Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(C)(=O)=O)c3)n2)n1
Yield: 47.5 %

Procedure:
To a stirred and cooled solution of 3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-phenylamine (example 326) (0.150 g, 0.369 mmol) in EtOAc (2 mL) and sat. NaHCO3-sol. (1 mL) was added methanesulfonyl chloride (1.0 mL, 13.6 mmol) and the mixture was stirred at 23° C. for 2 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (0.085 g, 47%). MS (ISP) 485.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Ca+2].[Br-:25].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.OS([O-])=O.[Na+]>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:25])[CH:15]=2)[NH:10][C:9]1=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2NC1=O
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Br)ccc2NC1=O
Reaction time: 18 h
Yield: 90.3 %

Procedure:
To a solution of 87D (750 mg, 2.42 mmol) in MeOH (12 mL) and CH2Cl2 (12 mL) stirring at RT under argon was added CaCO3 (484 mg, 4.83 mmol) and benzyltrimethylammonium tribromide (1.885 g, 4.83 mmol). After 18 h, 10% aqueous NaHSO3 (5 mL) was added to the reaction mixture, and stirring was continued for 30 min. Partial evaporation under vacuum was performed to remove nearly all of the organic solvents before the mixture was extracted twice with CH2Cl2. The combined extracts were washed with water, dried (MgSO4), and evaporated under vacuum. The resulting residue was chromatographed on silica gel eluted with 25% Et2O in CH2Cl2 to obtain the title compound (746 mg) as a white foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:11]([C:12]1[CH:4]=[CH:3][C:2]([C:7]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH:6]=2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: c1ccncc1
Reactant: Oc1ccccc1I
Product: CCc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A flask containing 5.4 g. (0.028 mol.) of cuprous 4-ethylphenylacetylide in 100 ml. of pyridine is thoroughly flushed with nitrogen. A solution of 6.19 g. (0.028 mol.) of o-iodophenol in 50 ml. of pyridine is added under nitrogen and the reaction mixture is stirred and heated at 120° for 22 hours. The pyridine is removed by distillation in vacuo, the residue is added to an ice-water mixture and the gummy precipitate is collected and dissolved in methylene chloride. The methylene chloride solution is washed with 3N hydrochloric acid and water and concentrated under reduced pressure to give a residue which is chromatographed on a silica gel "dry-column" to give 2-(4-ethylphenyl)benzofuran.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:4]([CH3:16])[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:16])=[C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1NS(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)c(N)cc1NS(C)(=O)=O
Yield: 96.2 %

Procedure:
A mixture of Intermediate 79A (175 mg, 0.66 mmol), zinc (432 mg, 6.61 mmol), ammonium chloride (354 mg, 6.61 mmol) in ethanol (10 mL) and water (5.0 mL) was heated to reflux for 30 min. The reaction mixture was concentrated, suspended in ethyl acetate and filtered. The filtrate was washed with water, aqueous NaHCO3 and brine, dried over MgSO4 and concentrated to give Intermediate 79 (149 mg, 96%) as a white solid. HPLC: Rt=0.453 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=235 [M+H]+. Intermediate 79 was used in the synthesis of Example 243.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.[F:26][C:27]1([F:38])[C:31]([F:32])=[C:30](F)[C:29]([F:35])([F:34])[C:28]1([F:37])[F:36]>CCOCC>[F:32][C:31]1[C:27]([F:26])([F:38])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]=1[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Reactant: C=Cc1ccc(-c2cc(Br)c(-c3ccccc3)s2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=Cc1ccc(-c2cc(C3=C(F)C(F)(F)C(F)(F)C3(F)F)c(-c3ccccc3)s2)cc1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
Compound 31 (6.41 g, 18.8 mmol) was dissolved in 500 mL anhydrous Et2O and cooled to −25° C. n-BuLi (2.5 M in hexane, 9.8 mL, 24.4 mmol) was added dropwise over 45 min. Lithiation was determined to be complete by TLC after the addition of approximately 7 mL. The lithiated species precipitated from solution. Octafluorocyclopentene (5.18 mL, 37.6 mmol) was added and the reaction mixture stirred at −70° C. for 1.5 hours before warming slowly to −20° C. over 30 min, to 0° C. for 30 minutes then to room temperature for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined organic fractions were washed with brine, dried over MgSO4 and concentrated under vacuum. Purification by column chromatography afforded 32 (5.73 g, 67% yield). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J=8.3, 2H), 7.46 (d, J=8.2, 2H), 7.45-7.35 (m, 6H), 6.74 (dd, J=17.6, 10.9, 1H), 5.81 (d, J=17.6, 1H), 5.31 (d, J=10.9, 1H).
Reaction SMILES: [O-]CCCC.[Li+].C([O:14][C:15](=[O:31])[NH:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[CH2:29][CH:28]3[CH:26]([CH2:27]3)[CH2:25]2)=[C:19]([F:30])[CH:18]=1)C1C=CC=CC=1.CO.[C:34]([NH:37][CH2:38][C@H:39](OC(=O)C)[CH2:40]Cl)(=[O:36])[CH3:35].[Cl-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O.O.C1COCC1>[CH:26]12[CH2:27][CH:28]1[CH2:29][N:24]([C:20]1[C:19]([F:30])=[CH:18][C:17]([N:16]3[CH2:40][C@H:39]([CH2:38][NH:37][C:34](=[O:36])[CH3:35])[O:14][C:15]3=[O:31])=[CH:22][C:21]=1[F:23])[CH2:25]2
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Reactant: O=C(Nc1cc(F)c(N2CC3CC3C2)c(F)c1)OCc1ccccc1
Agent: CCCC[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CC4CC4C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Lithium butoxide solution (1.6 mL of a 1.0 M THF solution, 1.6 mmol) was added to a cooled (0° C.) solution of [4-(3-aza-bicyclo[3.1.0]hex-3-yl)-3,5-difluoro-phenyl]-carbamic acid benzyl ester (0.180 g, 0.52 mmol) in DMF (0.35 mL) and MeOH (0.042 mL, 1.05 mmol). Solid (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl ester (0.203 g, 1.05 mmol) was then added and the solution allowed to warm to room temperature and stirred for 20 h. Saturated aqueous ammonium chloride (0.8 mL) was added, along with 7 mL of H2O and 6 mL of brine. The solution was extracted with three portions of dichloromethane and the combined organic phases dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (0-2% MeOH-DCM) to provide N-({(5S)-3-[4-(3-azabicyclo[3.1.0]hex-3-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl) acetamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[C:14]3[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Temperature: 70 °C
Yield: 77.6 %

Procedure:
A solution of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthalenecarboxylate (1.00 g, 3.0 mmol), tetrakistriphenylphosphine palladium (142 mg, 0.12 mmol) and 4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl-)phenol (799 mg, 3.6 mmol) in a mixture of 1,2-dimethoxyethane (16 mL) and 2M aqueous Na2CO3 (13 mL) was heated in a 70° C. oil bath for 90 minutes. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by chromatography on silica gel, hexane to 3:7 ethyl acetate:hexanes, to provide the title compound (0.648 g, 77.7%). 1H NMR (DMSO-d6): 9.65 (s, 1H), 8.94 (s, 1H), 8.18-8.13 (m, 2H), 8.05 (d, J=8 Hz, 1H), 7.85 (dd, J=2, 9 Hz; 1H), 7.60 (d, J=9 Hz, 2H), 7.56-7.53 (m, 1H), 6.90 (d, J=9 Hz, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH2:16][F:17])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:17][CH2:16][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH2:13][OH:14]
Reactant: CC(CF)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO)(CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A solution of 2-(benzyloxycarbonylamino)-3-fluoro-2-methylpropanoic acid (1.1 g, 4.9 mmol) in THF (16 ml) was cooled to 0° C., and triethylamine (518 mg, 6.1 mmol) was added, then ethyl chloroformate (663 mg, 6.11 mmol). A solution of sodium borohydride (370 mg, 9.8 mmol) in water (4 ml) was added, and the reaction warmed to RT over 4 h. The reaction was quenched with 1 M HCl, and extracted with EtOAc. The organic layers were combined, washed with sat. NaCl, dried on Na2SO4, and concentrated in vacuo. Flash chromatography (0% to 10% MeOH in DCM) afforded the title compound as a clear oil (915 mg, 77%). 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 3H), 3.4 (br s, 1H), 3.72-3.80 (m, 2H) 4.47 (dd, J=9.6, 18.4 Hz, 1H), 4.60 (dd, J=9.2, 18.8 Hz, 1H), 5.12 (s, 2H), 5.32 (s, 1H), 7.28-7.37 (m, 5H). 19F NMR (CDCl3, 376 MHz) δ −231.2 (t, J=48.9 Hz). 13C NMR (CDCl3, 100 MHz) δ 19.2 (d, J=4 Hz), 56.8 (d, J=17 Hz), 66.4 (d, J=4 Hz), 66.9, 85 (d, J=173 Hz), 128.1, 128.3, 128.6, 128.6, 136.0, 156.0.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=C[C:26]=1C(N)C>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH3:26])[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: CC(N)c1ccccn1
Agent: Cl
Product: Cc1nc(NC(C)c2ccccn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (1-pyridin-2-ylethyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 6H), 1.43-11.52 (m, 5H), 1.71-1.74 (m, 2H), 1.88 (s, 3H), 2.22 (s, 3H), 5.06-5.10 (m, 1H), 7.31 (t, J=8.06 Hz, 1H), 7.44 (d, J=8.06 Hz, 1H), 7.58 (d, J=8.06 Hz, 1H), 7.84 (t, J=8.06 Hz, 2H), 8.22 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 12.21 (bs, 1H); MS (ESI) m/z 326.5 (M+1)+.
Reaction SMILES: C(C1C=CSC=1C1SC=CC=1C1SC=CC=1C1SC=CC=1CCCCCCCCCCCC)CCCCCCCCCCC.BrC(CCCCCCCCCC)CC1SC=CC=1.C1C(=O)N(Br)[C:65](=[O:66])[CH2:64]1.[S:71]1[CH:75]=[CH:74][C:73]([CH2:76][OH:77])=[CH:72]1.C(Cl)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:65]([O:77][CH2:76][C:73]1[CH:74]=[CH:75][S:71][CH:72]=1)(=[O:66])[CH3:64].[S:71]1[CH:75]=[CH:74][C:73]([CH2:76][OH:77])=[CH:72]1
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCCCCCCC(Br)Cc1cccs1
Agent: CCCCCCCCCCCCc1ccsc1-c1ccsc1-c1ccsc1-c1sccc1CCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CC(=O)OCc1ccsc1

Procedure:
The syntheses of the initial hydroxymethyl polymer and O-alkyl derivatives are outlined in Schemes 1 and 2, respectively. The synthesis of the monomer 3,3′″-Didodecylquaterthiophene was obtained as reported in the literature in 75% yield by Stille coupling of two equivalents of 2-bromododecylthiophene with 5,5′-bis(trimethyltin)-2,2′-bithiophene.72 2,2′-Dibromo-3-3′″-didodecyl-quaterthiophene was then subjected to bromination using two equivalents of n-bromosuccinimide (NBS) in chloroform/acetic acid. The product was confirmed by the appearance of a singlet peak at 6.89 ppm in 1H NMR corresponding to the C—H proton at the 2-position of the thiophene ring. Thiophen-3-ylmethyl acetate was synthesized from thiophen-3-ylmethanol, which when subjected to acetylation using acetyl chloride in presence of DMAP as a catalyst resulted in the desired compound in good yield.73 Thien-3-ylmethanol was obtained from the reduction of thiophene-3-carboxaldehyde using LiAlH4. 1H NMR confirmed the product. A functionalized TTF derivative was synthesized by subjecting TTF to monolithiation using lithium diisoproplyamide as reported in the literature. The monolithiated product hence formed was formylated using N-methyl-N-phenylformamide, which then upon reduction with NaBH4 in methanol resulted in 4-formyltetrathiafulvalene.74 4-Formyltetrathiafulvalene was then substituted with 1,8-dibromooctane in a THF/DMF solvent mixture, which resulted in 4-(((8-bromooctyl)oxy)methyl)-2,2′-bi(1,3-dithiolylidene) in 65% yield. The product was confirmed by the disappearance of the —OH peak at 1.9 ppm and the appearance of two different types of triplet at 3.40 ppm and 3.42 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([OH:8])[CH2:4][O:3]1.O[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([O:8][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])[CH2:4][O:3]1
Reactant: CC1(C)OCC(O)CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(ON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2,2-dimethyl-[1,3]dioxan-5-ol (1.50 g, 11.35 mmol), N-hydroxyphthalimide (1.85 g, 11.35 mmol) and triphenylphosphine (2.98 g, 11.35 mmol) in anhydrous tetrahydrofuran (30 mL) at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.75 mmol). The resultant solution was allowed to warm to room temperature. After stirring for 3 hours, the mixture was concentrated in vacuo and charged with chloroform affording white solids. The solids were filtered off and filtrate was collected and concentrated. The residue was purified via silica column chromatography (4:1 hexanes/ethyl acetate) affording 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione as clear crystals (1.74 g, 55% over 2 steps): 1H NMR (400 MHz; DMSO-d6) δ 7.83 (s, 4H), 4.11-4.12 (m, 1H), 4.04-4.09 (m, 2H), 3.92-3.96 (m, 2H), 1.32 (s, 3H), 1.25 (s, 3H); MS (APCI+)=278.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[CH3:26][C:27]1([NH:31][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:22])[CH2:30][O:29][CH2:28]1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Reactant: CC1(N)COC1
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1(C)COC1
Yield: 32 %

Procedure:
As described for example 107, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) was converted, using 3-methyl-3-oxetanamine instead of 2-amino-2-methyl-1-propanol, to the title compound (39 mg, 32%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:4]1[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=[C:3]1[CH2:2][N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: CN1CCNCC1
Reactant: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CBr)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2nc3sc(S(N)(=O)=O)cc3c(=O)n2-c2ccccc2Cl)CC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
To 5.0 g of 3,4-dihydro-2-bromomethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 50 ml of dimethylformamide, 1.5 g of N-methylpiperazine and 3.2 g of potassium carbonate, and the mixture was stirred at 40° C. for 1.5 hours. The reaction mixture was poured onto water, and the mixture was extracted with ethyl acetate. The concentrated residue of the extract was crystallized from ethanol, followed by recrystallization of the obtained crystals from methanol-chloroform to afford 1.9 g of the title compound, m.p. 233.5°-234° C. (decomposition). The hydrochloric thereof showed m.p. of 246°-247° C. (decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Yield: 45.7 %

Procedure:
A suspension of (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (230 mg, 0.55 mmol) in DCM (6 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (121 mg, 0.896 mmol) and NH2OTHP (84 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (120 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[O:12][CH2:16][CH3:17])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15]
Reactant: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1c(F)cc2c(C)cc(=O)oc2c1F
Yield: 44.3 %

Procedure:
A solution of Compound 5 (0.10 g, 0.47 mmol) and ethyl iodide (112 μL, 1.4 mmol) in acetone (10 mL) is stirred at reflux with potassium carbonate (207 mg, 1.5 mmol) for 72 hours, during which additional ethyl iodide (2×200 μL) is added at 24 and 48 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated to a colorless solid. This solid is purified by preparative TLC (silica gel, 1000 μm plate, eluting with ethyl acetate/hexanes 1:1) to give 50 mg of nonfluorescent Compound 7 as a colorless solid. UV-vis (MeCN): 298 nm, ε=7,770 cm-1M-1 ; 279 nm, ε=11,080 cm-1 M-1. Rf (ethyl acetate/hexanes 3:2) 0.75. 1H NMR (CDCl3) 7.10 (dd, 1H), 6.28 (s, 1H), 4.38 (q, 2H), 2.39 (s, 3H), 1.42 (t, 3H). 19F NMR (CDCl3) 132.2 (t, 1F), 146.9 (d, 1F). Anal. calcd for C12H10O3F2 : C, 60.00; H, 4.20; N, 0.00; Found: C, 59.98; H, 4.27; N, 0.01.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:21]1[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 38 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.318 mmol) and (3,5-difluorophenyl)boronic acid (60.3 mg, 0.382 mmol) in 1,4-dioxane (2 mL) was added a 1M solution of sodium carbonate (40.5 mg, 0.382 mmol) in water (0.38 mL) and tetrakis(triphenylphosphine)palladium (0) (18.4 mg, 0.0159 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to provide the desired product (42 mg, 38.0%). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][NH:28][C:27]1=S>CN(C=O)C.[Hg](Cl)Cl>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:27]4[NH:28][CH2:29][CH2:30][N:26]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: S=C1NCCN1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: c1cc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)ccc1NC1=NCCN1
Temperature: 140 °C
Yield: 22 %

Procedure:
A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol0 and mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140° C. 16 hr. Then the reaction mixture was cooled to room temperature and filtered through Celite™. The filtration was concentrated and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine (9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H].