Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([CH:23]=[O:24])[C:10]2=[O:25])=[O:5])[CH3:2].S(=O)(=O)([OH:28])N.Cl([O-])=O.[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([OH:28])=[O:24])[C:10]2=[O:25])=[O:5])[CH3:2]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)Oc1cc2occ(C=O)c(=O)c2cc1OC(=O)OCC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC

Procedure:
The compound (1.05 g) obtained in (b) of Example 1 was dissolved in 31.5 ml of dichloromethane, and a solution of 1.05 g of sulfamic acid in 18.9 ml of water was added at 10° C. with stirring. Then, a solution of 525.6 mg of sodium chlorite in 1.2 ml of water was added. The solution was stirred at the same temperature for 1 hour, and allowed to separate. The dichloromethane layer was washed with water (once) and then with a saturated aqueous solution of sodium chloride (twice), and dried over magnesium sulfate. The solvent was distilled off, and ethyl ether was added to the residue to solidify it. The solidified product was collected by filtration, and dried to afford 950 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].CCCC(O[C@@]1(C(COC(C)=O)=O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@]4(C)C(=CC(C=C4)=O)[C@@H](F)C[C@H]3[C@@H]2CC1)=O.[N+:48]([O-])([OH:50])=[O:49]>S(=O)(=O)(O)O>[N+:48]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6])([O-:50])=[O:49]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.4 %

Procedure:
Into 100 mL of 96% sulfuric acid was placed 3,4-difluorobenzoic acid(11.95 g, 0.0756 mol). The solution was stirred at room temperature until the DFBA was dissolved, and then cooled to 0° C. Nitric acid (7.9 g of 90% fuming) was added dropwise to the cooled mixture. After addition, the solution was warmed to room temperature and stirred until completion of the reaction. After drying, 11.88 g of 2-nitro-4,5-difluorobenzoic acid was isolated. The material was identified by GCMS and 19F NMR analysis. An additional 2.41 g of product was obtained by extraction of the acid washes and removal of the solvent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([OH:32])[CH2:5]2.[H-].[Na+].I[CH2:36][CH3:37]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:36][CH3:37])[CH2:5]2
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1[C@@H]1c2ccc(Br)cc2C[C@H]1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of tert-butyl 4-{(3S)-4-[(1R,2R)-5-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (564 mg, 1.1 mmol) in tetrahydrofuran (20.00 mL) was added sodium hydride (448 mg, 17.75 mmol) at room temperature. After stirring for 10 min, iodoethane (1.42 mL, 17.75 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous ammonium chloride solution (20 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude product (488 mg, 82%). LC-MS [M+1]=536.3, 538.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2cnccn2)c1
Yield: 73.9 %

Procedure:
To dimethyl 5-bromoisophthalate (617 mg, 2.26 mmol) in toluene (10 ml), 2-tributylstannyl pyrazine (1 g, 2.71 mmol) was added followed by Pd(PPh3)4 (102 mg, 0.09 mmol). Then reaction mixture was refluxed for 22 h. Then the reaction mixture was filtered through celite and volatiles were removed under vacuum. Crude residue was column chromatographed (50% ethylacetate/50% Hexanes) to obtain 455 mg of dimethyl 5-(pyrazin-2-yl)isophthalate as a pale yellow solid.
Reaction SMILES: [CH3:1]N(N=O)C(N[N+]([O-])=O)=N.C(OCC)C.[OH-].[Na+].[S:18]1[C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1>C1COCC1>[CH3:1][O:28][C:27]([C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][S:18][C:22]=2[CH:23]=1)=[O:29]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ncsc2c1
Yield: 102 %

Procedure:
Add 1-methyl-3-nitro-1-nitrosoguanidine (5.0 g, 33.9 mmol) to a mixture of diethyl ether (20 mL) and 1N aqueous NaOH (20 mL) at ambient temperature. Separate the organic layer and add it slowly to a solution of benzothiazole-6-carboxylic acid (1.0 g, 5.58 mmol) in THF (50 mL) at 0° C. Evaporate the solvent to obtain the desired intermediate as a yellow solid (1.1 g, 100%). MS (ES+) m/z: 194 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=1.C([CH:19]([C:23]([OH:25])=[O:24])C(O)=O)(C)(C)C>>[C:9]([O:25][C:23](=[O:24])[CH2:19][C:10](=[O:12])[C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)([CH3:14])[CH3:13])([CH3:13])([CH3:10])[CH3:7]
Reactant: COc1cccc(C(C)(C)C(=O)O)n1
Reactant: CC(C)(C)C(C(=O)O)C(=O)O
Product: COc1cccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)n1

Procedure:
The title compound was synthesized from 2-(6-methoxy-pyridin-2-yl)-2-methyl-propionic acid and mono-tert-butyl malonic acid according to the method used for the synthesis of Compound PR4. The resultant was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9]([OH:11])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:12]([C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:20][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:22][CH2:23][N:24]1[C:9](=[O:11])[CH2:8][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc(C)c(CC(=O)O)s1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3sc(C)nc3C)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (2,4-dimethyl-thiazol-5-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials to afford product as an oil. LC/MS (Method B) 2.46 min, [M+1]+ 505. Potency class B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-:19].[Na+].OO>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(Br)cnc2C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.4) (2.6 g, 8.6 mmol) in DMSO (60 mL) was added sodium hydroxide (6.0 M in water, 1.4 mL, 8.6 mmol). The reaction mixture was cooled in an ice bath, and hydrogen peroxide (30% w/w solution in water, 2.0 mL, 20 mmol) was added. After 2 hours, the reaction mixture was diluted with water (100 mL) and stirred. After 10 min, the reaction mixture was filtered, and the collected solids were washed with water (2×50 mL) and dried under reduced pressure to afford 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide. 1H NMR (600 MHz, CD3OD) δ 9.63 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(OP([CH2:25][C:26]#[N:27])(=O)OCC)C.[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[CH:25][C:26]#[N:27])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4-Dimethylamino-4-phenyl-cyclohexanone (10.85 g, 50 mmole) and cyanomethanephosphonic acid diethyl ester (10.65 g, 12 mmole) were dissolved in DCM (100 ml). This solution was added dropwise with ice water cooling at a temperature of 5 to 10° C. with vigorous stirring to a solution of 40% aqueous NaOH (50 ml) and stirred for 2 h at RT. Working up was performed by combining the batch with ice (100 g). The organic phase was separated off. The aqueous phase was extracted with DCM (3×40 ml). The combined extracts were washed with saturated NaCl-solution (50 ml), dried over Na2SO4 and then evaporated. (4-Dimethylamino-4-phenylcyclohexylidene)acetonitrile was obtained as a yellow oil in a yield of 95% (11.4 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:18])[N:22]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1C1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a 20 mL vial were added (S)-1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (336 mg, 1.296 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (242 mg, 1.425 mmol) and Et3N (1.8 mL, 13 mmol) in DMF (7 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 25-50% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (147 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.51 (m, 3 H), 1.58-1.87 (m, 3 H), 1.91-2.07 (m, 1 H), 3.04-3.18 (m, 1 H), 3.43-3.60 (m, 3 H), 3.77-3.88 (m, 3 H), 3.90-4.08 (m, 2 H), 5.64-5.80 (m, 1H), 6.39-6.54 (m, 3 H), 6.56-6.67 (m, 2 H), 6.82-6.96 (m, 1 H), 7.54-7.66 (m, 1 H), 7.81-7.96 (m, 1 H),); ESI-MS m/z [M+H]+ calc'd for C20H24N8O, 393; found 393.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][CH:16]=[CH2:17])[C:10]=2[C:9](=[O:18])[NH:8][C:7]1=[O:19])[CH2:2][CH2:3][CH2:4][CH3:5].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][N:8]1[C:9](=[O:18])[C:10]2[N:11]([CH2:15][CH:16]=[CH2:17])[CH:12]=[N:13][C:14]=2[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1=[O:19]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Yield: 100 %

Procedure:
3-Pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20 g, 0.76 mmol), potassium carbonate (0.4 g, 2.9 mmol) and methyl iodide (0.5 ml, 4.9 mmol) were stirred and heated at 50° C. in DMF (5 ml) for 3 h. The solution was allowed to cool and separated between ethyl acetate and brine. The organics were isolated, dried (MgSO4) and concentrated to provide the title compound (0.21 g, 100%). m/z 277 [MH+]
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][S:13][C:9]=3[C:8](=[O:14])[N:7]3[CH2:15][CH2:16][CH2:17][C@H:6]3[C:5]=12.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][S:13][C:9]=3[C:8](=[O:14])[N:7]3[CH2:15][CH2:16][CH2:17][C@H:6]3[C:5]=12
Reactant: O=C1c2sccc2-n2cncc2[C@@H]2CCCN12
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2sccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
3.0 (12.2 mmol) of (S)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide are stirred at 65° for 40 minutes with 1.63 g (12.2 mmol) of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The organic phase is washed several times with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained (S)-1-chloro-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8 one of melting point 180°-183°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=2[NH:23][CH2:24][CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][N:27]2[CH3:31])=O)=[CH:6][CH:5]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.O.[OH-].[NH4+]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[N:23]([CH2:24][CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3[CH3:31])[C:15]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCC2CCCN2C)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCC2CCCN2C)cc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
2-(4-Ethoxy-phenyl)-N-{2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-5-nitro-phenyl}-acetamide 33 (60 mg, 0.141 mmol), Phosphorous pentachloride (33 mg, 0.158 mmol) were dissolved in anhydrous chloroform (10 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4.5 hours and cooled to room temperature overnight. The mixture was diluted with H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow solid 34 2-(4-Ethoxy-benzyl)-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-5-nitro-1H-benzimidazole Yield: 22 mg (38.3%). 1H NMR (DMSO) δ; 1.29 (t, 3H, J=7.0), 1.38-1.51 (m, 2H), 1.51-1.70 (m, 3H), 1.75-1.87 (m, 1H), 1.96-2.05 (m, 2H), 2.07 (s, 3H), 2.85-2.95 (m, 1H), 3.97 (q, 2H, J=7.0), 4.21 (t, 2H, J=7.9), 4.32 (s, 2H), 6.87 (d, 2H, J=8.5), 7.19 (d, 2H, J=8.5), 7.70 (d, 1H, J=9.0), 8.14 (dd, 1H, J=8.9, 2.1), 8.47 (d, 1H, J=2.1); MS (ESI): 409 (MH+, 100%).
Reaction SMILES: [CH3:1][N:2](C=O)C.[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1I.CCN(C(C)C)C(C)C.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[OH:6])[C:11]([O:13][CH3:14])=[O:12])#[N:2]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: CN(C)C=O
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(O)c(C#N)c1
Reaction time: 14 h
Yield: 144.6 %

Procedure:
To a solution of 1 in DMF (158 mg, 0.41 mmol) were added amino acid 2 (100 mg, 0.52 mmol) and DIEA (272 μL, 0.16 mmol). The reaction was stirred for 14 h. Methylamine (2 M in THF, 0.4 mL) and HBTU (295 mg, 0.78 mmol) were then added. The reaction mixture was stirred for 5 h. The product was purified by RP-HPLC using a mixture of acetonitrile and H2O to give 3 (105 mg, 63%). LRMS (M+H+) m/z 401.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]=[CH:6][C:7](=O)[CH2:8]C(OC)=O.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][O:23][C:24](=[O:29])/[CH:25]=[C:26](\[NH2:28])/[CH3:27]>CCO>[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][O:23][C:24]([C:6]1[CH:5]([C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([Br:1])[CH:3]=2)[C:25]([C:24]([O:23][CH2:22][CH:18]2[CH2:19][CH2:20][CH2:21][O:17]2)=[O:29])=[C:26]([CH3:27])[NH:28][C:7]=1[CH3:8])=[O:29]
Reactant: COC(=O)CC(=O)C=Cc1cccc(Br)c1
Reactant: C/C(N)=C/C(=O)OCC1CCCO1
Solvent: CCO
Product: CC1=C(C(=O)OCC2CCCO2)C(c2cccc(Br)c2)C(C(=O)OCC2CCCO2)=C(C)N1
Temperature: -10 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
A solution of 15 g (0.05 mol) of methyl 3-bromobenzylideneacetoacetate and 9.81 g (0.05 mol) of (tetrahydrofuran-2-ylmethyl)-3-aminocrotonate in 55 ml of abs ethanol, was refluxed with stirring, in the absence of light, for 10 hours. The reaction mixture was then cooled to −10° C., yielding a white solid (mp 138-40° C., EtOH) with a yield of 85%.
Reaction SMILES: C(O[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:48])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:25][C:24]=3[F:47])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=O.C([Si]([O:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([O:73][CH2:74][CH:75]2[CH2:77][O:76]2)[CH:68]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:47][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:77][C@H:75]([OH:76])[CH2:74][O:73][C:69]3[CH:70]=[CH:71][CH:72]=[C:67]([OH:66])[CH:68]=3)=[CH:12][CH:11]=2)[CH2:19][CH2:18]1)=[O:48]
Reactant: CC(C)(C)[Si](Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNOC=O)cc3)CC2)c(F)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc(OCC2CO2)c1)(c1ccccc1)c1ccccc1
Product: O=C(NCc1ccc(O)cc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(O)c3)cc2)CC1
Yield: 18.9 %

Procedure:
[2-(4-{1-[4-(tert-Butyl-dipheny-silanyloxy)-2-fluoro-benzylcarbamoyl]-piperidin-4-ylamino}-phenyl)-ethyl]-amino formate (1.05 g, 1.59 mmol) was reacted with tert-butyl-(3-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.642 g, 1.59 mmol) according to Procedure G to give the title compound (0.290 g, 0.3 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.005 g) and N-hydroxy-benzotriazole (HOBt)(0.642 g) in DMF (30 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(2.76 g) and triethylamine (2.005 ml). The mixture is stirred for 1 h at ambient temperature. This solution is added at 0° C. slowly to a solution of 1,4-diaminobenzene (0.43 g) and triethylamine (0.45 ml) in DMF (5 ml). After completion of the chemical reaction the mixture is evaporated at high vacuum and the residue is partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A colorless solid (0.735 g) is obtained in 55% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].CC1C=CC(S([CH2:20][N:21]=[CH2:22])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:22]=[N:21][CH:20]=2)[S:5][C:6]=1[CH3:7]
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1sc(C=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1sc(-c2cnco2)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-5-methylthiophene-2-carbaldehyde (A, 10.5 mmol) and p-tosylmethyl isocyanide (11 mmol) in methanol (80 mL) was added potassium carbonate (13 mmol) and the mixture was heated to 80° C. for 1 h. The solvent was removed in vacuo and diluted in DCM (100 mL) and water (100 mL). The organic layer dried, concentrated and purified by flash chromatography to give 5-(4-bromo-5-methylthiophen-2-yl)oxazole (B, 1.83 g) as yellowish solids.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([NH:5][C:6]([C:8]1[C:12]([NH:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](OC)=[O:21])[CH:16]=2)=[C:11]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([OH:31])=[CH:26][C:25]=2[OH:32])[O:10][N:9]=1)=[O:7])[CH3:4].Cl>CCO.O>[OH:21][CH2:20][C:17]1[CH:16]=[C:15]([CH2:14][NH:13][C:12]2[C:8]([C:6]([NH:5][CH2:3][CH3:4])=[O:7])=[N:9][O:10][C:11]=2[C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([OH:31])=[CH:26][C:25]=2[OH:32])[O:19][N:18]=1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1NCc1cc(C(=O)OC)no1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1NCc1cc(CO)no1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (2 eq) was added portionwise at 0° C. to a solution of methyl 5-((3-(ethylcarbamoyl)-5-(5-chloro-2,4-dihydroxyphenyl) isoxazol-4-ylamino)methyl)isoxazole-3-carboxylate (0.34 mmol, 150 mg) in EtOH 95% (5 ml). After 30 min, few drops of a 5% HCl solution were added to the mixture and the solvent was evaporated under vacuo. The crude reaction mixture was diluted with H2O (10 ml) and extracted with AcOEt (2×10 ml). The combined organic phases were washed with brine, dried and filtered. Solvent was removed under vacuo and the crude product was purified by flash chromatography on silica gel (AcOEt/light petroleum).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 4-chloro-4′-cyanobenzenesulfonanilide (4.03 g (13.8 mmol)) in 15 ml of acetic anhydride, 97% fuming nitric acid (0.61 ml (14.3 mmol)) was added dropwise with stirring at room temperature. After one hour's stirring at 50° C. the reaction mixture was poured into water to give crystals, which were then collected by filtration and washed with water to give 4.30 g (93%) of 4-chloro-4′-cyano-2′-nitrobenzenesulfonanilide as pale yellow crystals.