Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:25](=[CH:26][CH:27]=1)[O:24][C:13]1([CH2:18][CH2:17][N:16]([C:19](=[O:23])[NH:20][CH2:21][CH3:22])[CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:28]>O1CCOCC1.O>[CH2:21]([NH:20][C:19]([N:16]1[CH2:17][CH2:18][C:13]2([CH2:12][C:11](=[O:28])[C:10]3[C:25](=[CH:26][CH:27]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:29])=[O:4])[CH:9]=3)[O:24]2)[CH2:14][CH2:15]1)=[O:23])[CH3:22]
Reactant: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 M NaOH (0.148 ml, 0.591 mmol) was added to a solution of (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (220 mg, 0.591 mmol) in dioxane (3 ml) and water (3 ml) and the mixture was stirred at RT for 1 h. Further 4 M NaOH (0.073 ml) was added and the mixture was stirred for additional 2 h. Dioxane was removed under vacuum and the residue was acidified with 2 M HCl. The resulting precipitate was filtered to give (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid. The crude compound (163 mg) was dissolved in a mixture of DCM (3 ml) and TEA (0.126 ml, 0.91 mmol). EDC (174 mg, 0.91 mmol) and HOBT (61 mg, 0.45 mmol) were added at 0° C. and the resulting solution was stirred at RT for 1 h. NH2OTHP (66 mg, 0.56 mmol) was added and the mixture was stirred at RT for 4 h and then washed with 5% aqueous solution of NaHCO3. The organic phase was washed with water, dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.3) and the resulting (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with 4 M HCl in dioxane for 2 h. The precipitate was filtered and washed with DCM to give the title compound as a pale yellow powder (118 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
A mixture of 3.26 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 4.65 g of 2-methylpropan-2-yl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, 12.5 ml of a 3M solution of sodium carbonate and 350 mg of bis(triphenylphosphine)dichloropalladium(II) in 41 ml of dioxane is refluxed for 1 h 30. The mixture is diluted with 150 ml of water and 200 ml of ethyl acetate. The aqueous phase is extracted three times with 200 ml of ethyl acetate. The combined organic phases are washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 600 g of silica, elution being carried out with dichloromethane/ethyl acetate (99/1), so as to give 2.95 g of 2-methylpropan-2-yl 4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate in the form of a yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH2:31][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3F)CC2)cc1-c1cccs1

Procedure:
77 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(2-fluorophenyl)piperazine (34 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[C:38](O)=[O:39]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:28]4[N:29]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[O:31][C:27]=4[CH3:26])=[O:39])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cn3)cc2C1=O
Yield: 64 %

Procedure:
The compound of example 654 was prepared analogous to the compound of example 640 by reaction of compound of example 392 with 5-methyl-2-phenyloxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(Nc2ncccn2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ncccn2)ccc1C
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-methyl-5-(pyrimidin-2-ylamino)phenol (65 mg, 0.32 mmol) and Cs2CO3 (111 mg, 0.34 mmol) in acetone (3.2 mL) was treated with 4-bromo-2-methyl-2-butene (37 μL, 0.34 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 57% yield (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47](=[O:57])[C@@H:48]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:49]([CH3:51])[CH3:50])=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4]>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47](=[O:57])[C@@H:48]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:49]([CH3:51])[CH3:50])=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)c4)ccc3c2)[nH]1)C(C)C
Reaction time: 16.5 h
Yield: 27.9 %

Procedure:
Methyl (S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (150 mg, 0.178 mmol) was dissolved in DCM (9 mL) and MnO2 (155 mg, 1.78 mmol) was added. After stirring for 16.5 h, more MnO2 (619 mg, 7.12 mmol) was added and the reaction mixture was heated to reflux. 1.5 h later, 9 mL DCM were added and MnO2 (619 mg, 7.12 mmol) was added. After another 4 h, MnO2 (619 mg, 7.12 mmol) was added. After and additional 16 h, the reaction mixture was filtered over celite and concentrated. The crude residue was purified by HPLC to afford the title compound (42 mg, 29%). MS (ESI) m/z 847 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH3:14])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:14][C:4]1[C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=[C:12]([CH3:13])[C:3]=1[CH:1]1[CH2:2][O:23]1
Reactant: C=Cc1c(C)cc2c(c1C)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C1CO1)COC2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Ethenyl-4,6-dimethyl-2-benzofuran-1(3H)-one (150 mg, 0.797 mmol), mCPBA (275 mg, 1.59 mmol), were combined together in DCM (20 mL) and stirred at room temperature for 12 h. The reaction mixture was then diluted with DCM and washed with Na2S2O3 solution, NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then re-dissolved DCM, absorbed onto silica gel, concentrated, and loaded into silica column for separation giving 4,6-dimethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:7][C:6]([S:8][CH3:23])=[N:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)NC(=S)NC1c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, ethyl ester (1.0 g., 3.1 mmole) in dry acetone (10 ml.) is treated with finely ground potassium carbonate (1.0 g.) and methyl iodide (220 μl., 3.5 mmole). The reaction flask is tightly stoppered and the suspension is allowed to stir at room temperature overnight. It is then diluted with ethyl acetate and the white solid is filtered off. The filtrate is washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a light yellow foam. Crystallization from etherhexane provides 820 mg. of off-white crystalline product. This material is combined with that from another run (200 mg.) and triturated with hexane to give an analytically pure sample of 1,4-dihydro-6-methyl-2-(methylthio)-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester; m.p. 91.5°-93°. TLC (silica gel; ethyl acetate: hexane, 40:60) Rf =0.36.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH3:23][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])[CH:7]=[CH:6][C:5]=1[CH:8]1[CH2:22][N:12]2[C:13](=[O:21])[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10][CH2:9]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)c(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a mixture of 3-(4-amino-2-methylphenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (92 mg, 0.30 mmol) and triethylamine (0.125 mL, 0.90 mmol) in 2.5 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.057 mL, 0.45 mmol) and the reaction stirred at rt. After 2 hours, an additional 0.015 mL meta-tolyl isocyanate and 1.5 mL CH2Cl2 was added and the reaction continued for 20 hours. The reaction was quenched with 0.5 mL MeOH, stirred 5 minutes and then evaporated. The mixture was triturated with MeOH, filtered and rinsed with MeOH and EtOAc to give the title compound as an off-white solid (99 mg, 75%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.54 (d, J=3.2 Hz, 2H), 7.99 (dd, J=7.9, 1.5 Hz, 1H), 7.40-7.47 (m, 1H), 7.00-7.32 (m, 8H), 6.78 (d, J=7.0 Hz, 1H), 4.15-4.23 (m, 1H), 3.63-3.73 (m, 1H), 3.44-3.55 (m, 2H), 3.04-3.16 (m, 1H), 2.31 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:26](=[O:28])[CH3:27])=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Product: CC(=O)Nc1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1
Yield: 91 %

Procedure:
Following the general method as outlined in Intermediate 223, starting from tert-butyl{2-[(4-aminophenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 222) and acetyl chloride, the title compound was obtained in 91% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41]>C(#N)C>[CH:40]([NH:43][C:44]([N:13]1[CH2:12][CH2:11][CH:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]3[N:25]=[CH:24][C:23]4[CH2:22][CH2:21][C:20]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=5[C:18]=4[N:17]=3)[CH:4]=2)[CH2:15][CH2:14]1)=[O:45])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(C(=O)NC(C)C)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl]-acetamide are suspended in 1 mL acetonitrile and combined successively with 17 μL triethylamine and 22 μM isopropyl isocyanate. The yellow suspension is stirred for three hours at ambient temperature and then washed with aqueous potassium carbonate solution. The organic phase is evaporated down and the residue is purified by RP-HPLC. Yield: 30 mg yellow solid.
Reaction SMILES: [OH-:1].[K+].C1(C)C=CC=CC=1.[O:10]([C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19]([C:23]#[N:24])=[N:20][O:21][CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O>[O:10]([C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](=[N:20][O:21][CH3:22])[C:23]([NH2:24])=[O:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON=C(C#N)c1ccccc1Oc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 90275.7 %

Procedure:
85% Potassium hydroxide (1.19 g, 0,018 mol) and toluene (30 ml) were added to 2-phenoxy-α-methoxyiminobenzyl cyanide (E/Z=7/93)(3.78 g, 0.015 mmol). The mixture was stirred at 80° C. for 2.5 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with conc. hydrochloric acid, extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (3.66 g, Yield: 90.3%, E/Z=6/94).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O.O1CCCC1>[ClH:24].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:28]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1cccc(NC(=O)c2ccccc2Cl)c1)N1CCCC1
Temperature: 0 °C

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 2-chlorobenzoyl chloride, 0.96 g, 0.0053 moles, in 10 ml of tetrahydrofuran was added. This mixture was allowed to stir over the weekend. The mixture was then diluted with water to 100 ml and washed with 20 ml of chloroform. The mixture was made basic with 50% sodium hydroxide and extracted with 20 ml of chloroform (twice). The chloroform was dried with potassium carbonate, filtered and evaporated by vacuum evaporation. The residue was taken up in 20 ml of isopropanol, treated with 1 ml of concentrated hydrochloric acid, and then diluted to 250 ml with ether. The solid that precipitated was collected by filtration and washed with 10 ml of ether (twice). The solid was then recrystallized with methanol and ether and dried in the vacuum oven to provide N-(3-(((2-chlorophenyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.1 g, m.p. 145° C. (dec)
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[C:11]([C:14]1[CH2:28][C@@H:27]([O:29][Si](C(C)(C)C)(C)C)[C@H:26](/[CH:37]=[CH:38]/[C@@H:39]([O:47][Si](C(C)(C)C)(C)C)[CH2:40][C@H:41]([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([C:14]1[CH2:28][C@@H:27]([OH:29])[C@H:26](/[CH:37]=[CH:38]/[C@@H:39]([OH:47])[CH2:40][C@H:41]([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:13])[CH3:12]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(C)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(C)=O)C[C@H]1O
Reaction time: 15 h
Yield: 38.2 %

Procedure:
To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL) was added a hydrogen fluoride-pyridine solution (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-acetyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (12 mg, 0.019 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours, while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution of ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then subjected to thin layer chromatography for separation (ethyl acetate:hexane=3:1) to obtain methyl (11R,12S,13E,15S,17R)-9-acetyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (3.2 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](S(C)(=O)=O)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH:35][C@H:36]1[C@H:40]2[O:41][CH2:42][CH:43]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C@H:39]2[O:38][CH2:37]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:35][C@H:36]3[C@H:40]4[O:41][CH2:42][C@@H:43]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C@H:39]4[O:38][CH2:37]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC1CO[C@@H]2[C@H](O)CO[C@H]12
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[[6-chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo-[4,5-b]pyridin-1-yl]-methoxy]ethyl-trimethyl-silane (357 mg, 0.694 mmol), ethyl 2-[(3aR,6R,6aR)-6-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (180 mg, 0.832 mmol), and DBU (150 uL, 0.995 mmol) in DMF (1.0 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (200 ml), washed with water (5×30 ml), brine (1×10 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give the title compound as a mixture of isomers. C34H40ClN3O6Si 649.24 observed m/e: 650.28 (M+H)+ (Rt 1.09 and 1.17/2 min)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=c1ccc2cc(Br)ccc2[nH]1
Temperature: 80 °C
Yield: 88.2 %

Procedure:
To a solution of commercially available 6-bromo-1,2,3,4-tetrahydro-2-quinolinone (5.0 g, 22 mmol) and NBS (4.9 g, 27 mmol) in CHCl3 (80 mL) was added a catalytic portion of benzoyl peroxide at RT. The mixture was refluxed at 80° C. for 3 h, after which additional NBS (2.0 g) was added and the reaction refluxed overnight at 80° C. Additional NBS (0.9 g) was added into the reaction mixture which was refluxed at 80° C. for 5 h. The solid was filtered, washed with EtOH and dried to yield 6-bromoquinolin-2(1H)-one (4.35 g, 88% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.93 (d, J=2.8 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.64 (dd, J=2.0, and 8.8 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 6.55 (dd, J=2.0, and 9.6 Hz, 1H); LC-MS (EI) m/z: 224.0 (M+H+).