Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C1(C(O)=O)CCCCC1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Solvent: O=C(O)C1CCCCC1
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)C4CCCCC4)CC3)c12

Procedure:
Prepared according to a procedure analogous to that described for synthesis of [4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydro-2H-pyridin-1-yl]-phenylmethanone, except using cyclohexanecarboxylic acid. 1H NMR (400 MHz, CDCl3): δ=1.25-1.40 (m, 3H) 1.60 (br. s., 2H) 1.85 (dd, J=8.97, 2.65 Hz, 5H) 2.05 (dd, J=8.84, 3.28 Hz, 1H) 2.14-2.27 (m, 1H) 2.42-2.64 (m, 5H) 2.78 (br. s., 2H) 3.69-3.97 (m, 3H) 4.31 (br. s., 2H) 6.07 (br. s., 1H) 6.83 (br.s., 1H) 7.01 (d, J=5.05 Hz, 1H). MS (ES+): m/z 380.03 (100) [MH+]. HPLC: tR=2.27 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH3:15])[C:6]([O:16][CH3:17])=[CH:5][CH:4]=1)=[O:2].P([O-])(O)(O)=[O:19].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O1CCCC1.O>[CH2:12]([O:11][C:9]([C:8]1[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:1]([OH:19])=[O:2])=[O:10])[CH3:13]
Reactant: CCOC(=O)c1c(C=O)ccc(OC)c1OC
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)c1c(C(=O)O)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of ethyl 6-formyl-2,3-dimethoxybenzoate (5.24 g, 22 mmol), sodium dihydrogen phosphate (3.60 g, 30 mmol) and 2-methyl-2-butene (10.3 ml, 96.8 mmol) in t-butanol (20 ml), tetrahydrofuran (20 ml) and water (20 ml) was stirred at room temperature for 10 min. To the obtained mixture was added sodium chlorite (6.76 g, 74.8 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 2-(ethoxycarbonyl)-3,4-dimethoxybenzoic acid (4.51 g, 80.7%) as crystals.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C[Si](I)(C)C>C(#N)C>[NH2:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C#N)cn2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(c2ccc(C#N)cn2)CC1
Yield: 74.9 %

Procedure:
A solution of (5′-cyano-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester (93 mg) and trimethylsilyliodide (62 μL) in acetonitrile (1.5 mL) was heated to 45° C. for 20 minutes. The reaction mixture was cooled and concentrated under reduced pressure. The crude reaction mixture was purified by chromatography (silica gel, eluting with a gradient of 2% MeOH/CH2Cl2/0.1% NH4OH to 6% MeOH/CH2Cl2/0.1% NH4OH) to provide the titled compound (43 mg) as a yellow foam. MS (CI) m/z 217 (M+1)+; 1H NMR (300 MHz, DMSO) δ ppm 8.44 (s, 1H), 7.77 (d, 1H), 6.91 (d, 1H), 3.86-3.78 (m, 2H), 3.59-3.55 (m, 2H), 1.48-1.38 (m, 4H), 1.08 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[C:18](=O)[C:17]2[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)[Cl:28]>P(Cl)(Cl)(Cl)=O>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:28])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: COc1cccc2c(=O)c(C(=O)c3ccccc3)c[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Yield: 100 %

Procedure:
3-Benzoyl-8-methoxy-4(1H)-quinolone (3.2 g, 0.011 mol) was heated under reflux in a mixture of chloroform (50 ml) and phosphorus oxychloride (7 ml) for 45 minutes. The mixture was cooled and poured into a stirred mixture of sodium hydrogen carbonate solution, ice and chloroform. The organic phase was separated, washed with sodium hydrogen carbonate solution, water and brine. The dried solution was filtered and evaporated to afford 3-benzoyl-4-chloro-8-methoxyquinoline as a yellow oil (3.5 g, 100%).
Reaction SMILES: [CH:1]1([O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])(=O)=O>C(O)(=O)C>[Cl:21][CH2:16][C:15](=[O:17])[C:9](=[N:8][O:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOC1CCCCC1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC1CCCCC1)C(=O)CCl
Yield: 58.9 %

Procedure:
Ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.3 g.), acetic acid (41.3 ml.) and sulfuryl chloride (23.8 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4]1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][C:27]=1[O:33][CH3:34]>CN(C)C=O>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:3]2[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4]2)=[CH:28][C:27]=1[O:33][CH3:34]
Reactant: Nc1cn[nH]c1
Reactant: COc1cc(I)ccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CN(C)C=O
Product: COc1cc(-n2cc(N)cn2)ccc1Br
Temperature: 90 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of pyrazole-4-amine dihydrochloride (0.75 g, 4.79 mmol), salicylaldoxime (0.131 g, 0.96 mmol), cesium carbonate (4.69 g, 14.38 mmol), cuprous oxide (0.06 g, 0.29 mmol), 1-bromo-4-iodo-2-methoxybenzene (1.5 g, 4.79 mmol) and N,N-dimethyl-formamide (5 mL) were combined in a microwave vial fitted with an N2 inlet and magnetic stir bar. The reaction mixture was stirred under a nitrogen atmosphere at 90° C. overnight. The solution obtained was allowed to cool to RT, then filtered through celite and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromotography (10% to 60% EtOAc in heptanes) to give 1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-amine (250 mg, MS: 270.2 [M+H+].)
Reaction SMILES: CO.[C:3](Cl)(=[O:7])[C:4](Cl)=O.[BH4-].[Na+].S(=O)(=O)(O)O.[C:16]12(CS(O)(=O)=O)C(C)(C)[CH:20]([CH2:21][CH2:22]1)[CH2:19][C:17]2=[O:18]>ClCCl.C(O)C.O>[C@@H:4]12[C:3](=[O:7])[O:18][CH2:17][C@@H:16]1[CH2:22][CH:21]=[CH:20][CH2:19]2
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: O=C1OC[C@@H]2CC=CC[C@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cis-Cyclohexene-1,2-dicarboxylic anhydride (30.4 g, 200 mmol) in methanol (9 ml, 220 mmol) is heated at the boil for 1 h. Excess solyent is then evaporated. 33.2 g (180 mmol) of the resulting monomethyl ester are, at 0° C. and under argon, dissolved in 200 ml of dry dichloromethane and admixed dropwise with oxalyl chloride (32 g, 252 mmol). After the evolution of gas has ceased, stirring at room temperature is continued for 3 h. The solyent is then removed under reduced pressure and the residue is dissolved in 75 ml of THF. This solution is then added dropwise to a solution, kept at −40° C. and under argon, of sodium borohydride (13.6 g, 360 mmol) in 750 ml of absolute ethanol. After the evolution of gas has ceased, stirring at −40° C. is continued for 2 h, and the mixture is acidified to pH 2 using 4 N sulphuric acid and concentrated. The residue is admixed with 400 ml of water and extracted with MTBE. The ether phases are dried over magnesium sulphate, filtered and concentrated. The residue is then taken up in 200 ml of toluene, admixed with 10-camphorsulphonic acid (100 mg, 0.43 mmol) and heated in a water separator until TLC shows complete conversion. The solyent is then evaporated and the residue is distilled under reduced pressure (b.p.: 70° C./0.01 Torr).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[Br-].[CH:22]1([Zn+])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: [Zn+]C1CCCCC1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CCCCC2)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-cyano-4-(trifluoromethylsulfonyloxy)benzoate (0.7 g, 2.26 mmol) in tetrahydrofuran (30 mL) was added 0.5 M cyclohexylzinc(II) bromide solution in tetrahydrofuran (13.6 mL, 6.8 mmol) and bis(tri-tert-butylphosphine)palladium (0.058 g, 0.113 mmol) at room temperature. The mixture was heated under reflux for 2 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate solution and filtered through Celite®. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as an oil (0.24 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.33 (m, 1H), 1.42-1.53 (m, 4H), 1.77-1.84 (m, 1H), 1.86-1.95 (m, 4H), 2.99-3.08 (m, 1H), 3.93 (s, 3H), 7.45 (d, J=8.34 Hz, 1H), 8.17 (dd, J=8.15, 1.71 Hz, 1H), 8.27 (d, J=1.52 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(N)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NS(C)(=O)=O
Yield: 72 %

Procedure:
To a solution of compound from Step 4 (175 mg, 0.5 mmol) and Et3N (210 uL, 1.5 mmol) in 5 mL of CH2Cl2 at 0° C. was added MsCl (41 uL, 0.53 mmol) at 10 uL increment until starting material was no longer present by TLC. The mixture was quenched with saturated aqueous sodium bicarbonate, diluted with EtOAc and washed with 1 M HCl, water and brine, which was then dried (Na2SO4), filtered and concentrated to afford about 155 mg (0.36 mmol, 73%) of N-boc-4-[2-(2-methanesulfonylamino-2-methyl-propoxy)-phenyl]-piperazine as a yellow solid. LRMS (electrospray): 428.1 [M+1].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[C:11](O)(=[O:14])[CH2:12][OH:13].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CO>[OH:14][CH2:11][C:12]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)=[O:13]
Reactant: O=C(O)CO
Reactant: NCc1csc2cncn12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)NCc1csc2cncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 4 ml of methanol and 296 mg of THF containing 296 mg of 3-aminomethylimidazo[5,1-b]thiazole, 162 mg of glycolic acid, 26 mg of 1-hydroxybenzotriazole and 439 mg of 1,3-dicyclohexylcarbodiimide were added, and the mixture was then stirred at room temperature for 1 hour. Further, insolubles were removed therefrom by filtration, and after washing with methanol, the filtrate was concentrated under reduced pressure. To the resulting residue, dichloromethane and an aqueous potassium carbonate solution were added, and the crystal was collected by filtration. The organic layer was separated from the filtrate, and the aqueous layer was extracted five times with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was combined with the above crystal, and crystallization was then made from ethyl acetate. To the obtained crystal, 20 ml of water and 2.7 ml of a 1N aqueous hydrochloric acid solution were added, and insolubles were then removed therefrom by filtration. Afterward, anhydrous potassium carbonate was dissolved in the filtrate, and the resulting crystal was collected by filtration, and then washed with dichloromethane and water to obtain 267 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][C:11]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[N:4][CH:3]=1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:19])=[CH:12][C:11]=2[C:20]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[N:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2ncc(Cl)s2)c(C(=O)C2CCCC2)c1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNC(=O)Cc1ccc(NC(=O)Nc2ncc(Cl)s2)c(C(=O)C2CCCC2)c1
Yield: 70.2 %

Procedure:
2-{4-[3-(5-Chloro-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-N-(2-methanesulfonyl-ethyl)-acetamide (180 mg, 70%) was prepared from {4-[3-(5-chloro-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-acetic acid (204 mg, 0.5 mmol) and 2-methanesulfonyl-ethylamine (62 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>CCOCC.C([O-])(=O)C.[Na+]>[C:10]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])(=[O:11])[CH2:9][C:8]([CH3:7])=[O:12]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)=CCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)OCC=C(C)C
Yield: 75.4 %

Procedure:
A mixture of 3-methyl-2-buten-1-ol (21.2 g, 0.25 mole) and anhydrous sodium acetate (0.1 g) was cooled to 0°. Diketene (36 ml, 0.3 mole) was added dropwise over a period of 1.5 to 2 hours. The reaction mixture was then heated to 75°-80°, and this temperature was maintained for one hour. The mixture was diluted with ether. The ethereal solution was washed successively with aqueous 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over magnesium sulfate. The ether was evaporated, leaving a residue which was distilled under vacuum, affording 3-methyl-2-butenyl acetoacetate (32.1 g, 76% yield); bp 114°-117°/18-19 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13](OC(=O)C)[C:14]([N:16]([CH3:27])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH3:18])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl>[CH3:18][CH:17]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:14](=[O:15])[N:16]1[CH3:27]
Reactant: COc1cccc(C(C)N(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(C)N(C)C(=O)C2c1cc(OC)c(OC)c(OC)c1

Procedure:
A solution of the amide from step 2 above (4.2 g) in dichloromethane (60 ml) and trifluoroacetic acid (20 ml) was refluxed for 4 hours. The reaction mixture was concentrated to dryness and the residue was submitted to chromatography on silica gel using dichloromethane-ethyl acetate (6:4) as eluent. The first fraction was concentrated to dryness and the residue was crystallized from methanol giving diastereomer I, m.p. 135-140° C. The third fraction contained diastereomer II, which was recovered as an amorphous solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 55 °C

Procedure:
A mixture of 6.8 g of the product of Step A, 41 ml of dioxane and 8.15 ml of 2 N sodium hydroxide was heated on a water bath at 55° C. for 2 hours and was then cooled. 9.5 ml of 2 N hydrochloric acid were added to obtain a pH of 2-3 and the dioxane was distilled. Crystallization was effected and water diluted the mixture under stirring. The recovered precipitate was vacuum filtered, rinsed with water, empasted with ether and dried to obtain 5.87 g of the anti isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetic acid melting at 240° C. (decomp.).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[NH:14][C:13]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O.CC(=O)OCC.O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:25])[C:13]1=[O:24])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(=O)[nH]c2cnc(Cl)cc2c1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2cc(Cl)ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (3.3 g, 0.0089 mol), K2CO3 (2.468 g, 0.0178 mol) in acetone (10 mL) was added iodomethane (1.51 g, 0.01 mmol). The reaction was stirred at RT for 3 h then diluted with EA (20 mL) and water (5 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methyl pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (3 g, 87% yield) as a white solid. MH+ 384, TR=2.166 min. Used without further purification.
Reaction SMILES: [CH3:1][P:2]1(=[O:35])[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[CH:18][C:17]=3[NH:27]C(=O)OC(C)(C)C)=[O:14])=[CH:9][CH:8]=2)[O:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[C:10]1[CH:11]=[CH:12][C:7]([CH:4]2[O:3][P:2]([CH3:1])(=[O:35])[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2CCP(C)(=O)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP1(=O)CCC(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cc2)O1
Reaction time: 3 h

Procedure:
1,1-dimethylethyl [2-({[4-(2-methyl-2-oxido-1,2-oxaphospholan-5-yl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (95 mg, 0.185 mmol) was taken up in DCM (5 mL)/TFA (2 mL). After 3 hours, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give N-[2-amino-5-(2-thienyl)phenyl]-4-(2-methyl-2-oxido-1,2-oxaphospholan-5-yl)benzamide as a yellow solid. The title compound was obtained as a 1:1 mixture of diastereosiomers. MS: cal'd 413 (MH+), exp 413 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:40]1([NH:39][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nα -Benzyloxycarbonyl-L-phenylalanine (4.95 g, 16.5 mmol) was dissolved in dichloromethane (70 ml) and the solution was cooled to 0° C. and stirred during the addition of pentafluorophenol (3.35 g, 18.2 mmol), followed by EDC (3.49 g, 18.2 mmol). The mixture was allowed to warm to room temperature, stirred for a further 1 hour then cooled back to 0° C. Aniline (3.85 g, 41.4 mmol) was added dropwise and the mixture was warmed to room temperature then stirred overnight. The solution was washed twice with 1M sodium carbonate, twice with 1M hydrochloric acid and finally with brine before drying over anhydrous magnesium sulphate. The solution was filtered and evaporated to a white solid which was recrystallised from ethyl acetate-hexane. Yield: 2.57 g (41%). 1H-NMR; δ (CDCl3), 7.87 (1H, brs), 7.43-7.03 (15H, br m), 5.62 (1H, m), 5.08 (2H, s), 4.59 (1H, s) and 3.15 (2H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4].[CH3:15][C:16]([CH3:26])([CH:20]1[O:24][CH:23]([CH3:25])[CH2:22][O:21]1)[CH2:17][NH:18][CH3:19]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:18]([CH2:17][C:16]([CH3:15])([CH3:26])[CH:20]2[O:24][CH:23]([CH3:25])[CH2:22][O:21]2)[CH3:19])=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CNCC(C)(C)C1OCC(C)O1
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Solvent: CCOC(C)=O
Product: CC1COC(C(C)(C)CN(C)C(=O)Nc2nnc(S(=O)(=O)N(C)C)s2)O1

Procedure:
5-(N,N-Dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocynate dimer (6 grams) N-[2,2-dimethyl-2-(4-methyl-1,3-dioxolan-2-yl)ethyl]methylamine (6 grams) and ethyl acetate (20 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer. The reaction mixture is heated on a steam bath for a period of about 2 hours. Solvent is then stripped off using a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N'-[2,2-dimethyl-2-(4-methyl-1,3-dioxolan-2-yl)ethyl]-N'-methylurea as the residue.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>ClCCl>[F:1][C:2]([F:9])([F:8])[C:3]1([O:7][C:17](=[O:18])[O:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1(C(F)(F)F)CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1(C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
To 1-trifluoromethyl-cyclobutanol (2.2 g, 15 mmol) in dichloromethane (7.5 mL, 2M) was added pyridine (3 mL) and 4-nitrophenyl chloroformate (4 g, 18.3 mmol). The flask was sealed and stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (50 mL) and washed with 1M KHSO4(aq), saturated sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (gradient elution with 10% to 40% EtOAc in hexane) gave 2.2 g (48% yield) of carbonic acid 4-nitro-phenyl ester 1-trifluoromethyl-cyclobutyl ester as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, 2H), 7.50 (d, 1H), 2.78-2.85 (m, 2H), 2.58-2.70 (m, 2H), 1.9-2.1 (m, 2H).