Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25](O)=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O>[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[NH:1][C:2]2[C:3]([C:4]([NH2:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2nc(-c3cnccn3)[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A solution of 1.68 g (7.5 mmol) of 2,3-diaminobenzamide and 3.04 g (30 mmol) of triethylamine in 50 ml of dimethylformamide was stirred at room temperature for 1 hour. 0.93 g (7.5 mmol) of pyrazine-2-carboxylic acid and 1.01 g (7.5 mmol) of N-hydroxybenzotriazole (HOBt) were added. After stirring at room temp. for 15 minutes, the mixture was cooled to 0° C. 1.44 g (7.5 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) were added, and the mixture was stirred at room temp. for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate. The residue obtained after concentration in vacuo was taken up in 50 ml of glacial acetic acid and refluxed for 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was stirred in diethyl ether. The precipitate was removed by filtration and dried at 40° C. in vacuo. 1.11 g of brown crystals were obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)C.[CH3:23][NH2:24]>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH:24][CH3:23])=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: CN
Reactant: CCOC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Solvent: O
Product: CNC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A mixture of 500 mg of [4(4-fluoro-benzyloxy)-phenoxy]-acetic acid ethyl ester [Example 1b)] and 2 ml of methylamine (about 8 M in ethanol) was stirred at 80° C. during 18 h. For the working-up, the solution was cooled to room temperature and treated with water. The pure product precipitated and was collected on a filter funnel. After drying there were obtained 398 mg (86% of theory) of 2-[4-(4-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=290 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Cl:21][C:22]1[N:23]=[C:24]([N:27]([CH3:29])[CH3:28])[S:25][CH:26]=1>>[Cl:21][C:22]1[N:23]=[C:24]([N:27]([CH3:29])[CH3:28])[S:25][C:26]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C(F)(F)F)nc12
Reactant: CN(C)c1nc(Cl)cs1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C)nc3Cl)c(C(F)(F)F)nc12

Procedure:
Using a procedure analogous to Example 254D, 8-(1-ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (250 mg, 0.630 mmol) is coupled with (4-chloro-thiazol-2-yl)-dimethyl-amine (154 mg, 0.945 mmol) to provide desired product. 1H-NMR (CDCl3), δ 0.85 (t, J=7.4 Hz, 6H), 1.83 (m, 4H), 2.55 (s, 3H), 3.16 (s, 6H), 3.31 (m, 1H), 6.81 (s, 1H) ppm. ES-MS (m/z): calcd for C18H21ClF3N5S (M+H)+: 431.91; found: 432.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[N:8][C:7]2=O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2c(=O)nc[nH]c2cc1OC
Solvent: CN(C)C=O
Product: CCOc1cc2c(Cl)ncnc2cc1OC
Temperature: 100 °C
Yield: 68.5 %

Procedure:
A mixture of 6-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (560 mg, 2.54 mmol) in POCl3 (5 mL, 53.6 mmol) was treated with 1 drop of DMF and heated at 100° C. for 2 hours before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate) and concentrated to give 4-chloro-6-(ethyloxy)-7-(methyloxy)quinazoline (416 mg, 1.74 mmol, 69%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 7.46 (s, 1 H), 7.39 (s, 1 H), 4.26 (q, J=6.94 Hz, 2 H), 4.02 (s, 3 H), 1.44 (t, J=7.03 Hz, 3 H). MS (m/z) 239.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:23](=[O:24])[NH:22][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCCN=C=O
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
12.3 g. of 4-fluoro-4'-hydroxy-α-ethyl-benzhydrol, 4.68 g. of n-propyl-isocyanate and 0.7 g. of anhydrous, powdered potassium carbonate in 61 ml. of acetonitrile containing 15 μlit. of a 50% aqueous ethanol solution are refluxed under stirring. When the reaction is complete, the reaction mixture is cooled to room temperature, potassium carbonate is filtered off and acetonitrile is distilled off under reduced pressure. The residue is dissolved in benzene, the benzene solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and benzene is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 13.6 g. of the desired compound, melting at 107° to 108° C.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[OH:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Reactant: OB(O)c1cccc(O)c1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2cccc(O)c2)cc1

Procedure:
Compound (112) was prepared from compound (26) and (3-hydroxy-phenyl)-boronic acid by adapting the procedure of Example 27A. LC/MS System B; Rt=1.23 mins, m/z (ES−)=323 (M−H for C19H16O5).
Reaction SMILES: Cl[Si:2]([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C>[CH:9]1([Si:2]([CH2:14][CH:15]([CH3:17])[CH3:16])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)C[Mg]Br
Reactant: CCO[Si](Cl)(OCC)C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCO[Si](CC(C)C)(OCC)C1CCCC1
Reaction time: 6 h
Yield: 78 %

Procedure:
50 ml of dry diethyl ether and 14.0 gram (0.063 mole) of chlorocyclopentyldiethoxysilane (d) were charged in a 250 ml flask equipped with a reflux condenser and a stirring apparatus in an atmosphere of nitrogen and above prepared solution of isobutyl magnesium bromide was slowly added while keeping the internal temperature below 10° C. After completion of addition stirring was carried out at room temperature for 6 hours and at reflux temperature for 2 hours. To the resulting reaction mass 10-20 ml of saturated aqueous ammonium chloride solution was added drop wise to dissolve magnesium salt. The organic layer was separated from the aqueous phase, dried and evaporated to give crude cyclopentylisobutyldiethoxysilane. This crude was purified by fractional distillation under reduced pressure, yielding 12 gram (78%) of pure cyclopentylisobutyldiethoxysilane.
Reaction SMILES: [CH2:1]([CH:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:23]1[C:24]([F:30])=[N:25][CH:26]=[C:27]([Br:29])[CH:28]=1)[CH3:22])[CH:2]=C.C(=O)(O)[O-:32].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:29][C:27]1[CH:28]=[C:23]([C@:5]2([CH3:22])[CH:4]([CH2:1][CH2:2][OH:32])[S:9](=[O:11])(=[O:10])[C:8]([CH3:12])([CH3:13])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[N:6]2)[C:24]([F:30])=[N:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: C=CCC1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)C(CCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
To a solution of tert-butyl ((5R)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.988 g, 1.96 mmol) in MeOH (5 mL) and DCM (15 mL) at room temperature was added sodium bicarbonate (0.333 g, 3.96 mmol). The reaction mixture was cooled to −78° C. and ozone was bubbled through the solution. After 15 min, the solution turned blue and oxygen was bubbled through the mixture for 5 min. Sodium borohydride (0.154 g, 4.07 mmol) was added and the reaction mixture was removed from the −78° C. bath. The solution was warmed to room temperature, stirred for 1 h, and quenched with saturated NH4Cl, and diluted with EtOAc water. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated. Purification by flash column chromatography on silica gel (40 g, 20% to 60% EtOAc in hexanes) gave tert-butyl ((5R)-5-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.913 g, 1.80 mmol, 92% yield) as a mixture of isomers that was used in the next step without separation. LC/MS (ESI+) m/z=508 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[Li].O.Cl>ClCCl>[CH2:16]([O:23][C:7]1[C:2]([F:1])=[C:3]([CH2:12][C:13](=[O:15])[CH3:14])[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH.H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford 1.6 g of the desired compound which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 um 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH:water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)C(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1 -tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (128 mg, 0.47 mmol) in methanol (2 mL) at 0° C. was added portionwise sodium borohydride (18 mg, 0.47 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was then quenched with sat'd NH4Cl (2 mL), extracted with ethyl acetate (2×5 mL), dried (Na2SO4) and concentrated. A solution of this crude material in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (20 mg) and a trace of conc. H2SO4 at rt for 16 h. Filtration over Celite™ afforded 100 mg (84%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, J=8.3, 1H), 7.12 (ddd, J=8.8, 8.8, 1.5, 1H), 7.02 (d, J=7.0, 1H), 6.97 (ddd, J=7.4, 7.4, 1.0, 1H), 3.46 (s, 2H), 2.58 (s, 2H), 1.51 (s, 9H), 1.01 (s, 6H).
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[OH2:17].Cl>>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([C:2]([Cl:1])=[O:17])=[CH:4][CH:5]=1
Reactant: O
Reactant: FS(F)(F)(F)(F)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cl
Product: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
Into a 50 mL flask equipped with a stirrer were placed 16.08 g (50 mmol) of 4-trichloromethyl(pentafluorosulfanylbenzene) prepared in Example 1 and 406 mg (5 mol %) of FeCl3. The bath was heated to 70° C. to 75° C., and 900 mg (50 mmol) of water was added dropwise over at least 2 hours. HCl gas was generated during the addition. After the addition was complete, the mixture was heated with stirring for 1 hour. This mixture was distilled under reduced pressure to yield 5.59 g of 4-pentafluorosulfanylbenzoic chloride (product yield: 42%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11](O)=O)[CH3:10])=O)(C)(C)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C@@H:9]([NH2:8])[CH2:11][N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH2:23][CH2:24]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled solution of t-butoxycarbonyl D-alanine (9.45 g, 0.05 mol) and 1-(2-methoxyphenyl)piperazine (9.6 g, 0.05 mol) in 125 mL of CH2Cl2 was added diethyl cyanophosphonate (8.34 mL, 0.055 mol) in 50 mL of CH2Cl2 over 30 minutes followed by triethylamine (7.37 mL, 0.055 mol) in 50 mL of CH2Cl2 over 15 minutes. After 21/2 hours, the solution was washed with water (2×100 mL) and K2CO3 (2×100 mL of 10% aqueous), dried over anhydrous K2CO3 and evaporated to an oil. The crude 1-(t-butoxycarbonyl-D-alanyl)-4-(2-methoxyphenyl)piperazine was stirred in 200 mL of 4.5N HCl in ethyl acetate for 1 hour at room temperature, diluted with 400 mL of anhydrous diethyl ether, filtered, washed and dried in vacuo. The 1-(D-alanyl)-4-(2-methoxyphenyl)piperazine dihydrochloride was stirred in 200 mL of anhydrous tetrahydrofuran, treated with 225 mL of 1M BH3 in tetrahydrofuran, and refluxed 31/2 hours. After cooling in ice, the reaction was quenched with 140 mL of 2N aqueous HCl and refluxed 18 hours The tetrahydrofuran was removed on a Rotovapor, the aqueous solution was made basic with 6N sodium hydroxide and the amine was extracted into diethyl ether. The diethyl ether solution was dried over anhydrous K2CO3, filtered and acidified with 4.5N HCl in ethyl acetate. The salt was filtered, washed with diethyl ether, converted to free base in 2N NaOH and extracted into diethyl ether. After drying as above and evaporation, (R)-1-methyl-2-[4-(2-methoxyphenyl)-piperazinyl]ethylamine was obtained as an oil (11.8 g, 94.7% based on BOC-D-alanine). A sample was converted to the trihydrochloride sesquihydrate, mp. 219°-221° C.; [α]D25 =-26.4 c=0.99 MeOH. 1H NMR (DMSO-d6) δ: 1.32 (d, 3H), 3.8 (s, 3H), 6.9-7.0 (m, 4H). The IR curve was devoid of carbonyl peaks.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:17][CH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Temperature: 100 °C

Procedure:
A mixture of ethyl 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.1 g, 4.5 mmol, prepared as described in WO 2007/090748), N-bromosuccinimide (2.86 g, 16.1 mmol) and benzoyl peroxide (0.21 g, 0.9 mmol) in carbon tetrachloride (9 mL) was heated in a sealed vessel to 100° C. overnight. The mixture was diluted with dichloromethane (DCM), filtered and the solvent was removed in vacuo. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded the product, which on removal of solvent, was an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]=[N+:14]=[N-:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-hydroxybenzene sulfonyl chloride synthesized in Synthetic example 1 (3.76 g, 19.5 mmol, and 1.00 Eq) was dissolved in acetone (50 mL) and then water (50 mL) was added thereto. The obtained mixed solution was cooled to 0° C. and NaN3 (1.41 g, 21.7 mmol, and 1.11 Eq) was added to the solution slowly, followed by stirring at 0° C. for 1 hour. After the stirring, acetone was removed by the evaporator (30° C., 150 mbar) and a water layer was extracted with dichloromethane (3×30 mL). The obtained organic layer was dried with sodium sulfate and dichloromethane was removed by the evaporator. The product as oil (3.06 g, 15.4 mmol, and 79%) was dried in vacuo to obtain 4-hydroxybenzenesulfonyl azide.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2cc([N+](=O)[O-])ccc21
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 120 °C
Yield: 53.6 %

Procedure:
The mixture of tert-butyl 3-bromo-5-nitro-1H-indole-1-carboxylate (341.2 mg, 1.0 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (309.2 mg, 1.0 eq), (PPh3)4Pd (O) (231.1 mg, 0.2 eq), Na2CO3 (2M, 1.5 mL, 3.0 eq) and dioxane (10 mL) was degassed and heated at 120° C. in a microwave-oven synthesizer for 2 h. The mixture was cooled to room temperature and filtered through a celite pad to remove Na2CO3 and catalyst. EtOAc was used to wash the celite pad. The solvent was removed and the crude was purified by silica gel with chromatography (0%˜20% MeOH/DCM) to obtain the desired product tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (184.1 mg, isolated yield 54%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C=CCN1CCCNCC1
Solvent: CS(C)=O
Solvent: CO
Product: C=CCN1CCCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
1-Prop-2-enyl-1,4-diazepane (224 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (271 mg, 69%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=[CH:18]N(C)C)[N:3]=1.C([OH:25])(C)C.CS(O)(=O)=O>O>[Cl:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([NH:17][CH:18]=[O:25])[N:3]=1
Reactant: CC(C)O
Reactant: CN(C)C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Agent: CS(=O)(=O)O
Solvent: O
Product: O=CNc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-5-(4-chlorophenylethynyl)-2-dimethylaminomethyleneaminopyrimidine (65.1 g), isopropanol (585 mL), and water (36 mL) were combined and warmed to 60° C. Methane sulfonic acid (23.1 g) was added and heating at 60oC was continued for 1.5–2.0 hours or until HPLC analysis confirmed the absence of the starting material. The mixture was cooled to ambient temperature and held for 1.5 hours. The solids were removed by filtration and washed with isopropanol (100 mL). The filter cake was slurried in water (500 mL), basified with 1 N NaOH to pH 11, filtered, and the solids were rinsed with water. Vacuum drying at 50° C. provided predominantly 4-chloro-5-(4-chlorophenylethynyl)-2-formamidopyrimidine: 51.6 g.