Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33]N[CH2:31][CH2:30]1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)CC1
Yield: 38.2 %

Procedure:
Following the procedure of Example U1, 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.50 g, 1.2 mmol, from Example S1-A) and 1-methylpiperazine (0.46 g, 4.7 mmol) in DMF (5 mL) were reacted to give 0.22 g of the title compound.
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].[CH3:51]N(C)C=O.C(N1CN(C(C)(C)C)CN(C(C)(C)C)C1)(C)(C)C.[NH2:74][N:75]1[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]1>C(O)(=O)C>[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:31](/[CH:51]=[N:74]/[N:75]5[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]5)=[C:32]([OH:33])[C:5]([C:6]=2[C:10]3=[O:11])=[C:4]([C:34]=4[OH:35])[C:3]=1[OH:50])=[O:28]
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
Reactant: CN1CCN(N)CC1
Reactant: CN(C)C=O
Agent: CC(C)(C)N1CN(C(C)(C)C)CN(C(C)(C)C)C1
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(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
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(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)C4=O
Solvent: CC(=O)O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(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
Reaction time: 3 h

Procedure:
15 g. Rifamycin S are dissolved in 50 ml. dimethylformamide and 5.5 g. 1,3,5-tri-(tert.-butyl)-hexahydro-1,3,5-triazine are added to the solution. The reaction mixture is then kept at 75° C. for about 3 hours and 1-amino-4-methylpiperazine, acidified with acetic acid, added directly according to the procedure described in Example 1, followed by analogous working up to give substantially pure rifampicin.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23]>CC(C)=O>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCOCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOCCOc1cccc(C=O)c1
Yield: 19.6 %

Procedure:
A mixture of 3.66 g of 3-hydroxybenzaldehyde, 4.6 g of powdered potassium carbonate, and 5.5 g of 1-bromo-2-(2-methoxyethoxy)ethane in 40 ml of acetone is stirred and refluxed under nitrogen for 18 h, then cooled and filtered. The filtrate is concentrated under reduced pressure, and the residue partitioned between CH2Cl2 and 1N NaOH. The aqueous phase is extracted with two additional portions of CH2Cl2, and the combined organic extracts dried (MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 20% EtOAc in CH2Cl2 affords 1.32 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:24][CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 3-(4-methylpiperazin-1-yl)-propan-1-ol. LC/ESI-MS: m/z=351 [M+H].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:26][N:25]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[N:13]([CH2:12][CH2:11][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:14]=[CH:15]4)=[N:25][CH:26]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCN4CCCC4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.1 mL (13.3 mmol) pyrrolidine are added to a solution of 600 mg (1.33 mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl methanesulphonate in 12 mL DMF and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i. vac., the residue is taken up in a little DCM and the product is purified by chromatography (silica gel, cyc/EtOAc 2:1)
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2.[OH-:17].[Na+].[CH3:19]O.C(Cl)Cl>CN(C=O)C>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[C:10]2[CH:19]=[O:17]
Reactant: CO
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c2ccc(F)cc2c1C=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Dry DMF (0.6 mL) was added slowly to POCl3 (0.9 mL) at room temperature under nitrogen atmosphere, and the mixture stirred for 5 minutes. 5-fluoro-2-methyl-1H-indole (149 mg, 1.0 mmol) was dissolved in 5 mL dry DMF and added slowly to the rapidly stirring mixture to keep the temperature below 35° C. After stirring for 2 h at room temperature, the reaction mixture was poured into 30 mL ice water. The aqueous layer was basified (30 mL 1.0 N NaOH) and extracted into methylene chloride. The organic layer was washed with water (1×50 mL), brine (1×50 mL), and dried over Na2SO4. The solvent was removed in vacuo to yield an off-white solid. The solid was brought up in 1:3 MeOH/methylene chloride and filtered through a short plug of silica to remove colored impurities. The dried-down solid was then washed with dry acetonitrile to provide the product 5-fluoro-2-methyl-1H-indole-3-carbaldehyde as a crystalline white solid (105 mg, 55% yield) after drying. 1H NMR (400 mHz, DMSO-d6) δ 12.10 (s, 1H), 10.03 (s, 1H), 7.72 (dd, J=9.7, 2.6 Hz, 1H), 7.38 (dd, J=8.8, 4.5 Hz, 1H), 7.01 (dt, J=9.2, 2.6 Hz, 1H), 3.34 (s, 1H), 2.68 (s, 3H).
Reaction SMILES: C([C@:4]1([OH:19])[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7]C(C(=O)C)=[C:5]1[C:16](=[O:18])C)(=O)C.[Li+].[Br-].CO.O.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>CC#N>[O:12]=[CH:11][C@@H:8]([C@H:9]([C@@H:4]([C@@H:5]([CH2:16][OH:18])[OH:32])[OH:19])[OH:10])[OH:7]
Reactant: CC(=O)C1=C(C(C)=O)[C@](O)(C(C)=O)[C@H](O)[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h

Procedure:
To a solution of the crude triacetyl glucal 3 (9.54 g, 35.0 mmol) in CH3CN (150 mL) was successively added LiBr (3.65 g, 42.0 mmol), MeOH (2.25 g, 70.2 mmol), and p-toluenesulfonic acid monohydrate (p-TsOH.H2O, 954 mg) at room temperature. After being stirred for 3 h, the reaction mixture was concentrated to a small volume, diluted with cold 5% NaHCO3 solution, and extracted with CHCl3. The organic extract was washed with ice-water, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed on silica gel (150 g) using 30% AcOEt-hexane to give 8 (9.01 g, 92% from D-glucose) (α-anomer:β-anomer=ca. 10:1). 8a was isolated as a single isomer, while 8b was obtained as a mixture of 8a and 8b.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[IH:12].C(O)(=O)C>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:12])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: I
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(I)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 2 liter single-neck round bottom flask with a mechanical stirrer was charged 2-amino-6-chloropurine (41.0 g, 242 mmol). The flask was cooled in an ice-water bath. The the reaction flask was charged HI (47% solution, pre-cooled in a refrigerator, 250 mL) in one portion. The resulting suspension was stirred for 16 hours at ice-water bath temperature. Water (500 mL) was charged to the reaction flask. The suspension was stirred at 0° C. for 1 hour. The precipitate was filtered and washed with water (3×250 mL). The filter cake was transferred to a 250 mL filtration flask. 6 M NaOH solution (85 mL) was added to the solid through the filter to rinse out residual solid and wash into the filter flask. The solution obtained was added slowly to a boiling solution of acetic acid (25 mL) and water (250 mL). The resulting suspension was cooled to room temperature and stirred at room temperature for 2 hours. The solid was collected by centrifugation, washed with water (2×250 mL), followed by heptane (250 mL). The solid was first spin-dried on the centrifuge for 30 minutes and then dried in a vacuum oven overnight to provide the desired product (61.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)sc2C(=O)O)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 33b, 1.3 g, 3.08 mmol) was suspended in ethanol (30 ml) and solution of NaOH (0.61 g, 15.4 mmol) in water (3 ml) was added to it at 25° C. The reaction mixture was then heated at about 75° C. under stirring for 3 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (5 ml) and cooled using ice bath. To the cooled mixture was then added aqueous 10% HCl to bring pH to between 5 and 6. The mixture so obtained was extracted with ethyl acetate (3×25 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.10 g, 90.9%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].O.[C:9]1(C)[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+].[Cl-].[Na+].O.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1.O>>[F:1][C:2]([F:7])([F:6])[C:3]([NH:5][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1[CH:32]=[CH:28][CH:29]=[C:30]([OH:31])[CH:14]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)C(F)(F)F
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(NCCCCc1cccc(O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of THP-phenol 136 (0.72 g, 2.08 mmol), p-toluenesulfonic acid monohydrate (0.366 g) in THF:H2O (3:1, 20 mL) was stirred at room temperature for 3.5 hr. The reaction mixture was treated with aqueous NaHCO3-brine solution, layers were separated and aqueous layer extracted with EtOAc. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc-hexanes gradient) gave 2,2,2-trifluoro-N-(4-(3-hydroxyphenyl)butyl)acetamide as a colorless oil, which was taken into the next step. Yield (0.438 g, 96%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C(O[C:17](=[O:19])[CH3:18])(=O)C.S(=O)(=O)(O)O>O>[C:4]([O:5][C:4]1[CH:3]=[C:2]([CH:10]=[C:8]([O:9][C:17](=[O:19])[CH3:18])[C:6]=1[O:7][C:6](=[O:7])[CH3:8])[C:1]([OH:12])=[O:11])(=[O:5])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
In a one liter round bottom flask, with a magnetic stirrer, were combined gallic acid (170.1 g, 1.0 mole) and acetic anhydride (566 ml, 6 moles). The slurry was stirred as sulfuric acid (1.06 ml) was added. The temperature rose rapidly from 21° C. to 75° C. over about 1 minute and the slurry became a clear yellow solution. The mixture was stirred and allowed to cool to ambient temperature over 20 minutes. The solution was then poured into a stirred, four liter Erlenmeyer flask containing three liters of water. After 2.5 hours, white crystalline product was isolated by filtration and washed 3 times with 500 milliliters of water. The product was dried in a stream of air for 3 hours and then vacuum dried overnight. Yield was 262 grams, which was 88% of theoretical yield. Melting point was 166°-168° C. NMR conducted as in the preceeding preparation, but using (CDCl3) gave as peaks, in ppm: 2.30 (s, 9H), 7.86 (s, 2H), 11.95 (broad, 1H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[NH:4].[CH3:26][C:27]([CH3:29])=O>>[CH3:26][C:27]1([CH3:29])[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[C:13]([OH:15])=[O:14])=[CH:9][CH:10]=2)[NH:4]1
Reactant: N=C(NO)c1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Reactant: CC(C)=O
Product: CC1(C)NC(c2ccc(CC(C(=O)O)c3cccc(C(F)(F)F)c3)cc2)=NO1
Yield: 40 %

Procedure:
A solution of 3-[4-(N-hydroxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid (200 mg, 0.57 mmol, example 258/259 b 1)) in acetone (50 ml) was refluxed for 8 hours per day for five days. The reaction mixture was evaporated in vacuo and the residue was purified by prep. HPLC (HPLC conditions: Purospher(R)Star HP-18e (10 μm), acetonitrile/water+1% TFA, 10% to 100% acetonitrile) to give 90 mg of the desired product (40%). MS m/z: 393.1 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[H][H].[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CCOC(C)=O>[Si:14]([O:4][C:3]1[CH:2]=[CH:1][C:2]([CH:3]=[O:4])=[CH:1][CH:5]=1)([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 8 h

Procedure:
To a dry 100 ml round bottom flask was added 1.31 g of 2. To this was added 50 ml of dry THF, followed by the careful addition of 298 mg NaH (H2 is evolved). After evolution of hydrogen ceased, 1.93 g of TBSCl was added. The reaction was allowed to stir overnight. The solution was then diluted with 100 ml EtOAc, and washed sequentially with water and then brine. The organic layer was then dried with MgSO4 and the solvent removed by evaporation. NMR on the crude product corresponded with the protected aldehyde 4.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:29][C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:42](=[O:49])([O:46][CH2:47]I)[S:43][CH2:44][CH3:45]>O.C(Cl)Cl>[C:42](=[O:49])([S:43][CH2:44][CH3:45])[O:46][CH2:47][O:35][C:34](=[O:36])[CH2:33][CH2:32][C:30](=[O:31])[NH:29][C:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)O
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)CCC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
To a mixture of acid 73 (519 mg, 1.01 mmol) in H2O (3 mL) and CH2Cl2 (3 mL) was added NaHCO3 (176 mg, 2.09 mmol) and TBAHSO4 (342 mg, 1.01 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (192 mg, 0.77 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 3 h and was diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 20-60% EtOAc in CH2Cl2 as eluent, to furnish compound 74 (351 mg, 72%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.94-1.98 (m, 6H), 2.20-2.24 (m, 6H), 2.43 (t, J=6.9 Hz, 2H), 2.70 (t, J=6.9 Hz, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.81 (s, 2H), 5.98 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[C:27]([NH2:28])=[CH:26][NH:25][N:24]=2)=[O:22])=[CH:16][CH:15]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[C:27]([NH:28][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=3[F:1])=[CH:26][NH:25][N:24]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: COc1cccc(C(=O)O)c1F
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCCl
Product: COc1cccc(C(=O)Nc2c[nH]nc2C(=O)Nc2ccc(F)cc2)c1F
Yield: 62.3 %

Procedure:
2-Fluoro-3-methoxybenzoic acid (0.047 g, 0.28 mmol), 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (Example 2B) (0.055 g, 0.25 mmol), EDC (0.58 g, 0.30 mmol) and HOBt (0.041 g, 0.30 mmol) were stirred at room temperature in DMSO (1.25 ml) for 5 hours. The reaction mixture was poured into water (30 ml) and the resultant solid was collected by filtration and dried in a vacuum oven to give the title compound as a grey solid (0.058 g, 63%). (LC/MS: Rt 3.99, [MH]+ 372.98).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[B:34]1(B2OC(C)(C)C(C)(C)O2)[O:38]C(C)(C)C(C)(C)[O:35]1.C([O-])(=O)C.[K+]>CS(C)=O>[O:16]=[C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[C:2]([B:34]([OH:38])[OH:35])[CH:3]=[C:4]1[C:17]1[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[N:18]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 95 °C

Procedure:
4 g of 6-chloro-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxy-methyl) -1H-benzimidazol-2-yl]-2H-pyridazin-3-one (example 46), 4.1 g of bis(pinacolato)diboron, 0.19 g of (1,1 ′-bis(diphenylphosphine)-ferrocene)palladium(II) chloride-dichloromethane complex and 2.3 g of potassium acetate are dissolved in 60 ml of DMSO. The solution is degassed with argon and heated at 95° C. for 2.5 hours. For workup, 600 ml of water are added, the mixture is extracted several times with dichloromethane and the organic phase is washed with saturated sodium chloride solution and dried using a phase separator cartridge. After the solvent has been distilled off, the crude product is purified by preparative RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].ClC(Cl)(Cl)[C:13]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[N:21]2)=[O:14].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:13]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[N:21]2)=[O:14]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2nn1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc2nn1

Procedure:
The title compound was prepared using 3,4-dichlorobenzylamine, the product from Example 16A, DBU and the procedure described in Example 1B. MS (ESI+) m/z 362 (M+)+; 1H NMR (DMSO-d6) δ 2.88 (s, 3H), 4.36 (d, 2H), 7.10 (t, 1H), 7.34 (dd, 1H), 7.59 (m, 2H), 7.76 (t, 1H), 8.04 (d, 2H), 8.19 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH:27]=[O:28])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH:29]O.Cl>[OH-].[Na+]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]([C:27]([OH:29])=[O:28])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccc(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
100 mg of compound 2 (0.269 mmol) are dissolved in 50 mL of 0.1 N NaOH and 158 mL (1.6 mmol) of 35% H2O2 are added. The mixture is left to stand at ambient temperature for 18 h. The mixture is cooled to 0° C. and adjusted to pH 2 with 2N HCl. The solid is filtered out and washed with water. Drying is performed in a vacuum oven at 40° C. Product: 54 mg. Formula: C22H21N5O2 (m.w. 387.43). Yield 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-benzenesulfonyl chloride.