Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NO
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
15.00 g (54 mmol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 4.20 g (60 mmol) of hydroxylamine hydrochloride were taken up in 300 ml of methanol, and a solution of 3.18 g (30 mmol) of sodium carbonate in 80 ml of water was added dropwise. After the mixture had been stirred for 12 hours at room temperature, the methanol was distilled off, the residue was diluted with water and the mixture was extracted with diethyl ether. After the organic phase had been dried, the solvent was removed. This gave 14.40 g (91% of theory) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH:12]([OH:15])CO)[CH:9]=[C:8]([C:16]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:26]=[CH:25]4)([OH:21])[C:17]([F:20])([F:19])[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1>CC(C)=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH:12]=[O:15])[CH:9]=[C:8]([C:16]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[N:26]=[CH:25]4)([OH:21])[C:17]([F:20])([F:19])[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCC(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Solvent: CC(C)=O
Solvent: O
Product: O=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Reaction time: 72 h

Procedure:
To a room temperature solution of 3-(4-chloro-7-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[3,2-d]pyrimidin-5-yl)propane-1,2-diol (95 mg, 0.18 mmol, 1 equiv.) in 3 mL of acetone and 1 mL of water was added NaIO4 (120 mg, 0.56 mmol, 4 equiv.). After 3 days, the mixture was filtered and the filtrate concentrated to near dryness. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated in vacuo to afford (4-chloro-7-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[3,2-d]pyrimidin-5-yl)acetaldehyde which was used without further purification.
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][C:7]12[C:25](=[O:26])[CH2:24][CH2:23][CH:8]1[CH:9]1[C:14]([CH2:15][CH2:16]2)=[C:13]([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:12](=O)[CH2:11][O:10]1>C1(C)C=CC=CC=1>[CH3:6][C:7]12[CH2:16][CH2:15][C:14]3[CH:9]([O:10][CH2:11][C:12]4[C:13]=3[CH2:17][CH2:18][C:19](=[O:21])[CH:20]=4)[CH:8]1[CH2:23][CH2:24][C:25]2=[O:26]
Reactant: CC(=O)CCC1=C2CCC3(C)C(=O)CCC3C2OCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC12CCC3=C4CCC(=O)C=C4COC3C1CCC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 25% (w/w) solution of sodium methoxide in methanol (2.71 mL, 12.8 mmol, 1 eq) was added to a stirred solution of the crude 3a-Methyl-6-(3-oxo-butyl)-1,2,4,5,9a,9b-hexahydro-3aH-9-oxa-cyclopenta[a]naphthalene-3,7-dione in toluene (200 mL) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h. The reaction was then quenched with a 10:1 (v/v) of ammonium chloride/potassium bisulfate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried with magnesium sulfate. The resulting solution was filtered, evaporated and the residue purified by flash chromatography using 30-50% ethyl acetate in hexane to yield the title compound as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13](O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH:21]([NH2:23])[CH3:22].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:22][CH:21]1[CH2:20][NH:19][C:13]([C:12]2[CH:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=2)=[N:23]1
Reactant: CC(N)CN
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Temperature: 25 °C
Yield: 29.4 %

Procedure:
To a solution of 2-benzamidoisonicotinic acid (0.50 g, 2.06 mmol) and 1,2-diaminopropane (0.35 mL, 4.12 mmol) in 1,4-dioxane (20 mL) was added phosphorus oxychloride (0.94 mL, 10.30 mmol) dropwise at ambient temperature under nitrogen atmosphere. The resulting solution was refluxed for 15 hours, cooled to ambient temperature and concentrated in vacuo to dryness. The residue was diluted with saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (4×50 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate followed by 9:1:0.1 ratio of ethyl acetate, methanol and triethyl amine to give N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide as a pale yellow foam (0.17 g, 29%): MS (ES+) m/z 281.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[C:4]([F:13])[C:3]=1F.C(=O)([O-])[O-].[K+].[K+].[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[F:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1c([N+](=O)[O-])cc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c([N+](=O)[O-])cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Temperature: 80 °C

Procedure:
To a solution of the product of Example 52A (500 mg, 2.4 mmol) in acetonitrile (20 mL) was added potassium carbonate (660 mg, 4.8 mmol) and tert-butyl piperazine-1-carboxylate (900 mg, 4.8 mmol) and the mixture was heated to 80° C. for 3 hours. After cooling, the mixture was filtered, concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 20/1 petroleum ether/ethyl acetate to provide the title compound. MS: 374 (M+H+).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]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.[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].CN(C1C=CC=CN=1)C.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:28]([Si:32]([CH3:34])([CH3:33])[O:27][CH2:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1-trityl-1H-imidazol-4-yl)-ethanol (5.21 g, 14.7 mmol) in DMF (20 mL) is added tert-butylchlorodimethylsilane (2.44 g, 16.1 mmol), dimethylaminopyridine (0.179 g, 1.47 mmol) and imidazole (3.00 g, 44.1 mmol). The reaction mixture is stirred for 2 h at room temperature. It is then diluted with ethyl acetate and washed with water thrice. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethanol, 7:3) to give 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1-trityl-1H-imidazole product, which is used in the next step without further purification; MS (ESI) m/z 469.3 (M+H)
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(#N)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:9][C@H:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: C[C@H](N)c1ccccc1
Reactant: COC(=O)CBr
Solvent: CC#N
Product: COC(=O)CN[C@@H](C)c1ccccc1

Procedure:
Scheme 1 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 1, benzyl N-((1S)-1-(1H-4-imidazolylmethyl)-2-2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethyl[(1S)-1-phenylethyl]amino-2-oxoethyl)carbamate. Reaction of (S)-α-methylbenzylamine with methyl bromoacetate was carried out in acetonitrile in the presence of dilsopropylethylamine as the base to give methyl-2-[(1S)-1-phenylethyl]aminoacetate. Methyl-2-[(1S)-1-phenylethyl]aminoacetate was then coupled to Cbz-His(trityl) in methylene chloride with HATU as coupling agent, and diisopropylethylamine as the base. The resulting product was saponified using lithium hydroxide at 0° C., followed by coupling with β,β-dimethylphenethylamine in methylene chloride, with HBTU as coupling agent, and diisopropylethylamine as the base. The trityl group was removed by treatment with 50% TFA in methylene chloride. The β,β-dimethylphenethylamine was prepared from benzyl cyanide, which was treated with 2 equivalents of sodium hydride in tetrahydrofuran (THF) and 2 equivalents of methyl iodide in THF followed by hydrogenation (H2, Pd/C, ammonia) and treatment with HCl to give the HCl salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[N:25]1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: Cn1cc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (85.8 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (42.9 mg) in DMF (1.42 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg). The mixture was stirred at room temperature overnight, and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (114.8 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:10]([OH:18])[CH:11]([OH:17])[CH2:12][S:13][CH:14]([CH3:16])[CH3:15])=O)(C)(C)C.[ClH:23].O1CCOCC1>O1CCOCC1>[ClH:23].[NH2:8][C@@H:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:10]([OH:18])[CH:11]([OH:17])[CH2:12][S:13][CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(O)CSC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(O)C(O)CSC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
21 mg of (2RS,3RS,4S)-4-(tert-butoxycarbonyl)amino-1-isopropylthio-6-methyl-2,3-heptanediol was dissolved in 0.3 ml of dioxane, and 0.32 ml of a 3.6M hydrogen chloride/dioxane solution was added thereto. The mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure from the reaction solution to obtain 16.9 mg of (2RS,3RS,4S)-4-amino-1-isopropylthio-6-methyl-2,3-heptanediol hydrochloride as colorless oily substance.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7](I)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>C1COCC1>[CH:1]1([N:4]2[CH:8]=[C:7]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: Ic1cnn(C2CC2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
In a flask 1-cyclopropyl-4-iodo-1H-pyrazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution cooled to 0° C. Isopropylmagnesium chloride (2.0 M in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture stirred at 0° C. for 45 min, after which 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 2.60 mmol) was added and the mixture allowed to warm to room temperature over 1 h. The mixture was quenched with 50% sat aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with sat. NaCl, dried over MgSO4 and the solution was concentrated. The residue was purified by SiO2 chromatography (20-50% EtOAc/heptane) to afford 405 mg (83%) of 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester as a colorless viscous oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 0.47 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (d) above] and 0.8 g of ethyl 2-bromo-4-phenylbutyrate in 7 ml of dimethylformamide was added 1.0 g of sodium carbonate. The reaction mixture was stirred at 70° C. for 18 hours and then dissolved in ethyl acetate and an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The residue was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached). The first eluted isomer A was an oily compound in a yield of 0.27 g.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].O.[I-:6].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:14].[OH-].[Na+]>O1CCCC1>[I-:6].[SH:3][CH2:2][CH2:1][S:4][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:14]
Reactant: C[n+]1ccccc1F
Reactant: SCCS
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[n+]1ccccc1SCCS
Temperature: 23 °C

Procedure:
To a mixture of 1,2-ethanedithiol (0.63 mL, 7.5 mmol), water (21 mL) and tetrahydrofuran (4 mL) were added simultaneously 2-fluoro-1-methylpyridinium iodide, described by G. B. Barlin and J. A. Benbow, J.C.S. Perkin II, 790 (1974), (0.90 g, 3.72 mmol) and 1N sodium hydroxide solution (5-6 mL) to keep the pH of the mixture between 6 and 7. When the addition of 2-fluoro-1-methylpyridinium iodide was completed, the reaction mixture was stirred at 23° C. while the pH was kept at 7.1 by the addition of the 1N sodium hydroxide solution. When the pH of the mixture was stabilized at 7.1, the solvents were evaporated under high vacuum until dryness. The solid was triturated in ether (3×10 mL) and in acetonitrile (2×8 mL). The ether solution was dried (MgSO4) and concentrated to give 0.10 g of N-methyl-2(1H)-pyridothione. The acetonitrile solution was dried (MgSO4) and concentrated to give 0.74 g of 2-(2-mercaptoethylthio)-1-methylpyridinium iodide and/or fluoride mixed with some inorganic salts; ir (KBr) νmax : 1617 (pyridinium) cm-1, 1Hmr (DMSO-d6) δ: 2.75-3.1 (m, 2H, CH2SH), 3.4-3.9 (m, CH2S and SH), 4.17 (s, 3H, CH3 on pyridinium), 7.6-9.2 (m, 4H, H's of pyridinium). The acetonitrile insoluble material (0.38 g) was 1,2-di(1-methylpyridinium-2-thio)ethane diiodide or/and difluoride or monoiodidemonofluoride mixed with some inorganic salts; 1Hmr (DMSO-d6) δ: 3.90 (4H, s, SCH2CH2S), 4.21 (6H, s, CH3 's on pyridinium), 7.7-9.1 (8H, m, H's of pyridiniums). The thiol was used without any further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[N:16]([CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), in DMF (70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and petroleum ether, the solid was collected by filtration and dried under vacuum to give 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[C:2]1=2>CCO.C(Cl)Cl>[O:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[C:2]1=2
Reactant: OCc1cc2ccc3ccc4ccccc4c3c2o1
Solvent: ClCCl
Solvent: CCO
Product: O=Cc1cc2ccc3ccc4ccccc4c3c2o1
Yield: 91.2 %

Procedure:
Using the procedure outlined in Example 14B, phenanthro[4,3-b]furan-2-methanol (18A) gave a 91.2% yield of phenanthro[4,3-b]furan-2-carbaldehyde, mp 169°, (C,H), (95% EtOH/CH2Cl2).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:23]2=[CH:22][C:21](=[O:28])[C@@:20]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH3:30][CH2:31][O:32]C(C)=O>[Pd]>[C:31]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][C:21](=[O:28])[C@@:20]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)(=[O:32])[CH3:30]
Reactant: CCOC(C)=O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC(=O)[C@]12C
Agent: [Pd]
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Reaction time: 16 h
Yield: 80 %

Procedure:
10% Pd/C (900 mg) was added to a solution of compound 1.9a (2.0 g, 4.5 mmol) in EtOAc (150 mL) and the resulting slurry was hydrogenated in a Parr apparatus (50 psi) at 50° C. for 16 h. At this point the reaction was determined to be complete by TLC. The mixture was filtered through a small plug of Celite® and the solvent was removed under vacuum, providing compound 2.0a (1.6 g, 80% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:12]N1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([Br:11])[C:5]2=[N:10][CH:9]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cn2c(Br)cnc2c(Br)n1

Procedure:
A solution of 0.8 g (2.9 mmol) of 6,8-dibromoimidazo[1,2-a]pyrazine and 1.2 g of N-bromosuccinimide in 40 ml of chloroform is brought to reflux for two hours. After being cooled, the organic solution is treated with aqueous Na2CO3 solution. The chloroform phase is collected and then evaporated. 1 g -(Yld=97%) of 3,6,8-tribromoimidazo[1,2-a]pyrazine (m.p. 161° C.) is obtained.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]2[C:21](=O)[NH:22][C:23]3[CH2:31][CH2:30][CH:29]=[CH:28][C:24]=3[S:25](=[O:27])(=[O:26])[C:19]=2[CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[S:25](=[O:27])(=[O:26])[C:19]=2[CH:18]=1
Reactant: O=C1NC2=C(C=CCC2)S(=O)(=O)c2cc(C(F)(F)F)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: O=S1(=O)c2ccccc2NC(=S)c2ccc(C(F)(F)F)cc21
Yield: 84.2 %

Procedure:
Phosphorus pentasulphide (1 g) was added to a solution of 3-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one-5,5dioxide (1 g, 3 mmol) in pyridine (20 ml) and heated under reflux for 6.5 hr. A further 500 mg of phosphorus pentasulphide was added and the mixture heated for a further 6 hr before being allowed to cool overnight. The mixture was added to hot water (100 ml) with stirring. Filtration of the cooled mixture and recrystallisation from ethanol gave the title compound as a yellow solid (650 mg, m.p. 275°-278° C., Rf 0.4, hexane/EtOAc 2:1).
Reaction SMILES: [CH3:1][S:2]([NH:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:25]([F:28])([F:27])[F:26])=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=O)[N:19]=[CH:18]3)[CH:13]=2)[NH:8][C:7]1=[O:29])(=[O:4])=[O:3].Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:31][N:32]([CH3:33])[C:22]([C:20]1[N:19]=[CH:18][N:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:25]([F:26])([F:28])[F:27])[NH:8][C:7](=[O:29])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3=[O:16])[CH:21]=1)=[O:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cnc(C(=O)O)c3)cc2c1=O
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid (120 mg, 0.277 mmol) in 10 ml of dimethylformamide is treated with dimethylamine hydrochloride (46 mg, 0.554 mmol), N-3-dimethylaminopropyl-N′-ethyl-carbodiimide hydrochloride (60 mg, 0.305 mmol), N-hydroxybenzotriazole (11 mg, 0.08 mmol) and triethylamine (0.1 ml, 0.72 mmol). The solution is heated to 100° C. for 1 hour, cooled to room temperature, evaporated in vacuo and the residue chromatographed over silica gel to give 22 mg (0.048 mmoles, 17%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H -imidazole-4-carboxylic acid dimethylamide, m.p. 284 -286° C., ES-MS: m/z 461 [M+H]+.