Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:5].[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>O1CCOCC1.[Cl-].[Na+].O>[OH:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][OH:32])[C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:5]
Reactant: O=C(NCCCN1CCOCC1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: OCCNCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCCCN1CCOCC1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N(CCO)CCO

Procedure:
2-Chloro-N-[3-(4-morpholinyl)propyl]-3,5-dinitrobenzamide (12h) (0.5 g, 1.34 mmol) was reacted with diethanolamine (0.5 g) in p-dioxane (10 mL) at room temperature for 3 h. The reaction mixture was poured into brine, extracted with EtOAc (3×70 mL), and the combined organic phases were dried and concentrated under reduced pressure to give crude 2-[bis(2-hydroxyethyl)amino]-N-[3-(4-morpholinyl)propyl]-3,5-dinitrobenzamide. This was dissolved in CH2Cl2 (100 mL), cooled in an ice-bath, and treated with Et3N (1.5 mL) followed by MsCl (0.7 mL) in one portion. After stirring for 10 min, sat. NaHCO3 (100 mL) was added and the mixture was stirred for a further 30 min, then the aqueous phase was extracted with CH2Cl3 (2×70 mL). The combined organic phases were dried and evaporated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc/MeOH (20:1 to 9:0) to give yield 2-[{2-[(methylsulfonyl)oxy]ethyl}-2-({[3-(4-morpholinyl)propyl]amino}carbonyl)-4,6-dinitroanilino]ethyl methanesulfonate (13h) (0.75 g, 93%) as a foam;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1cccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ncccc1C#N
Temperature: 85 °C
Yield: 65.6 %

Procedure:
To a 250-mL, round-bottomed flask containing a large magnetic stir bar were added 2-chloro-3-cyanopyridine (1.39 g, 10.0 mmol), 2-methoxyphenylboronic acid (1.82 g, 12.0 mmol), and dichlorobis(triphenylphosphine)palladium(II) (351 mg, 0.50 mmol). Isopropyl alcohol (50 mL) and 2M sodium carbonate solution (50 mL) were added. The flask was stoppered and immersed in an oil bath heated to 80-90° C. The biphasic mixture was stirred vigorously and heated for 8 hours. After cooling to room temperature, ethyl acetate (50 mL) was added and the black mixture was transferred to a separatory funnel. The aqueous layer was removed and subsequently extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown oil. The product was crystallized from ethyl acetate/hexanes to give 1.38 g (66%) of the title compound as a tan powder.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:23]1([CH:28]=[CH:29][C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:28]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:29][C:30]#[N:31])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a stirred suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 158 mg, 0.50 mmol) and 3-cyclopentylacrylonitrile (8, 122 mg, 1.0 mmol, 2.0 equiv) in dimethyl sulfoxide (DMSO, 1.0 mL, 14 mmol) at room temperature was added powder potassium carbonate (K2CO3, 10.4 mg, 0.075 mmol, 0.15 equiv). The reaction mixture was then stirred at room temperature for 5 h. The reaction mixture became a clear solution in 2 h. When LCMS showed the reaction was deemed complete, the reaction was quenched with water (H2O, 5 mL) and extracted with ethyl acetate (EtOAc, 3×15 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 172.6 mg, 210 mg theoretical, 82% yield) as a white solid. For 20: 1H NMR (CDCl3, 400 MHz) δ ppm 8.87 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 7.47 (d, 1H, J=3.9 Hz), 6.75 (d, 1H, J=3.9 Hz), 6.24 (s, 2H), 4.25 (m, 1H), 3.12 (dd, 1H, J=17.0, 8.7 Hz), 2.95 (dd, 1H, J=17.0, 3.9 Hz), 2.58 (m, 1H), 1.95 (m, 1H), 1.72-1.52 (m, 5H), 1.25 (m, 2H), 1.14 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].[CH:18]1C2N(C=NC=2)C(=S)NN=1>>[Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[S:11][CH3:18]
Reactant: S=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Reactant: S=c1[nH]ncc2cncn12
Product: CSc1nncc2c(Br)nc(-c3ccccc3)n12

Procedure:
The procedure of Example 29 is repeated substituting an equimolar amount of 8-bromo-6-phenyl-imidazo[1,5-d]-as-triazine-4(3H)-thione for the imidazo[1,5-d]-as-triazine-4(3H)-thione employed in that example. There is thus obtained the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]2.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:57][CH2:58][CH2:59]O)[CH:49]=1.C(OC(=O)C)C.[ClH:74]>C(OCC)(=O)C.O1CCCC1>[ClH:74].[ClH:74].[ClH:74].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:63]=[CH:64][N:65]=[CH:66][CH:67]=2)[CH2:57][CH2:58][CH2:59][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]3)[CH:49]=1
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Reactant: O=c1[nH]ccc2cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]ccc2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc12
Reaction time: 8 h

Procedure:
Triphenyl phosphine(51 mg) and di-tert-butyl azodicarboxylate (45 mg) were added to a tetrahydrofuran (THF) solution(1.5 ml) of 6-hydroxy-2H-isoquinolin-1-one(29 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol(40 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=1:0→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(0.06 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and was dried to produce the title compound(31.4 mg) as a white powder.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1>C(OCC)(=O)C.O>[NH2:13][C@@H:9]([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: N[C@H](CCc1ccccc1)C(=O)O

Procedure:
After the completion of the reaction, an extractant such as ethyl acetate is added to the reaction mixture which separates the reaction mixture into an upper layer and a lower layer. The upper layer contains D-HPAE in ethyl acetate and the lower layer contains L-HPA in water. After separating the lower layer from the upper layer, the extractant, i.e., ethyl acetate, can be vaporized to obtain D-HPAE, which can be chemically hydrolyzed to obtain D-homophenylalanine. L-HPA can be separated from the lower layer by adjusting its solution pH to about 6.3 to cause the precipitation thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[CH3:40][CH:41]1[NH:46][CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]1.BrC1C=C(OC)C=C2C=1CCC(=O)N2C1C(Cl)=CC=CC=1Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18]([N:46]2[CH2:45][CH2:44][NH:43][CH2:42][CH:41]2[CH3:40])(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CCNCC4C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-[(2-methylpiperazin-1-yl)sulfonyl]-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (COMPOUND CCC8) and tert-butyl 3-methylpiperazine-1-carboxylate by a procedure analogous to that described in EXAMPLE CCC25, STEP B. Mass spectrum (ESI) 729 (M-t-Bu+1).
Reaction SMILES: C([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH-:36])=O)CCCCCCCCCCCCCCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[OH-].[Na+]>C1COCC1.CCOCC>[CH2:32]([NH:36][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]/[CH:26]=[CH:25]\[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCC/C=C\CCCCCCCC([NH-])=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCCCCCCCCCC
Yield: 85 %

Procedure:
20 ml 1M LiAlH4 in ether are provided under argon inert gas in a 250 ml three-neck flask having a dropping funnel and a reflux condenser and subsequently a solution of 7.59 g (15 mmol) palmityloleoylamide in 80 ml THF added dropwise within 20 minutes. The mixture is refluxed for 2.5 hours, then another 5 ml 1 M LiAlH4 in ether is added and refluxed for another 2.5 hours. Excess hydride is decomposed using 6 M NaOH under ice bath cooling and the precipitate is filtered off. The precipitate is extracted twice with 40 ml of hot MtBE each, the combined organic phases dried over Na2SO4 and the solvent removed using a rotary evaporator. The residue is crystallised from 100 ml MtBE at −20° C. 6.23 g (12.7 mmol) corresponding to a yield of 85% of a colourless crystalline solid are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].O.[CH2:68]([OH:72])[CH2:69]CC>C(OC(=O)C)(=O)C>[C:68]([NH:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66])(=[O:72])[CH3:69]
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: CCCCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CO[C@H]1C(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CNC(C)=O)[C@@H]1O
Reaction time: 0.58 h

Procedure:
A suspension of 39.0 mg (41.2 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid in 2.0 ml of acetic anhydride is placed in an ultrasonic bath (Branson 1200) at room temperature for 35 minutes. Water (2 ml) and n-butanol (2 ml) are added to the reaction mixture and the volatile materials removed under reduced pressure to a residue which is suspended in 2 ml of acetone and the suspension filtered through glass wool. The desired product (the acetone insoluble product) is recovered as a white solid by dissolving in 2 ml water followed by lyophylization.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39](Cl)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(Cl)nn12
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 60 °C
Yield: 50.7 %

Procedure:
1.25 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.20 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycine ethyl ester were dissolved in 20 ml of N,N-dimethylformamide; 1.33 ml of N-ethyldiisopropylamine was added, followed by stirring under heating at an external temperature of 60° C. for 7.5 hours. After cooling, cold aqueous sodium bicarbonate was added; the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was recrystallized from ethanol-ethyl acetate fir (1:3), collected by filtration, and dried, to yield 1.17 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:20][CH2:21]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: COCCN1CCNCC1
Reactant: C=C1CCN(c2ccc(Cl)cc2)C1=O
Solvent: CC#N
Product: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Yield: 76.4 %

Procedure:
0.85 g of 1-(4-chlorophenyl)-3-methylene-2-pyrrolidinone and 0.71 g of 4-(2-methoxyethyl)piperazine were mixed with 3 ml of acetonitrile. The mixture was refluxed for 3.5 hours. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column chromatography using a mixed solvent (chloroform/methanol=20/1) to obtain 1.1 g of 1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](Cl)(=[O:20])[CH3:19].O>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:20])[CH3:19])=[CH:16][CH:17]=1
Reactant: Fc1ccccc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccccc2F)cc1
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, methylene chloride (100 ml) was added to aluminum chloride (20.1 g) and then, to thereto was added dropwise at room temperature a solution obtained by dissolving 2-fluorobiphenyl (20.0 g) and acetyl chloride (10.7 ml) in methylene chloride (100 ml). After stirring for 4 hours, a small amount of water was added to the reaction mixture, and then the mixture was subjected to extraction with chloroform. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a recrystallization method from ethanol, to obtain 1-(2'-fluoro-biphenyl-4-yl)-ethanone (17.53 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]([CH2:60][OH:61])[C:36]([NH:38][C@@H:39]([C@H:50]([OH:59])[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:37].[O:62]1[CH2:67][CH2:66][N:65]([CH2:68][C:69](O)=[O:70])[CH2:64][CH2:63]1>CN(C=O)C>[OH:59][C@H:50]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)[C@H:39]([NH:38][C:36](=[O:37])[C@@H:35]([NH:34][C:69](=[O:70])[CH2:68][N:65]1[CH2:66][CH2:67][O:62][CH2:63][CH2:64]1)[CH2:60][OH:61])[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@@H](N)CO)C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
Sequentially HATU (509 mg, 1.34 mmol) and DIEA (0.78 mL, 4.5 mmol) were added to a 0° C. solution of (2S,3R)-benzyl 2-((S)-2-amino-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 474 mg, 1.12 mmol) and 2-morpholinoacetic acid (162 mg, 1.12 mmol) in DMF (8 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was washed with EtOAc to afford (2S,3R)-benzyl 3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoate (349 mg, 67% yield) as a colorless solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]=4[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=3)[CH:10]=2)[CH:5]1[OH:34])=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])(=O)=O>C(Cl)Cl>[N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]=4[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=3)[CH:8]=[CH:7][C:6]=2[CH:5]1[O:34][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=NC1CCc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2C1O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Racemic 2-azido-6-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (130 mg, 0.28 mmol) was dissolved in CH2Cl2 (694 μL). To this solution was added 2,6-lutidine (129 μL, 1.1 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (133 μL, 0.55 mmol). The reaction was stirred at room temperature for 1 h. After that, the solution was loaded onto a 12 g ISCO column and purified by ISCO Combiflash Companion (0% ethyl acetate-hexane for 3 min then ramp to 20% ethyl acetate-hexane over 5 min then 20% ethyl acetate-hexane for 8 more min, product came out 8-10 min) to afford racemic-3-(6-azido-5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (130 mg, 0.22 mmol, 80%) as a white solid: LCMS=605.34 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Brc1cccnc1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2N)n1
Agent: [Pd]
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 2-amino-4-methylthiazole instead of 2-chloro-4-aminopyridine to yield 6-Methyl-2-(4-methyl-thiazol-2-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as a light yellow solid. MS (ISP): m/e=349.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide as an off-white solid, MS (ISP): m/e=249.4 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a yellow solid, MS (ISP): m/e=326.0 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1.[H-].[Na+]>O1CCCC1>[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:12][CH2:1][CH:3]([OH:5])[CH2:4][S:12][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([CH3:6])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(CS)cc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CSCC(O)CSCc2ccc(C)cc2)cc1

Procedure:
Epibromohydrin (1.37 g.) in 2 ml. dry tetrahydrofuran is added to a stirred suspension of the salt obtained by mixing 3 g. of 4-methylbenzyl mercaptan and 550 mg. of sodium hydride (56% dispersion in mineral oil) in 60 ml. dry tetrahydrofuran. The resulting solution is heated at reflux for 4 hours. Thereafter, the solvent is removed and 30 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extracts washed with water, dried over magnesium sulfate and evaporated to dryness to yield 1,3-bis(4'-methylbenzylthio)-2-propanol.