Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[CH:29])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35](=[O:37])=[O:36]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[C:29][C:35]([OH:37])=[O:36])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=C=O
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (45 ml) was added dropwise to a solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (132 g) in tetrahydrofuran (1 l.) keeping the temperature below -40°. The mixture was stirred at -60° for 2 hours and then carbon dioxide gas was passed through the solution for 30 minutes with cooling in an acetone/solid carbon dioxide bath. The mixture was allowed to warm to 0° while the passage of carbon dioxide gas was continued and then it was quenched with water (1 l.) and the layers separated. The aqueous layer was extracted into ether (500 ml) and the combined organic layers were washed with water, diluted with dichloromethane, washed with 1M HCl, dried over MgSO4 and evaporated. The residue was triturated with methanol and the resulting solid collected, washed with cold (-20°) methanol and dried to give 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}but-2-ynoic acid, (83.7 g), m.p. 150°-152°.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:22]=[O:23])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:32])C.S(=O)(O)[O-].[Na+].ClCCl>N1C=CC=CC=1>[CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([OH:32])=[O:23])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Reactant: CCOC(C)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C(=O)O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(N-cyclohexyl-4-(3-formyl-4-nitrophenyl)oxybutyramidyl)acetate (3.5 g) in dry pyridine (20 ml) under a blanket of nitrogen was added solid tetra-N-butylammonium permanganate portionwise over 1 hour. The reaction was stirred at room temperature for 1 hour and was then poured into ethyl acetate/6M hydrogen chloride (100 ml each). Solid sodium bisulfite was added to decolorize the solution and the layers were separated. The aqueous layer was washed with ethyl acetate (2×50 ml). The combined organic layers were washed with 1M HCl (3×50 ml) and brine (2×50 ml), dried, filtered and evaporated to give a syrup which foamed at high vacuum from dichloromethane to yield methyl 2-(N-cyclohexyl-4-(3-carboxy-4-nitrophenyl)oxybutyramidyl)acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]P(=O)(OCC)OCC)[CH:2]=1.C(O[K])(C)(C)C.[CH:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=2)[NH:26][N:25]=1)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:22]/[C:24]2[C:32]3[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=3)[NH:26][N:25]=2)[CH:2]=1
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Agent: CC(C)(C)O[K]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 67 %

Procedure:
Diethyl pyridin-3-ylmethylphosphonate was redissolved in DMF (50 mL), cooled to 0° C. and treated with tBuOK (6.72 g, 60 mmol) portion wise over 3 min; the reaction turned a dark reddish brown. After stirring for 3 min at 0° C., a solution of 3-formyl-1H-indazole-6-carbonitrile (3.42 g, 20 mmol) in DMF (25 mL) was added dropwise by pipette over 5 min. After addition, the resulting mixture was stirred for 1 h at 0° C. before quenching with ice (100 mL). The reaction mixture was cooled to 0° C. and slowly acidified with 2M HCl until pH 5. During this addition, a copious amount of precipitate was formed. After stirring for 2 min at this temperature, sat NaHCO3 was added slowly until pH 8 and the mixture was stirred for an additional 2 min. Water was added until the total volume reached 600 mL. After stirring for 10 min, the resulting precipitate was collected by suction filtration and rinsed thoroughly with water, then dried under high vacuum to give the title compound (3.30 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H, NH), 8.89 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 4.42 (d, J=8.4 Hz, 1H), 8.22-8.17 (m, 2H), 7.74 (d, J=16.8 Hz, 1H), 7.59 (d, J=18.0 Hz, 1H, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J=10.0 Hz, 1H, partially overlapping with the doublet at 7.59 ppm), 7.43 (dd, J=8.0 Hz, 5.6 Hz, 1H); MS ESI 247.0 [M+H]+, calcd for [C15H10N4+H]+ 247.1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[H][H]>[Pd]>[CH:3]([OH:4])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Product: OC(C(F)(F)F)C(F)(F)F
Yield: 90 %

Procedure:
Approximately 100cc of Pd/C catalyst is packed into a ½″ diameter pipe reactor. Approximately 1 g/min of the hexafluoroacetone and 500cc/min hydrogen gas is fed into the reactor at atmospheric pressure and 180° C. Hexafluoro-2-propanol is produced in greater than 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:19](O)=O>O1CCCC1>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=3)=[CH:3][C:2]=2[N:1]=[CH:19]1
Reactant: CC(O)c1ccc(Oc2ccc(N)c(N)c2)cc1
Reactant: O=CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(Oc2ccc3[nH]cnc3c2)cc1

Procedure:
Crude 1-{4-[(3,4-diaminophenyl)oxy]phenyl}ethanol was dissolved in 10 mL of tetrahydrofuran and 5 mL of 88% formic acid and heated at 100 degrees Centigrade for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and saturated NaHCO3. The organic layer was separated and washed twice with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in 10 mL of THF and heated at 100 degrees centigrade with 5 mL of aqueous 10% LiOH for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated to give crude 1-[4-(1H-benzimidazol-5-yloxy)phenyl]ethanol, which was carried on crude to the next step without further purification. (M+1) 239.0, 1.39 min (LC/MS method B)
Reaction SMILES: CN(C)C([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[N:7]=[CH:6]1)=O.Br[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][N:22]=1.C[O-].[Na+]>C(#N)C.CO>[OH:13][CH2:12][CH2:11][CH2:10][C:8]1[N:7]([CH2:20][C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][N:22]=2)[CH:6]=[N:5][CH:9]=1
Reactant: BrCc1noc2ccccc12
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: OCCCc1cncn1Cc1noc2ccccc12
Reaction time: 3 h

Procedure:
A solution containing 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl)-imidazole (6.7 g, 0.025 mole), and 3-bromomethyl-1,2-benzisoxazole (5.3 g, 0.025 mole) in anhydrous acetonitrile (30 mL) is stirred at reflux for 72 hours. The reaction mixture is cooled and mixed with a solution of sodium methoxide (3 g, 0.055 mole) in methanol (30 mL). The resulting solution is stirred at reflux for 26 hours. The solvents are evaporated and the residue is taken up in 1N hydrochloric acid (30 mL). This solution is allowed to stand at ambient temperature for 3 hours and is then made basic (pH 9) by addition of 50% aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride (2×25 mL) and the combined extracts are washed with water (2×20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give crude 3-[(5-(3-hydroxypropyl)-1H-imidazol-1-yl)methyl]-1,2-benzisoxazole which is purified by trituration with acetone (15 mL), m.p. 129°-131° C. The compound forms a hydrochloride hemihydrate, m.p. 155°-157° C. when its solution in isopropanol is treated with ethereal hydrogen chloride.
Reaction SMILES: C([O:8]C1C=CC(C(=O)C)=CC=1CO)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH:35]=[O:8])=[O:36])=[CH:30][C:29]=1[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cc(C(=O)C=O)ccc1OCc1ccccc1

Procedure:
The compound was sbtained as an ethanol hemiacetal, mp 125°-128° (ethanol-water) by the process of Description 54 replacing 1-(4-benzyloxy-3-hydroxymethylphenyl)ethanone by 1-(4-benzyloxy-3-methanesulphonamidophenyl)ethanone. (CDCl3) 8.75 (3H, t, J=6 Hz), 7.05 (3H, s), 5.90-6.40 (2H, m), 4.90 (1H, b), 4.80 (2H, s), 4.46 (1H, s), 2.90 (1H, d, J=8 Hz), 2.60 (5H, s), 2.20 (1H, s), 2.09 (1H, dd, J=8 Hz, 2 Hz), 1.80 (1H, d, J=2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A mixture of fluorobenzene (104.4 g, 1.09 mol, Aldrich) and succinic anhydride (93.5 g, 0.93 mol) in 1,2-dichlorobenzene (530 mL) was heated to 50° C. Aluminum chloride (245 g, 1.84 mol) was added portionwise keeping the temperature below 60° C. After 4 h at 60° C. followed by 5 h at 80° C., the reaction mixture was poured into a mixture of concentrated HCl (200 mL) and ice water (2 L). The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried and concentrated in vacuo. The residue was poured into hexane (2 L) and the resulting solid was filtered and washed with pentane to give 164.1 g (89%) of 3-(4-fluorobenzoyl)propionic acid as a white solid. m.p., 102-104.5° C. (lit J. Org. Chem. 26, 2667, 1961; m.p., 102.5-103.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31]CNC[CH2:27]2)=[N:18]1.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10]2[CH2:12][CH2:27][N:26]([C:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:17][N:18]=3)[CH2:31][CH2:11]2)[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c(C=CN2CCN(c3nsc4ccccc34)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dichloro-4-(2-dimethylaminoethenyl)-nitrobenzene (15 g, 0.057 mol) and 4-(1,2-benzisothiazol-3-yl)-piperazine (18.9 g, 0.086 mol) were combined in acetic acid (150 ml) and stirred overnight at room temperature under a nitrogen atmosphere. The slurry was poured slowly into a mixture of hexanes (300 ml) and isopropanol (300 ml) with stirring. The product was isolated by filtration as a brick red solid and washed with hexanes. The yield was 23.4 g, 93%; mp 194°-5° C. NMR (CDCl3) δ 8.05 (s, 1), 7.95-7.80 (m, 2), 7.56-7.35 (m, 3), 7.01 (d, 1), 5.60 (d, 1), 3.95-3.46 (m, 8). Analysis Calculated for C19H16N4O2Cl2S: C, 52.41; H, 3.70; N, 12.87. Found: C, 52.05; H, 3.36; N, 12.58.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>C(N(CC)CC)C>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 4.17 g. (0.01 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide is treated with 2 ml. of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol. of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([F:34])=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:34][C:5](=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[C:19]([CH:26]([CH3:27])[CH3:28])[C:18]=3[O:29][CH2:30][CH:31]([F:32])[F:33])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(F)=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=C(F)C(=O)O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 2-Fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid was isolated as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.1 Hz, 1H, Ar—H), 7.58 (d, J=7.3 Hz, 1H, Ar—H), 7.41 (d, J=3.0 Hz, 1H, furan-H), 7.34 (t, J=7.6 Hz, 1H, Ar—H), 7.31 (d, J=2.2 Hz, 1H, Ar—H), 7.17 (d, J=2.2 Hz, 1H, Ar—H), 5.52 (tt, J=55.2 Hz, J=4.1 Hz, 1H, O—CH2—CF2H), 3.52 (dt, J=13.6 Hz, J=4.1 Hz, 2H, O—CH2—CF2H), 3.41 (m, 1H, CH3—CH—CH3), 2.95 (m, 1H, CH3—CH—CH3), 2.56 (d, J=3.5 Hz, 3H, C═C—CH3), 1.31 (d, J=6.7 Hz, 6H, CH3—CH—CH3), 1.29 (d, J=6.8 Hz, 6H, CH3—CH—CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13](OS(C)(=O)=O)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:36][CH2:35]3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1nnn(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(C)c2nnn(-c3cccc(Cl)c3)n2)CC1
Yield: 37 %

Procedure:
The title compound (12.3 mg, 37%, yellow oil) was prepared from methyl sulfonic acid 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (27.7 mg, 0.091 mmol) using potassium carbonate (13.8 mg, 0.100 mmol) and 1-ethoxycarbonyl piperazine (13.3 uL, 0.091 mmol) in acetonitrile (4 mL) at 80° C. overnight. The product was purified was by chromatography using a silica SPE tube (10% MeOH/CH2Cl2) followed by a second chromatography using a silica SPE tube (5% MeOH/CH2Cl2). 1H NMR (CDCl3) δ (ppm): 8.17 (s, 1H), 8.07 (dt, 1H), 7.50 (m, 2H), 4.29 (q, 1H), 4.10 (q, 2H), 3.52 (m, 4H), 2.56 (m, 4H), 1.64 (d, 3H), 1.24 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[F:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([F:23])[CH2:29][CH2:28]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCC(F)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCC(F)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(4-fluoro-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as an orange solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[NH:27][C:28]([CH:30]1[CH2:32][CH2:31]1)=[NH:29]>>[CH:30]1([C:28]2[N:29]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][S:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:27]=2)[CH2:32][CH2:31]1
Reactant: N=C(NO)C1CC1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 91 mg (0.91 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 141 mg (40% of theory)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]#[N:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC#N)ccc3o2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4Cc4nnn[nH]4)ccc3o2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-cyanomethylphenylmethoxy)benzofuran-2-yl]thiazole (0.40 g), sodium azide (0.58 g) and ammonium chloride (0.66 g) in N,N-dimethylformamide (4 ml) was stirred at 110° C. for 8 hours. After being cooled, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with chloroform, successively with a mixture of chloroform and methanol (10:1). The fractions containing object compound were combined and concentrated under reduced pressure to give 5-{2-(2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxymethyl]phenylmethyl}-1H-tetrazole (0.21 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C([N:14](CC)CC)C.O>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH2:6])=[O:4].[Br:1][CH2:2][C:3]([NH2:14])=[O:4].[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CCN(CC)CC
Reactant: O=C(Br)CBr
Agent: C1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)CBr
Temperature: -15 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a 1 L three-necked flask equipped with a magnetic stir bar, reflux condenser and addition funnel, was added bromo acetyl bromide (82.8 g, 0.41 mole) in CHCl3 (170 mL). The addition funnel was charged with a solution of piperazine (0.2 mole, 17.2 g) and triethylamine (70 mL) in CHCl3 (180 mL). The flask was chilled to -15° C. by means of a CH3CN/liquid N2 bath, and the amine was slowly added to the acid bromide. After the addition was complete the mixture was allowed to warm to ambient temperature and was stirred for 1 hour. The flask was then cooled to 0° C. and H2O (100 mL) was slowly added. The mixture was diluted with CHCl3 (500 mL) and the layers were separated. The organic layer was extracted with H2O (5×50 mL), 0.05N NaOH (5×50 mL) and H2O (200 mL), and dried (Na2SO4). The dark orange solution was filtered and concentrated to a beige solid. The material was purified by filtration through a bed of silica gel. The product eluted with 2-5% methanol/CH2Cl2. After combining and concentrating the desired fractions, 15.0 g (49.2%) of a white solid was obtained. The title product was recrystallized from warm 2-propanol (400 mL) affording 9.95 g. 1H NMR (CDCl3): δ 3.61 (dt, 6 H), 3.85 (s, 4 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]1>CN(C=O)C>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:22][O:21]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C=O)cc2)O1
Temperature: 150 °C

Procedure:
1.79 g (14.6 mmol) of p-hydroxybenzaldehyde are dissolved in absolute DMF (10 ml), and 14.2 g (102.5 mmol) of potassium carbonate and 3.3 g (22.0 mmol) of (R)-(+)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane are added. The mixture is heated at 150° C. for 24 h. The mixture is then concentrated using a rotary evaporator, and the residue is partitioned between dichloromethane and water. The combined organic phases are extracted with dichloromethane (three times, 20 ml each), washed with sat. sodium chloride solution and dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5:1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13]C1C=CC([N+]([O-])=O)=C(O)C=1.CI>>[F:13][C:7]1[CH:2]=[CH:3][C:4]([O:11][CH3:12])=[C:5]([CH:6]=1)[NH2:8]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Solvent: CI
Product: COc1ccc(F)cc1N
Yield: 98 %

Procedure:
Reduction of 1-fluoro-3-methoxy-4-nitrobenzene (0.11 mol) (prepared by methylation of 5-fluoro-2-nitrophenol with methyl iodide was carried out according to Step (b) of Example XII to provide 14.8 g (98% yield) of 5-fluoro-2-methoxyaniline used without further purification.