Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([OH:33])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[CH:10]=1.[C:34](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2cc([N+](=O)[O-])c(Oc3ccc(CC(=O)O)cc3Cl)cc2n1COCC[Si](C)(C)C
Agent: [Cs+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an N2 atmosphere, 2-(3-Chloro-4-(2-methyl-6-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-benzo[d]imidazol-5-yloxy)phenyl)acetic acid (0.376 g, 0.764 mmol) was dissolved in DMF (3 mL). Cesium carbonate (0.274 g, 0.841 mmol) was added and the reaction was stirred at room temperature for 5 min. Iodomethane (0.052 mL, 0.841 mmol) was added and the reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with diethyl ether and washed with water. The layers were separated and the aqueous layer was washed with additional diethyl ether. The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 10% to 30% isopropanol in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 506.0 (M+H).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[NH2:6][C:7]([C:9]1[C:10]([Cl:23])=[C:11]([CH:16]=[CH:17][C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[C:12]([O:14][CH3:15])=[O:13])=[O:8]>C1(C)C=CC=CC=1>[Cl:23][C:10]1[C:9]([C:7]2[O:8][C:2](=[O:3])[S:4][N:6]=2)=[C:18]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)SCl
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(N)=O)c1Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2nsc(=O)o2)c1Cl
Yield: 70.5 %

Procedure:
9.80 g (75 mmol) of chlorocarbonylsulfenyl chloride were added dropwise to a solution of 4.37 g (15 mmol) of methyl 3-aminocarbonyl-2-chloro-4-methylsulfonylbenzoate in 150 ml of dry toluene. The mixture was stirred under reflux for 48 hours, and the solvent was then removed under reduced pressure and the residue was chromatographed over silica gel (eluent: ethyl acetate/cyclohexane=1/1). 3.70 g (70% of theory) of methyl 2-chloro-3-(1,3,4-oxathiazolin-2-on-5-yl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (75 mg, 89%), MS (ISP) m/z=336.4 [(M+H)+], mp 290° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@:5]([OH:11])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[H-].[Na+].[Br:15][C:16]1[N:21]=[C:20]([C:22]2([CH3:37])[CH2:24][N:23]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26])[C:19]([F:38])=[CH:18][CH:17]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C@:5]([O:11][CH2:37][C:22]([C:20]1[C:19]([F:38])=[CH:18][CH:17]=[C:16]([Br:15])[N:21]=1)([NH:23][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35])(=[O:26])=[O:27])[CH3:24])([CH3:10])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Reactant: CC1(c2nc(Br)ccc2F)CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (715 mg, 3.84 mmol) in DMF (4 ml) was added NaH (55%) (154 mg, 3.84 mmol) at room temperature and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 6-bromo-3-fluoro-2-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine (800 mg, 1.922 mmol) in DMF (9 ml) was added and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was poured onto a mixture of ice/2N HCl/t-butyl-methylether. The organic layer was washed with sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. Silica gel chromatography (cyclohexane/ethyl acetate) afforded the title compound as a mixture of 2 diastereoisomers. 300 mg (26% yield). TLC (cyclohexane/ethyl acetate 2:1) Rf=0.42; LCMS RtH5=1.25 min (100%, TIC ES+ 602, 604).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:8]2[CH:19]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-2-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 377 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15](=[O:16])[CH2:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>ClCCl.FC(F)(F)C(O)=O.C(OCC)(=O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:12]2[CH2:13][CH2:14][C:15](=[O:16])[CH:11]2[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCC(=O)C2c2ccc(C(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C2C(=O)CCC2c2ccc(N)cc2)cc1
Yield: 59.7 %

Procedure:
A mixture of Example 7G (1.3 g, 3.19 mmol) in dichloromethane (12 mL) and trifluoroacetic acid (4 mL) was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (30 mL×3) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=2:1, v/v) to afford the title compound (586 mg, 1.906 mmol, 59.8% yield) as a solid. LC/MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([S:15](=[O:17])(=[O:16])[NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:3][C:2]=1[CH3:1])=[O:14]
Reactant: Nc1nccs1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2nccs2)ccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 75.5 %

Procedure:
Synthesized according to general procedure 70. Under an N2 atmosphere, a mixture of 3-methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (7.5 g, 24.9 mmol) and 2-aminothiazole (2.49 g, 24.9 mmol), and pyridine (15 mL) was stirred at RT for 19 h. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2,2,2-trifluoro-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (6.87 g, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=366.1; tR=1.13 min.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O.[NH2:24][C:25]1[N:29]([CH3:30])[NH:28][C:27](=[O:31])[CH:26]=1>C(O)C>[C:1]([O:4][CH2:5][C:6]1[NH:24][C:25]2[N:29]([CH3:30])[NH:28][C:27](=[O:31])[C:26]=2[CH:18]([C:17]2[CH:20]=[CH:21][C:22]([F:23])=[C:15]([Br:14])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: CCOC(=O)C1=C(COC(C)=O)Nc2c(c(=O)[nH]n2C)C1c1ccc(F)c(Br)c1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
Ethyl 4-(acetyloxy)-3-oxobutanoate (0.19 g, 1 mmol), prepared as described in (S. Husband, W. Fraser, C. J. Suckling, H. C. Wood, Tetrahedron, (1995) 51(3), 865), 3-bromo-4-fluorobenzaldehyde (0.2 g, 1 mmol) and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 24 hours in a sealed tube. The reaction mixture was evaporated under reduced pressure and chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide 0.1 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.03 (t, 3H), 2.1 (s, 3H), 3.46 (s, 3H), 3.92 (q, 2H), 4.95 (s, 1H), 5.12 (q, 2H), 7.18 (m, 1H), 7.22 (t, 1H), 7.38 (dd, 1H), 9.43 (s, 1H); MS (ESI−) m/z 468(M−H)−.
Reaction SMILES: OC1C=C(O)C=C[C:3]=1[CH:9]([C:20]([CH:22]([C:33]1[CH:38]=CC(O)=CC=1O)[C:23]1C=CC(OC)=[C:25]([O:31]C)[CH:24]=1)=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([O:43]C([O-])[O-])C.N1CCOCC1>CN(C)C=O>[OH:31][C:25]1[CH:24]=[C:23]2[C:22]([C:20](=[O:21])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:3][O:43]2)=[CH:33][CH:38]=1
Reactant: COc1ccc(C(C(=O)C(c2ccc(OC)c(OC)c2)c2ccc(O)cc2O)c2ccc(O)cc2O)cc1OC
Reactant: CCOC([O-])[O-]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
14.4 g (0.05 mole) of 2,4-dihydroxy-phenyl-(3',4'-dimethoxy-benzyl)-ketone are reacted with 10.5 g (0.07 mole) ethyl-orthoformate in 10 ml of dimethyl-formamide in the presence of 1 ml morpholine. The reaction mixture is maintained at 80°-85° C., and in the second hour a solid precipitates. After 6 hours 1OO ml of chloroform are added to the mixture, the precipitated substance is filtered and dried. 7-hydroxy-3',4'-dimethoxy-isoflavone is obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BrH:12].CN([CH2:16][CH:17]([CH3:21])[C:18](Br)=[O:19])C>C(=S)=S>[Br:12][C:17]([CH3:21])([CH3:16])[C:18]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:19]
Reactant: Br
Reactant: CC(CN(C)C)C(=O)Br
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(Br)C(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A slurry of 14 g. (0.105 mole) of anhydrous aluminum chloride in 14.4 g. (0.150 mole) of fluorobenzene and 24 ml. of carbon disulfide is cooled to 15°C. To it is added 0.100 mole of α-(dimethylaminomethyl)propionyl bromide hydrobromide over 10-15 minutes at 15°-20°C. The reaction is stirred for five minutes at 20°C and then quenched on ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-bromo-4'-fluoro-2-methylpropiophenone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[C:15]([I:16])=[C:6]([C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[O:8])[C:5]([I:17])=[C:4]([C:3]=1[I:26])[C:18]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[O:19])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-Amino-N,N'-bis(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide (300 g) was suspended in acetic anhydride (1.5 1) at 90° (in an oil bath) and then p-toluenesulphonic acid (3 g) was added. The mixture was heated for 41/2 hours and then cooled slowly to room temperature. The product was collected on a filter and washed with small amounts of acetic anhydride. Yield: 353 g. The product was suspended in a mixture of methanol (600 ml) and water (300 ml) at room temperature and the pH was adjusted to about 11.5 by adding 5N sodium hydroxide (200 ml). This mixture was heated at 50° C. and more 5 N sodium hydroxide (235 ml) was added dropwise in such a manner that the pH was kept at about 10.5. After 2-3 hours the pH did not decrease, and the hydrolysis was completed. After cooling to room temperature the mixture was acidified with 6 N hydrochloric acid to about pH 6. After stirring for two hours at room temperature, the mixture was cooled to 3° for 2-3 days. The product was collected on a filter, suspended in water (500 ml) and filtered again. Yield: 257 g. Melting point: above 270°. (Found: C 25.68; H 2.85; I 51.0; N 6.03. Calc. for C16H20I3N3O7 : C 25.72;H 2.70; I 50.96; N 5.62) TLC (precoated TLC Plates Silica Gel 60 F-254 from Merck A.G. and developed in CHCl3 : MeOH=70:30) showed one spot with Rf value 0.38.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[O:57][CH2:58][C:59]([CH3:62])([CH3:61])[CH3:60])=CC=1)([O-])=O.C(N(CC)CC)C>C(O)(=O)C>[CH3:60][C:59]([CH3:62])([CH3:61])[CH2:58][O:57][C:56](=[O:55])[N:37]=[C:36]([NH2:38])[C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzamidine acetic acid salt (6 g) and DMF (500 mL), carbonic acid 2,2-dimethylpropyl ester 4-nitrophenyl ester [CAS No. 158810-98-1] (3.06 g) and triethylamine (4.64 mL) were added, and the resulting mixture was stirred overnight at room temperature. Acetic acid (5 mL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (6.5 g).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:32][C:31]([C:30]([O:34][CH3:35])=[O:33])=[C:16]2[CH:17]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: C#CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OCc1cc[n+](N)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn2ccc(CO[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-amino-4-((tert-butyldimethylsilyloxy)methyl)pyridinium 2,4-dinitrophenolate Y-4 (13.4 g, 31.6 mmol) in DMF (60 mL) were added methyl propiolate (2.7 g, 31.6 mmol) and K2CO3 (6.5 g, 47.4 mmol). The reaction was stirred at room temperature for 24 h, then treated with water. The resulting mixture was extracted with ethyl acetate (100 ml×3), the combined organic layers were washed with water, brine and dried over Na2SO4, then concentrated in vacuo, the residue was purified by silica gel chromatography to afford the title compound (2.9 g). MS (m/z): 321 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>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.O>[O:38]1[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:2]3[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]4[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=4[CH:3]=3)=[CH:27][C:28]=2[S:41]([CH3:44])(=[O:42])=[O:43])[CH2:40][CH2:39]1
Reactant: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)OC1(C)C
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: CC#N
Solvent: O
Product: CC(C)Nc1nc(-c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)cc2ncn(C)c(=O)c12
Temperature: 140 °C

Procedure:
7-Chloro-5-(isopropylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (60 mg, 0.24 mmol), crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(methylsulfonyl)-N-(2-morpholinoethyl)benzenamine (240 mg, ˜0.28 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and Na2CO3 (102 mg, 0.96 mol) in a mixed solvent of acetonitrile (4 mL) and H2O (4 mL) were added to a 20 mL microwave tube and sealed. The tube was then heated in a Microwave Reactor at 140° C. for 10 minutes. The solvent was removed and the crude product purified by silica column using 7% MeOH in DCM to give the final product as a pale solid. ESI-MS m/z 501.2 (MH+); 1H NMR (DMSO-d6) δ 8.71 (d, J=7.2 Hz, 1H), 8.46 (d, J=2.4 HZ, 1H), 8.40 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.77 (t, J=4.8 Hz, 1H), 3.59 (m, 4H), 3.42 (s, 3H), 3.33 (m, 4H), 3.20 (s, 3H), 2.62 (m, 2H), 2.44 (s, 3H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N:11]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrCCOCCBr
Reactant: N#Cc1cc(N)cc(Cl)c1N
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCOCC2)cc(Cl)c1N
Temperature: 180 °C
Yield: 91 %

Procedure:
2,5-Diamino-3-chloro-benzonitrile (387 mg), bis-(2-bromoethyl)ether (0.35 mL) and N,N-diisopropyl-ethylamine (1.25 mL) were mixed in N,N-dimethylformamide (4 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (20 mL) was added and the crude mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo to furnish 0.50 g (91%) of the title compound as a brown solid. LC-MS (m/z) 238 (MH+); tR=2.31, (UV, ELSD) 85%, 95%. 1H NMR (500 MHz, DMSO-d6): 2.97 (m, 4H), 3.69 (m, 4H), 5.59 (s; 2H), 7.04 (d, 1H), 7.29 (d, 1H).
Reaction SMILES: [NH:1]1[C:5]([N:6]2[CH2:11][CH2:10][CH:9]([C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:7]2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C.CC(C)=O>[CH3:23][CH:22]([N:3]1[N:2]=[N:1][C:5]([N:6]2[CH2:11][CH2:10][CH:9]([C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:7]2)=[N:4]1)[CH3:24]
Reactant: C[C@@H](O)C1CCN(c2nnn[nH]2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nnc(N2CCC([C@@H](C)O)CC2)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
A solution of (1R)-1-[1-(1H-tetrazol-5-yl)-4-piperidinyl]ethanol (256 mg, 1.3 mmol) in DMF (1 mL) and acetone (5 mL) was treated with potassium carbonate (359 mg, 2.59 mmol) at room temperature. After stirring for 15 min, 2-iodopropane (661 mg, 3.89 mmol) was added and the mixture was heated at 50° C. for 3 h. The salt was removed by filtration and washed by EtOAc. After concentration, the crude product was purified by chromatography on a silica gel column using MeOH/CH2Cl2 gradient (2.5% to 12.5%) to give 225 mg (69%) of (1R)-1-{1-[2-(1-methylethyl)-2H-tetrazol-5-yl]-4-piperidinyl}ethanol. 1H NMR (400 MHz, CDCl3): δ 4.85 (septet, 1H, J=6.8 Hz), 4.24-4.07 (m, 2H), 3.63 (quint, 1H, J=6.2 Hz), 2.94-2.81 (m, 2H), 2.00-1.89 (m, 1H), 1.76-1.68 (m, 1H), 1.59 (d, 6H, J=6.8 Hz) 1.53-1.31 (m, 4H), 1.22 (d, 3H, J=6.2 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(SC)nc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate, 250 mL of methanol and 5 mL of 30% sodium methoxide in methanol was stirred under nitrogen at room temperature for 5 hrs, quenched with 10 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 100 mL of saturated sodium bicarbonate and 200 mL of ethyl acetate and the extracts dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1)=215.1; 1H NMR (400 MHz, CDCl3) 8.85 (s, 1H), 4.1 (s, 3H), 4.05 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:14])[C:5]=2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c(Br)csc12
Product: Clc1ncnc2c(Br)csc12

Procedure:
7-Bromothieno[3,2-d]pyrimidin-4(3H)-one (0.9 g, 3.89 mmol) in POCl3 was heated under reflux for 2 hours and excess of POCl3 was removed under reduced pressure. The residue was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give 0.91 g of the compound 65A: 1H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.78 (s, 1H). ESI (+)/MS: 248 (M−H)+.