Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]([CH3:16])[N:6]=[C:7]([O:13][CH2:14][CH3:15])[C@H:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:35][CH2:36]I>>[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:35][CH2:36][C@:5]1([CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[N:9][C@@H:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:13][CH2:14][CH3:15])=[N:6]1
Reactant: FC(F)(F)c1cccc(Sc2ccc(CCI)c(Cl)c2)c1
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1C
Product: CCOC1=N[C@](C)(CCc2ccc(Sc3cccc(C(F)(F)F)c3)cc2Cl)C(OCC)=N[C@H]1C(C)C

Procedure:
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and 2-chloro-1-(2-iodoethyl)-4-(3-trifluoromethylphenylthio)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>O1CCCC1.CCCCCC>[O:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([S:20]([Cl:23])(=[O:22])=[O:21])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1
Reactant: Brc1ccc(OC2CCOCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(Cl)c1ccc(OC2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2.8 g of 4-(4-Bromo-phenoxy)-tetrahydropyran in 75 mL of dry tetrahydrofuran was added 7.5 mL of n-butyllithium (1.6 N in hexane) at −78° C. After stirring at −78° C. for 2 hours the reaction mixture was allowed to warm to −40° C. and a solution of 4.1 mL of sulfuryl chloride in 75 mL of dry hexane was added within 15 minutes. Stirring was continued for 1 hour at −30° C. and subsequently for another hour at 5° C., The mixture was poured on ice, extracted with diethyl ether and the ether extract washed with cold water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=4/1) yielding 0.62 g of 4-(tetrahydropyran-4-yloxy)-benzenesulfonyl chloride as a colorless oil. EI-MS: 276 (M+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=[O:6])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:32]([O:35][CH:36]1[C:37]([OH:76])([CH3:75])[CH2:38][CH2:39][CH:40]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])[CH2:41][C:42]([O:44][CH:45](/[C:50](/[CH3:66])=[CH:51]/[CH:52]=[CH:53]/[CH:54]([CH3:65])[CH2:55][CH:56]2[O:64][CH:57]2[CH:58]([CH3:63])[CH:59](O)[CH2:60][CH3:61])[CH:46]([CH3:49])[CH:47]=[CH:48]1)=[O:43])(=[O:34])[CH3:33]>ClCCl.C(OCC)(=O)C>[C:32]([O:35][CH:36]1[C:37]([OH:76])([CH3:75])[CH2:38][CH2:39][CH:40]([O:67][Si:68]([C:71]([CH3:72])([CH3:73])[CH3:74])([CH3:69])[CH3:70])[CH2:41][C:42]([O:44][CH:45](/[C:50](/[CH3:66])=[CH:51]/[CH:52]=[CH:53]/[CH:54]([CH3:65])[CH2:55][CH:56]2[O:64][CH:57]2[CH:58]([CH3:63])[CH:59]([O:6][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH2:60][CH3:61])[CH:46]([CH3:49])[CH:47]=[CH:48]1)=[O:43])(=[O:34])[CH3:33]
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: CCOCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethoxyacetic acid (23 mg, 0.22 mmol), dicyclohexylcarbodiimide (55 mg, 0.27 mmol) and dimethylaminopyridine (5.4 mg, 0.27 mmol) were added to a solution of (8E,12E,14E)-7-acetoxy-3-t-butyldimethylsiloxy-6,21-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (29 mg, 0.044 mmol) in dichloromethane (3 mL) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (Kanto silica gel 60N, spherical, neutral, 40 to 100 μm, eluate; hexane:ethyl acetate=70:30) to obtain the title compound (28 mg, 85%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCCCC2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 409.25 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40]3[CH:41]=[N:42][CH:43]=[C:44]([CH:46]=[O:47])[CH:45]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:48][CH3:49])=[O:5])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=3)[C:22]([C:40]3[CH:41]=[N:42][CH:43]=[C:44]([CH2:46][OH:47])[CH:45]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:48][CH3:49])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3cncc(C=O)c3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3cncc(CO)c3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 1 h
Yield: 71 %

Procedure:
(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-formylpyridin-3-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (118 mg) is dissolved in tetrahydrofuran (1.5 ml), then thereto is added 1M-diisobutylaluminum hydride-tetrahydrofuran solution (0.33 ml) dropwise under ice-cooling and the mixture is stirred for 1 hours under nitrogen flow under ice-cooling. A aqueous saturated ammonium chloride solution is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=1:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-hydroxymethylpyridin-3-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (84 mg). MS (m/z): 691 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Product: Fc1ccc(Cn2cnc3c(N4CCOCC4)nc(Cl)nc32)cc1

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with 1-(bromomethyl)-4-fluorobenzene via General Procedure C to give 4-(2-chloro-9-(4-fluorobenzyl)-9H-purin-6-yl)morpholine which was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 50 mg of 142 as a white solid. MS (Q1) 406.2 (M)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH2:29]([N:37]([CH2:39]NC1C=CC=CC=1)[CH3:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:38][N:37]([CH2:39][C:9]1[CH:8]=[CH:7][C:12]([NH:4]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(CCc1ccccc1)CNc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CCc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and (N-phenethyl-N-methyl-aminomethyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/ethanol=10:1) C34H33N3O3
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>O1CCOCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=[CH:12][C:3]=1[CH:2]=[O:1]
Reactant: O
Reactant: Cc1cnc2ccccc2n1
Solvent: C1COCCO1
Product: O=Cc1cnc2ccccc2n1

Procedure:
To a solution of SeO2 (2.3 g, 20.9 mmol) and water (1 mL) in 1,4-dioxane (25 mL) at reflux was added 2-methylquinoxaline (2 g, 13.9 mmol) in 1,4-dioxane (4 mL). After refluxing for 4 h, the reaction mixture was filtered. The filtrate was concentrated and purified by column chromatography to give 500 mg of the desired product. LC-MS: m/z 159 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([CH2:13][C:14](OC)=[O:15])[C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Na]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[CH2:13][C:14]([OH:15])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]1=[O:12]
Reactant: COC(=O)CC(=O)N(CC(=O)OC)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)CN1CC(O)=C(C(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
196.5 g (0.75 mol) of N-(2-methoxycarbonylacetyl)iminodiacetic acid dimethyl ester dissolved in 200 ml of methanol are added dropwise to a solution of 17.1 g of sodium (0.75 mol) in 900 ml of methanol. The reaction mixture is then heated under reflux for 12 hours, cooled to room temperature and concentrated to dryness by evaporation under a water-jet vacuum. The yellowish residue is dissolved in 500 ml of water, filtered over a layer of diatomaceous earth and then 160 ml of semi-concentrated aqueous hydrochloric acid are added. After stirring for a further one hour the resulting crystals are filtered off, washed with acetone and dried. 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetic acid methyl ester is obtained having a melting point of 192° (decomposition).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:17][CH:18]([N:20]([CH3:22])[CH3:21])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CO.O>[C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:17][CH:18]([N:20]([CH3:21])[CH3:22])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CC(CCCCC(=O)O)(c1ccccc1)c1ccccc1)N(C)C
Yield: 20.9 %

Procedure:
Ethyl 6,6-diphenyl-8-dimethylaminononanoate (863 mg) was taken up in methanol (7 ml) and treated with 1M KOH in methanol (7.4 ml). The mixture was refluxed under Ar for 2.5 hours, and cooled. The pale yellow solution was concentrated to dryness to provide a clear pale yellow glass. The residue was taken up in H2O (2 ml) and treated dropwise with 1N HCl to pH 6. This solution was then evaporated to dryness and dissolved in 12 ml of methanol to yield a precipitate which was filtered. This procedure was repeated, using 8 ml of methanol, and the filtrates were evaporated to dryness. A 250 mg portion, dissolved in methanol (12 ml), was purified by PTLC. Development with 30% methanol/CHCl3 produced a major band (Rf range 0.12-0.31), which was scraped off the plate and eluted with methanol. The methanolic extracts were evaporated, and the residue was coevaporated twice with toluene (3 ml) to yield 167 mg of 6,6-diphenyl- 8-dimethylaminononanoic acid, as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(F)cc1F
Product: COc1ccc(-c2cc(Nc3ccc(F)cc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis-(4-methoxyphenyl)-6-chloropyridazine (264.2 mg, 0.809 mmol) and 2,4-difluoroaniline were reacted as starting materials at 100° C. for 12 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (328.8 mg, 97.0%). Melting point: 177.4-178.0° C. (chloroform-diethyl ether-hexane).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH3:9])[S:4][N:3]=1.S(=O)(=O)(O)[OH:11]>>[OH:1][C:2]1[C:6]([C:7](=[O:11])[NH2:8])=[C:5]([CH3:9])[S:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1snc(O)c1C#N
Product: Cc1snc(O)c1C(N)=O
Temperature: 113 °C

Procedure:
A mixture of 60 g of 3-hydrox-4-cyano-5-methyl-isothiazole and 150 ml of concentrated sulfuric acid (d = 1.838) was heated for 15 minutes at 113°C and after allowing the temperature to return to 45°C, the mixture was added to ice with stirring. The precipitate formed was recovered by vacuum filtration, was washed with water and then with acetone and dried to obtain 51.5 g of 3-hydroxy-4-carbamoyl-5-methyl-isothiazole melting at 248°-250°C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16](=[O:27])[N:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)[CH:18]=1.O>C(Cl)Cl>[Br:1][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]2=[O:27])=[CH:20][CH:21]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: O=c1ccc(Cl)cn1-c1ccc(CBr)cc1
Temperature: -20 °C
Reaction time: 6 h

Procedure:
To N-bromosuccinimide (0.166 g, 0.929 mmol) in CH2Cl2 (3 mL) at 0° C. was added dimethylsulfide (0.082 mL, 1.11 mmol). The resulting suspension was cooled to -20° C. and a solution of the alcohol from Step 1 (0.146 g, 0.62 mmol) in CH2Cl2 was added dropwise over 2 minutes. The reaction mixture was stirred at 0° C. for 6 hrs and then poured into water and extracted with CH2Cl2. The extracts were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 1:1 as eluent) to afford the title compound as a white solid.
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]5[N:37]=[C:38]([C@@H:41]6[CH2:46][C@@:45]7([CH3:47])[C@H:43]([CH2:44]7)[N:42]6C(OC(C)(C)C)=O)[NH:39][CH:40]=5)=[CH:32][CH:31]=3)[CH:24]=[CH:23]4)[N:19]=2)[CH2:13][C@@:12]2([CH3:55])[C@@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1.CO>[CH3:47][C@@:45]12[CH2:44][C@@H:43]1[NH:42][C@H:41]([C:38]1[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:14]7[CH2:13][C@@:12]8([CH3:55])[C@H:10]([CH2:11]8)[NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=1)[CH2:46]2
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(C)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5c[nH]c([C@@H]6C[C@]7(C)C[C@@H]7N6C(=O)OC(C)(C)C)n5)ccc4c3)cc2)c[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@]12C[C@@H](c3nc(-c4ccc(-c5ccc6cc(-c7c[nH]c([C@@H]8C[C@]9(C)C[C@@H]9N8)n7)ccc6c5)cc4)c[nH]3)N[C@H]1C2
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (250 mg. 0.344 mmol) in MeOH (5 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 231 mg). LC-MS retention time 3.09 min; Calcd. for C34H35N6: 527.29 m/z Found 527.35 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.CCN(C(C)C)C(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=O)[O:25]C(=O)[CH2:23]2>C1COCC1.Cl>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:25])[O:5][C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:23]2
Reactant: O=C1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cc2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
N,N′-Carbonyldiimidazole (747 mg, 4.61 mmol, 1.50 equiv.) was added to a stirred mixture of ethyl hydrogen malonate (0.543 mL, 4.61 mmol, 1.50 equiv.) in THF (15 mL) and the mixture was stirred at room temperature. After 15 min, Hunig's base (1.072 mL, 6.14 mmol, 2.00 equiv.) was added followed by dropwise addition of 6-bromoisochroman-1,3-dione (740 mg, 3.07 mmol) in THF (10 mL). Upon completion, the reaction was diluted with 0.5 N HCl (10 mL), extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15% EtOAc/hexanes to give 683 mg of ethyl 2-(6-bromo-1-oxo-1H-isochromen-3-yl)acetate as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:13]>>[ClH:13].[N:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCCC1
Agent: Cl
Product: O=C(O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
Ethyl 1-piperidineacetate (1.26 g, 7.4 mmol) was added to 3M hydrochloric acid solution (12 ml), which was then refluxed for 2 hours, stirred for 1 day at a room temperature, then concentrated under a reduced pressure. The resulting residue was dissolved in methanol and reconcentrated. The resulting solid was suspended in ethyl ether, filtered and dried under a reduced pressure to give 0.87 g of the titled compound. (Yield 65.3%). NMR(D2O): 1.0(m, 2H), 1.4(m, 4H), 2.5(m, 2H), 3.1(m, 2H), 3.5(s, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20]Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(SCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Product: O=c1ncc(Cl)cn1CSc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 4-nitro-1-(chloromethylthio)benzene (10 mmol) in a manner similar to that described in Example 2. The reaction time was 31/2 h. Yield: 1.79 g (60%) of the N- and O-isomers in the ratio 5:2. The O-isomer was extracted from the mixture with chloroform, and the remaining N-isomer, the title compound, was recrystallized from MeOH/HOAc; m.p. 165° C. (Found C44.64; H3.03. Calc. for C11H8ClN3O3S: C44.37; H2.71) 1H NMR (DMSO-d6): δ 5.50 (CH2), 7.4-8.3 (Ph), 8.51 (H-4 and H-6, s). IR (KBr): 1660 cm-1 (CO). MS [70 eV, m/z (% rel. int.)]: 297/299 (5/2,M), 143/145 (100/31).
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[CH:28]=2)=[CH:4][C:5](=[O:26])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14]C2CCCCO2)=[O:12])[CH:7]=1.FC1C(C2C=CC(N3N=CC=N3)=CC=2)=CC(=O)N(CC[C@@](C)(S(C)(=O)=O)C(NO)=O)C=1>>[F:1][C:2]1[C:3]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[CH:28]=2)=[CH:4][C:5](=[O:26])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][OH:14])=[O:12])[CH:7]=1
Reactant: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Product: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)NO)S(C)(=O)=O
Yield: 69.4 %

Procedure:
The title compound (66.8 mg, 68.4%) was prepared as a white solid from (2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (115 mg, 0.20 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide, Example 26, Step E. MS (LCMS) m/z 482.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.09-2.23 (m, 1 H) 3.11 (s, 3 H) 3.70-3.87 (m, 1 H) 3.97-4.14 (m, 1 H) 6.58 (d, J=7.61 Hz, 1 H) 7.25-7.35 (m, 2 H) 7.45-7.67 (m, 4 H) 8.06 (d, J=6.44 Hz, 1 H) 9.23 (s, 1 H) 11.08 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH3:56][C:57]1([OH:61])[CH2:60][NH:59][CH2:58]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([N:59]4[CH2:60][C:57]([OH:61])([CH3:56])[CH2:58]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CC1(O)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
To a DMF (1.0 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 85 mg, 0.26 mmol) was added HATU (118 mg, 0.31 mmol) and 3-methylazetidin-3-ol 2,2,2-trifluoroacetate (63 mg, 0.31 mmol) at ambient temperature, followed by addition of DIEA (0.14 mL, 0.78 mmol) at 0° C. After stirring for 5 minutes at ambient temperature, the reaction was directly purified by reverse-phase chromatography (5 to 45% acetonitrile/water) to yield the final product as white solid (84 mg, 82%). LCMS (apci) m/z=397.1 (M+H).