Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C:23]([OH:25])=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([C:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][N:14]=3)=[O:25])[CH2:39][CH2:40]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1nccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1nccc2ccccc12)N1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.9 g of 1,1′-carbonyldiimidazole is added to a solution of 1 g of isoquinoline-1-carboxylic acid in 100 ml of tetrahydrofuran (THF), and the mixture is stirred at room temperature for 2 hours. 1.6 g of 1-[2-(4-fluorophenyl)ethyl]piperazine and 2.4 ml of triethylamine are added to this mixture, which is stirred for a further 80 hours. ConventionaL work-up gives {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-1-ylmethanone.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.ClC(OCC(C)C)=O>CN(C=O)C.O>[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1nc2cnccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1nc2cnccc2s1
Temperature: 60 °C
Yield: 16.2 %

Procedure:
A mixture of 2-aminothiazolo[4,5-c]pyridine (530 mg, 3.5 mmole), 2.0 ml of N,O-bistrimethylsilylacetamide (BSA) and 7 ml of dimethylformamide was heated at 60° C. with stirring. The resulting clear solution was added to the chilled mixed anhydride solution which was prepared from N-t-butyloxycarbonyl glycine (700 mg, 4 mmoles), triethylamine (404 mg, 4 mmoles) and isobutyl chloroformate (546 mg, 4 mmoles) in 10 ml of dry DMF at -10° C. The reaction mixture was stirred 2 days at room temperature and then diluted with water and extracted with 450 ml of ethyl acetate. The extracts were combined, evaporated and triturated with chloroform to give 175 mg of the title compound. Additional product (155 mg) was obtained from the mother liquor. Total yield was 330 mg (30%), which was recrystallized from CH3OH. Mp. 204°~208° C. (dec.).
Reaction SMILES: [Na].CC[O-].[Na+].[CH3:6][NH:7][C:8]([NH:12][CH2:13][CH2:14][SH:15])=[N:9][C:10]#[N:11].Cl.[CH3:17][N:18]([CH2:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26]Cl)[N:25]=1)[CH3:19]>C(O)C>[CH3:6][NH:7][C:8]([NH:12][CH2:13][CH2:14][S:15][CH2:26][C:24]1[N:25]=[C:21]([CH2:20][N:18]([CH3:19])[CH3:17])[S:22][CH:23]=1)=[N:9][C:10]#[N:11]
Reactant: CNC(=NC#N)NCCS
Reactant: CN(C)Cc1nc(CCl)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
About 0.6 g of sodium were added to 50 ml. of dry ethanol under an N2 atmosphere, thus forming sodium ethylate in ethanol. 0.91 g of N-methyl-N'-(2-mercapto)ethyl-N"-cyanoguanidine (prepared by the procedure of U.S. Pat. No. 4,093,621) dissolved in 10 ml. of anhydrous ethanol was added thereto and the resulting mixture stirred at room temperature for about 1 hour. Next, 1.59 g of 2-dimethylaminomethyl-4-thiazolylmethylchloride hydrochloride was added thereto in portions over a 1 hour period. After the addition had been completed, the reaction mixture was stirred for an hour at room temperature and was then heated to refluxing temperature for an additional hour. The ethanol was removed from the reaction mixture by evaporation and ethyl acetate plus water (10:1) were added to the residue. The pH of the aqueous phase was adjusted to pH=8 with 1N aqueous hydrochloric acid. The ethyl acetate extract was separated and the ethyl acetate removed by evaporation. The residue was subjected to high pressure liquid chromatography (silica-20:80 ethanol/ethyl acetate). Fractions containing the desired product as shown by tlc were combined and the solvent evaporated therefrom. 1.10 g of N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine were obtained. The physical properties were substantially identical with those obtained in Example 4 for the same compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH:24]=[N:23][C:22]3[C:21](=[O:25])[NH:20][C:19]([NH2:26])=[N:18][C:17]2=3)[CH:10]=1>C(O)(=O)C>[Br:1][C:24]1[N:16]([CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:17]2[N:18]=[C:19]([NH2:26])[NH:20][C:21](=[O:25])[C:22]=2[N:23]=1
Reactant: Nc1nc2c(ncn2Cc2cccnc2)c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Nc1nc2c(nc(Br)n2Cc2cccnc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-Bromosuccinimide (1.59 g; 8.95 mmol) was added to a suspension of 9-[(3-pyridyl)methyl]guanine (2.0 g; 8.14 mmol) in glacial acetic acid (20ml) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water and filtered. The crude product was triturated with water, filtered, and washed with water and dried. Yield 1.91 g; mp>300° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)C.[CH2:17]([O:24]C(CO)CO)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH:16]1[CH2:1][O:3][CH:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[O:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(COc1cccc(Cl)c1)OCC
Reactant: OCC(CO)OCc1ccccc1
Product: Clc1cccc(OCC2OCC(OCc3ccccc3)CO2)c1

Procedure:
Using the procedure of Example 47, (3-chlorophenoxy)acetaldehyde diethyl acetal and 2-benzyloxy-1,3-propanediol were reacted to give 5-benzyloxy-2-(3-chlorophenoxymethyl)-1,3-dioxane, nD25 1.5587. The ir spectrum was consistent with the assigned structure. The nmr spectrum indicated 40% cis isomer and 60% trans isomer.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.Cl>C(OCC)C>[Cl:9][C:5]1[CH:4]=[C:3]([C:13]2([OH:17])[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]2)[CH:8]=[CH:7][CH:6]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC1CCCC(=O)C1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC1CCCC(O)(c2cccc(Cl)c2)C1
Temperature: 0 °C
Yield: 42.8 %

Procedure:
For example, magnesium turnings (6.4 g, 0.26 mole) were flame-dried, the containing glassware was cooled, and 3-bromochlorobenzene (50 g, 0.26 mole), in 50 ml of diethyl ether was added. As the reaction began, an additional 200 ml of diethyl ether was added, and the reaction mixture was heated under reflux for 0.5 hour. To the refluxing reaction mixture was added dropwise, during a 0.5 hour period, 3-methylcyclohexanone (29.2 g, 0.26 mole) in 100 ml of diethyl ether. Upon complete addition, the reaction mixture was heated under reflux for an additional 0.5 hour, then poured into 500 ml of ice-water containing 50 ml of hydrochloric acid. The mixture was extracted with three 200 ml portions of diethyl ether. The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride. After separation, the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to an oil. The oil was purified by distillation using a Kugelrohr distilling system at 85°/0.05 mm for 2.5 hours to give 1-(3-chlorophenyl)-3-methylcyclohexan-1-ol (25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20].C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([C:7]2[C:6]3[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(Cl)ccc1S2
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1

Procedure:
111.4 G. of 8-chloro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one in 1 l. of absolute benzene are mixed together with 268 ml. of carbethoxypiperazine and within 1 hour at 20°-25° with a solution of 65 ml. of titanium tetrachloride in 500 ml. of absolute benzene. The resulting reaction mixture thereafter is heated under reflux conditions over a period of 20 hours. The reaction mixture is then poured over a mixture of 500 ml. of saturated aqueous sodium bicarbonate solution and 700 ml. of water with strong stirring, subsequently filtered, and washed again with chloroform. After an equilibrium is reached between both phases, the organic phase is dried and evaporated, whereby there is obtained 1-carbethoxy-4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine as a dark brown viscous oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3,4-dichlorobenzenesulfonyl chloride (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 3,4-dichloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: O[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.C1(=O)[O:20][CH2:19][CH2:18][O:17]1>C(N(CC)CC)C>[OH:17][CH2:18][CH2:19][O:20][C:3]1[C:4]2[C:5](=[O:15])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:2]=1
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: O=C1OCCO1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2-c2cccc(OCCO)c21
Yield: 63 %

Procedure:
Following the procedure described in Example 29, 2-hydroxyfluoren-9-one (Aldrich) was reacted with ethylene carbonate and triethylamine to obtain 2-hydroxyethoxyfluoren-9-one (63% yield), with a melting point of 118-119° C. The title compound, with a melting point of 131.5-133° C., was obtained in 96% yield by the previously described DBU-catalyzed reaction with VDM in heptane.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:16]=[O:17])[C@@H:12]([CH3:15])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Si]([C:22]([F:25])([F:24])[F:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:16]([OH:17])[C:22]([F:25])([F:24])[F:23])[C@@H:12]([CH3:15])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 5-chlorothiophene-2-sulfonyl isoleucinal (770 mg, 2.6 mmol, see Example 118, parts 1&2) in THF (5 mL) was added TMS-CF3 (5 mL, 0.5M in THF). The resulting mixture was treated with TBAF (250 μL, 1M in THF). The cold bath was removed and the reaction was stirred at 25° C. overnight. The reaction was quenched with HCl (25 mL, 2M) and the resulting solution was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL) then dried over MgSO4. The residue was submitted to RP-HPLC (see example 155 for procedure) to give 74 mg of the desired product (m/z=364.0 (M−H), rt=1.23 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:27]([NH:29][CH2:30][CH2:31][O:32][CH3:33])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([O-:34])=[C:14]([C:27]([NH:29][CH2:30][CH2:31][O:32][CH3:33])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[Na+:36]
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2nccn2C)c1=O
Agent: [Na+]
Agent: [OH-]
Product: COCCNC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(Cc2nccn2C)c1=O
Yield: 89 %

Procedure:
In a manner similar to that described in example 474, from 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[(1-methyl-1H-imidazol-2-yl)methyl]-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (506 mg, 1.09 mmol described in example 467) and 1 N sodium hydroxide (1.06 mL) was prepared sodium 7-[(4-fluorophenyl)methyl]-1-[(1-methyl-1H-imidazol-2-yl)methyl]-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (473 mg, 89% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.72 (s, 1 H), 8.14 (s, 1 H), 7.92 (s, 1 H), 7.27-7.23 (m, 2 H), 7.08-7.03 (m, 2 H), 6.96 (s, 1 H), 6.71 (s, 1 H), 5.34 (s, 2 H), 3.94 (s, 2 H), 3.59 (s, 3 H), 3.38-3.33 (m, 4 H), 3.23 (s, 3 H); MS m/z 466 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:22]=O>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:22][C:21]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:19]([Cl:18])[CH:20]=3)[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CC(C)(CNc1ccnc2cc(Cl)ccc12)NCc1ccc(Cl)c(Cl)c1

Procedure:
1.25 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.88 g of 3,4-dichlorobenzaldehyde were heated under reflux in 10 ml of ethanol for 3 hours. In order to complete the reaction, the solvent was evaporated in a vacuum. The resulting Schiff's base was again taken up in 20 ml of ethanol and reduced to the amine by the addition of 0.19 g of sodium borohydride. Excess reducing agent was decomposed after 2 hours by the addition of 10 ml of glacial acetic acid. The turbid solution was then evaporated on a rotary evaporator. 10 ml of methanol were added to the residue and the mixture was again evaporated. Addition of methanol and evaporation were repeated twice. The evaporation residue was then taken up in 25 ml of water. The pH was adjusted to 10 by the addition of dilute sodium hydroxide solution, separating the product. The product was purified by recrystallization from 45 ml of ethyl acetate. Yield: 1.09 g (53%), m.p. 178-179° C.
Reaction SMILES: C([NH:5][C:6]([C:8]1[C:9]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)(=[O:22])=[O:21])=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1)=O)(C)(C)C.S(Cl)(Cl)=O>>[Cl:14][C:11]1[N:10]=[C:9]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)(=[O:22])=[O:21])[C:8]([C:6]#[N:5])=[CH:13][N:12]=1
Reactant: CC(C)(C)NC(=O)c1cnc(Cl)nc1NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: N#Cc1cnc(Cl)nc1NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
125 mg (0.27 mmol) of 2-chloro-4-[3-(3-nitro-benzenesulfonylamino)-propylamino]-pyrimidine-5-carboxylic acid-tert-butylamide is mixed with 4 ml of thionyl chloride and stirred under reflux for 19 hours. The reaction mixture is concentrated by evaporation. It is mixed with water and toluene and evaporated to the dry state in a rotary evaporator. 110 mg (0.27 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:42])[CH2:20]3)=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:33][CH:34]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCNC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCN(C(=O)c3ccccc3)C2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 542 and benzoyl chloride, and by the reaction and purification in the same manner as in Example 39, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[CH:22][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](C(=O)C)=[CH:14][C:13]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=[C:30]([C:35]([O:37]O)=[O:36])C=1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[C:35]([O:37][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:24]([CH2:26][CH3:27])=[CH:25][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:21])[CH:14]=1)(=[O:36])[CH3:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(OC(C)=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
To a solution of 1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone (3 g, 8.24 mmol) in dry dichloromethane (30 ml), was added PTSA (0.047 g,0.247 mmol). The reaction mixture was cooled in an ice bath and mCPBA (50% H2O) (2.84 g, 8.24 mmol) was added portionwise. The resulting mixture was stirred at RT for 3 days, then concentrated at 35-40 C. The residue was purified by column chromatography, (pet ether:EtOAC). The resulting solid was dissolved in pet ether, filtered then concentrated the yield the title compound (1.6 g; 51%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[CH:23][C:22]=2[F:30])=[CH:18][C:17]=1[F:33]>CN(C=O)C>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([CH2:28][O:29][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:23][C:22]=2[F:30])=[CH:18][C:17]=1[F:33]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(Cl)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and (4-(4-chloro-3-fluorophenoxy)-3,5-difluorophenyl)methanol (78 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: C(O[C:4]([CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=[O:5])C.[CH2:26]([NH2:28])[CH3:27]>CO>[CH2:26]([NH:28][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=[O:5])[CH3:27]
Reactant: CCOC(=O)C1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a stirred solution of 3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 69, within Step 6, 108 mg, 0.31 mmol) in MeOH (1 mL) is added EtNH2 (2 mL, 4.0 mmol, 2.0 M solution in THF). The reaction mixture is stirred for 1 h at room temperature. Solvent is removed and the residue purified by column chromatography (10% MeOH/CH2Cl2) to give the title compound as a pale yellow solid (100 mg, 93%), 1H NMR (300 MHz, DMSO) δ 8.46 (t, 1H), 7.65-7.38 (m, 4H), 5.05 (dd, 1H), 4.99 (d, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.87 (t, 2H), 3.20-3.10 (m, 2H), 1.04 (t, 3H); MS for C17H18FN3O4 m/z 348.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>CCCCCC>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][C:21]([NH:20][CH:17]([CH3:19])[CH3:18])=[O:22])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCCCCC
Product: CC(C)NC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 63 %

Procedure:
A mixture of 14 g (0.06 mole) of 2-amino-5-chlorobenzophenone and 40 ml of isopropyl isocyanate was refluxed for 3 hrs. The solid that formed was suspended in 25 ml of hexane, and then collected on a filter and recrystallized from ethanol to give 12.0 g (63%) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea as colorless needles: mp 190°-192°; 1H nmr (CDDl3) δ1.19 ppm (d, J=6 Hz, 6H), 3.98 ppm (m, 1H), 4.95 ppm (m, NH), 7.2-7.8 ppm (m, 7H), 8.5 ppm (d, J=10 Hz, 1H) and 10.1 ppm (NH); 13C nmr (DMSO-d6) δ195.4 ppm (C=O) and 153.9 ppm (NHCO).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]([C:34]2[C:42]([F:43])=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=2[F:44])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:45].O1CCOCC1>>[ClH:45].[F:43][C:42]1[CH:41]=[C:37]([CH:36]=[C:35]([F:44])[C:34]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:23]1)[C:38]([OH:40])=[O:39]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 127 mg of 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoic acid was added 3.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue were added THF, isopropanol, and diisopropylether, and the precipitated solid was isolated by filtration, and dried under reduced pressure to obtain 78 mg of 3,5-difluoro-4-[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]benzoic acid hydrochloride as a pale pink solid.