Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.O1CCCC1.[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH2:9][C:10](O)=[O:11]>>[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[CH2:9][CH2:10][OH:11]
Reactant: NC(CC(=O)O)c1cccc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Product: NC(CCO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
With ice cooling and under argon, 10.9 ml (10.94 mmol) of borane-tetrahydrofuran complex (1M in THF) were introduced. Then 850 mg (3.65 mmol) of 3-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid were added. After 5 minutes, the cooling bath was removed and the mixture was stirred at RT overnight and for 4 h at reflux. After cooling to RT, pieces of ice were added until the evolution of gas came to an end. The mixture was rendered alkaline with 1M aqueous sodium hydroxide solution, diluted with water to a volume of approximately 150 ml, and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 744 mg (85% of theory) of the title compound in 92% purity.
Reaction SMILES: [CH3:1][S:2]([CH2:5]P(=O)(OCC)OCC)(=[O:4])=[O:3].CC(C)([O-])C.[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[N:38]=[C:37]([NH:39][C:40]3[CH:44]=[C:43]([CH3:45])[NH:42][N:41]=3)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=O)=[CH:23][CH:22]=1.Cl>C1COCC1.CCOC(C)=O.[Pd]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:29]2[N:38]=[C:37]([NH:39][C:40]3[CH:44]=[C:43]([CH3:45])[NH:42][N:41]=3)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:23][CH:22]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(CS(C)(=O)=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reaction time: 0.08 h
Yield: 4.8 %

Procedure:
To diethyl methylsulfonylmethylphosphonate (746 mg, 3.24 mmol) in THF (20 mL) at 0° C. was added potassium t-butoxide (1.0 M in THF, 3.25 mL, 3.25 mmol) and the mixture was stirred for 5 min. Then (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (375 mg, 1.08 mmol) was added and the mixture was stirred at rt for 4 h. The mixture was treated with 1 N HCl and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine and then concentrated to a residue (700 mg), which was subjected to silica gel chromatography eluting with 1-10% MeOH/DCM to give impure material. To a portion of this material (166 mg) in EtOAc (5 mL) was added 10% Pd—C (166 mg) and the mixture was stirred under a hydrogen atmosphere at rt overnight. The mixture was filtered and to the filtrate was added palladium on carbon (10%). The mixture was stirred under a hydrogen atmosphere for several hours, and then filtered. The filtrate was concentrated to a solid, which was triturated with ether to afford 2-(1-(4-fluorophenyl)-2-(methylsulfonyl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (22 mg). 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3 H) 2.87 (s, 3H) 3.85 (m, 1H) 4.34 (m, 1H) 4.68 (bs, 1H) 6.45 (s, 1H) 7.15 (t, 2H) 7.49 (m, 3H) 7.76 (m, 2H) 8.56 (d, 1H) 10.36 (s, 1H) 12.17 (s, 1H); LC-MS (ESI) m/z 426 (M+H)+.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][N:33]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:14][C:15]=1OS(C(F)(F)F)(=O)=O)#[N:9].C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:8]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][N:33]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:14][C:15]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:9]
Reactant: COC(=O)c1ccnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)c1
Reactant: Cc1ccccc1
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: OB(O)c1ccccc1
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(-c3ccccc3)c(C#N)c2)c1
Temperature: 100 °C

Procedure:
87 mg of tetrakis(triphenylphosphine)palladium was added to a toluene (25 ml) suspension of 966 mg of methyl 2-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)isonicotinate, 610 mg of phenylboronic acid and 518 mg of potassium carbonate, followed by heating at 100° C. in an argon atmosphere for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30) to obtain 758 mg of methyl 2-(2-cyanobiphenyl-4-yl)isonicotinate. (2) 758 mg of this compound was dissolved in a mixture of 10 ml of methanol and 10 ml of THF, and 7.2 ml of aqueous 1 M sodium hydroxide solution was added thereto, followed by heating at 60° C. for 13 hours. The reaction mixture was cooled to room temperature, neutralized with 1 M hydrochloric acid, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol and water to obtain 472 mg of 2-(2-cyanobiphenyl-4-yl)isonicotinic acid. (3) 414 mg of this compound was dissolved in 15 ml of ethanol, and 1.5 ml of aqueous 1 M sodium hydroxide solution was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain 430 mg of sodium 2-(2-cyanobiphenyl-4-yl)isonicotinate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11]
Reactant: CCOC(=O)CNC
Reactant: Cc1cccc(Cl)c1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1N1C(=O)CN(C)C1=S
Yield: 55.7 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 9.2 g of 2-chloro-6-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (7.1 g) as an orange solid (7.1 g), m.p. 142°-145° C. Anal. Calcd. for. C11H11N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (El, M.+) m/z 254.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([Cl:13])=[C:11]([CH:14]2[CH2:16][CH2:15]2)[N:10]=[C:9]([C:17]2[S:18][C:19]([S:22](=[O:29])(=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:21]=2)[N:8]=1)(=O)=O.[NH2:32][C:33]1[N:37](C(OC(C)(C)C)=O)[N:36]=[C:35]([CH:45]2[CH2:47][CH2:46]2)[CH:34]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:24]([NH:23][S:22]([C:19]1[S:18][C:17]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[C:12]([Cl:13])=[C:7]([NH:32][C:33]3[NH:37][N:36]=[C:35]([CH:45]4[CH2:47][CH2:46]4)[CH:34]=3)[N:8]=2)=[CH:21][CH:20]=1)(=[O:28])=[O:29])([CH3:26])([CH3:25])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(OS(=O)(=O)C(F)(F)F)c(Cl)c(C3CC3)n2)s1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)c(Cl)c(C3CC3)n2)s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 2-(5-(N-tert-butylsulfamoyl)thiophen-2-yl)-5-chloro-6-cyclopropylpyrimidin-4-yl trifluoromethane sulfonate (200 mg, 0.38 mmol, 1.0 eq), tert-butyl 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylate (129 mg, 0.58 mmol, 1.2 eq), Ph3P (30 mg, 0.11 mmol, 0.3 eq), Ph(Ph3P)4 (44 mg, 0.038 mmol, 0.1 eq) and K2CO3 (158 mg, 1.14 mmol, 3 eq) in dioxane (5 mL) was stirred at 100° C. for 3 h. The mixture was extracted with EtOAc. The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EtOAc/MeOH=1:1:0.1) to provide N-tert-butyl-5-(5-chloro-4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (60 mg, 32%) as a white solid. LC-MS (m/z)=493.9 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][N:5]=[C:4]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[CH:10]=2)[CH:3]=1.[NH2:15][NH2:16].CC(O)C>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[CH:10]=2)[N:5]=[CH:6][C:7]=1[NH:15][NH2:16]
Reactant: NN
Reactant: Cc1cc(-c2cc(F)c(F)cn2)on1
Solvent: CC(C)O
Product: Cc1cc(-c2cc(F)c(NN)cn2)on1
Temperature: 65 °C
Yield: 91.6 %

Procedure:
A 330 mL pressure vessel was charged with 4,5-difluoro-2-(3-methylisoxazol-5-yl)pyridine (3.6695 g, 18.7 mmol), hydrazine (3.53 ml, 112 mmol), and IPA (93.5 ml, 18.7 mmol), sealed, then heated at 65° C. for 3 hours. The mixture was filtered; the solid was triturated with sat. aqueous NaHCO3 solution and washed with water (2×20 mL). 1-(4-fluoro-6-(3-methylisoxazol-5-yl)pyridin-3-yl)hydrazine (3.5668 g, 91.6% yield) was isolated as a white powder.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:20]>[Pt](=O)=O>[ClH:20].[C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc(-c2ccc(C(C)(C)C)s2)c1
Agent: O=[Pt]=O
Agent: Cl
Product: COC(=O)C1CCNC(c2ccc(C(C)(C)C)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
Methyl 2-(5-tert-butylthiophen-2-yl)isonicotinate (2.02 g, 7.34 mmol) was dissolved in hydrogen chloride (1.25 M in MeOH, 11.74 mL, 14.67 mmol) and stirred at room temperature for 30 min. The solvent was evaporated in vacuo. The residue was dissolved in MeOH (20 mL), platinum(IV) oxide (0.050 g, 0.22 mmol) added and the reaction mixture hydrogenated in a Büchi hydrogenator at 5 bar and room temperature for 3 h. Additional platinum(IV) oxide (0.050 g, 0.22 mmol) was added and the hydrogenation continued for 3 h. The reaction mixture was filtered through celite, washed with MeOH and the filtrate evaporated in vacuo. The residue was redissolved in MeOH (15 mL) and platinum(IV) oxide (0.167 g, 0.73 mmol) added. Hydrogenation was continued for 3 h. Additional platinum(IV) oxide (0.167 g, 0.73 mmol) was added and the hydrogenation continued for 2 h. The reaction mixture was filtered through celite, washed with MeOH and the filtrate evaporated in vacuo to yield methyl 2-(5-tert-butylthiophen-2-yl)piperidine-4-carboxylate hydrochloride (2.360 g, 101%) as a black oil. MS m/z 282 (M+H)+
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:3])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(OC(=O)Cl)cc1
Product: C#CCC1CCN(C(=O)Oc2ccc(OC)cc2)CC1

Procedure:
4-(methoxy)phenyl chloroformate (5.00 g, 26.8 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.60 g, 20.9 mmol) according to general procedure 1. Yield=5.02 g, 90%. m/z MH+=274.06. HPLC rt=12.2 min.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)(=O)C.[Rh]>[NH:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccncc2[nH]1
Agent: [Rh]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c([nH]1)CNCC2
Reaction time: 168 h
Yield: 97 %

Procedure:
Ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate (4.225 g, 22.21 mmol) was dissolved in acetic acid (150 mL) and 5% Rh/Al2O3 (9.144 g, 0.2 eq.) was added. The suspension was hydrogenated (45 Bars) at rt for 4 days then at 50° C. for 7 days. The catalyst was removed by filtration through a Celite pad, was washed with acetic acid and the filtrate was evaporated. The residue was dissolved in DCM, washed with saturated aqueous solution of NaHCO3 and aqueous phases were extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the title compound (4.183 g, 97%). HPLC purity: 92%. M+(LC-MS (ESI)): 195, M−(LC-MS (ESI)): 193
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][Si](C(C)(C)C)(C)C)/[CH:6]=[CH:7]/[C:8]1[CH:12]=[C:11]([SH:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=1.COC1C=C(C=C(OC)C=1O[Si](C(C)(C)C)(C)C)/C=C/C1C=C(O)N(C2C=CC=CN=2)N=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:6]=[CH:7][C:8]1[CH:12]=[C:11]([SH:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=1
Reactant: COc1cc(/C=C/c2cc(S)n(-c3ccccn3)n2)ccc1O[Si](C)(C)C(C)(C)C
Agent: COc1cc(/C=C/c2cc(O)n(-c3ccccn3)n2)cc(OC)c1O[Si](C)(C)C(C)(C)C
Product: COc1cc(C=Cc2cc(S)n(-c3ccccn3)n2)ccc1O
Yield: 96 %

Procedure:
The title compound was prepared in the same manner as in Example C-13, except that an equimolar amount of Compound 9j prepared in Example C-10 was used in place of Compound 9i.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]([O:17][P:18]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([N+](CCCC)(CCCC)CCCC)CCC.O.CO.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOCC>[C:21]([O:20][P:18]([O:25][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of methyl 3-(bromomethyl)benzoate (1.08 g, 4.71 mmol) in DMF (20 mL) was added tetrabutylammonium di-tert-butyl phosphate (2.34 g, 5.19 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ether and washed sequentially with 10% LiCl solution and brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g, detecting at 254 nM, and monitoring at 220 nM). Concentration of appropriate fractions provided Preparation 46A (1.38 g, 82%): HPLC: RT=3.163 min (H2O/MeOH with TFA, CHROMOLITH® ODS, 4.6×50 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=359 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.94-7.89 (m, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.58-7.48 (m, 1H), 5.01 (d, J=8.4 Hz, 2H), 3.86 (s, 3H), 1.41 (s, 18H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9]O[Si](C)(C)C(C)(C)C)=[C:6](O)[N:5]=[C:4]([S:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[N:3]=1.N1C=CC=CC=1C.P(Cl)(Cl)([Cl:40])=O>>[Cl:40][C:6]1[C:7]2[CH2:8][CH2:9][NH:1][C:2]=2[N:3]=[C:4]([S:19][CH2:20][C:21]2[C:22]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:28]=[CH:29][CH:30]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCc1c(N)nc(SCc2ccc3ccccc3c2)nc1O
Solvent: Cc1ccccn1
Product: Clc1nc(SCc2cccc3ccccc23)nc2c1CCN2
Temperature: 22 °C
Reaction time: 8 h

Procedure:
2-(4-amino-6-hydroxy-2-(2-naphthylmethyl)thio-5-pyrimidinyl)-1-(dimethyl-tert-butylsilyloxy)ethane (Cpd #280; 104 mg, 0.23 mmol) is treated with 2-picoline (28 μL, 0.28 mmol) and phosphorus oxychloride (0.22 ml, 2.3 mmol). The solution is heated to reflux for 2 hours, stirred overnight at 22° C. then heated again to reflux for an additional hour. The solution was cooled and ice is added. The resultant solid was filtered, washed with cold 50% ethanol, and dried under vacuum. The recovered solids, 81 mg are purified by chromatography (SiO2, 4:1 hexane/ethyl acetate): 64 mg (0.19 mmol, 85%), mp 107-110° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1.O>C1COCC1>[C:1]([NH:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncnc2cc(NC(C)=O)ncc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Acetyl chloride (0.70 mL, 9.84 mmol) is added to a solution of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.20 g, 1.04 mmol) (described in a previous experimental) and Eton (1.51 mL, 10.8 mmol) in THF at 0° C., and then the mixture is stirred at 20° C. for 4 h. Water (50 mL) was added, then the solution was extracted with EtOAc (3×50 mL). Evaporation and chromatography on alumina (1% EtOH/CHCl3) yields 7-acetylamino-4-methylthiopyrido[4,3-d]pyrimidine (0.12 g, 49%) as a yellow solid. 1H NMR (DMSO) δ 11.05 (1H, s), 9.30 (1H, s), 9.02 (1H, s), 8.38 (1H, s), 2.71 (3H, s), 2.18 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]#[CH:12])=O)=[CH:4][CH:3]=1.[BrH:13].O>O1CCOCC1>[Br:13][CH2:12][C:11]1[C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:8][CH:10]=1
Reactant: C#CCS(=O)c1ccc(C)cc1
Reactant: Br
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2scc(CBr)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
In 110 mL of dioxane, was dissolved 7.18 g (40.3 mmol) of the compound obtained in Example 11. The resulting solution was refluxed at 100° C. for 100 minutes The refluxed solution was then cooled, and 7.42 g (44 mmol) of a 48% hydrobromic acid was added. The obtained mixture was allowed to stand at room temperature for 1 hour. Water was then added, and the obtained mixture was extracted with ethyl acetate. The resulting extract was dried with magnesium sulfate and vacuum concentrated to provide 9.04 g of 3-(bromomethyl)-5-methylbenzo[b]thiophene. The yield was 93%.
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][C@H:4]1[CH2:8][O:7][C@@:6]([C@@H:10]2[C@:18]3([CH3:19])[C@H:13]([C@@H:14]([OH:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)([CH3:9])[CH2:5]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][C@H:4]1[CH2:8][O:7][C@@:6]([C@@H:10]2[C@:18]3([CH3:19])[C@H:13]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)([CH3:9])[CH2:5]1
Reactant: CC(C)(O)C[C@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O)CCC[C@@]32C)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(O)C[C@H]1CO[C@](C)([C@H]2CC[C@H]3C(=O)CCC[C@@]32C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
A solution of 14a (100 mg, 0.32 mmol) in dry CH2Cl2 (10 mL) was treated with PDC (pyridinium dichromate, 0.5 g, 1.3 mmol). The mixture was stirred at room temperature for 20 h, the mixture was filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 3×5.5 cm, 20% EtOAc-hexanes) to give 1R (90 mg, 91%, white solid, mp: 82° C.).
Reaction SMILES: C[N:2]([C@@:10]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=O)OC(C)(C)C.C(N(CC)CC)C.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28](F)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:26]=1[CH3:46])#[N:24]>CS(C)=O>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28]([N:12]2[CH2:13][CH2:14][C@:10]([CH3:15])([NH:2][CH3:3])[CH2:11]2)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:26]=1[CH3:46])#[N:24]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@@]1(C)CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Yield: 21.1 %

Procedure:
A dimethyl sulfoxide (1 ml) solution of tert-butyl methyl[(3S)-3-methylpyrrolidin-3-yl]carbamate (I-348) (318 mg, 1.48 mmol) and triethylamine (241 μl, 1.73 mmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (400 mg, 1.24 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (3 ml), and with cooling with ice, trifluoroacetic acid (6 ml) was added, followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution and water were added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was recrystallized from isopropyl ether to obtain the entitled compound (109 mg, 21%) as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:26]([C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)(=[O:28])=[O:27])[CH:21]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:35]([N:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:24][CH2:23]2)[S:26]([C:29]1[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=1)(=[O:28])=[O:27])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a cooled stirred solution of 6-[Benzyl-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (391 mg, 0.80 mmol) in dichloromethane (20 ml). The mixture was allowed to warm to room temperature and stirred for 3 hrs then cooled and quenched with 2M NaOH until slightly basic. After diluting the reaction mixture with dichloromethane (100 ml) the organic phase was partitioned, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (304 mg, 80% yield). HPLC retention time 2.97 min. Mass spectrum (ES+) m/z 383 (M+H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.