Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[CH:34]=[N:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=34)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:42])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[CH:34]=[N:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=23)[CH:30]=[CH:29][N:28]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.03 mmol) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was then heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and this solution was washed three times with water, then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (160 mg, 72%) as a tan solid after trituration with diethyl ether; 1H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES+ MH+ 432.72.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=1)[C:5](N[C@@H](C1C=CC=CC=1)CO)=[O:6])[CH3:2].C(=O)([O-])[OH:42].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=1)[C:5]([OH:6])=[O:42])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)N[C@H](CO)c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 90 °C
Yield: 54 %

Procedure:
(2S)-2-Ethoxy-N-[(1S)-2-hydroxy-1-phenylethyl]-3-{4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl}propanamide (0.45 g, 0.84 mmol) was dissolved in a mixture of 1M sulphuric acid (17 ml) and dioxane/water (1:1.39 ml) and heated to 90° C. for 88 h. The pH of the mixture was adjusted to 3 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 ml) and the organic phase was washed with water (50 ml), brine (25 ml), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in petroleum ether to afford the title compound (0.19 g, 54%) as a white solid. mp: 89-90° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:45]([Si:49]([CH3:60])([CH3:59])OCCN1C=CC(N)=N1)([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl>[C:45]([Si:49]([CH3:60])([CH3:59])[O:23][CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:3]=[CH:2][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][CH:5]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[N:17]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
The 3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 3, 184 mg, 0.62 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (31 μL, 0.62 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (144 μL, 1.24 mmol) was added dropwise. A strong exotherm and bubbling were observed. The solution continued to stir at 0° C. for 10 min. The 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 150 mg, 0.62 mmol) was added as a solution in methylene chloride (3 mL), the ice bath was removed and the solution continued to stir at 25° C. for 25 min. The solution was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (150 mg, 44%) as a white foam: ESI-LRMS m/e calcd for C26H41N3O4SSi [M+] 519.26, found 520.36 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:23]1[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)[N:20]=2)[CH:25]=[N:24]1
Reactant: CN(C)CCO
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(N5CCN(C)CC5)cc4)n3)cnn2CCN(C)C)cc1
Temperature: 0 °C

Procedure:
To the suspension of 90 mg (0.211 mMol) of [4-(4-methyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 25) in 4.5 mL of THF is added 38 mg (0.426 mMol) of 2-dimethylamino-ethanol (Fluka) and 122 mg (0.465 mMol) of triphenylphosphine (Fluka). The yellowish suspension is cooled to 0° C. and treated with 81 mg (0.465 mMol) of DEAD*. The mixture is stirred without cooling for 17 h, followed by heating for 24 h at 60° C. After cooling to rt, the reaction mixture is filtered and washed with 5 mL of THF. The filtrate is concentrated under reduced pressure and the crude product is purified by repeated chromatography on silica gel, eluting with CH2Cl2/MeOH (9:1) and CH2Cl2/MeOH/H2O 70:30:5 to obtain the title compound as beige crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]2[C:18]3[S:19][CH:20]=[C:21]([CH3:22])[C:17]=3[C:16]3=[N:23][CH:24]=[N:25][N:15]3[C:14]2=[O:26])=[CH:10][CH:9]=1.[C:29](=O)([O-])[O-:30].[K+].[K+]>CN(C)C=O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:18]3[S:19][C:20]([CH:29]=[O:30])=[C:21]([CH3:22])[C:17]=3[C:16]3=[N:23][CH:24]=[N:25][N:15]3[C:14]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3c(C)csc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(=O)n3ncnc3c3c(C)c(C=O)sc32)cc1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
Phosphorus oxychloride (1.47 ml, 15.8 mmol) was added to N,N-dimethylformamide (13 ml) and the mixture was stirred for 20 minutes. 6-(4-Methoxybenzyl)-9-methylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (1.29 g, 3.94 mmol) was added as a solid and the mixture was heated at 90° C. for 45 minutes. The mixture was cooled to room temperature and poured into a mixture of ice (30 mL) and potassium carbonate (5 g). After the ice had melted the pH was 8-9. The mixture was extracted with dichloromethane (3×30 mL) and the combined extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under vacuum. The residue was purified by flash LC (20-100% ethyl acetate in hexanes) to afford the aldehyde (0.87 g, 62%) as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 3.01 (s, 3H), 3.78 (s, 3H), 5.38 (s, 2H), 6.86-6.88 (m, 2H), 7.44-7.46 (m, 2H), 8.33 (s, 1H), 10.12 (s, 1H). LCMS (MH+, 355.0).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1>>[N:12]1([CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([N:19]3[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]3)=[CH:3][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1ccc([C@H]2C[C@@H]2CN2CCCCC2)cc1
Reactant: O=c1cccn[nH]1
Product: O=c1cccnn1-c1ccc([C@H]2C[C@@H]2CN2CCCCC2)cc1

Procedure:
Following the general procedure, reaction of 7b (2.67 g assayed, 9.08 mmol) with 3(2H)-pyridazinone (1.14 g, 11.8 mmol) afforded a solution of the free base of 8b in an assayed yield of 2.61 g (93% assay yield, 95% peak area).
Reaction SMILES: [C:1](=[O:47])([O:16][C:17]1[C:18]([CH3:46])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH3:45])([CH2:29][CH2:30][CH2:31][CH:32]([CH3:44])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:43])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:21][CH2:20]2)[O:2][CH2:3][CH:4]1[O:15][CH:5]1[CH2:6][O:7]CC1C=CC=CC=1.C(O)C.[H][H]>[C].[Pd].C(O)(=O)C>[C:1](=[O:47])([O:16][C:17]1[C:18]([CH3:46])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH3:45])([CH2:29][CH2:30][CH2:31][CH:32]([CH3:44])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:43])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:21][CH2:20]2)[O:2][CH2:3][CH:4]1[O:15][CH:5]1[CH2:6][OH:7]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 80.2 %

Procedure:
A mixture comprising 6.5 g (0.01 mol) of 4-benzyloxy-2,3-epoxybutyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 1 g of 5% palladium carbon, 150 ml of ethanol and 5 ml of acetic acid was catalytically reduced with hydrogen at an initial pressure of 4 kg/cm2 until no hydrogen was absorbed any more (approximately 6 hours). After filtering off the catalyst, the filtrate was concentrated to thereby reduce the amount to 1/3, poured into water and extracted with ether. Then the extract was successively washed with an aqueous solution of sodium hydrogencarbonate and water, and dried. After distilling off the solvent, the obtained oily residue was purifed by column chromatography (silica gel, hexane/ethyl acetate) to thereby give 4.5 g of the title compound as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:7][C:8]1[C:13]([NH2:14])=[C:12]([C:15]2[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:11]=[CH:10][N:9]=1)[CH2:5][CH3:6].[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([N:7]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:13]=2[N:14]=[C:25]([CH3:27])[C:24]1=[O:28])[CH2:5][CH3:6]
Reactant: CC[C@H](COC)Nc1ncnc(-c2ccc(OC)nc2C)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(-c3ccc(OC)nc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(1-Methoxymethyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.2 g, 0.63 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.70 ml, 6.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.0 mg of (R)-8-(1-methoxymethyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 651a). 1H NMR (300 MHz, CDCl3) δ ppm 8.93 (s, 1 H), 7.62 (d, J=8.42 Hz, 1 H), 6.64 (d, J=8.42 Hz, 1 H), 4.23 (m, 1H), 3.94 (s, 3 H), 3.68 (m, 2 H), 3.25 (s, 3 H), 2.45 (s, 3H), 2.34 (s, 3 H), 1.22 (m, 2H), 0.82 (t, J=7.51 Hz, 3 H). MS (EI) 370.3 [(M+H)+, 100].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15].C(O)(=O)C>C1(C)C=CC=CC=1>[S:15]=[C:14]1[NH:1][C:2]2[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Methyl 3-amino-4-hydroxyphenylacetate (5.43 g, 0.03 mol) was suspended in toluene (60 ml) and 1,1′-thiocarbonyldiimidazole (5.34 g, 0.03 mol) was added. The resultant mixture was stirred for 30 minutes, then acetic acid (10 ml) was added and the mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate The organic extract was dried over magnesium sulfate, filtered and the filtrate was evaporated to give methyl (2,3-dihydro-2-thioxo-5-benzoxazolyl)acetate (6,2 g) as a light brown solid, m.p. 120-122° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O1CCOCC1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O[C@@H]1CCNC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
8 g (46 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene 1,80 ml of dioxane and 8.14 g (0.095 mol) of (R)-(+)-3-pyrrolidinol are respectively placed in the reactor. The mixture is refluxed for one hour. The reaction medium is poured into a mixture of water (100 ml)-ice (200 g). A yellow product precipitates. This product is filtered off, washed with water (3×30 ml) and then dried under vacuum at 45° C. 8.38 g (75%) of 1-(3-methoxy-4-nitrophenyl)pyrrolidin-3-ol (2) are thus recovered.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8])=O.[C:13]([C:15]1[CH:20]=CC(O)=[CH:17][CH:16]=1)#[N:14]>O>[CH3:9][C:6]([O:5][C:3]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:2]=1)([CH3:10])[C:7]#[CH:8]
Reactant: C#CC(C)(C)OC(=O)C(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Solvent: O
Product: C#CC(C)(C)Oc1ccc(C#N)cc1

Procedure:
The 1,1-dimethyl-2-propynyl trifluoroacetate solution, maintained at 0° C., was added to the 4-cyanophenol solution over a 35 minute period while keeping the temperature at ~0° C. The resulting mixture was stirred at ~0° C. (ice bath). After stirring for 90 minutes, water (10 mL) was added and the resulting mixture was concentrated at reduced pressure. The residue was partitioned between water (50 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (3×50 mL), 1N NaOH (2×50 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (8.93 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:38])[CH2:36]Cl)[CH2:30][CH2:29]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:36][C:35]([NH:34][CH:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:39]=[CH:40][C:41]([Cl:42])=[C:24]([Cl:23])[CH:25]=4)[CH2:33][CH2:32]3)=[O:38])[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(CCl)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=[N+]([O-])c1cc(-c2csc(S)n2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
4-(4-Chloro-3-nitrophenyl)-2-mercaptothiazole (0.5 g) was dissolved in dimethylformamide (20 mL), and potassium carbonate (0.7 g) was added to the solution. Then, N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]chloroacetamide (0.6 g) was added, and the mixture was stirred at room temperature for 3 hrs. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give the title compound (0.7 g) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl.C(N(CC)CC)C>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2-Nitrobenzyl alcohol (1 g, 6.5 mmol) was dissolved in 40 ml of dry DCM and 1.36 ml of triethylamine. p-toluenesulfonyl chloride (1.24 g, 6.5 mmol) was added and the solution was stirred for 2 hours before quenching with water. The organic layer was separated and washed with 1 N HCl (1×50 ml), water (1×50 ml), 2 N NaOH (1×50 ml), water (1×50 ml) and brine (1×50 ml). The organic layer was dried over anhydrous Na2 SO4 and concentrated under reduced pressure to give a dull white solid, which was further purified by flash chromatography (silica gel, dichloromethane/ethanol=9.5:0.5) to give 2-nitrobenzyl tosylate, 22 (1.57 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.08-7.99 (dd, J=9.21 & 8.04 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.72-7.62 (m, 3H), 7.50 (d, J=8.85 Hz, 1H) 7.33 (d, J=8.43 Hz, 2H), 4.93 (s, 2H), 2.42 (s, 3H). 13C-NMR (60 MHz, CDCl3) δ 149.33, 146.12, 137.71, 135.27, 134.11, 133.09, 132.69, 132.57, 128.12, 123.89, 42.72, 20.64. MS (ESI): m/z 329.9 [(M+Na)]+.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[SH:10].Cl[CH:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].O>CO>[CH2:14]([CH:13]([S:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:4])[C:16]([CH2:17][CH2:18][CH3:19])=[O:20])[CH3:15]
Reactant: Cc1cc(S)c(C)o1
Reactant: CCCC(=O)C(Cl)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC(=O)C(CC)Sc1cc(C)oc1C
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, reflux condenser and thermometer is placed a solution of 0.27 g (0.005 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The sodium methoxide solution is cooled using a water bath to 25° C. A solution of 0.64 g (0.005 moles) of 2,5-dimethyl-3-furan thiol in 3 ml of absolute methanol is then added to the sodium methoxide solution dropwise from a pipette while maintaining the temperature of the reaction mass between 22° C and 28° C. While maintaining the temperature of the reaction mass at 23° - 35° C, 3-chloro-4-heptanone (0.74 g; 0.005 moles) in 1 ml absolute methanol is added dropwise. The reaction mass is then stirred for a period of 1 hour while maintaining the temperature at 23° C. After this 1 hour period, 15 ml of water is added with stirring and the reaction mass temperature rises to 28° - 30° C. The reaction mass is cooled to 25° C using a water bath and now exists in an aqueous phase and an organic phase. The aqueous phase (pH=6) is extracted with two 6 ml portions of n-hexane; and the hexane extracts and organic phase are combined, washed with a 4 ml portion of saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting material is gravity filtered and concentrated on a rotary evaporator at 25° - 35° C and 15 mm Hg pressure, yielding a crude yellow oil weighing 1.2 g. The desired product is isolated by GLC trapping (8 foot × 1/4 inch SE-30 Column), and NMR, IR and Mass Spectral analyses yield the information that this material has the structure: ##SPC16##
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.23 g), potassium carbonate (0.96 g), 1-(bromomethyl)-2-fluorobenzene (0.66 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.93 g, 59%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([OH:9])=O)=[CH:4][O:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:7]([C:5]1[NH:6][C:2](=[O:1])[O:3][CH:4]=1)=[O:9]
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1coc(=O)[nH]1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1coc(=O)[nH]1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-4-carboxylic acid (step 1) and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;