Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:22]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40].[NH2:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])[CH:33]=[CH:34][C:35]=3[CH3:36])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40]
Reactant: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(2-phenylethyl)benzamide (156 mg, 0.28 mmol) in dichloromethane (11 mL) was added 1,1-dimethylethyl (2-aminoethyl)methylcarbamate (75 μL, 0.42 mmol) and triethylamine (78.7 μL, 0.56 mmol). The reaction mixture was stirred at room temperature for 16 hours then applied to the flash chromatograph to afford the titled compound 147 mg (79%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([OH:30])([CH3:29])[CH2:4][NH:5][C:6]([C:8]1[C:13]([N:14]2C(C)=CC=C2C)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=1)=[O:7].Cl.NO.CCN(CC)CC>CCO.O>[F:32][C:2]([F:1])([F:31])[C:3]([OH:30])([CH3:29])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([C:25]([F:27])([F:26])[F:28])[N:9]=1)=[O:7]
Reactant: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)NCC(C)(O)C(F)(F)F
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(O)(CNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 98 °C

Procedure:
To a stirred solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (985 mg, 2.064 mmol) in 2:1 EtOH/H2O (7.5 ml) was added hydroxylamine hydrochloride (1.43 g, 20.64 mmol) followed by NEt3 (575 ml, 4.13 mmol). The reaction mixture was heated to reflux (˜98° C.) for 11.5 hours and then allowed to cool to RT. The solvent was removed in vacuo and the resulting residue was partitioned between EtOAc (25 ml) and water (25 ml). The aqueous layer was separated and extracted with EtOAc (2×25 ml) and the combined organic extracts were washed with brine (50 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-25% EtOAc in iso-hexane to afford the title product as a pale yellow solid; LC-MS: Rt 1.24 min; MS m/z 400.0 [M+H]+; Method 2minLC_v003.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:25])[N:14]2[CH3:26])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=3)[C:15](=[O:25])[N:14]2[CH3:26])[CH2:10][CH2:11][N:37]2[CH2:38][CH2:39][CH:34]([N:29]3[CH2:30][CH2:31][CH2:32][NH:33][C:28]3=[O:27])[CH2:35][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)c1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CN(C)c1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 55.9 %

Procedure:
3-(3,4-Dichlorophenyl)-3-[5-(dimethylamino)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionaldehyde (0.2 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.093 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.085 g); MS: m/z=558(M+1); NMR: 1.60 (broad,3), 1.78 (broad,3), 2.14 (broad,3), 2.73 (broad,3), 3.02 (m,3), 3.57 (m,3), 4.37 (broad,1), 4.74 (broad,1), 7.27 (m,6). Analysis for C29H37Cl2N5O2.2.0 HCl.2.0 H2O: Calculated: C, 52.18; H, 6.49, N, 10.49; Found: C, 51.94; H, 6.71; N, 10.27.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9](=[CH:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:1][C:2]1[C:11]2[O:10][C:9](=[CH:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CC(=CN2CCOCC2)Oc2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC(=CN2CCOCC2)Oc2c(OCc3ccccc3)cccc21
Temperature: 70 °C
Yield: 70 %

Procedure:
8-Hydroxy-2-(4-morpholinylmethylene)-4H-1-benzopyran-4-one (261 mg, 1 mmole) is suspended in 7 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension is treated successively with potassium carbonate (829 mg, 6 mmole) and benzyl bromide (150ul, 1.3 mmole) and the reaction mixture is warmed to 70° C. for 1 h. The mixture is cooled to room temperature and the acetonitrile is removed in vacuo. The residue is washed with 1×25 ml dichloromethane and the insoluble material is removed by filtration. The filtrate is concentrated in vacuo to a yellow oil. The oil is chromatographed over 15 g silica gel (230-400 mesh)eluting with 3% methanol/dichloromethane and collecting 6 ml fractions. Fractions 12-27 are combined and concentrated to afford a colorless oil which is crystallized from diethyl ether to provide 246 mg (70%) of the title compound as a white solid, mp. 107°-107.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]2[N:9]=[N:10][N:11]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cccc2nnnn12
Yield: 25.4 %

Procedure:
2,5-Dibromopyridine (1.0 g, 4.2 mmol), sodium azide (412 mg, 6.3 mmol) and NH4Cl (339 mg, 6.3 mmol) were heated in 20 mL DMF to 100° C. for 16 h. The mixture was diluted with 150 mL EtOAc, washed with H2O (2×) and sat'd NaCl then dried over Na2SO4 and concentrated. Flash chromatography (30 g silica, 2/1 hexane/EtOAc eluant) afforded 212 mg (25%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13]C(SC)=[N:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[CH:24]=[CH:25][CH:26]=2)[C:10]1=[O:41].ClC1C=CC=C(C(OO)=[O:50])C=1.[CH3:53][S:54]([CH3:56])=[O:55].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:53]([S:54]([CH3:56])(=[O:50])=[O:55])=[N:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[CH:24]=[CH:25][CH:26]=2)[C:10]1=[O:41]
Reactant: CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(n1)N(c1cccc(CCCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 180 mg (0.3 mmol) of 2-[3-[3-[3-(2,4-dichlorophenyl)-7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-propyl]-isoindole-1,3-dione in 10 ml of dichloromethane was treated with 200 mg (0.6 mmol) of 3-chloroperbenzoic acid (50% w/w water) and the mixture stirred at ambient temperature for 18 hours. 0.1 ml of dimethyl sulfoxide was added. After a further 15 minutes 10 ml of dichloromethane and 20 ml of saturated aqueous sodium bicarbonate were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 190 mg (100%) of 2-[3-[3-[3-(2,4-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-propyl]-isoindole-1,3-dione as a white solid. [Mass spectrum (ESI) MH+ =636].
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-]>ClCCl.N1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH:23]([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Cc1ccccc1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCC(C)OC(=O)c1ccc(OC(C)=O)cc1
Yield: 87 %

Procedure:
Thionyl chloride (25 ml) was added to 10 mmols of p-acetoxybenzoic acid, and the mixture was refluxed for 5 hours. Excess thionyl chloride was then completely removed. Thirty milliliters of toluene were added to the obtained chloride, and 7.1 mmols of R-(-)-2-hexanol and 3 ml of pyridine were added dropwise, followed by conducting the reaction overnight at room temperature. After the reaction, 50 ml of dichloromethane was added, and the organic layer was washed with a hydrochloric acid aqueous solution, a sodium hydroxide aqueous solution and water in this sequence. Subsequently, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed. The obtained composition was purified by silica gel column chromatography to obtain 1-methylpentyl p-acetoxybenzoate in a yield of 87%.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(-c2cc3ccccc3s2)cc1
Product: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
Acylation of 2-phenylbenzothiophene with 4-methoxybenzenesulfonyl chloride as described above gives 3-(4-methoxyphenylsulfonyl)-2-phenylbenzothiophene.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1)=[O:3])[CH3:6]
Reactant: On1nnc2ccc(Cl)cc21
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)On1nnc2ccc(Cl)cc21
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of ethyl chloroformate (2.17 g.) in benzene (10 ml.) was added dropwise to a solution of 1-hydroxy-6-chloro-1H-benzotriazole (3.38 g.) and triethylamine (2.80 ml.) in benzene (30 ml.) under ice-cooling and stirring. Benzene (30 ml.) was further added to the mixture and the reaction temperature was slowly elevated to room temperature. The mixture was allowed to stand overnight. Precipitated crystals were filtered off and the filtrate was concentrated. Benzene was added to the residue and an insoluble material was filtered off. The filtrate was concentrated to give 1-ethoxycarbonyloxy-6-chloro-1H-benzotriazole (2.2 g.), crystals. The precipitated crystals filtered off and the insoluble material in benzene were mixed and then washed with water, a sodium bicarbonate aqueous solution, 1N hydrochloric acid and water, and recrystallized from methanol (75 ml.) to give the desired compound (3.5 g.), white needles, mp 160° to 162° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32]S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.7 g) was dissolved in 10 mL dry THF and 1320 mg triphenylphosphine and 691 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 minutes, then 992 μL DIAD was added dropwise. The reaction was stirred at room temperature for 3 hours and was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc). The resulting residue was dissolved in 20 mL dry DMF, then 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature. The reaction was stirred for 30 minutes and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The aqueous layer was washed again with diethyl ether and the organic layers were combined. The organic layer was washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column)) to give 1.05 g of the product after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.27-7.19 (m, 4H), 7.12 (m, 2H), 6.98 (m, 2H), 6.83 (d, 1H), 6.66 (d, 1H), 6.58 (m, 1H), 5.12-5.08 (m, 3H), 4.30 (m, 1H), 4.00 (m, 1H), 3.66 (s, 3H), 3.42 (m, 1H), 3.23 (m, 1H), 2.77 (m, 2H), 1.7-1.5 (m, 2H), 0.78 (t, 3H). LCMS: m/z 607.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2S[C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=[O:37].CO.C(Cl)Cl>C(O)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:37][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)s1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(Cl)cc3)o2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080 g, 0.304 mmol) and 5-(4-chorophenyl)thiophene-2-carbaldehyde (0.063 g, 0.304 mmol) in acetic acid 5 mL is added β-alanine (2.7 mg, 0.030 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.038 g, 0.084 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.81 (dm, J=9.0 Hz, 2H), 7.41 (dm, J=9.3 Hz, 2H), 7.14 (m, 5H), 6.98 (s, 2H), 6.42 (s, 1H), 5.51 (d, J=8.7 Hz, 1H), 3.75 (dd, J=11.7, 11.0 Hz, 1H), 3.55 (dd, J=15.3, 3.9 Hz, 1H). MS (ES−, m/z): 451.1 (M−−1, 100.0).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[NH2:31][OH:32]>CS(C)=O.O>[OH:32][N:31]=[C:27]([C:26]1[CH:29]=[CH:30][C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])=[CH:24][CH:25]=1)[NH2:28]
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: NO
Solvent: CS(C)=O
Solvent: O
Product: NC(=NO)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.30 g, 32.9 mmol) in dimethyl sulfoxide (10 mL) was added 50% wt solution of hydroxylamine in water (2 mL). The reaction was heated with stirring at 80° C. for 1 h, then cooled to ambient temperature and the product was precipitated by adding distilled water (25 mL). The solid was filtered and air dried to afford N′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide (1.32 g, 93%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50 (m, 1H), 5.10 (s, 1H); MS (ES+) m/z 428.0 (M+1).
Reaction SMILES: C(O)COCCOCCO.[FH:11].[F-].[K+].[C:14]([O:18][CH2:19][CH:20]1[CH2:22][O:21]1)([CH3:17])([CH3:16])[CH3:15].O>COC(C)(C)C>[C:14]([O:18][CH2:19][CH:20]([OH:21])[CH2:22][F:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: F
Reactant: CC(C)(C)OCC1CO1
Agent: [F-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: OCCOCCOCCO
Solvent: O
Product: CC(C)(C)OCC(O)CF
Temperature: 130 °C
Reaction time: 7.5 h
Yield: 61 %

Procedure:
A 1.5 L 4-necked sulfonation flask equipped with magnetic stirring bar, reflux condenser, thermometer and an argon in/outlet, was charged with 333.3 mL triethylene glycol, 235.2 g (3.012 mol) finely ground potassium hydrogendifluoride and 200 g (1.536 mol) 2-tert-butoxymethyl-oxirane. The suspension was heated under stirring at an internal temperature of 130° C. for 7.5 h. The mixture was allowed to cool to RT over night, treated with 670 mL water and 350 mL tert-butyl methyl ether, the phases were separated and the aqueous phase was extracted with 350 ml tert-butyl methyl ether. The combined organic phases were washed with 350 mL brine, dried over sodium sulfate, filtered and evaporated. The brown oily residue (286 g) was distilled to provide 141 g (61%) 1-tert-butoxy-3-fluoro-propan-2-ol as colorless liquid, b.p. 80-93° C./70-40 mbar. GC composition: 1.1% 2-tert-butoxymethyl-oxirane, 95.1% 1-tert-butoxy-3-fluoro-propan-2-ol and 3.8% of 3-tert-butoxy-2-fluoro-propan-1-ol. 1H-NMR (CDCl3, 300 MHz): 4.45 (dxm, JH,F=46, —CH2—F); 3.93 (m, br, H—C(2); 3.45 (m, —CH2—O); 2.55 (d, br, J=6, OH); 1.20 (s, C(CH3)3).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH-:18].[Na+].[CH3:20]O>O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[N:3][C:2]([O:18][CH3:20])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CO
Reactant: Fc1ccc(-c2cn3cc(Br)ncc3n2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1cn2cc(-c3ccc(F)cc3)nc2cn1
Yield: 59 %

Procedure:
6-Bromo-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from General Procedure B with 5-bromo-2-aminopyrazine and 2-bromo-4′-fluoroacetophenone, 1.05 g, 3.59 mmol), and 10% sodium hydroxide (6 mL) were combined in MeOH (12 mL). The reaction was heated in the microwave at 150 watts to about 100° C. for about 30 minutes. The reaction was cooled, diluted with water (50 mL), and filtered to provide 2-(4-fluorophenyl)-6-methoxyimidazo[1,2-a]pyrazine (0.513 g, 59%) on drying: LC/MS (Table 1, Method b) Rt=1.74 min; MS m/z: 244.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[CH2:20](O)[C:21]#C.C[O-].[Na+]>>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=1)[C:20]#[CH:21]
Reactant: C#CCO
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Agent: C[O-]
Agent: [Na+]
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
10 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester, 30 of propargyl alcohol and 0.5 g of sodium methoxide are heated to reflux for 1/2 an hour The excess propargyl alcohol is thereupon slowly (5 hrs.) distilled off. The residue is poured onto water and extracted with diethyl ether. The ether solution is dried with sodium sulfate and evaporated. The dark-yellow p-[(1,5-dimethylhexyl)oxy]benzoic acid propargyl ester obtained is purified over Kieselgel.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].Cl[C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:7])[C:3]1[S:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][N:4]=1
Reactant: CN(C)C(=S)NN
Reactant: CCOC(=O)C(=O)Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nnc(N(C)C)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of 4,4-dimethyl-3-thiosemicarbazide (2.0 g, 16.8 mmol) and ethyl chloro-oxo-acetate (2.3 g, 16.8 mmol) were mixed under an inert atmosphere and cooled to 0° C. in an ice bath. Sulfuric acid (2 mL) was added slowly. After the effervescence ceased, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 3 hours. To the white heterogeneous mixture, ethyl acetate (100 mL) was added and the organic layer was washed twice with 2% sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residual solid was dissolved in ethyl acetate and the desired compound was precipitated with ether to yield the ethyl 5-(dimethylamino)-1,3,4-thiadiazole-2-carboxylate (IIIc) (1.9 g, 9.4 mmol). The ester, (IIIc) was dissolved in anhydrous methyl acetate (4 mL) and solution purged with an inert atmosphere. To this yellow solution sodium hydride (60% dispersion in mineral oil, 0.53 g, 13.25 mmol) was added providing a light yellow precipitate. The reaction mixture was then heated to 65° C. and it turned to a light green precipitate. Additional methyl acetate (4 mL) was added and in ten minutes the reaction mixture became a tan solid. The reaction was removed from the heat and an additional methyl acetate (20 mL) was added. The mixture was neutralized with acetic acid. The solid was filtered off and the filtrate was evaporated. The solid from the filtrate was washed with ether to yield the desired β-ketoester, ethyl 3-[5-(dimethylamino)(1,3,4-thiadiazol-2-yl)]-3-oxopropanoate, (Vd) (5.2 mmol) as a yellow solid. A mixture of the β-ketoester (Vd) (1.2 g, 1.31 mmol), ethanol (2 mL) and hydrazine hydrate (0.063 g, 1.96 mmol) was heated to 65° C. for two hours. The precipitate was filtered to obtain the pyrazolone (VIi) (0.075 g, 0.36mmol) as a light yellow solid.