Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[F:17])[S:13][C:12]([CH3:19])([CH3:18])[CH2:11][C:10]2=[O:20])(=O)=O.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>CCN(CC)CC.CN(C=O)C.O.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>[CH3:18][C:12]1([CH3:19])[CH2:11][C:10](=[O:20])[C:9]2[C:14](=[CH:15][C:16]([F:17])=[C:7]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:8]=2)[S:13]1
Reactant: CC1(C)CC(=O)c2cc(OS(=O)(=O)C(F)(F)F)c(F)cc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)c(F)cc2S1
Temperature: 95 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-7-fluoro-thiochroman-6-yl trifluoromethanesulfonate (Compound 205, 1.28 g, 3.57 mmol) in 6.0 mL Et3N and 15.0 mL DMF was sparged with argon for 15 minutes. To this solution was added trimethylsilylacetylene (2.0 g, 20.4 mmol) and bis(triphenylphosphine)-palladium(II) chloride (100.0 mg, 0.14 mmol). The solution was heated to 95° C. for 6 hours, cooled to room temperature and stirred overnight. The solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl and dried over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3 to 5% EtOAc/hexanes) afforded 850.0 mg (78%) of the title compound as an orange solid. 1H NMR (300 MHz, CDCl3)δ: 8.22 (1H, d, J=7.5 Hz), 6.92 (1H, d, J=9.3 Hz), 2.85 (2H, s), 1.46 (6H, s), 0.25 (9H, S).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH2:11][CH2:12][OH:13])[CH3:10]>O1CCCC1>[C:4]([O:13][CH2:12][CH2:11][N:9]([CH3:10])[CH3:8])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CN(C)CCO
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)CCC(=O)O
Reaction time: 2 h

Procedure:
In a two liter four neck flask equipped with stirrer, thermometer, condenser and addition funnel were charged succinic anhydride (200 g) and tetrahydrofuran (1400 ml). A homogeneous solution of succinic anhydride in tetrahydrofuran was made when the pot temperature reached 50° C. with external heating. Dimethylaminoethanol (178 g) was added at a rate that the exothermic reaction kept the pot temperature at 55° C. to 60° C. The reaction mixture was digested at 50° C. for a period of two hours after the addition of dimethylaminoethanol was completed. A first crop of crystalline product was collected by filtration and a second crop of product was collected from the mother liquor after concentration to 250 ml by means of reduced pressure distillation. These products were combined and dried in a vacuum over at 40° C. and 3 mm Hg pressure. The total yield was 303 g, 80% of the theoretical yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]3[C:16]([CH3:24])([C:21]([NH2:23])=[O:22])[CH2:17][C:18]([CH3:20])([CH3:19])[C:12]3=[C:11]2[CH3:25])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:26]O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([CH3:15])=[C:13]3[C:16]([CH3:24])([C:21]([NH2:23])=[O:22])[CH2:17][C:18]([CH3:19])([CH3:20])[C:12]3=[C:11]2[CH3:25])=[CH:8][CH:9]=1)([O:3][CH3:26])=[O:2]
Reactant: CO
Reactant: Cc1c2c(c(C)n1-c1ccc(C(=O)O)cc1)C(C)(C(N)=O)CC2(C)C
Product: COC(=O)c1ccc(-n2c(C)c3c(c2C)C(C)(C(N)=O)CC3(C)C)cc1

Procedure:
Reaction of the 2-(4-carboxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide described above in Example 20BZ with methanol in the presence of a small amount of a mineral acid affords 2-(4-carbomethoxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.C(Br)(Br)(Br)Br>C(OCC)(=O)C.O1CCCC1>[F:14][C:13]([F:15])([F:16])[C:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH:3]=[CH:2]2)=[CH:6][CH:7]=1)=[O:17]
Reactant: O=C(Nc1ccc2c(c1)C(O)CC2)C(F)(F)F
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)C=CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a mixture of 1-hydroxy-6-(trifluoroacetamido)indane (4.37 g), triphenylphosphine (7.01 g), methylene chloride (70 ml) and tetrahydrofuran (7 ml), at 0° C., was added carbon tetrabromide (8.87 g) in four portions. After 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 4 h. Ethyl acetate was added and the solution was washed (water, brine), dried (MgSO4) and evaporated. The residue was flashed chromatographed, eluting with methylene chloride, to give 6-(trifluoroacetamido)-3H-indene (3.09 g, 76%) as a colorless solid; mp 131.5°-132.5° C.; MS(CI), m/e=228(M+H).
Reaction SMILES: N1C=CC=C(C[N:8]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[C:9]2[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:11][CH:10]=2)C=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[CH3:41][N:42]([CH3:45])C=O>>[N:42]1[CH:45]=[CH:12][CH:11]=[C:10]([CH2:9][NH:8][C:15](/[CH:14]=[CH:13]/[C:12]2[CH:11]=[CH:10][C:9]([N:8]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=2)=[O:17])[CH:41]=1
Reactant: O=C(O)C=Cc1ccc(N(Cc2cccnc2)C(=O)C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)CN(C(=O)C(F)(F)F)c1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Yield: 30 %

Procedure:
A suspension of N-(3-pyridylmethyl)-4-[(trifluoroacetyl)amino]cinnamic acid (1.55 g) and potassium carbonate (1.84 g) in 10 ml dimethylformamide was stirred with 0.7 ml t-butyl bromoacetate for 24 hours. After removal of inorganic salts by filtration, insoluble components precipitated from water were filtered off. The filtrate was extracted with ethyl acetate and the organic layer was washed with water and brine, and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give a residue, which was then separated and purified via column chromatography on silica gel (chloroform:methanol=50:1) to provide t-butyl [[4-[(E)-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl](trifluoroacetyl)amino]acetate (582 mg, 30%).
Reaction SMILES: [CH:1]1(CN2C(=O)C3NC(C4C=CC(COCCOCCOCCOCCOCCOCCOCCOCCOCCOC)=CC=4)=NC=3N(CC3CCCCC3)C2=O)CCCCC1.[CH:62]1([CH2:68][N:69]2[C:77](=[O:78])[C:76]3[N:75]=[C:74]([C:79]4[CH:89]=[CH:88][C:82](/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86])=[CH:81][CH:80]=4)[NH:73][C:72]=3[N:71]([CH2:90][CH:91]3[CH2:96][CH2:95][CH2:94][CH2:93][CH2:92]3)[C:70]2=[O:97])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1.C1(CN2C(=O)C3N=C(C4C=CC=C(/C=C/C(N5C=CN=C5)=O)C=4)NC=3N(CC3CCCCC3)C2=O)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CO>[CH3:1][O:86][C:85](=[O:87])/[CH:84]=[CH:83]/[C:82]1[CH:81]=[CH:80][C:79]([C:74]2[NH:73][C:72]3[N:71]([CH2:90][CH:91]4[CH2:92][CH2:93][CH2:94][CH2:95][CH2:96]4)[C:70](=[O:97])[N:69]([CH2:68][CH:62]4[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]4)[C:77](=[O:78])[C:76]=3[N:75]=2)=[CH:89][CH:88]=1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccc(-c2nc3c([nH]2)c(=O)n(CC2CCCCC2)c(=O)n3CC2CCCCC2)cc1
Agent: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
In the manner of Example 36, part (b), (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid was converted to (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder. Such a sample (2.50 g, 4.62 mmol) was stirred at reflux in acetonitrile (75 ml) with potassium carbonate (1.28 g, 9.25 mmol) and methanol, (10 ml) for 24 hours. The mixture was cooled to room temperature and filtered and the filtrate-wash was adjusted to pH ˜3 by addition of 6N hydrochloric acid. The resulting precipitate was filtered and washed with methanol and dried to give (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid methyl ester (1.70 g, 74%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J=8.2 Hz, 2H, phenylCH), 7.83 (d, J=8.4 Hz, 2H, 2 phenylCH), 7.63 (d, J=15.9 Hz, 1H, CH═), 6.70 (d, J=15.9 Hz, 1H, CH—), 3.95 (d, J=7.0 Hz, 2H, CH2N), 3.75 (d, J=6.8 Hz, 2H, CH2N), 3.70 (s, 3H, CH3), 2.0-1.50 and 1.20-0.80 (m, 22H, 2C6H11).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13][NH2:14].C(O)C>CCOCC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: CCO
Product: N#CCC(=O)NCc1ccc(Cl)c(Cl)c1
Reaction time: 42 h

Procedure:
A solution of 113.3 g. (1.002 moles) of ethyl cyanoacetate and 176.4 g. (1.002 moles) of 3,4-dichlorobenzylamine in 400 ml. of absolute ethanol is heated at reflux with stirring for 42 hours which upon cooling the entire solution solidifies. The latter is broken-up, slurried in ether, isolated by filtration and dried in vacuo to give 179.8 g. of product as a white solid, m.p. 144°-5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:5][C:6]1[N:7]([CH2:15][CH2:16][C:17]([O-:19])=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:3][CH3:4].[NH2+]1CCCCC1.[CH2:26]([O:33][CH2:34][CH:35]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][CH2:34][CH:35]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:6]=2[CH2:5][N:2]([CH3:1])[N:3]1[CH3:4])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CNN(C)Cc1cc2ccccc2n1CCC(=O)[O-]
Reactant: O=CCOCc1ccccc1
Agent: C1CC[NH2+]CC1
Product: CN1Cc2c(c3ccccc3n2CCC(=O)O)C(COCc2ccccc2)N1C

Procedure:
Compound 4 was reacted with benzyloxyacetaldehyde, which was chosen as a model small molecule aldehyde for its UV absorption and aqueous solubility properties, to produce the azacarboline product (Compound 5). To a solution of Compound 4 (16.2 mg, 46.8 mmol) in aqueous acetonitrile (1:3 water:acetonitrile, 800 μL) was added benzyloxyacetaldehyde (7.23 μL, 51.5 μmol, 1.10 equiv). After 1 h, the solution was purified by C18 silica gel chromatography (0-100% acetonitrile in water with 0.1% acetic acid). Toluene was added to the eluent to aid in removal of residual acetic acid, and the product was isolated as a pale brown oil (16.2 mg, 41.2 μmol, 88%). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.8 Hz, 1H), 7.38-7.34 (m, 2H), 7.34-7.30 (m, 3H), 7.18-7.15 (m, 2H), 7.08-7.05 (m, 1H), 4.65 (d, J=12.4 Hz, 1H), 4.58 (d, J=12.4 Hz, 1H), 4.28-4.18 (m, 2H), 4.10 (m, 1H), 3.91 (t, J=9.0 Hz, 1H), 3.81 (s, 1H), 3.76-3.64 (m, 2H), 2.69 (t, J=6.8 Hz, 2H), 2.63 (s, 3H), 2.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 175.08, 138.74, 136.27, 131.75, 128.42, 127.92, 127.60, 126.61, 121.43, 119.61, 118.74, 109.33, 105.41, 73.46, 71.94, 61.61, 44.16, 41.33, 39.19, 34.98, 31.17. HRMS (ESI) calcd for C23H28N3O3 [M+H]+: 394.2131. found: 394.2120.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>CCO>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:19][OH:20])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=O)CO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2c1C(=NO)CO2
Temperature: 25 °C
Yield: 174.2 %

Procedure:
A mixture of 4-methoxy-benzofuran-3-one (CAS 7169-35-9) (4.9 g, 19 mmol), sodium acetate (3.06 g, 38 mmol) and hydroxylamine hydrochloride (2.58 g, 38 mmol) in EtOH (40 ml) was refluxed for 6 h. Cooled to room temperature, filtered the precipitate off, washed with EtOH and dried in high vacuum to give 4-methoxy-benzofuran-3-one oxime as a white solid (5.93 g, 100%); MS: m/e=180.2 (M+H+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O.C(O)(=O)[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])O.[H][H].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>OCC(CO)O>[C:6]([OH:8])(=[O:7])[C:4]([CH2:9][C:10]([OH:12])=[O:11])=[CH2:3]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: [H][H]
Solvent: OCC(O)CO
Solvent: O
Product: C=C(CC(=O)O)C(=O)O
Temperature: 204 °C
Reaction time: 1 h

Procedure:
The process of WO2010/059925 was reworked as follows (derived from Examples 1 and 12): 20 grams of glycerol reagent grade and 40 grams of citric acid monohydrate were mixed The mixture was brought under nitrogen to a temperature of 140° C. while stirring, and kept under nitrogen at that temperature for a period of one hour. The resulting prepolymer was heated to 204° C. for a period of one hour. Uncontrollable foaming took place resulting in an inhomogeneous foam. The material discolored to yellow and had poor mechanical properties. Combustion analysis showed a carbon content of 43.76% and a hydrogen content of 5.56%, showing that about 5-10% of the citric acid decarboxylated to form itaconic acid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:15]2[O:14][C:13]([S:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]4[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=4[CH:38]([CH3:40])[CH3:39])=[O:27])[CH2:21][CH2:20]3)=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=O.C(O)(=O)C.O.[NH2:47]N>CO>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[C:15]3[O:14][C:13]([S:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]([NH:28][C:29]5[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=5[CH:38]([CH3:40])[CH3:39])=[O:27])[CH2:23][CH2:24]4)=[N:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[N:47]1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3cccc(C(=O)C=CN(C)C)c3o2)CC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3cccc(-c4cc[nH]n4)c3o2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a solution of the enamine (245 mg, 0.4 mmol) in methanol (6 ml) were added acetic acid (123 mg, 2.05 mmol) and hydrazine monohydrate (102 mg, 2.05 mmol) followed by stirring at room temperature for 15 hours. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, hexane:acetone=5:3) to provide 129 mg (yield 58%) of the desired compound as colorless needles.
Reaction SMILES: C([N:8]1[C:16]2C=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=C1C)C1C=CC=CC=1.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N+:20]=[N-:21].[CH3:28]CO>>[N:19]([C:22](=[CH:10][C:11]1[CH:16]=[N:8][CH:14]=[CH:13][C:12]=1[O:17][CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N+:20]=[N-:21]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCO
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Product: CCOC(=O)C(=Cc1cnccc1OC)N=[N+]=[N-]
Reaction time: 4 h

Procedure:
A homogeneous mixture of 3-formyl-4-methoxypyridine 1 (7.0 g, 54.7 mmol) and ethyl azidoacetate (5.0 g, 36.4 mmol) in anhydrous EtOH (50 mL) was added through a dropping funnel to a well-stirred solution containing Na (0.1.24 g, 54.7 mmol) in anhydrous EtOH (30 mL) under N2 at −15° C. The mixture was stirred at that temperature for 4 h. During this time the precipitated solid was filtered and washed with ice cooled ethanol (30 mL). The compound was dried under vacuum oven for 3 h to get pure title compound 2 as white crystalline solid. Mp 92-95° C.; Yield: 4.8 g, 53%; ESI MS: m/z 248.9 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[S:9][C:10]2[C:15](=[O:16])[NH:14][C:13](=[S:17])[NH:12][C:11]=2[N:18]=1.[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CS(C)=O>[NH2:7][C:8]1[S:9][C:10]2[C:15](=[O:16])[N:14]=[C:13]([S:17][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:20]=3[F:19])[NH:12][C:11]=2[N:18]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1nc2[nH]c(=S)[nH]c(=O)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc2[nH]c(SCc3cccc(F)c3F)nc(=O)c2s1
Reaction time: 72 h

Procedure:
Potassium t-butoxide solution (0.45 ml of 1M solution in tetrahydrofuran) was added to a stirred solution of 2-amino-5,6-dihydro-5-thioxo-thiazolo[4,5-d]pyrimidin-7(4H)-one (0.09 g) [Cited: Indian J. Chem., Sect. B (1989), 28B(11), 964-5.] and 2,3-difluorobenzyl bromide in dimethyl sulphoxide (2 ml). After stirring for 3 days, the reaction mixture was poured onto water to give and the subtitle compound, isolated by filtration.
Reaction SMILES: [C:1]([CH:6]1[C:11]2[NH:12][C:13](=[O:15])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)([O:3]CC)=[O:2].[OH-].[Na+].Cl>O>[C:1]([CH:6]1[C:11]2[NH:12][C:13](=[O:15])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1CCCc2sc(=O)[nH]c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCc2sc(=O)[nH]c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A mixture of 6.8 g of 4-carbethoxy-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one and 6 ml of 10 N sodium hydroxide in 100 ml of water was refluxed for 3 hours and then cooled to 20° C. 6 ml of 10 N hydrochloric acid were added thereto and the mixture was vacuum filtered. The precipitate was washed with acetone and 1 g of the raw product was taken up in a solution of 0.42 g of sodium bicarbonate in 40 ml of water. The mixture was stirred for 1 hour, was washed with ethyl acetate and was acidified with 1 N hydrochloric acid. The mixture was vacuum filtered and the precipitate was washed with water and dried to obtain 0.5 g of 4-carboxy-2,3,4,5,6,7-hexahydrobenzothiazole-2-one melting at 192° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O.[CH2:19]([Cl:21])Cl>>[Cl:21][C:19]1[C:12](=[CH:11][OH:17])[CH2:13][CH2:14][CH2:15][C:16]=1[CH:9]=[O:10]
Reactant: CN(C)C=O
Reactant: O=C1CCCCC1
Reactant: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=CC1=C(Cl)C(=CO)CCC1
Temperature: 0 °C

Procedure:
S1 was synthesized as reported procedure. Zhang, Z.; Achilefu, S. Org. Lett., 2004, 6, 2067-2070. A solution of POCl3 (37 mL, 397 mmol) in CH2Cl2 (35 mL) was slowly added to an ice-cooled solution of DMF (40 mL, 516 mmol) in CH2Cl2 (40 mL). After the addition was finished, cyclohexanone (10 g, 100 mmol) was added dropwisely. The resulted reaction mixture was refluxed for 2 h. The mixture was then cooled in ice. Water (200 mL) was added slowly while the mixture was stirred. The mixture was stirred for 1 h. The organic layer was collected and the water layer was extracted with additional CH2Cl2 (40 mL×3). The combined organic layers were dried over Na2SO4 and then evaporated. The residue was taken up in a mixture of AcOEt-diethylether (3:1), and the mixture was washed with water (30 mL×5) to remove DMF. The combined organic layers were dried over Na2SO4 and then evaporated. The residue was treated with pentane (200 mL) to give 4.2 g (23%) of S1 as yellow crystalline solid. LRMS (ESI): calculated for [(M+H)+] 173.1. found 173.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29](=[O:31])[CH3:30]>C1COCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:28][C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CC(=O)Oc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of 5b (1.02 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) was stirred at room temperature for 30 min and then chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) was added in one portion. The resulting mixture was continued to stir at room temperature for 24 h (monitored by TLC). After this period, it was poured into ice water (100 ml) and the pale yellow solid thus obtained was crystallized from dichloromethane and ether to afford 2-Acetoxy-8-(2-oxopropoxy)quinoline (5c) (0.85 g, 66%). mp: 79°-80° C.; 1H-NMR (CDCl3): δ2.16 (s, 3H, OAc), 2.42 (s, 3H, 3'-CH3), 4.85 (s, 2H, OCH2), 7.06 (d, 3-H), 7.26-7.67 (m, 3H, Ar--H), 8.08 (d, 4-H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:19][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NC1CCc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NC2CCc3ccccc32)n1
Temperature: 160 °C
Yield: 86.9 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (500 mg, 3.09 mmol), 2,3-dihydro-1H-inden-1-amine (500 mg, 3.78 mmol) and triethylamine (2 mL) in NMP (3 mL) was heated to 160° C. for 2 hours in a BiotageInitiator® microwave synthesizer. The reaction mixture was evaporated and purified by SiO2 chromatography eluting with 1:3 petroleum ether/THF to afford the title compound (700 mg) as a yellow solid. LC-MS (ES) m/z=261 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH2:34]1[C@@H:38]2[CH2:39][CH2:40][CH:41]([OH:42])[C@@H:37]2[CH2:36][NH:35]1.C(N(CC)CC)C>CN(C=O)C>[OH:42][CH:41]1[C@@H:37]2[CH2:36][N:35]([C:2]3[N:3]=[C:4]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:26][N:27]=4)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=3)[CH2:34][C@@H:38]2[CH2:39][CH2:40]1
Reactant: OC1CC[C@H]2CNC[C@@H]12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Yield: 83.7 %

Procedure:
A solution of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (115 mg, 0.22 mmol), (3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-ol (73 mg, 0.57 mmol) and triethyl amine (34 mg, 46 μL, 0.33 mmol) in DMF was heated to 90° C. for 90 minutes. The solvent was removed under reduced pressure and the crude material was purified by silica gel column chromatography using 5-60% EtOAc in DCM to yield tert-butyl N-[5-[(3aR,6aS)-6-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (104 mg, 83%). LC/MS m/z 465.5 [M+H-Boc]+.