=8.5, 6.1 Hz), 4.96 (1H, t, J=5.0 Hz), 5.52 (1H, t, J=4.2 Hz), 6.02 (1H, s), 7.05 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.9, 2.1 Hz), 7.22-7.27 (1H, m), 7.30-7.37 (3H, m), 7.62 (1H, d, J=9.9 Hz), 7.79 (1H, d, J=1.9 Hz), 8.16 (1H, s).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13].[Cl-].[NH4+]>O1CCCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[Cl:13]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A solution of methylmagnesium bromide (4.8 mL, 3M, 14.4 mmol) was added dropwise to the solution of 4-bromo-3-chlorobenzaldehyde (1.52 g, 7.0 mmol) in tetrahydrofuran at −40° C. Then the mixture was stirred at 25° C. for 3 hrs. Saturated ammonium chloride solution (10 mL) was added to the mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give 1-(4-bromo-3-chlorophenyl)ethanol as a white solid (1.32 g, 81%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), δ 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (d, J=3.6, 1H), δ 4.70 (m, 1H), 1.30 (d, J=6.6, 3H).
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([C:7](OC)=[O:8])[C:3](OC)=[O:4].[BH4-].[Na+]>CO>[CH3:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([CH2:3][OH:4])[CH2:7][OH:8]
Reactant: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.5 %

Procedure:
To a stirred solution of dimethyl 2-methyl-2-(4-nitrophenyl)malonate (5 g, 18.72 mmol, 1.0 eq) in methanol (50 mL) was added NaBH4 (2.12 g, 56.17 mmol, 3.0 eq) at 0° C. and stirred at RT for 16 h. The solvent was evaporated and the residue was diluted with water (50 mL). The product was extracted with EtOAc (2×60 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, evaporated under reduced pressure. The crude product obtained was purified by CC using EtOAc/PE (1:1) to get 2-methyl-2-(4-nitrophenyl)propane-1,3-diol (1.6 g 40%; TLC system: EtOAc/PE (1:1), Rf: 0.2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.IC>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 53 %

Procedure:
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 195 mg (53%) of the title compound and 110 mg (30%) of the compound of Preparative Example 13.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH3:24])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>>[F:23][C:19]1[C:20]([F:22])=[CH:21][C:15]2[S:14][C:13]([NH:12][C:10]3[N:9]([CH3:24])[C:8]4[CH:25]=[CH:26][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)=[N:17][C:16]=2[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 47.6 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (265 mg) was prepared by following General Procedure E starting from 2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester (579 mg) and lithium hydroxide (260 mg). LC/MS: m/z 361.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.75 (bs, 1H), 12.35 (bs, 1H), 8.15 (s, 1H), 7.96 (t, 1H), 7.85 (d, 1H), 7.57 (s, 1H), 7.48 (d, 1H), 3.62 (bs, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2O[CH:18]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1.[NH3:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[NH:38][CH:18]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1
Reactant: CC(Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)co2)cc1)NCC(O)c1cccc(Cl)c1
Reactant: N
Solvent: CO
Product: CC(Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)c[nH]2)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 120 °C

Procedure:
A solution of 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl] phenoxymethyl]-5-benzyloxy-4H-pyran-4-one (2 g) in methanol (10 ml) was treated with ammonia solution, SG 0.88, (5 ml) and heated to 120° C. in a sealed vessel for 18 hours. After evaporation of the solvent in vacuo the residue was crystallised from ethanol to give 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]-propyl]phenoxymethyl]-5-benzyloxy-1H-pyrid-4-one (1.6 g , which was dissolved in methanol and the solution acidified with 2M hydrochloric acid solution to pH 1.5-2.0 and hydrogenated at room temperature and pressure over 10% palladium on charcoal. After filtration and evaporation of the solvent in vacuo the residue was treated with 1.2M sodium hydrogen carbonate solution (5 ml) and extracted with ethyl acetate (3×50 ml), dried (magnesium sulphate), filtered and evaporated under reduced pressure to give an oil. This was dissolved in methanol and treated with methanolic hydrogen chloride. Evaporation in vacuo gave 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-1H-pyrid-4-one dihydrochloride as a (37:63) mixture of diastereoisomers.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:7][N:6]1[C:2]([NH:1][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:3]([NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)CNC(=O)OC(C)(C)C)c1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of tert-butyl 2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-2-oxoethylcarbamate (307 g) in N,N-dimethylformamide (1.5 L) was added triphenylmethyl chloride (334 g). To the mixture was added triethylamine (318 ml) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous citric acid solution, water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with acetonitrile (1.5 L) and dried in vacuo to give tert-butyl 2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoethylcarbamate (468 g).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)[CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[C:38]([O:37][C:35]([N:6]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)[CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.7 %

Procedure:
To a solution of (3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (0.72 g) in THF:MeOH (3:7, 10 mL) solution, 2 N LiOH solution (4 mL) was added and 0° C., and the resulting reaction mixture was stirred at room temperature for 10 hours. After completion of the reaction, 1N HCl (8 mL) was added to neutralize the base, extracted with ethyl acetate, organic layer was washed with water, brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the product (0.68 g). LCMS (m/z): 587.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4]
Reactant: [I-]
Reactant: CCC(OC(=O)CCl)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
To a mixture of (±)-7-[1-[(chloroacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (100 mg, 0.26 mmol) in acetone (10 mL) was added sodium iodide (150 mg, 1.0 mmol), and the resulting solution was heated at reflux for 1 h. Upon cooling, a solid precipitate appeared. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and H2O. The organic extract was washed with H2O (3×), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (CDCl3) d 8.35 (s, 1H), 8.22 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.81 (m, 1H), 7.66 (m, 1H), 7.38 (s, 1H), 5.91 (dd, J=7.9, 6.0 Hz, 1H), 5.26 (two s, 2H), 3.84 (d, J=10.1 Hz, 1H), 3.75 (d, J=10.1 Hz, 1H), 2.36 (s, 3H), 2.10-1.83 (m, 2H), 1.03 (t, J=7.4 Hz, 3H). Anal. Calcd for C21H19IN2O3.1/2 H2O: C, 52.19; H, 4.17; N, 5.80. Found: C, 52.16; H, 4.05; N, 5.39.