Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH3:2].[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][C:7]1([CH3:24])[CH3:23].CO.OO.O>C1CCCCC1>[CH:2]1([O:5][N:6]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]2([CH3:24])[CH3:23])[CH2:1][CH2:9][CH2:8][CH2:7][CH2:23]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: C1CCCCC1
Solvent: CO
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 55 °C
Yield: 40 %

Procedure:
A solution of 0.101 g (0.37 mmol) of ferric chloride hexahydrate and 0.115 g (1.9 mmol) of glacial acetic acid in 2 ml of water is added to a mixture of 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 27 ml of methanol, and 18 ml of cyclohexane. The mixture is heated to reflux, 55° C. A solution of 4.9 g (72 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.25 hours to the reaction mixture while the temperature is brought to and maintained at reflux. After the peroxide is added, the reaction mixture tests negative for hydrogen peroxide. The yield of the title compound, after work-up with ethyl acetate and purification by flash chromatography, is 2.63 g (40% yield, GC assay 100%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>O>[C:18]([N:8]1[CH2:7][CH2:6][C:5]2([O:1][C:2](=[O:11])[NH:3][CH2:4]2)[CH2:10][CH2:9]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCC2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1NCC2(CCN(C(=O)OCc3ccccc3)CC2)O1
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a mixture of 9.5 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one and 75 ml water, at 0°, are added 6.3 g sodium bicarbonate and 10.9 g benzyl chloroformate. The mixture is stirred 18 hours at 0°, acidified with 10 N hydrochloric acid and stirred four hours at room temperature. The mixture is extracted with three 50 ml portions of dichloromethane. Removal of solvent affords 14.4 g 8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 126°-128°.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH2:13]([O:15][C:16](=[O:30])[CH:17]([C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][C:19](=O)[CH3:20])[CH3:14].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:13]([O:15][C:16]([C:17]1[CH:18]=[C:19]([CH3:20])[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=2)[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])[CH3:14]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: CN(C)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C)n(-c2cccc(N(C)C)c2)c1-c1ccccc1

Procedure:
N,N-Dimethyl-1,3-phenylenediamine dihydrochloride (5 mmol, 1.0 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), triethylamine (10 mmol, 10 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents removed under vacuum. The crude material was purified over silica gel and yielded the named product (m.p. 111.7° C.-114° C.).
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].[C:20]1(C)[C:21](S(O)(=O)=O)=[CH:22][CH:23]=[CH:24][CH:25]=1>C(O)CCCCC>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][CH2:22][CH2:21][CH2:20][CH2:25][CH2:24][CH3:23])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCCCCCO
Product: C#CCN1CCC(OCCCCCC)N(c2nnc(S(C)=O)s2)C1=O

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), hexyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hexyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.Cl.[NH4+].[Cl-]>CO.C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H](CO)c1ccc(Cl)c(F)c1)N1CCc2cnc(NC3CCOCC3)nc2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 70 (1.236 g, 2.191 mmol) in 15% MeOH/DCM (75 mL) was added slowly HCl (2.19 mL, 8.763 mmol) and the reaction was stirred at RT for 20 min. Saturated NH4Cl was added slowly and the resulting solution extracted with DCM. The organic layer was separated and concentrated. The crude residue was purified by SiO2 chromatography eluting with an MeOH/DCM gradient (4 to 5% MeOH) to afford 0.841 g (85.3%) of I-14: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.38 (t, 1H), 7.14 (dd, 1H), 7.08 (d, 1H), 5.28 (d, 1H), 4.97 (m, 1H), 4.89 (d, 1H), 4.39 (s, 2H), 4.06-3.90 (m, 4H), 3.86 (m, 1H), 3.76-3.60 (m, 2H), 3.55 (dt, 2H), 2.69 (t, 2H), 2.26 (t, 1H), 2.02 (d, 2H), 1.53 (m, 2H); LCMS (ACPI-pos) m/z 450.0 (M+H)+.
Reaction SMILES: C[CH:2]1[CH:7]([CH3:8])[S:6][C:5]2[S:9][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:11][C:4]=2[C:3]1=O.[CH2:17]([NH2:19])[CH3:18].[BH4-].[Na+].O1CCC[CH2:23]1>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:17]([NH:19][CH:3]1[CH2:2][C:7]([CH3:8])([CH3:23])[S:6][C:5]2[S:9][C:10]([S:12]([NH2:15])(=[O:13])=[O:14])=[CH:11][C:4]1=2)[CH3:18]
Reactant: CC1Sc2sc(S(N)(=O)=O)cc2C(=O)C1C
Reactant: C1CCOC1
Reactant: CCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Yield: 69 %

Procedure:
A solution of 5,6-dihydro-5,6-dimethyl-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (3.00 g, 0.011 mol) in dry tetrahydrofuran (40 ml) and benzene (40ml) was cooled to -10° C. and condensed ethylamine (15 ml, 10.8 g, 0.24 mol) was added rapidly with stirring. Titanium tetrachloride 1.14 g, 0.006 mol) was added over 20 minutes while maintaining the temperature below 0° C. The mixture was stirred at ambient temperature for 2.5 hours, filtered, and the solid was washed with tetrahydrofuran. The combined filtrate and washings were evaporated in vacuo and the residue was suspended in absolute methanol (105 ml). With stirring under nitrogen, sodium borohydride (0.53 g, 0.014 mol) was added portionwise over 15 minutes and the mixture was stirred at ambient temperature for 21 hours. After acidification with concentrated hydrochloric acid, the mixture was concentrated in vacuo. The residue was distributed between water (100 ml) and ethyl acetate (100 ml), and the aqueous layer was separated and extracted with ethyl acetate (2×50 ml). The water layer then was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×250 ml). The combined extracts were washed with water (3x), dried over sodium sulfate, and evaporated in vacuo. The residue was crystallized as the hydrochloride salt from ethanolic hydrogen chloride to afford 2.60 g (69%) of pure product.
Reaction SMILES: [Br:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:16].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:20][CH:19]=1>>[Br:1][C:2]1[C:14]([O:15][CH2:28][CH2:27][CH2:26][CH2:25][S:24][C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:11])([CH3:12])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:16]
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: CC1(C)OC(=O)Nc2c1cc(O)c(Br)c2Br
Product: Cc1ccc(SCCCCOc2cc3c(c(Br)c2Br)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 7,8-dibromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methylphenylmercapto)-butylchloride.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].O>OS(O)(=O)=O>[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Fuming HNO3 90% (549.0 g, 7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution of HNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14° C., stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55° C. under high vacuum overnight to yield 1035.9 g (75%) of compound 2 as a yellowish solid. HPLC was 98 a % (220 nm) and 100% (254 nm). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (1H, apparent dt, J 1.9, 7, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ −153.9, −131.5, −120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C—F, dt, J 251, 10), 148 (C—F, dd, J 265, 13), 154 (C—F, dd, J 265, 10), 163 (COOH). IR νmax/cm−1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/C(=N\O)/C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[C:23](#[N:25])[CH3:24]>CC(N(C)C)=O>[CH3:24][C:23]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:25]=1
Reactant: CC#N
Reactant: C/C(=N/O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a cooled (5° C.) solution of (1Z)-1-(2,4-dihydroxyphenyl)ethanone oxime (9.7 g, 57.7 mmol) in acetonitrile (65 mL) and dimethylacetamide (11 mL) was added phosphorus oxychloride (5.6 mL, 60.3 mmol) drop wise. The temperature was not allowed to exceed 10° C. during the addition. After 1 hrs stirring at room temperature the yellow slurry was poured on a mixture of sodium hydrogen carbonate and ice. The resulting precipitate was filtered off and dried yielding 6.3 g (73%) the titled compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a stirred solution containing 11.5 g (0.05 mole) of 3,5-ditrifluoromethylphenol, 3.3 g (0.05 mole) of 85% potassium hydroxide, 200 ml of N,N-dimethylformamide and 10 ml of water, 0.055 mole of methyl bromoacetate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 22 hours. After cooling to 25° C., 500 ml of water and 500 ml of ethyl ether were added; and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 mm of Hg. A product with a melting point of 65°-67° C. (after recrystallization from heptane) was obtained with a yield of 99%.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:40]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:40].[Na+:40].[Na+:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.030 g, 0.054 mmol) in ethanol (3 mL) was added NaOH (6.40 mg, 0.161 mmol) in 0.500 mL of water. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue washed with ethyl acetate (2×8 mL), acetone (2×8 mL) and acetonitrile (2×8 mL) to afford trisodium (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (3) (0.028 g, 0.046 mmol, 85% yield) as a pink solid. 1H NMR (400 MHz, deuterium oxide) δ (ppm) 4.54 (s, 2H), 7.11 (d, J=7.78 Hz, 1H), 7.18-7.26 (m, 2H), 7.28-7.41 (m, 5H), 7.61-7.79 (m, 3H), 8.28 (d, J=4.52 Hz, 1H), 8.89-8.95 (m, 1H), 9.08 (d, J=2.01 Hz, 1H), 9.20 (d, J=1.76 Hz, 1H); LCMS Method D: retention time 1.24 min, [M+l]=469. HPLC Method C: Purity 95.1%, retention time 6.18 min, HPLC Method E: Purity 94.0%, retention time 12.16 min. Elemental Analysis: Compound was hygroscopic and accurate EA not obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH2:32]([NH:34][CH3:35])[CH3:33]>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:34]([CH2:32][CH3:33])[CH3:35]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C24H26N6O2, 430.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([OH:19])[C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[O:9][C:7]=2[N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH3:29].O>CN(C)C=O>[CH3:1][S:2][C:3]1[N:4]([CH2:27][CH2:28][CH3:29])[C:5](=[O:19])[C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[O:9][C:7]=2[N:8]=1.[CH3:1][S:2][C:3]1[N:4]=[C:5]([O:19][CH2:27][CH2:28][CH3:29])[C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[O:9][C:7]=2[N:8]=1
Reactant: CSc1nc(O)c2nc(-c3cccc(C)c3)oc2n1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cccc(C)c3)nc12
Product: CCCn1c(SC)nc2oc(-c3cccc(C)c3)nc2c1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
7.1 g of 5-methylsulfanyl-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidin-7-ol were dissolved in 50 ml of dimethylformamide, and 14.4 g of potassium carbonate and then 3.2 g of 1-bromo-propane were added. The suspension was stirred at 60° C. for 5 h and then, after cooling, poured onto 150 ml of water. The precipitate was filtered off with suction. The obtained mixture of regioisomers was separated by silica gel chromatography (method SC1). Besides 2.3 g of 5-methylsulfanyl-6-propyl-2-(3-methyl-phenyl)-6H-oxazolo[5,4-d]pyrimidin-7-one (LC/MS (method LC1): Rt=2.16 min; m/z=316.14 [M+H]+), 3.4 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1([CH3:15])[CH2:14][O:13]1>CC#N.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]([CH3:15])([OH:13])[CH3:14])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CC1(C)CO1
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (5 g, 24.63 mmol), NaH2PO4 monohydrate (3.23 g, 23.40 mmol) and 2,2-dimethyloxirane (3.02 g, 41.9 mmol) in MeCN (90 ml) and H2O (10.00 ml) was stirred at 150° C. in a steel bomb for 4 hours. After cooling to RT, the mixture was diluted with a solution of saturated NaHCO3 (80 ml) and extracted with EtOAc (80 ml). The EtOAc extracts were dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on a silica gel column (120 g) employing a 10 min gradient ranging from hexane to 30% EtOAc/hexane to elute 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol (6.25 g, 22.72 mmol, 92% yield) as clear oil. LC MS at t=2.24 min. (m Na=297) PHENOMENEX® S5 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 6H), 3.79 (s, 2H), 3.84 (s, 3H), 6.77 (d, J=8.31 Hz, 2H), 7.01 (s, 1H), 7.26 (s, 1 H).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])C.C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>CN(C=O)C.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>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:4]([C:6]1[S:10][C:9]([C:38]2[S:37][CH:36]=[CH:40][CH:39]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:19]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1sc(-c2cccs2)nc1CN(CC(=O)OCC)Cc1ccc(OC)cc1OC

Procedure:
A solution of 2-Bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1 g, 2 mmol, example 96(b), 2-(tributylstannyl)thiophene (1.26 mL, 2 mmol), dichlorobis(triphenylphosphine)palladium II (140 mg, 0.2 mmol) in 13 mL anhydrous DMF was heated to 130° C. for 20 min. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 15-70% ethyl acetate in hexanes) to give 867 mg of a yellow oil. MS (ESI+): m/z 527.2 (M+23)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:13](=[O:15])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 225.5 %

Procedure:
To a solution of 5-fluoroanthranilic acid (10.0 g, 65.5 mmol) in THF (143 mL) was added solid triphosgene (6.70 g, 22.6 mmol, 0.35 equiv). The reaction mixture was stirred at rt overnight and the resulting suspension was filtered and dried to afford 9.23 g (79%) of 5-fluoroisatoic anhydride: 1H NMR (400 MHz, DMSO-d6) δ 7.14 (M, 1H), 7.60 (M, 2H), 11.72 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:26]=[CH:25][C:10]2[S:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]([C:14](=[O:17])[NH:15][CH3:16])[C:9]=2[CH:8]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[S:11][C:10]3[CH:25]=[CH:26][C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])=[CH:8][C:9]=3[C:13]=2[C:14](=[O:17])[NH:15][CH3:16])=[CH:19][CH:20]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl trifluoromethanesulfonate (0.32 g, 0.74 mmol), 3-boronobenzoic acid (0.18 g, 1.1 mmol), cesium carbonate (0.36 g, 1.1 mmol), dioxane (6.2 mL) and water (1.2 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.016 mmol). The solution was maintained at 95° C. for 90 min. The solution was cooled to room temperature, concentrated and suspended in ethyl acetate (20 mL) with stirring for 1 h. The mixture was filtered, washed with water (3×20 mL) and air dried to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid as a grey solid which was used without further purification. LCMS: retention time: 2.132 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 406 (MH+).