Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]>C(O)(C)(C)C.[Rh]>[NH2:1][CH2:2][CH:3]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC
Agent: [Rh]
Solvent: CC(C)(C)O
Product: CCOC(OCC)P(=O)(CC(CN)C1CCCCC1)OCC
Reaction time: 20 h

Procedure:
A solution of 3.45 g of ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate in 25 ml of tertiary butanol is added to 2.0 g of 5% rhodium in alumina, suspended in 25 ml of tertiary butanol. The resulting mixture is hydrogenated at an atmosphere of 150 bar and temperature of 100° C. for a period of 20 hours. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is chromatographed on silica gel using ethanol as eluent to give ethyl 3-amino-2-cyclohexylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=47.1 and +47.0 ppm (CDCl3).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([NH2:64])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and morpholin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.41 (m, 2 H) 1.59-1.86 (m, 8 H) 2.94 (br. s., 4 H) 3.31 (s, 3 H) 3.67 (br. s., 4 H) 3.94 (s, 3 H) 4.16 (t, 2 H) 4.38-4.54 (m, 1 H) 7.45 (d, J=8.7 Hz, 1 H) 7.48 (s, 1 H) 8.14 (d, 1 H) 8.23 (s, 1 H) 8.57 (br. s., 1 H) 9.57 (s, 1 H). [M+H] calc'd for C26H33F2N7O4 546; found 546.
Reaction SMILES: [OH:1][C@H:2]([CH3:24])[CH2:3][NH:4][C:5]([CH3:23])([CH3:22])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])=[O:8].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])(=O)=O>C(Cl)Cl>[CH2:41]([Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[O:1][C@H:2]([CH3:24])[CH2:3][NH:4][C:5]([CH3:23])([CH3:22])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])=[O:8])[CH3:42]
Reactant: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](C)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a stirred solution of 660 mg (1.48 mmol) of the intermediate obtained in Step B in 3 mL of methylene chloride at room temperature was added 1.1 mL of N,N-diisopropylethylamine (0.81 g, 4.2 eq.) followed by 0.71 mL of triethylsilyl trifluoromethanesulfonate (0.83 g, 2.1 eq.). The resulting mixture was stirred at room temperature for 2 hours then partitioned between ethyl acetate and saturated aqueous sodium chloride (buffered to pH 9 with 2 drops of ammonium hydroxide). The organic layer was separated, washed with buffered brine, dried over magnesium sulfate, filtered and solvents evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/0.1% ammonium hydroxide in methanol (85:15), to afford 480 mg (1.07 mmol, 72%) of product. 1H NMR (200 MHz,CD3OD): 0.63 (q,8 Hz,6H), 0.97 (t,8 Hz,9H), 1.14 (s,6H), 1.18 (d,6 Hz,3H), 2.05 (m,1H), 2.28 (d,2Hz,2H), 2.35-3.00 (m,5H), 4.01 (m,1H), 4.44 (dd;8,12 Hz;1H), 7.05 (d,8 Hz,1H), 7.10-7.35 (m,3H). FAB-MS: calculated for C24H41N3O3Si 447; found 448 (M+H, 100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH:16]=O)=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:36][NH2:37].[BH4-].[Na+]>C1COCC1.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH2:16][NH:37][CH3:36])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C=O)c2s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CNC)c2s1
Yield: 91 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (140 mg, 0.28 mmol) was stirred in a 7M solution of methylamine in THF (8 mL) in a microwave tube equipped with a stirrer. The reaction was irradiated to 80° C. for 1 h in a CEM explorer microwave with stirring. After cooling, the solvents were removed under reduced pressure, the resulting residue dissolved in anhydrous MeOH (8 mL) and the reaction transferred to a round bottomed flask equipped with a calcium chloride drying tube. Sodium borohydride (43 mg, 1.12 mmol) was added and the reaction stirred at rt for 18 h. After this time LCMS indicated 70% conversion to the desired material. The reaction was diluted with water (20 mL), extracted with EtOAc (3×20 mL) and the combined organic extracts washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a glassy brown/grey solid 130 mg (91% yield).
Reaction SMILES: [C:1]([O:8][CH2:9]C)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].COC[C:14]([O:16][CH3:17])=[O:15].[CH3:18][O-].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[CH:1]([O:8][CH3:9])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH3:18]
Reactant: C[O-]
Reactant: COCC(=O)OC
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC)C(=O)OCC
Temperature: 75 °C
Yield: 40.5 %

Procedure:
A mixture of diethyl oxalate (27.5 ml, 1 eq.) and methyl methoxyacetate (20 ml, 1 eq.) was added dropwise to a slurry of sodium methoxide (16.4 g, 1.5 eq.) in toluene (350 ml) at 45-50° C. After dropping, the resulting solution was heated to 70-80° C. for 2 hrs and poured into 70 ml of 14% HCl with cooling. The resultant mixture was extracted with EA and the combined organic layers were washed with brine and dried in vacuo to give 16.7 g (40.5%) of a product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C(OCC)=O)=[CH:4][CH:3]=1.[CH3:14][Mg]Br.[Cl-].[NH4+].C([O:21][CH2:22][CH3:23])C>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:22]([CH3:23])([OH:21])[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(Br)cc1
Temperature: 40 °C
Yield: 93 %

Procedure:
A solution of 4 g (16.5 mmol) of ethyl 4-bromophenylacetate in 60 ml of diethyl ether was treated with 26 ml (36.4 mmol) of a 1.4M solution of methylmagnesium bromide in toluene/tetrahydrofuran (3:1) and the mixture heated at 40° C. for 1 hour and then cooled. 100 ml of saturated aqueous ammonium chloride were added and the phases separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 3.5 g (93%) of 1-(4-bromophenyl)-2-methyl-propan-2-ol as a colorless oil. [Mass spectrum (ESI) MH+ =229].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:40])([C:31]([F:39])([F:38])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[CH:28]=[CH:29][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:40])[C:31]([F:38])([F:39])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])=[CH:24][CH:23]=2)[C:26]1=[O:30])[CH3:13]
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 13.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.83 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.56 g of 1-[4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-2(1H,3H)-imidazolone, 0.30 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-2(1H,3H)-imidazolone was obtained as a colorless viscous oil.
Reaction SMILES: B(O)(O)C1C=CC(F)=NC=1.O1CCN(CCOC2C=CC(C3C=CC(CC#N)=NC=3)=CC=2)CC1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([CH2:56][C:57](OC)=[O:58])=[N:54][CH:55]=3)=[CH:46][CH:45]=2)[CH2:37][CH2:36]1.FC1N=CC(C2C=CC(OCCN3CCOCC3)=CC=2)=CC=1.[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>>[O:35]1[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][O:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:51]=[CH:52][C:53]([CH2:56][C:57]([NH:90][CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)=[O:58])=[N:54][CH:55]=3)=[CH:48][CH:49]=2)[CH2:39][CH2:40]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: OB(O)c1ccc(F)nc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with hydrochloric acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH2:12][N:13](C3C=CC=CC=3C#N)[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:10]=[CH:11][C:4]=2[O:3]1.[BH4-].[Na+].[NH4+:30].[Cl-].O>CO>[O:1]=[S:2]1(=[O:27])[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][N:13]([C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:30])=[CH:4][CH:11]=3)[N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: N#Cc1ccccc1N(Cc1ccc2c(c1)C=NS(=O)(=O)O2)n1ccnc1
Reactant: [NH4+]
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc3c(c2)CNS(=O)(=O)O3)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a suspension of +[N-[(2,2-dioxido-1,2,3-benzoxathiazin-6-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (0.40 g, 1.05 mmol) in methanol (8 ml) was added portionwise NaBH4 (0.08 g, 2.11 mmol) and the reaction mixture was stirred at room temperature for 3 h. After addition of a saturated solution of NH4Cl (3 ml) and water (40 ml), the precipitate obtained was filtered, washed with water and dried to give a white solid. Crystallization from ethyl acetate with ethanol yielded the expected product (0.40 g, 82%, mp: 190° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:13])=O)[N:3]=1.[SH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[CH2:23]1[CH2:33][CH2:32][N:31]2[C:26](=NCCC2)[CH2:25][CH2:24]1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([S:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH2:13][CH2:25][C:26]2[CH:24]=[CH:23][CH:33]=[CH:32][N:31]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1SCCc1ccccn1
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 500 mg (2.31 mmol) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile in 10 ml DME were added 482 mg (3.46 mmol) 2-mercapto-ethylpyridine and 0.88 ml (5.77 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ethyl acetate to afford 300 mg (33%) 2-amino-4,6-bis-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 395 (M+H+, 100).
Reaction SMILES: [C:1]1([CH3:10])[C:2](N)=[C:3]([NH2:8])[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:11]([NH:14]C(C)C)(C)[CH3:12].C(Cl)(=[O:20])C.O>ClCCl>[NH2:8][C:3]1[C:4]([CH3:7])=[CH:5][C:6]([NH:14][C:11](=[O:20])[CH3:12])=[C:1]([CH3:10])[CH:2]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1ccc(C)c(N)c1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(C)c(N)cc1C
Reaction time: 8 h

Procedure:
To a solution of p-xylenediamine (2.0 g) in dichloromethane (200 ml) maintained below 10° C. was added N,N-diisopropylamine (2.52 ml) followed by the dropwise addition of acetylchloride (1.15 g). The mixture was allowed to attain room temperature and stirred overnight. Water (120 ml) was added and the suspension filtered. The filtered solid was washed with dichloromethane (2×100 ml) and water (100 ml). All filtrates were combined and the organic layer separated. The organic layer was washed with water, dried (MgSO4) and evaporated to give the title product as a solid, m.p. 133-5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][Cl:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([O:10][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC(O)CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC(CCCCl)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, 6-chloro-3-hydroxy-hexanoic acid methyl ester (2); 66.5 g {(GC purity; 79.1%, pure amount; 52.6 g (0.295 mol)}, triethylamine (44.7 g, 0.443 mol) and toluene (250 ml) were added to a 500 ml capacity flask, followed by cooling to 5° C. Methanesulfonyl chloride (37.0 g, 0.325 mol) was added dropwise thereto, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 6-chloro-3-methanesulfonyloxy-hexanoic acid methyl ester (3).
Reaction SMILES: O=C1C2CCCCC=2C(=O)N1CC(C1(C)OCCO1)C(OC)=O.[NH2:24][CH2:25][CH:26]([C:31]1([CH3:36])[O:35][CH2:34][CH2:33][O:32]1)[C:27]([O:29][CH3:30])=[O:28].[F:37][C:38]1[CH:48]=[CH:47][C:46]([F:49])=[C:40]2[C:41]([O:43][C:44](=O)[C:39]=12)=[O:42]>>[F:37][C:38]1[CH:48]=[CH:47][C:46]([F:49])=[C:40]2[C:39]=1[C:44](=[O:43])[N:24]([CH2:25][CH:26]([C:31]1([CH3:36])[O:32][CH2:33][CH2:34][O:35]1)[C:27]([O:29][CH3:30])=[O:28])[C:41]2=[O:42]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Agent: COC(=O)C(CN1C(=O)C2=C(CCCC2)C1=O)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.27 g, 31%) in the same manner as described in the above example 5. (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.47 g, 2.47 mmol) and 3,6-difluorophthalic anhydride (0.50 g, 2.72 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]([O:15][C:16](=[O:24])[NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(O)CCC>[C:11]([O:15][C:16](=[O:24])[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:20][CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]cnc23)CC1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
To a mixture of 6-chloropurine (0.050 g, 0.323 mmol) and piperidin-4-yl carbamic acid tert-butyl ester (0.129 g, 0.646 mmol) in n-butanol (3.2 ml) was added triethylamine (0.225 ml, 1.617 mmol). After heating at 100° C. for 20 hours, solvent was removed and the resulting solid triturated with a DCM/methanol mix (3 ml/5 ml). Filtration gave the desired product as a white solid (0.080 g, 78%). LC/MS: (LCT) Rt 5.37 [M+H]+ 319.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[Br:18][CH2:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C.O>ClCCl>[Br:18][CH2:19][CH2:20][CH2:21][NH:22][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
A mixture of 2,2-diphenylacetic chloride (6.00 g, 26.0 mmol), 3-bromo-1-aminopropane hydrobromide (5.69 g, 26.0 mmol) and triethylamine (10.9 mL, 78.0 mmol) in dichloromethane (100 mL) was stirred at 25° C. for 24 hours. Water (100 mL) was added into the reaction mixture and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed (Hexanes:EtOAc 2:1) to afford the desired product (6.67 g, 77.5%). 1H NMR (400 MHz, CDCl3) δ δ 7.30-7.17 (m, 10H), 6.64-6.55 (m, 1H), 4.86 (s, 1H), 3.29-3.19 (m, 4H), 1.95-1.85 (m, 2H); ESMS m/e: 332.21 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:29][OH:30]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14]([NH:29][OH:30])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 76.8 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (1.00 g, 2.71 mmol), N,N′-carbonyldiimidazole (461 mg, 2.84 mmol) and hydroxylamine hydrochloride (208 mg, 2.99 mmol) in tetrahydrofuran (6 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (800 mg, 77% yield): mp, 163.0-165.0° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 3.11 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.67 (t, J=7.8 Hz, 1H, NCH), 6.90 (br s, 2H, Ar), 7.02 (br s, 1H, Ar), 7.86 (br s, 4H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 3C NMR (DMSO-d6) δ14.67, 34.22, 50.18, 55.44, 63.71, 111.73, 112.36, 119.65, 123.11, 131.18, 131.21, 134.56, 147.67, 148.53, 165.97, 167.61. Anal. Calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.43; H, 5.04; N, 7.20.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:7]=1[NH2:8])[CH2:2][CH2:3][CH3:4].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C1(C)C=CC(S([CH2:31][N+:32]#[C-:33])(=O)=O)=CC=1.[H-].[Na+]>C1(C)C=CC=CC=1.C(COC)OC.O>[CH2:1]([O:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:7]=1[N:8]1[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:33][N:32]=[CH:31]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(CC)c1N
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CCCCOc1cccc(CC)c1-n1cncc1C(=O)OCC
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
13.5 g (0.07 mol) of 2-butoxy-6-ethylaniline are heated on a water separator with 11.8 g (0.099 mol) of ethyl glyoxylate in 100 ml of toluene until water formation is complete. The mixture is evaporated, the residue is dried in a high vacuum and taken up in 30 ml of dimethoxyethane, and the solution is added dropwise with 13.4 g (0.069 mol) of p-toluenesulfonylmethyl isocyanide to a suspension of 4.3 g (0.14 mol) of 80% strength sodium hydride (white oil) in 20 ml of dimethoxyethane at -20° C. When the gas evolution is complete, the mixture is hydrolyzed by adding water dropwise, the reaction products are extracted with methylene chloride, and the solvent is evaporated. The residue is taken up in 50 ml of ethanol, 20 g of potassium carbonate are added, and the mixture is stirred for 2 hours at 50° C. After evaporation, the residue is taken up in toluene/water, the organic phase is dried and evaporated, and the residue is chromatographed through a silica gel column (petroleum ether/ethyl acetate 8:2). 12.1 g (55% of theory relative to aniline employed) of ethyl 1-(2-butoxy-6-ethylphenyl)imidazole-5-carboxylate, a pale yellow oil, are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20]>C(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]=[C:19]=[S:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccncc1N
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ccncc1N=C=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 137b (14.54 mg, 0.0600 mmol) in anhydrous DCM (1.0 mL) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 mL). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down to afford crude 137c which was taken directly onto the next step without purification.