Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:24])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a dry nitrogen atmosphere 10 g (0.05 mole) of 2-biphenylcarboxylic acid was dissolved with stirring in 116 ml of dry toluene. Pyridine, 4.2 g (0.054 mole), was then added to the reaction mixture followed by 6.4 g (0.054 mole) of thionyl chloride. The reaction mixture was stirred at room temperature for two hours, then filtered to remove a white precipitate. The toluene was removed from the filtrate under reduced pressure to give [1,1'-biphenyl]-2-carbonyl chloride as a liquid residue, which was used without purification in Step B below.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[O:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-:16].[Na+]>C(C(C)=O)C>[I:16][CH2:2][CH2:3][C:4]1[O:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [I-]
Reactant: Cc1nc(-c2ccccc2)c(CCCl)o1
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1nc(-c2ccccc2)c(CCI)o1
Reaction time: 20 h

Procedure:
A mixture of 5-(2-chloroethyl)-2-methyl-4-phenyloxazole (9.8 g), sodium iodide (9.9 g) and methyl ethyl ketone (150 ml) was refluxed with stirring for 20 hours. The solvent was distilled off and the residue was diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give an oil of 5-(2-iodoethyl)-2-methyl-4-phenyloxazole, yield 11.5 g (82.9%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10]>C(#N)C>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:9](=[O:10])[C:8]([F:15])([F:14])[F:7]
Reactant: CNCCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC#N
Product: CNCCCNC(=O)C(F)(F)F
Temperature: 85 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
N-Methyl-1,3-diaminopropane (50 g, 0.56 mol) was dissolved in 200 mL acetonitrile followed by addition of ethyl trifluoroacetate (154 ml, 1.28 mol). The reaction mixture was stirred overnight at 85° C. The solvent was then removed in vacuo to yield the depicted product as a brown oil (101 g, 98.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnn(-c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn(-c2ccc(F)cc2)c1
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-nitropyrazole (0.820 g, 3.96 mmol) and 10% Pd/C (0.133 g, 50% wet by wt) in EtOH (50 mL) was fitted onto a Parr apparatus and agitated under H2 at 40 psi for 40 min. The reaction mixture was then filtered through filter paper. The filtrate was collected and concentrated in vacuo to give 1-(4-fluorophenyl)pyrazol-4-amine as an oil (0.675 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Reactant: OCc1ccc(B(O)O)cc1
Product: O=c1ccc(-c2ccc(CO)cc2)cn1Cc1ccc(Cl)cc1
Yield: 52.1 %

Procedure:
According to Scheme 25 Step 2: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 3.30 mmol, 1.00 g, Example 2 Step 1) and 4-(hydroxymethyl)phenylboronic acid (1.5 eq, 5.00 mmol, 0.76 g) according to the procedure described for Example 1 Step 3. Reaction conditions: overnight at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using CH2Cl2/MeOH 98/2 as the eluent to afford 1-(4-chlorobenzyl)-5-(4-(hydroxymethyl)phenyl)pyridin-2(1H)-one (1.72 mmol, 0.62 g, 52%) as a brown oil LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.47 min; MS m/z (CI) [MH]+=326, 328.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:18]>O.ClCCl>[C:6]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:1][CH2:2][CH2:3][Br:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: Br
Solvent: O
Solvent: ClCCl
Product: BrCCC=C(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
At 0° C., cyclopropyl-diphenyl-carbinol (10.0 g) is dissolved in a hydrogen bromide solution 48% (40 ml). After being subjected to agitation for 5 hours at 0° C., the medium is diluted with water and dichloromethane, then the organic phase is washed three times with water. The organic phase is dried on MgSO4, filtered and concentrated to obtain the expected product as an orange oil (11.89 g).
Reaction SMILES: N#N.Br[C:4]1[S:5][C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:7][N:8]=1.[Li]CCCC.CN([CH:23]=[O:24])C.[NH4+].[Cl-].Cl>CCOCC>[CH3:14][C:9]1([C:6]2[S:5][C:4]([CH:23]=[O:24])=[N:8][CH:7]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CN(C)C=O
Reactant: CC1(c2cnc(Br)s2)OCCO1
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CCOCC
Product: CC1(c2cnc(C=O)s2)OCCO1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-bromo-5-(2-methyl-[1,3]dioxolan-2-yl)thiazole (5.00 g, 20.00 mmol) in dry Et2O (40 mL) was added to a n-BuLi (8.40 mL of a 2.5M solution in hexanes, 21.00 mmol) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before DMF (2.5 mL, 32.29 mmol) was added dropwise. The reaction mixture was stirred at −60° C. for 1 h. Sat. aq. NH4Cl (100 mL) was added, followed by aq. 1N HCl (50 mL). The layers separated and the aq. layer extracted with Et2O (5×). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as an orange oil. TLC:rf (1:1 hept-EA)=0.50. LC-MS-conditions 01: tR=0.78 min; [M+H]+=199.93.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[O:25][CH3:26])=[CH:6][C:5]=1[OH:27]>CO.[OH-].[Na+]>[CH3:26][O:25][C:18]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([OH:27])[CH:6]=1
Reactant: COC(=O)c1ccc(OCCCCCCc2cccc(OC)c2OC)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CCCCCCOc2ccc(C(=O)O)c(O)c2)c1OC
Yield: 82 %

Procedure:
A solution of 0.45 g (1.2 mmol) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid methyl ester in 25 mL of methanol and 8 mL of 1N sodium hydroxide was refluxed for 7 hours. Workup as in Example 24 and recrystallization from methanol gave 0.36 g (82% yield), mp 115°-116° of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH2:28][CH3:29])[CH:22]=3)[O:18][N:17]=2)=[CH:11][C:10]=1[CH2:30][CH3:31])(C)(C)C>Cl>[CH2:30]([C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH2:28][CH3:29])[CH:22]=3)[O:18][N:17]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][CH2:7][C:6]([OH:32])=[O:5])[CH3:31]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)OC(C)(C)C)c(CC)c3)no2)cc(C)n1
Agent: Cl
Product: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(CC)c3)no2)cc(C)n1

Procedure:
A solution of the above 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid tert. butyl ester in 6 N aq. HCl (10 mL) is stirred at 65° C. for 18 h. The solvent is evaporated and the residue is suspended in MeCN. The solid material is collected, washed with additional MeCN and dried under high vacuum to give 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (135 mg) as a white powder; LC-MS: tR=0.86 min, [M+1]+=380.13.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:44][CH2:43]1)=[O:16]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 68.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (504 mg, 1.26 mmol, 69%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:29]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:30]
Reactant: COc1cccc(CN)c1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1cccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c1

Procedure:
Prepared analogously to Example 1 from 3-methoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: FC(F)(F)C(O)=O.C([CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]1[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].O>ClCCl>[N:16]1([C:21]2[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:15][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)Nc1cccnc1N1CCNCC1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Nc1cccnc1N1CCNCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a stirred solution of 2-(Boc-piperazinyl)-3-(i -propylamino)pyridine 4 (1.426 g, 4.45 mmol) in dichloromethane (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, at room temperature for 1 h 15 min. Additional quantities of TFA (2.0 mL) were added. The mixture was stirred at room temperature for another 23 h. Sat. K2CO3 solution was slowly added to quench the reaction (gas ↑). Small amount of water was added to help the layers separation. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×25 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the product in quantitative yield. 1H-NMR (CDCl3): 7.681 (dd, J=5.0 Hz and 1.5 Hz, 1 H, Ar—H), 6.890 (dd, J=8.0 Hz and 5.0 Hz, 1 H, Ar—H), 6.800 (dd, J=8.0 Hz and 1.5 Hz, 1 H, Ar—H), 4.170 (d, J=7.5 Hz, 1 H, NH), 3.567-3.485 (m, 1 H, CH), 3.046 (s, 8 H, 4 CH2), 1.983 (br, 1 H, NH), 1.234 (d, J=6.0 Hz, 6 H, 2 CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27]C1CC2C(=CC=C(O)C=2)OC1C1C=CC=CC=1>>[CH3:27][CH:15]1[CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:12]=2)[O:17][CH:16]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC1Cc2cc(O)ccc2OC1c1ccccc1
Product: CC1Cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2OC1c1ccccc1

Procedure:
2-(3-Methyl-2-phenylchroman-6-yloxy)-5nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 600 mg of 3-methyl-2-phenylchroman-6-ol. The product was purified by column chromatography using heptane-2-propanol (20:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.59 (dd, 1H, J 9.1, 2.8 Hz), 7.43-7.36 (m, 5H), 7.19 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.6 Hz), 6.95 (dd, 1H, J 8.7, 2.6 Hz), 6.86 (d, 1H, J 8.7 Hz), 4.73 (d, 1H, J 9.3Hz), 2.85 (dd, 1H, J −16.7, 5.0 Hz), 2.64 (dd, 1H, J −16.5, 10.9 Hz), 2.18 (m, 1H), 0.77 (d, 3H, J 6.7 Hz).
Reaction SMILES: [C:1]([N:4](C(OC(C)(C)C)=O)[N:5]1[CH2:10][C:9]([CH:11]=[O:12])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2].[CH3:28][Mg+].[Br-]>C1COCC1>[C:1]([NH:4][N:5]1[CH2:10][C:9]([CH:11]([OH:12])[CH3:28])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: C[Mg+]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)NN1CC(C(C)O)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (1.15 g, 3.00 mmol) [prepared according to Example 1, Step F] in THF (11.0 mL) at 0° C. was slowly added MeMgBr (3M solution in Et2O, 1.50 mL, 4.50 mmol) via syringe. The reaction mixture was allowed to warm to room temperature and stirred for another 20 h. The reaction mixture was quenched with sat NH4Cl solution and the aqueous layer extracted EtOAc. After washing of the combined organic layers with brine and drying (Na2SO4), the solvent was removed in vacuo to give the desired product as a viscous oil. LCMS (Method I) RT 1.19 min. [M+Na]+ 323.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[C:17]([CH2:20][Br:8])[CH:16]=[CH:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccc(Br)c2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cccc(Br)c2c1
Reaction time: 0.02 h
Yield: 100 %

Procedure:
To boiling CCl4 (250 mL) was added NBS (20.4 g, 0.114 mol) and AIBN (1.4 g, 0.009 mol). After 1 minute, a solution of 1-bromo-7-methylnaphthalene (24.1 g, 0.109 mol) in CCl4 (15 mL) was added all at once. Within 1 minute, the reaction became quite exothermic and the heating mantle was removed for several minutes. Heating was resumed for 30 minutes. The mixture was cooled, filtered, and the filtrate was concentrated to give an off-white solid (32.7 g). The product was combined with similarly prepared material (32.6 g) and recrystallized from ethyl acetate/hexane to give the product (29.6 g, 45%).
Reaction SMILES: Cl.[C:2]1([S:8]([NH:11][C:12]2[CH:36]=[CH:35][C:15]3[N:16]([CH2:29][C:30]([O:32]CC)=[O:31])[C:17]([CH2:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:2]1([S:8]([NH:11][C:12]2[CH:36]=[CH:35][C:15]3[N:16]([CH2:29][C:30]([OH:32])=[O:31])[C:17]([CH2:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cn1c(Cc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(Cc2nc3cc(NS(=O)(=O)c4ccccc4)ccc3n2CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
200 mg (0.379 mmol) of 4-[(5-benzenesulphonylamino-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride are dissolved in 10 ml ethanol and stirred at 40° C. for 90 minutes after the addition of 1 ml 2N sodium hydroxide solution. The solvent is distilled off, the residue diluted with 20 ml water and acidified with glacial acetic acid. The precipitated product is suction filtered and dried.
Reaction SMILES: C(O[C:4]([C:6](=[CH:12][NH:13][C:14]1[C:18]([O:19][CH3:20])=[CH:17][S:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:20][O:19][C:18]1[C:14]2[NH:13][CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=[O:5])[C:15]=2[S:16][CH:17]=1
Reactant: CCOC(=O)C(=CNc1cscc1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(OC)csc2c1=O
Reaction time: 0.33 h

Procedure:
To a refluxing solution of diphenyl ether (250 ml) was added ethyl 2-ethoxycarbonyl-3-(4-methoxy-3-thienylamino)prop-2-enoate (25 g, 0.0836 mol) portionwise. On completion of the addition, refluxing was continued for a further 20 minutes. The reaction mixture was allowed to cool and then diluted with petroleum ether (b.p. 40°-60°) (400 ml) to give a dark brown solid. This was collected by filtration, washed with petroleum-ether (b.p. 40°-60°) (100 ml) and dried. The solid was recrystallized from DMF (30 ml) to give the title compound as a pale purple solid, 12.7 g, m.p. 244°-247°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:19](I)([CH2:21][CH3:22])[CH3:20]>C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH:19]([CH2:21][CH3:22])[CH3:20])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: CCC(C)I
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)Sc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g), sodium hydrogen carbonate (2 g), saturated sodium hydrogen carbonate (100 ml), and sec.-butyl iodide (2.2 g) is stirred for 6 hours at 55° C. After cooling, 5-amino-3-sec.-butylthio-4-phenoxybenzoic acid is precipitated by addition of hydrochloric acid until pH 2.5. After collection, recrystallization from aqueous ethanol, and drying in vacuo at 80° C, the compound is obtained with a melting point of 157°-159° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: OCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 28 g of the crude 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is treated with 24 g of imidazole. A solution of 30.3 g of tert-butyldimethyl-chlorosilane in 46 ml of tetrahydrofuran is then added dropwise and the mixture is stirred at room temperature for 4 hours. The reaction mixture is poured into water, extracted by shaking with diethyl ether, and the organic phase is washed 4 times with water, dried over sodium sulphate and concentrated. The crude product is chromatographed on silica gel using hexane/diethyl ether. 42 g of the title compound are obtained as a colourless liquid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]23[CH:16]([CH:17]=[N:18][OH:19])[CH:15]2[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH:7]=[CH:8][C:9]=1[Cl:10].[CH2:27](I)[CH3:28]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]23[CH:16]([CH:17]=[N:18][O:19][CH2:27][CH3:28])[CH:15]2[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(C)OC(=O)N1CC2C(C=NO)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a suspension of sodium hydride (23 mg, 0.96 mmol, 60% suspension in mineral oil) in dry DMF (2 mL) at 0° C. under nitrogen atmosphere, was added a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-((hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 0.38 mmol), obtained in step-1 of example 6, in DMF (2 mL). The reaction mixture was stirred at the same temperature for 30 min followed by the addition of ethyl iodide (0.06 mL, 0.74 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as confirmed by TLC, the reaction mixture was quenched by saturated solution of ammonium chloride and the crude compound was extracted with ethyl acetate. The organic layer was washed with water, separated, dried over anhydrous sodium sulphate and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 EtOAc: Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((ethoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (75 mg, 50%) as a viscous oil as a mixture of isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:20]1(=[O:24])[CH2:23][CH2:22][CH2:21]1>CCOCC>[OH:24][C:20]1([C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccccc1C1(O)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To phenyl-carbamic acid tert-butyl ester (2 g, 10.4 mmol) in ether (30 mL) at 0° C. was added t-BuLi (15 mL, 26 mmol, 1.7 M) and the reaction solution stirred for 3 hours prior to the addition of cyclobutanone (1.2 mL, 15.6 mmol). The reaction mixture was allowed to warm to room temperature. Upon completion by thin-layer chromatography (TLC), the reaction was poured into ice-cold saturated ammonium chloride (100 mL) and extracted with ethyl acetate (50 mL). The organics were dried over sodium sulfate, concentrated, and purified on a silica gel column (10% ethyl acetate/hexane) to give tert-butyl [2-(1-hydroxycyclobutyl)-phenyl]carbamate (0.86 g, 32%) as a white solid. 1H NMR (DMSO-d6): δ 8.48 (s, 1H), 7.8 (d, 1H, J=7.92 Hz ), 7.35 (dd, 1H, J=7.7, 1.4 Hz), 7.25 (td, 1H, J=7.5, 1.6 Hz), 7.03 (td, 1H, J=7.5, 1.3 Hz), 2.51-2.49 (m, 2H), 2.43-2.39 (m, 2H), 2.28-2.25 (m, 2H), 1.45 (s, 9H). MS (ESI) m/z 190 ([M+H]+); MS (ESI) m/z 188 ([M−H]−);