Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:3]([O:10][CH3:11])[CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C=O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 51 %

Procedure:
To 400 mg (2.60 mmol) of 4-fluoro-3-methoxybenzaldehyde diluted in 10 ml of dimethylsulfoxide are respectively added 483 mg (2.60 mmol) of tert-butyl piperazine-1-carboxylate, then 394 mg (2.85 mmol) of potassium carbonate. The solution is heated to 90° C. for 40 h, then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 8:2) to yield 425 mg of tert-butyl 4-(4-formyl-2-methoxyphenyl)piperazine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1.[CH:28]([O:41][C:42]([NH:44][C:45]1[NH:46][C:47](=[O:58])[C:48]2[N:49]=[CH:50][N:51]([CH2:54][C:55](O)=[O:56])[C:52]=2[N:53]=1)=[O:43])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:55](=[O:56])[CH2:54][N:51]4[CH:50]=[N:49][C:48]5[C:47](=[O:58])[NH:46][C:45]([NH:44][C:42]([O:41][CH:28]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)=[O:43])=[N:53][C:52]4=5)[CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2cc(Cl)ccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4cc(Cl)ccc4s3)C(=O)C2)c(=O)[nH]1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(5-chloro-benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.62 (brs, H), 11.25 (brs, 1H), 8.42–8.39 (m, 1H), 7.96 (s, 0.6H), 7.82 (s, 0.4H), 7.78 (m, 1H), 7.46 (d, 4H), 7.39 (t, 4H), 7.31 (t, 2H), 6.87 (s, 1H), 5.17 (s, 1.2H), 5.06 (s, 0.8H), 4.53 (s, 0.8H), 4.29 (s, 1.22H), 4.25 (t, 1.2H), 4.08–4.06 (m, 2H), 3.87 (t, 0.8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]([NH:15][NH2:16])[N:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[N:13][N:12]3[C:23](=[O:24])[NH:16][N:15]=[C:11]3[C:10]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2cnnc(NN)c2-c2ccncc2)cc1
Product: COc1ccc(-c2cnn3c(=O)[nH]nc3c2-c2ccncc2)cc1

Procedure:
The title compound was prepared by reacting 1-(5-(4-methoxyphenyl)-4-(pyridin-4-yl)pyridazin-3-yl)hydrazine with carbonyldiimidazole (CDI) by procedures analogous to those described in Example 279F to give 7-(4-methoxyphenyl)-8-(pyridine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. LC/MS (method A): RT=1.37 min, (M+H)+=320.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[CH3:17][O:18][CH2:19][C:20]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])=[O:21]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane (420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in an ice-methanol bath under nitrogen atmosphere (−9° C.). To this mixture was added dropwise a solution of methoxyacetyl chloride (24.8 g) in dichloromethane (180 mL) over 1 hour period at the temperature. After addition, the reaction mixture was stirred at the temperature for 1 hour and at ambient temperature for 2 hours. The mixture was quenched with 1N hydrochoric acid (600 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as dark orange oil (38.1 g, 84.7%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:22]C1C=C(C=CC=1)C=O>>[Br:22][C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(Br)c2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 52 but using 3-bromobenzaldehyde in place of 3-iodobenzaldehyde. Solid (11 g, 28%);
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B2OCCCO2)=[C:20]([F:30])[C:19]=1[O:31][CH3:32].[F-].[Cs+].C(#N)C>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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([O:31][CH3:32])[C:20]=2[F:30])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16]
Reactant: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(Cl)c(N)c2F)c1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A 50 mL Schlenk flask was charged with propan-2-yl 4-amino-3,6-dichloro-5-fluoropicolinate (2.162 g, 8.09 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (2.775 g, 11.35 mmol) and CsF (2.601 g, 17.12 mmol). Acetonitrile (20 mL) and water (7 mL) were added. The solution was evacuated/backfilled with nitrogen (5×). Solid bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2; 281 mg, 4.9 mol %) was added. The solution was evacuated/backfilled with nitrogen (5×) and then heated at 70° C. under nitrogen for 3 h. After 3 h, the reaction mixture was allowed to cool to room temperature. The aqueous layer was separated. Water (20 mL) was added to the organic layer. The resulting dark brown precipitate was filtered and washed with water. The solid was dissolved in EtOAc (60 mL) and filtered to remove a small amount of black solid. The EtOAc solution was treated with activated carbon (175 mg) and filtered to give a wine-colored solution. Evaporation under reduced pressure gave a dark red solid. Purification (120 g silica column; 0-50% EtOAc-hexane gradient) gave a white solid (2.59 g, 82%): mp 110.6-112.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 5.32 (septet, J=6.3 Hz, 1H, CHMe2), 5.07 (br s, 2H), 3.97 (d, JF-H=1.0 Hz, 3H, OMe), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 164.2 (CO2R), 153.8 (d, JF-C=254 Hz, C5/C2′), 145.5 (d, JF-C=258 Hz, C5/C2′), 145.0 (d, JF-C=5 Hz), 144.4 (d, JF-C=14 Hz), 140.0 (d, JF-C=13 Hz), 137.5 (d, JF-C=14 Hz), 129.7 (d, JF-C=3 Hz), 125.4 (d, JF-C=2 Hz, C5′/C6′), 125.2 (d, JF-C=3 Hz, C5′C6′), 122.7 (dd, JF-C=14, 4 Hz, C1′), 114.6 (C3), 70.2 (CHMe2), 61.5 (d, JF-C=4 Hz, OMe), 21.6 (CHMe2); 19F NMR (376 MHz, CDCl3) δ −128.16 (dd, JF-F=33.3 Hz, JF-H=2.5 Hz, phenyl F), −138.35 (d, JF-F=33.4 Hz, pyridine F5). Anal. Calcd for C16H14Cl2F2N2O3: C, 49.12; H, 3.61; N, 7.16. Found: C, 49.30; H, 3.69; N, 7.08. The product was found to be 97.5% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:20][CH2:19][CH2:18]5)[O:16][C:13]4=[CH:14][CH:15]=3)=[CH:6][N:5]2[CH:31]=1.C(O)(=O)C.[H][H]>CCO.O=[Pt]=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:18][CH2:19][CH2:20]5)[O:16][C:13]4=[CH:14][CH:15]=3)[CH2:6][N:5]2[CH:31]=1
Reactant: Cc1cn2cc(-c3ccc4c(c3)C3(COC(N)=N3)C3(COC3)C3(CCC3)O4)ccc2n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cn2c(n1)CCC(c1ccc3c(c1)C1(COC(N)=N1)C1(COC1)C1(CCC1)O3)C2
Temperature: 25 °C
Reaction time: 38 h
Yield: 83.2 %

Procedure:
A suspension of 6′-(2-methylimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (66 mg, 0.16 mmol), acetic acid (27 μl, 0.06 mmol) and PtO2 (13 mg) in EtOH (3.3 ml) was stirred at room temperature under the hydrogen atmosphere at 3 atm for 8 hours. To the mixture was added acetic acid (63 μl), and the mixture was stirred at room temperature under hydrogen atmosphere at 3 atm for 38 hours. The mixture was filtrated through celite pad. And then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silicagel column chromatography (28% NH4OH/EtOH/CHCl3=2:20:80) followed by trituration in iPr2O and filtration to give 6′-(2-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (56 mg).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C[Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:9]([NH:21][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCNC1=NC(=O)NOC1
Yield: 88.2 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 2.22 g (0.012 mole) of dodecylamine and 20 ml of hexamethyldisilazane in 40 ml of freshly distilled dry dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 2.5 g (88 percent) of 5-dodecylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:15]=[C:16]3O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C1(P(Cl)([Cl:34])=O)C=CC=CC=1>>[Cl:34][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH:13]=[C:14]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(O)c3c2)c1
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(Cl)c3c2)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinolin-1-ol (130 mg, 0.395 mmol) in phenylphosphonic dichloride (5 mL) was stirred at 120° C. overnight. After the reaction was completed, the mixture was added to ice-water slowly. The pH was adjusted to 7 by slow addition of NH3H2O at 0° C. Then the mixture was extracted with dichloromethane (100 mL×3). The combined organic layer were dried over MgSO4, filtered and concentrated in vacuo to give 130 mg of crude lxix-a as a white solid, which was used directly in the next step without purification. LCMS m/z=346.9 (M+1) (Method B) (retention time=1.80 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].C(O)(=O)C.[N+:19]([O-])([O-:21])=[O:20].[K+].OS(O)(=O)=O>O>[OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH2:6][C:5]2=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(=O)c2c(ccc(O)c2[N+](=O)[O-])O1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 250 mL round bottom flask equipped with a magnetic stir bar was added 3 (810 mg, 4.2 mmol) and 15 mL of glacial acetic acid. The mixture was stirred at room temperature until all of the solid dissolved. To a 25 mL vial was added KNO3 (469 mg, 4.6 mmol) and just enough distilled water to dissolve all the KNO3. The aqueous KNO3 solution was transferred to the reaction flask with a pipet. The reaction flask was lowered into an ice water bath (˜10° C.). Concentrated H2SO4 (1 mL) was added drop-wise. The mixture was stirred until all starting material was consumed, as monitored by TLC analysis. Ethyl acetate (20 mL) was added, and the biphasic mixture was transferred into a 500 mL separatory funnel. Saturated aqueous Na2CO3 was added cautiously until the aqueous layer was pH˜7. The aqueous phase was extracted in ethyl acetate (3×20 mL), the combined organic phases were washed with brine (1×50 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry crude product was passed through a silica gel column using 25:1 CH2Cl/EtOAc as eluent (Rf=0.3). The product gives off a red color on an analytical silica gel plate illuminated with a shortwave UV lamp. The fractions containing the pure product were transferred to a pre-weighed flask, the solvent was evaporated and the concentrate was dried under high vacuum. The reaction furnished 715 mg (72%) of 4 as a yellow solid. 1H NMR (300 MHZ, CDCl3): δ 7.70 (bs, 1H), 7.21 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 2.76 (s, 2H), 1.46 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 188.9, 154.4, 145.0, 126.4, 124.7(2), 113.1, 80.6, 49.0, 26.4; HRMS (EI+): calculated for C11H11NO5[M+] m/z 237.0637, found 237.0633.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH3:20][S:17]([O:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])[CH2:13]1)(=[O:18])=[O:19]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCC(=O)NC(N)=O)C1

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (3.00 g) in a mixture of methanol (30 ml) and tetrahydrofuran (60 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 5 hours in the presence of 20% palladium hydroxide on carbon (1 g). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (20 ml) and water (20 ml) was dropwise added a solution of allyl chloroformate (0.82 ml) in tetrahydrofuran (2 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (15 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (1.11 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[N:64]=[C:35]2[C:36]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)=[C:37]([CH3:53])[C:38]([C:40]3[N:44]([C:45]4[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=4)[N:43]=[CH:42][CH:41]=3)=[CH:39][N:34]2[N:33]=1.C(OC(N(C)CCCC(OC(OCC(C)C)=O)=O)=O)(C)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:31][C:32]1[N:64]=[C:35]2[C:36]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:62])([F:63])[F:61])[CH:55]=3)=[C:37]([CH3:53])[C:38]([C:40]3[N:44]([C:45]4[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=4)[N:43]=[CH:42][CH:41]=3)=[CH:39][N:34]2[N:33]=1)[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: CC(C)COC(=O)OC(=O)CCCN(C)C(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCN(C)C(=O)OC(C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: -22 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (109 mg, 0.50 mmol) in THF (5 mL) was treated with 4-methyl-morpholine (101 mg, 1.0 mmol) followed by isobutyl chloroformate (68 mg, 0.5 mmol) and cooled to −22° C. under argon. The reaction mixture was stirred for 20 mins while warming to −15° C. After re-cooling to −24° C., 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 230 mg, 0.50 mmol) was added and the resulting suspension was slowly warmed to RT and stirred for 16 hrs. The reaction mixture was treated with a fresh batch of 1-({[(4-{[(tert-butoxy)carbonyl] (methyl)-amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (218 mg, 1.0 mmol) in THF (5 mL), 4-methyl-morpholine (101 mg, 1.0 mmol) and isobutyl chloroformate (137 mg, 1.0 mmol) at RT. The reaction mixture was stirred at RT for 24 hrs and then heated at 60° C. for 7 hrs. After standing at RT for 18 hrs, the volatiles were removed in vacuo and the resulting residue was purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM. The product containing fractions were concentrated in vacuo and the resulting residue (456 mg, 0.5 mmol) in THF (5 mL) was treated with a fresh batch of 1-({[(4-{[(tert-butoxy)carbonyl] (methyl)amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (1.09 g, 5.0 mmol) in THF (20 mL), 4-methyl-morpholine (760 mg, 7.55 mmol) and isobutyl chloroformate (680 mg, 5.01 mmol) at RT. The resulting mixture was heated at 50° C. for 65 hrs and then purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM followed by 10% MeOH in DCM affording the title compound (241 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>O>[Cl:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: CSc1nccc(-c2cccnc2Cl)n1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CSc1nccc(-c2cccnc2Oc2ccc(Cl)nc2)n1
Temperature: 120 °C

Procedure:
A mixture of cesium carbonate (5.03 g, 15.4 mmol), 6-chloropyridin-3-ol (1.00 g, 7.72 mmol), and 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (1.83 g, 7.72 mmol) was sealed and heated to 120° C. overnight. The reaction was cooled slightly and poured slowly into a rapidly stirring solution of 250 mL water. A tan precipitate resulted which was collected by filtration through a 0.45 micron filter. The solid was washed 3× with water, then dried in vacuo overnight to give 4-(2-(6-chloropyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine as a tan solid. MS m/z=331 [M+H]+. Calc'd for C15H11ClN4OS: 330.8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(-n2cnnn2)cc(I)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N

Procedure:
To a solution of 1-(4-amino-3-iodo-5-methylphenyl)tetrazole (5 g) in acetonitrile (80 cm3) was added ethyl acrylate (2 g), triethylamine (2 g) and palladium acetate (0.1 g). The mixture was heated under reflux for 11/2 hours, cooled and then partitioned between water (100 cm3) and dichloromethane (100 cm3). The aqueous phase was re-extracted with more dichloromethane (100 cm3) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane: methanol, 20:1. Combination and evaporation of appropriate fractions gave a solid which on recrystallisation from ethyl acetate/methanol afforded yellow needles of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate, m.p. 210°-211°, (3.45 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][CH2:28][C:29](=[O:35])[N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[NH:20][C:19](=[O:37])[C:18]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:38]3[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=3)[C:19](=[O:37])[NH:20]2)=[CH:25][C:24]=1[CH2:27][CH2:28][C:29](=[O:35])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(CCC(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-oxo-3-pyrrolidin-1-yl-propyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (9.0 mg in 2.0 dry methylene chloride) was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 9:1) to give the title compound (7.0 mg). MASS: 536 (M+H)