Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C([O:8]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[CH:69]=[C:68]([CH2:70]C(O)=O)[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][N:51]([C:70]([C:68]5[O:67][N:66]=[C:65]([CH3:64])[CH:69]=5)=[O:8])[CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.4 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride 5 (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-5-isoxazoleacetic acid (0.135 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (4/96). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(3-methylisoxazol-5-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.224 g). 1H NMR Spectrum: (DMSO d6) 1.54-1.76 (m, 2H), 2.05 (m, 2H), 2.22 (s, 3H), 3.32 (m, 1H), 3.47 (m, 1H), 3.82 (m, 1H), 3.93 (m, 1H), 3.96 (s, 3H), 4.00 (s, 2H), 4.92 (m, 1H), 6.23 (s, 1H), 7.29 (m, 1H), 7.36 (s, 1H), 7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H)+ 526.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:5]=2[CH:6]=1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[O:13][N:23]=[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:15]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2cc(C(=O)O)ccc2o1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Cc1cc2cc(-c3nc(-c4cccnc4)no3)ccc2o1

Procedure:
The title compound was prepared according to Method C using 2-methylbenzofuran-5-carboxylic acid (Chembridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3H), 6.58-6.97 (m, 1H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 8.40-8.55 (m, 2H), 8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[Br:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Br:18][CH2:19][CH2:20][CH2:21][C:22]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)=[O:23]
Reactant: O=C(Cl)CCCBr
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COc1ccncc1
Product: O=C1C=CN(C(=O)CCCBr)C(c2ccc(F)cc2)C1

Procedure:
6.66 g of the title compound was obtained from 4-methoxypyridine (2.0 mL), 4-fluorophenylmagnesium bromide (1.0 M solution in THF, 20.7 mL), and 4-bromobutyryl chloride (2.4 mL) according to the method described in Tetrahedron Letters, 1986, vol. 27, p. 4549-4552. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].Br[CH2:16][C:17]#CC.[H-].[Na+].CN(C)C=O.O1CC[CH2:29][CH2:28]1>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:28][CH3:29])[CH2:13][C:14]#[C:16][CH3:17])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(NCC)ncn1
Reactant: C1CCOC1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CC#CC)ncn1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 5 ml of tetrahydrofuran were dissolved 153 mg of 4-(2-butynyloxy)-6-(ethylamino)pyrimidine and 117 mg of 1-bromo-2-butyne, to which 40 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 7 hours. Then, 2 ml of N,N-dimethylformamide was further added, and the mixture was stirred at room temperature for 3 hours. Then, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 176 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-(2-butynyl)amino)pyrimidine (the present compound (109)).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH2:18].[CH3:19][N:20](C)[CH:21]=[O:22]>>[OH:1][N:2]=[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:17]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:4][CH:3]=2)[NH:20][C:21](=[O:22])[CH2:16][CH2:15]3)=[O:18])[CH2:10][CH2:11]1
Reactant: CN(C)C=O
Reactant: ON=C(CCN1CCNCC1)c1ccccc1
Reactant: O
Product: O=C1CCc2cc(C(=O)N3CCN(CCC(=NO)c4ccccc4)CC3)ccc2N1
Reaction time: 24 h

Procedure:
127 Milligrams of succinimide 3,4-dihydrocarbostyril-6-carbostyril-6-carboxylate and 123 mg of (3-hydroxyimino-3-phenylpropyl)piperazine were dissolved in 2 ml of dimethylformamide, then this mixture was stirred for 24 hours. To the reaction mixture was added water, then extracted with chloroform and this extracted was washed with water and with an aqueous solution saturated with sodium chloride. Next, the washed extract was dried with anhydrous potassium carbonate, then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was recrystallized from ethanol to yield 102 mg of 6-[4-(3-hydroxyimino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.semihydrate. White powdery substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccnc3)C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine (0.45 g, 1.16 mmol) in dichloromethane (6 mL). Cool in an ice bath. Add methanesulfonyl chloride (0.015 mL, 1.15 mmol) and triethylamine (0.032 mL, 1.6 mmol). After 1 hour, dilute the reaction mixture with dichloromethane and extract with brine. Separate the layers and extract the aqueous layers twice with dichloromethane. Combine the organic layers. Dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C(N(CC)CC)C.C1C=CC=CC=1.[N+:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1)([O-:33])=[O:32]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=1)=[O:5]
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1OCc1ccc([N+](=O)[O-])cc1
Yield: 86.7 %

Procedure:
To a mixture of 1.36 g (0.005 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, 0.51 g (0.005 mol) of triethylamine, 20 ml of benzene and 10 ml of N,N-dimethylformamide was added with stirring 0.86 g (0.005 mol) of 4-nitrobenzyl chloride at room temperature. The resulting mixture was then heated under reflux for 3 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and 30 ml of water and 30 ml of ethyl acetate were added thereto. After stirring the mixture for a while, an organic layer was separated, washed with water and 5% aqueous sodium bicarbonate and dried. Then the solvent was distilled off therefrom. The resulting oil (2.02 g) was subjected to column chromatography (silica gel, eluting with benzene/ethyl acetate 1:1) to give 1.76 g of the title compound (yield 87%), m.p. 116.5°-117.5° C.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(c2nccc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC1(N)CCN(c2nccc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.22 g (0.0068 mol) of 4-t-butoxycarbonylamino-1-(4-chloropyrimidin-2-yl)-4-methylpiperidine (step c) in 25 ml of anhydrous methylene chloride is cooled under a nitrogen atmosphere and 5 ml of anisole and 25 ml of trifluoroacetic acid are added slowly. The mixture is stirred for 1 hour at room temperature and 25 ml of a 30% solution of NaOH are added slowly. The reaction medium is extracted with methylene chloride and dried over Na2SO4 and the solvent and the anisole are evaporated off under reduced pressure. The residue is purified by chromatography using CH2Cl2 /MeOH=9/1 as the eluent to give 4- amino-1-(4-chloropyrimidin-2-yl)-4-methylpiperidine as the base, which is treated with maleic acid in an ethanol/isopropyl ether mixture. The maleate obtained in this way is isolated by filtration (m.p. 154°-155° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCCC2)cc1
Temperature: 100 °C
Reaction time: 13.5 h
Yield: 83.3 %

Procedure:
A mixture of 4-bromophenol (40 g, 231 mmol), cyclopentylbromide (50 ml, 462 mmol), NaOH (18.5 g, 462 mmol) and DMF (150 mL) was stirred at 100° C. for 13.5 h, poured into water (300 mL) and extracted with t-BuOMe (4×100 mL). The combined organic extracts were washed with water (2×100 mL), brine, dried (Na2SO4), concentrated and distilled in vacuo to yield the sub-title compound (46.4 g, 94%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15])[CH3:8]>C(#N)C.C(Cl)Cl>[CH2:7]([C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:15])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCc1oncc1C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CCc1oncc1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.2 mol (17.0 g) of piperidine is added dropwise to 0.1 mol (16.0 g) of 5-ethyl-4-isoxazolecarboxylic acid chloride dissolved in 200 ml of acetonitrile, at room temperature with stirring. Stirring is continued for 20 minutes and the mixture is then cooled to room temperature and the piperidine hydrochloride precipitated is filtered off with suction. The filtrate is concentrated under reduced pressure. An oily residue is obtained, and is taken up in 200 ml of methylene chloride, and the mixture is washed first with 100 ml of 2N hydrochloric acid and then with water. After drying over sodium sulfate, the mixture is concentrated under reduced pressure and the oily residue is distilled under reduced pressure (bulb tube distillation). N-(5-Ethyl-4-isoxazolylcarbonyl)-piperidine of boiling point (7 mbar) 90°-110° C. is thus obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[C:44]([CH3:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:36]4[O:37][C:38]5[C:44]([CH3:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:39]=5[N:40]=4)=[CH:33][CH:34]=3)[C:10]=12
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.515 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.235 g, 0.644 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a yellow powder (0.185 g, 72%). 1H NMR (DMSO-d6, 400 MHz) 2.30-2.49 (m, 2H), 2.41 (s, 3H), 2.49 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 3.17 (m. 2H), 3.24 (s, 3H), 3.45 (t, 2H), 5.40 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.85 (s, 1H); RP-HPLC Rt 11.477 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 499 (MH+).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][N:10]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)CCl.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1ON>CN(C=O)C>[N:2]1([CH2:8][CH2:9][N:10]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@@H:11]([C:13]([O:15][CH:55]2[CH2:56][CH2:57][CH2:58][CH2:59][O:54]2)=[O:14])[CH3:12])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NOC1CCCCO1
Reactant: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@H](C)C(=O)O)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@H](C)C(=O)OC3CCCCO3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 36.2 %

Procedure:
To the solution of N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, monohydrochloride from Example 4d (3.61 g, 7.20 mmol) in dry DMF was added EDC (2.57 g, 13.4 mmol), 4-methylmorpholine (2.96 mL, 26.96 mmol), and N-hydroxybenzotriazole (1.81 g, 13.4 mmol) at zero degrees C. After stirring for 45 minutes at zero degrees C., O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.88 g, 16.0 mmol) was added and the solution was left stirring at room temperature overnight. The reaction was concentrated and partitioned between water and ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried with MgSO4, and concentrated to a white solid (2.4 g). Chromatographic purification (40% acetone in hexane) afforded N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, tetrahydro-2H-pyran-2-yl ester, (1.43 g, 34.6% yield) as a white solid. The proton NMR and MIR were consistent for N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, tetrahydro-2H-pyran-2-yl ester. Anal. calc'd for C27H37N3O6S2 : C, 57.53; H, 6.62; N, 7.45; S, 11.38. Found: C, 57.43; H, 6.80; N, 7.34; S,11.34.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[O:2]1.O[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1>>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:4][C:3]=2[O:2]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)OCO3)cc1

Procedure:
3,4-Methylenedioxybenzyl alcohol 18-1 (6.2 g, 40.0 mmol) and ethyl 4-hydroxybenzoate 18-2 (6.65 g, 40.0 mmol) were reacted as in Example 14. The desired ester 18-3 was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[CH:52]=[N:51][CH:50]=[CH:49][N:48]=1>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[CH:52]=[N:51][CH:50]=[CH:49][N:48]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnccn1
Reactant: CSc1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 14.9 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-propionic acid (529 mg, 2.0 mmol) and triphenylphosphine (892 mg, 3.4 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (605 mg, 3.4 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of the N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminopyrazine (476 mg, 5.0 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid solution (40 mL) and then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 65/35 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-propionamide (102 mg, 15%) as a white solid: mp 128-130° C., [α]23589=−103.1° (c=0.032, chloroform); EI-HRMS m/e calcd for C19H23N3OS (M+) 341.1562, found 341.1563.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:27]=[O:28])[CH:10]=2)[CH2:6][O:7]1
Reactant: CC1(C)OCc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OCc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1,1-dimethyl-1,3-dihydro-isobenzofuran (1.41 g, 6.3 mmol) in anhydrous THF (10 mL) was added under Argon at −78° C. 2.5 M nBuLi in hexane (2.7 mL, 6.6 mmol) and after stirring for 0.5 h at −78° C. DMF (0.98 mL, 12.5 mmol) was added. After stirring for 2 h at −78° C. the reaction mixture was added to 0.5 N cold aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi-Flash, 40 g silicagel, hexane-EtOAc 95:5 to 50:50) as a light yellow oil: TLC (hexane-EtOAc 1:1) Rf=0.50; HPLC RtA=1.43 min; 1H NMR (400 MHz, CDCl3): δ10.02 (s, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 5.11 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[C:20]1[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.50 g, 1.7 mmol) and (3,5-difluorophenyl)boronic acid (0.31 g, 2.0 mmol) in 1,4-dioxane (10 mL) was added a 1N solution of sodium carbonate in water (2.2 mL, 2.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.096 g, 0.083 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, concentrated, and purified on silica gel (0-45% ethyl acetate/hexanes) to give the desired product (0.30 g, 53%). LCMS calculated for C14H10F2N5OS (M+H)+: m/z=334.1. Found: 334.0.
Reaction SMILES: Cl.N[CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].C1N2CN3CN(C2)CN1C3.[OH2:29].Cl>C(O)(=O)C.O>[C:10]([C:9]1[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[C:5]([OH:18])[C:4]=1[CH:3]=[O:29])([CH3:13])([CH3:12])[CH3:11]
Reactant: O
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.60 mmol) of the product of Example 19 (as the hydrochloride salt) in 10 mL of acetic acid-water (11:3) was added 0.75 g (5.35 mmol) of hexamethylenetetramine. The mixture was refluxed for 3 h then treated with 6 mL of water and 3 mL of conc. hydrochloric acid. Heating was continued for 10 min at which point the reaction mixture was cooled and concentrated in vacuo to remove the acetic acid. The residue was partitioned between EtOAc and water, and the aqueous layer was separated and extracted. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.