Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]2[N:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=[C:21]2[CH:20]1[CH2:32]OS(C)(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]2[N:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=[C:21]2[CH:20]1[CH2:32][N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COS(C)(=O)=O
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1Cn1cnnc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
To a solution of 47 mg (0.683 mmol) of [1,2,4]triazole in 1.0 mL of DMF was added 189 mg (1.365 mmol) of potassium carbonate. The mixture was heated at 50° C. for 15 min. To this was added 182 mg (0.455 mmol) of 7-N-(tert-butoxycarbonyl)-8-(methanesulfonyloxymethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine. The mixture was stirred at 50° C. for 14 h. DMF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with three portions of ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated to give 107 mg of an orange oil. The mixture was eluted on a preparative TLC plate (silica gel, 50% ethyl acetate/hexane). The plate was scraped and the product eluted from the silica gel with 80:15:1 chloroform/methanol/ammonium hydroxide to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4].Cl.[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Cl)[CH3:23]>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH2:23][CH2:22][N:24]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4]
Reactant: CNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCn1c(C(=O)NC)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 70 °C

Procedure:
According to the procedure described in Example 1, 28.5 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid methylamide are treated with 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is heated at 70° C. for 5 hours, then cooled and poured into 4 liters of ice-water. After the addition of 200 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is digested with ether, removed by filtration and washed with ether, and there is obtained a first portion of crude 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide having a melting point of 187°-190° C. The ethereal filtrate is extracted with 1-N sulfuric acid and the acidic extract is made alkaline at 0°-5° C. with concentrated ammonia solution. Then, the separated oil is extracted with methylene chloride and the solution dried over sodium sulfate. After evaporation, there is obtained an oil which crystallizes from ether, and is obtained as a second portion of reaction product; melting point 187°-190° C. Both portions of the reaction product are recrystallized together from ethanol, and 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide is obtained in the form of colorless needles having a melting point of 190°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)[NH:9][C:5]=2[C:4]=1[S:24]([C:27]1[C:38]([CH3:39])=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=1[CH3:40])(=[O:26])=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:46]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:46])[NH:9][C:5]=2[C:4]=1[S:24]([C:27]1[C:28]([CH3:40])=[CH:29][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=1[CH3:39])(=[O:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(SCc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(S(=O)Cc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Reaction time: 16 h

Procedure:
Solutions of methyl {4-[(5-methoxy-2{[4-methoxy,3,5-dimethyl(2-pyridyl)methyl]thio}benzimidazolyl)sulfonyl]-3,5-dimethylphenoxy}acetate (Intermediate A5, 7.1 g, 0.12 mol) in 100 mL of tetrahydrofuran and 3-chloroperoxybenzoic acid (2.6 g, 0.15 mol) in 20 mL of the same solvent were cooled in a freezer for 1 hr and then mixed. The solution was left in the freezer for about 16 hr, diluted with ethyl acetate, and washed with several portions each of 5% sodium metabisulfite, 5% sodium bicarbonate, and saturated sodium chloride. The organic phase was concentrated and then purified on flash silica gel (hexanes→ethyl acetate→1% methanol in ethyl acetate). The title compound recovered weighed 3.3 g (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:18])[CH:8]=1.[H-].[Na+].[CH:25](I)([CH3:27])[CH3:26].[Na+].[Cl-]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[C:12]([O:17][CH:25]([CH3:27])[CH3:26])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:18])[CH:8]=1
Reactant: CC(C)I
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(O)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OC(C)C)c2n1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
4-(3,4-Dichlorobenzylamino)-2-methylquinolin-8-ol (example 41, 70.0 mg, 0.210 mmole) was suspended in dimethylformamide (5 mL) and mixed with sodium hydride (60% in paraffin liq., 9.24 mg). After stirring for 30 min isopropyliodide (37.5 mg, 0.221 mmole) was added dropwise and the mixture was kept under stirring at RT for 16 hrs. Diluted NaCl solution was added and the mixture was extracted with ethyl acetate. The organic phases were dried and concentrated and the residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 90:10. Precipitation in Isopropanol/iso-propyl ether/HCl gave a brownish salt (15 mg, 17%). ESI-MS [M+H]+=375.1/379.2 calculated for C20H20Cl2N2O=375 g/mole
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])[C:3]([OH:5])=[O:4].[C:15]([O-:18])([O-:17])=O.[Na+].[Na+].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O.O1CCOCC1>[CH:27]1[C:26]2[CH:25]([CH2:24][O:17][C:15]([NH:1][C@@H:2]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]([NH:14][C:21]([O:23][CH2:24][CH:25]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[C:11]([OH:13])=[O:12])[C:3]([OH:5])=[O:4])=[O:18])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Reactant: N[C@@H](C/C=C\C[C@H](N)C(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](C/C=C\C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S,S)-2,7-Diamino-Z-oct-4-enedioic acid (0.050 g, 0.25 mmol) and Na2CO3 (0.21 g, 20.0 mmol) were dissolved in 3 ml water and 2 ml dioxane. The solution was cooled to 0° C. and a solution of FmocCl (0.26 g, 1.0 mmol) in 1 ml dioxane was added. This mixture was stirred at 0° C. for 3 hours and came to ambient temperature overnight. After extraction with diethyl ether it was acidified by addition of hydrochloric acid. The solution was extracted with chloroform and the amino acid was crystallized from chloroform/hexane. The compound was further purified by flash chromatography (chloroform/acetic acid 9/1).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[F:39][C:40]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41]1.[H-].[Na+]>C(Cl)Cl.C(#N)C>[F:39][C:40]1([F:45])[CH2:44][CH2:43][N:42]([CH2:30][C:27]2[CH:28]=[CH:29][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=4)/[N:13]([C@H:14]4[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]4)[C:12]=3[CH:26]=2)[CH2:41]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(F)(F)C4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed at reduced pressure, and the residue was dried in vacuo for 5 minutes. The residue was resuspended in ACN (1 mL) and cooled to 0° C. A suspension of 3,3-difluoropyrrolidine hydrochloride (317 mg, 2.210 mmol) and sodium hydride (88 mg, 2.210 mmol) in ACN (1 mL) was added, and the reaction was stirred overnight at RT. The solvent was removed at reduced pressure, and the residue was redissolved in 2 mL of MeOH. The residual material was purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-N-(6-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (59 mg, 49.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 8.32 (s, 2H), 7.63 (brs, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.24 (brs, 2H), 7.15, (d, J=8.0 Hz, 1H), 4.87 (brs, 1H), 4.02-4.05 (m, 1H), 3.69 (s, 2H), 2.89 (t, J=13.1 Hz, 2H), 2.71-2.77 (m, 4H), 2.53 (brs, 1H), 2.27 (m, 2H), 2.12-2.15 (m, 2H), 1.62-1.73 (m, 4H), 1.10 (d, J=5.6 Hz, 6H). MS, m/z (C29H34F3N5O2): calcd, 541.3. found, 541.8 [M+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[O:23].Cl[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.Cl.ClCC1C=CC=CN=1>C(#N)C>[NH3:9].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([NH:24][C@H:25]1[CH2:29][CH2:28][N:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:26]1)=[O:23]
Reactant: O=C(N[C@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N
Product: O=C(N[C@H]1CCN(Cc2ccccn2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (0.052 g) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide (108.2 mg) [see Example 4] and 2-(chloromethyl)pyridine in acetonitrile (6.8 ml, 0.055M) at 0° C. [2-(Chloromethyl)pyridine was prepared from 2-(chloromethyl)pyridine hydrochloride by partitioning between diethyl ether and saturated aqueous sodium hydrogen carbonate solution. The separated organic phase was washed with brine, dried over magnesium sulphate and the solvent removed under reduced pressure. The residual free base was immediately dissolved in acetonitrile and used]. The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 93:7:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-(2-pyridinylmethyl)pyrrolidin-3-yl]-2-piperidinecarboxamide (63.1 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[NH:20][S:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH3:37].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:12]=1[N:20]([CH2:36][CH3:37])[S:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:23])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CS(=O)(=O)N(CC)c1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 0.387 g of ethyl [[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl]sulfamoyl]acetate in 5 mL of N,N-dimethylformamide were added 0.131 g of potassium carbonate and 0.169 g of ethyl iodide at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.342 g of ethyl [[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenyl](ethyl)sulfamoyl]acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])[N:15]=[CH:16][C:11]=2[CH:10]=1.[OH-].[Na+].C(O)(=O)C>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cccc(C(=O)O)c3)nc21

Procedure:
A quantity of 0.065 g (0.139 mmol) of 3-[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-benzoic acid, ethyl ester of Example 89 was dissolved in 75 mL of boiling methanol. 2N Sodium hydroxide (2 mL) was added, and the clear solution was maintained at reflux for 2 hours. The solution was concentrated with stirring to ca. 15 mL volume. The turbid solution was filtered hot to remove traces of solid. The filtrate was concentrated to ca. 4 mL volume. Water (5 mL) was added to give a turbid mixture. Glacial acetic acid (1 mL) was added to precipitate a flocculent solid. The solid was filtered, washed well with water, and dried; wt 0.048 g. Purification was accomplished by dissolution in 4 mL of warm dimethylformamide and addition of 20 mL of ether, The crystals that slowly separated from the clear solution were filtered and washed with ether and then water (to remove any traces of sodium acetate); wt 0.025 g; mp >300° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O1[C:19]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20]2)[O:18]CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CC(C)=O.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([N:21]3[CH2:22][CH2:23][C:19](=[O:18])[CH2:20]3)=[CH:25][CH:26]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2CCC3(C2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(=O)C3)cc2)cc1

Procedure:
4-Butoxybenzoic acid was reacted with 4-(1,4-dioxa-7-azaspiro[4,4]non-7-yl)phenylamine by method E. The resulting amide (0.25 g) in acetone (10 ml) was mixed with para-toluenesulfonic acid (monohydrate, 109 mg), and the mixture was refluxed for 8 hours. After addition of triethylamine (0.5 ml), the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 352.44 (C21H24N2O3); MS (ESI): 353 (M+H+) was obtained in this way.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[F:20])=[N:7][C:6]=2[CH:21]=1.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].C(CC(=O)C)(=O)C>CN1C(=O)CCC1.Cl[Cu]>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]4[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=4[F:20])=[N:7][C:6]=3[CH:21]=2)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3o2)c(F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)CC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(N4CCN(Cc5ccccc5)CC4)ccc3o2)c(F)c1
Temperature: 130 °C
Reaction time: 15 h
Yield: 40.7 %

Procedure:
Intermediate 28 (490 mg, 1.32 mmol), N-Benzylpiprazine (280 mg, 1.6 mmol), K2CO3 (190 mg, 1.4 mmol), CuCl (6.5 mg, 0.05 mmol), acetyl acetone (17 mg, 0.12 mmol) were dissolved in NMP (2 ml). This reaction mixture was stirred at 130° C. for 15 h under N2 atmosphere. Work up (EtOAc/H2O) followed by column purification on 60-120 mesh silica gel using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded 5-(4-benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole (250 mg) as a yellow solid. 5-(4-Benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole (130 mg, 0.28 mmol) dissolved in DCM (15 ml) and added isopropylchloro formate (102 mg, 0.84 mmol). This mixture was stirred at reflux for 18 h. Work up (DCM/H2O) followed by purification of the crude by column chromatography on 230-400 mesh silica gel using a gradient mixture of EtOAc and Petether (30:70) as eluent afforded the titled compound (25 mg) as a pale-yellow solid. M.P.: 231-234° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.28 (d, J 8.7, 1H), 7.96 (d, J 1.6, 1H), 7.68-7.64 (m, 2H), 7.57-7.47 (m, 2H), 4.95 (septet, J 6.2, 1H), 3.71-3.63 (m, 4H), 3.12-3.06 (m, 4H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1([S:15]([C:18](=[CH:23]OCC)[C:19](OC)=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[OH:20][C:19]1[C:5]2[C:3](=[C:2]([F:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:23][C:18]=1[S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccccc1
Reactant: Nc1ccccc1F
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(c1ccccc1)c1cnc2c(F)cccc2c1O
Temperature: 260 °C
Reaction time: 6 h
Yield: 3.3 %

Procedure:
2-Fluoroaniline 7(1) (3.82 g, 0.0344 mol) and methyl 2-phenylsulfonyl-3-ethoxy-acrylate 7(2) (9.59 g, 0.0355 mol) were mixed together in biphenyl ether (21.5 ml). The mixture was stirred in an opened flask for 6 h at 250-270° C. Ethanol was distilled during the first 30 min. After the reaction was completed (LCMS control) the mixture was cooled, the formed solid was filtered off, dissolved in ethanol and solution was boiled with charcoal. After filtration from charcoal ethanol was evaporated, the residue was subjected to chromatography on silica, eluent—gradient of solvent system CHCl3:ethyl acetate=from 10:1 to 5:1. The residue after evaporation of fractions, comprising the final product was washed with ether, it gave 345 mg (3.3%) of 4-hydroxy-3-phenylsulfonyl-8-fluoroquinoline 7(3).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[N:10]([CH2:41][CH:42]=[CH2:43])[C:11]1[C:16](=O)[N:15]2[C@H:18]([C:25](N(C(OC(C)(C)C)=O)C3C=CC=CC=3)=[O:26])[CH2:19][C@:20]([N:22]=[N+:23]=[N-:24])([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.[Li+].[OH-:48].[O-:49]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH2:41]([N:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:44])[C:11]1[C:16](=[O:48])[N:15]2[C@H:18]([C:25]([OH:49])=[O:26])[CH2:19][C@:20]([N:22]=[N+:23]=[N-:24])([CH3:21])[C:14]2=[N:13][CH:12]=1)[CH:42]=[CH2:43]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)N=[N+]=[N-]
Reactant: [OH-]
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)C[C@@]2(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
To a solution of 18e (480 mg, 0.800 mmol) in 10 mL THF/H2O (4:1) at 0° C., was added 30% H2O2 (1.28 mL, 11.3 mmol) and IN LiOH (1.28 mL, 1.28 mmol). The mixture was stirred at 0° C. of 45 min, then Na2SO3 (1.51 g, 12 mmol) was added. The mixture was stirred 30 min, then evaporated in vacuo. The residue was diluted with Et2O and extracted with 0.1 N NaOH (3×). The combined aqueous was acidified to pH 3 with conc. HCl, then was extracted with EtOAc (5×). The combined organic extract was washed with brine, dried (Na2SO4) and concentrated to afford 272 mg (80%) of a acid 18f, which was used in the following step with out further purification. MS (ESI) 447.3 (M+Na+), 423.2 (M−H+).
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:10]([O:24][Si](C(C)(C)C)(C)C)[C:9]=1[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33].[N:38]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[NH:38])=[C:10]([OH:24])[C:9]=1[S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34]
Reactant: N#CN
Reactant: N#CNC(=N)N
Reactant: Cc1ccccc1N=C=Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC(=N)N(C#N)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Yield: 32 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-methylphenyl)carbodiimide (400 mg, 0.83 mmol), cyanamide (139.4 mg, 3.32 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) were reacted, followed by desilylation with Cesium fluoride (152 mg, 1.0 mmol) to form the desired product (110 mg, 32%). EI-MS m/z 408.2 (M+). 1H NMR (DMSO-d6) δ 2.22 (s, 3H), 2.86 (s, 6H), 7.20 (m, 5H), 7.60 (d, 1H), 8.63(s, 1H), 8.96 (s, 1H), 10.50 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17]C1C=CC(N)=CC=1>>[F:17][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]2[OH:1]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Product: CCOC(=O)c1cnc2ccc(F)cc2c1O

Procedure:
The title compound was prepared following the procedure described in Step 1 for the synthesis of 2a using 4-fluoroaniline instead of aniline. 1H NMR (DMSO-d6) δ (ppm): 1.15 (3H, t, J=7.080 Hz), 4.1 (2H, q, J=7.08 Hz), 7.61 (1H, dd, J=8.30, 2.93 Hz), 7.68 (1H, dd, J=9.03, 4.63 Hz), 7.80 (1H, dd, J=9.27, 2.93 Hz), 8.56 (1H, s). m/z 236.5 (MH+).