Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1C(=O)N([I:42])C(=O)C1>C(Cl)Cl.CC(OC)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:12]3=[C:11]([I:42])[C:10]=2[CH:9]=1)#[N:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 0 °C
Yield: 98.5 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.576 g, 1.251 mmol) was dissolved in DCM (12.51 mL). The reaction mixture was cooled to 0° C., and NIS (0.295 g, 1.313 mmol) was added while stirring. After stirring at 0° C. for 50 min, the reaction mixture was diluted with MTBE (60 mL), washed with water (2×20 mL), 2 M sodium thiosulfate (2×12.5 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give the title compound as a light-yellow solid (0.723 g) without further purification. LCMS m/z=587.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.36 (d, J=6.06 Hz, 6H), 1.40 (s, 9H), 2.34-2.45 (m, 1H), 2.52 (dd, J=15.92, 9.85 Hz, 1H), 2.87 (dt, J=18.60, 8.45 Hz, 1H), 2.99 (dd, J=15.92, 3.54 Hz, 1H), 3.57-3.65 (m, 1H), 4.05 (m, 1H), 4.17 (m, 1H), 4.75 (dt, J=12.13, 6.06 Hz, 1H), 5.06 (s, 2H), 6.83-6.85 (m, 1H), 6.85-6.89 (m, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.67 (dd, J=8.72, 2.15 Hz, 1H), 7.70 (d, J=2.15 Hz, 1H).
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[CH2:19][O:18][C:17]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1.N>C1(C)C=CC=CC=1.C1C=CC=CC=1.CO>[C:47]([C:46]1[CH:49]=[CH:50][C:43]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH2:1])=[O:21])=[CH:44][CH:45]=1)#[N:48]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C1COC(=O)N1CCO
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1ccc(OCCNC(=O)OCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.61 ml (1.35 mmol) of a 2.2M solution of diethyl azodicarboxylate in toluene is added dropwise to a solution of 0.13 g (0.88 mmol) of 3-(2-hydroxyethyl)-1,3-oxazolidine-2,4-dione, prepared in Step 2.1, 0.35 g (1.35 mmol) of triphenylphosphine and 0.10 g (0.89 mmol) of 4-hydroxybenzonitrile in 2 ml of benzene, cooled using an ice bath. The reaction mixture is subsequently stirred at ambient temperature for 16 hours. It is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 99/1 then 98/2 mixture of dichloromethane and ethyl acetate. The product is taken up in 1.5 ml of a 7M solution of ammonia (10.5 mmol) in methanol. This solution is stirred for one hour. The precipitate is filtered off and washed with ethyl acetate, to give 0.035 g of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromo-5-methylbenzoic acid (215 mg, 1.0 mmol) in DCM (4 mL) and DMF (1 drop) at 0° C. was slowly added oxalyl chloride (0.13 mL, 1.5 mmol). The reaction mixture was stirred at rt for 1 h and to it was added additional oxalyl chloride (0.13 mL, 1.5 mmol). The reaction mixture was stirred for 1 h, added with MeOH (2 mL) and stirred for 6 h. The mixture was treated with Na2CO3 to pH of 9 and extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (15:1) to give methyl 2-bromo-5-methylbenzoate (210 mg; yield 92%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J=1.6 Hz, 1 H), 7.53 (d, J=8.8 Hz, 1 H), 7.15 (q, J=3.2 Hz, 1H), 3.92 (s, 3 H), 2.33 (s, 3 H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24](=[O:25])[N:15]3[CH2:16][NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]3=[N:13]2)=[CH:8][CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:3][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24](=[O:25])[N:15]3[CH2:16][NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]3=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2nc3n(c2=O)CNc2ccccc2-3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(CO)cc2)nc2n1CNc1ccccc1-2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-[4-(Ethoxycarbonyl)phenyl]-5,6dihydro-1,2,4-triazolo-[4,3-c]-quinazolin-3-one (Compound 18) (1 g, 3.0 mmol) was mixed with THF at 0° C. DIBAL (1.5M in Toluene, 4.6 ml) was added to the reaction dropwise and stirred for 10 min. at 0° C. The reaction was quenched with 10% NaOH solution and extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to afford 2-[4-(hydroxymethyl)-phenyl]-5,6dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 19), m.p. 152-154° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
5.4 g of 3-fluoro-4-nitrophenol and 4.8 ml of 4-methylaniline were mixed and stirred for 6 hours at 120° C. After cooling, it was taken up in ethyl acetate and water and extracted three times with 1N aqueous hydrochloric acid. The combined aqueous phases were extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was crystallized.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 2-thiopheneacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)[N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:3][CH2:2]1.C1C=CC2N([OH:39])N=NC=2C=1.C(N([CH:46]([CH3:48])C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(O)(=O)C>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([C:14]2[N:13]=[C:12]3[C:8]([N:9]=[CH:10][N:11]3[CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:46](=[O:39])[CH3:48])[CH2:28][CH2:29]3)=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:15]=2)=[CH:17][N:18]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCNCC4)c3n2)cn1
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)N1CCC(Cn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
5-(6-Morpholino-9-(piperidin-4-ylmethyl)-9H-purin-2-yl)pyrimidin-2-amine (75 mg) was reacted with excess acetic acid, 2 eq HOBT, 5 eq diisopropylethylamine and 2 eq N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in 1 mL of DMF. Upon completion, the reaction was extracted with ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was concentrated and purified via reverse phase HPLC to give 18.9 mg 107 as a white solid. MS (Q1) 438.3 (M)+
Reaction SMILES: [CH3:1][CH:2]([CH:6]([S:8][CH3:9])[CH3:7])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:21]([NH:22][CH2:23][CH3:24])=[CH:20][N:19]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:31])[CH:30]=2)[N:18]=1>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:16][C:17]1[C:21]([N:22]([CH2:23][CH3:24])[C:3](=[O:4])[CH:2]([CH3:1])[CH:6]([S:8][CH3:9])[CH3:7])=[CH:20][N:19]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:31])[CH:30]=2)[N:18]=1.[Cl:16][C:17]1[C:21]([N:22]([CH2:23][CH3:24])[C:3](=[O:4])/[C:2](/[CH3:1])=[CH:6]\[CH3:7])=[CH:20][N:19]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([F:31])[CH:30]=2)[N:18]=1
Reactant: CSC(C)C(C)C(=O)O
Reactant: CCNc1cn(-c2cncc(F)c2)nc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C/C=C(/C)C(=O)N(CC)c1cn(-c2cncc(F)c2)nc1Cl
Product: CCN(C(=O)C(C)C(C)SC)c1cn(-c2cncc(F)c2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.3 %
Yield: 22.06 %

Procedure:
To a solution 2-methyl-3-(methylthio)butanoic acid (0.154 g, 1.039 mmol) in dichloromethane (1 mL) at room temperature was added 1 drop of dimethylformamide. Oxalyl dichloride (0.178 ml, 2.078 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (1 mL) and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (0.5 mL) and the solution was added to a solution of 3-chloro-N-ethyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine (0.100 g, 0.416 mmol) and 4-dimethylaminopyridine (0.254 g, 2.078 mmol) in dichloromethane (1.5 mL) and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purify by chromatography (0-100% ethyl acetate/hexanes) to give N-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-(methylthio)butanamide (34 mg, 0.092 mmol, 22.06%) as a faint yellow oil and (Z)-N-(3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methylbut-2-enamide (38 mg, 0.118 mmol, 28.3% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1[C:18](O)=[CH:19][CH:20]=[C:21]2[C:26]=1[O:25][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:22]2>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:17]([CH3:16])=[C:26]2[C:21]([CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:25]2)=[CH:20][CH:19]=1)(=[O:5])=[O:4]
Reactant: Cc1c(O)ccc2c1OC(c1ccccc1)CC2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1OC(c1ccccc1)CC2
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Step 2 Trifluoromethanesulfonic anhydride (0.613 mL, 3.63 mmol) was added dropwise to a solution of 8-methyl-2-phenylchroman-7-ol (671 mg, 2.79 mmol) in DCM (10 mL) and pyridine (10 mL) at 0° C. After 30 min, the mixture was diluted with EtOAc (70 mL), washed with water (2×30 mL) and brine (30 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 85:15 hexane-EtOAc) to give 8-methyl-2-phenylchroman-7-yl trifluoromethanesulfonate as colorless liquid (925 mg, 89%). 1H NMR (400 MHz, chloroform-d) δ 7.28-7.61 (5 H, m), 6.97 (1 H, d, J=8.58 Hz), 6.79 (1 H, d, J=8.58 Hz), 5.11 (1 H, dd, J=10.23, 2.31 Hz), 2.99 (1 H, ddd, J=16.73, 11.11, 5.83 Hz), 2.68-2.88 (1 H, m), 2.17-2.32 (4 H, m), 1.88-2.12 (1 H, m). Mass spectrum m/z 390.0 (M+H)+.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28](/[CH:39]=[CH:40]/[C:41]2[CH:46]=[C:45]([F:47])[C:44]([C:48]([F:51])([F:50])[F:49])=[C:43]([F:52])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:52][C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[C:45]([F:47])[C:44]=1[C:48]([F:49])([F:50])[F:51]
Reactant: Fc1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc(F)c1C(F)(F)F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2cc(F)c(C(F)(F)F)c(F)c2)cc1O
Yield: 10 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethenyl]-pyridazine (Intermediate 77) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography (silica, eluting with 5-100% acetonitrile in water with acid modifier) to afford a white solid, which was recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 6-{2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one as a white solid (0.079 g, 10%).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:11]([CH:35]([CH3:37])[CH3:36])[CH2:12][C:13]([C:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:16]=1)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:4]([N:11]([CH:35]([CH3:37])[CH3:36])[CH2:12][C:13]([C:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:16]=1)([OH:14])[CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: Cc1c(C(=O)CN(Cc2ccccc2)C(C)C)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(C(C)(O)CN(Cc2ccccc2)C(C)C)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Methyl magnesium bromide (0.1 ml, 0.144 mmol) was added dropwise into the solution of 2-(benzyl-isopropyl-amino)-1-[5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-ethanone (61 mg, 0.12 mmol) in 0.5 ml THF at room temperature. After 2 h, the reaction mixture was then partitioned with ethyl acetate and saturated NH4Cl. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 30% ethyl acetate/hexanes) to give the title compound 4A-1 as a white waxy solid (24 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH:9]1[CH2:10][CH2:11][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:20]([NH2:23])[C:21]#[CH:22]>C(O)C>[CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH:9]1[CH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[N:23][C:12]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C1CCC2CC1CC(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1CC2CC(Cc3cccnc32)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A flask charged with a stir bar, 2-benzyl-2-aza-bicyclo[3.3.1]nonane-3,6-dione (for preparation see J. Chem. Soc., Perkin Trans. 1, 1999, 1157-1162; 0.80 g), NaAuCl4.2 H2O (30 mg), propargylamine (0.45 mL), and ethanol (5 mL) is heated at 100° C. with microwave irradiation for 10 min. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate/methanol 6:4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:19][CH2:20][CH2:21][Cl:22])([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: ClCCCBr
Reactant: COC(=O)C1Sc2cc(Cl)ccc2OCC1=O
Product: COC(=O)C1(CCCCl)Sc2cc(Cl)ccc2OCC1=O

Procedure:
Methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate is treated with 1-bromo-3-chloropropane in the same manner as described in Reference Example 25 to give methyl 7-chloro-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as a colorless oil.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=[O:2].[Br:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([CH3:26])=[CH:18]2.C([O-])([O-])=O.[Na+].[Na+].OO>C(Cl)Cl>[Br:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]([CH3:26])[C:18]2=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C[n+]1ccc2c(Br)ccc([N+](=O)[O-])c2c1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccc2c(Br)ccc([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 5-bromo-2-methyl-8-nitroisoquinolinium tosylate (20.0 g) in CH2Cl2 (400 mL) was added aq. Na2CO3 (5%, 400 mL) and hydrogen peroxide (30%, 20 mL). The resulting mixture was stirred at room temperature for 16 h, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5×100 mL). The combined organic layer was washed with water (100 mL), dried over sodium sulfate and evaporated to give the crude product, which was purified by column chromatography on silica gel (EtOAc/CH2Cl2 (1:9)) to give 2.2 g of the desired product (yield: 8%). 1H NMR (CDCl3, 300 MHz): δ=3.60 (s, 3 H), 6.90 (d, J=7.8 Hz, 1 H), 7.28 (d, J=7.2 Hz, 1 H), 7.30 (d, J=7.2 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [Br:1]C1CC(=O)NC1=O.[O:9]=[C:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=3[NH:15][C:14]=2[CH:13]=[CH:12][NH:11]1>CN(C=O)C>[CH3:26][O:25][C:23]([C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:10](=[O:9])[NH:11][CH:12]=[C:13]([Br:1])[C:14]=3[NH:15][C:16]=2[CH:17]=1)=[O:24]
Reactant: O=C1CC(Br)C(=O)N1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1cc[nH]c(=O)c12
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(Br)c[nH]c(=O)c12
Reaction time: 4 h

Procedure:
Bromosuccinimide (0.633 g, 3.56 mmol) was quickly added to a stirred mixture of methyl 1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (0.783 g, 3.23 mmol) in DMF (20 mL) at room temperature. The reaction was exothermic and turned brown. The reaction mixture was stirred for four hours. at room temperature. LC-MS showed complete conversion to the desired product mass. The reaction mixture was poured in to 200 ml water with stirring, then filtered. The residue was washed with water, then slurred in hot methanol, and filtered. The residue was then dried under vacuum overnight to give Methyl-4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate as a light brown solid. [0.898 g, 2.80 mmol, 87% yield]. The product had an HPLC Retention Time=2.703 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 320.86, 322.86
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH3:2].[BrH:20]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][CH2:8][CH:9]([Br:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)C(C)(C)CCC=Cc1ccccc1Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CCCC(Br)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.14 %

Procedure:
6-(2-Chlorophenyl)-2,2-dimethylhex-5-enoic acid ethyl ester (15 g, 53.6 mmol) was dissolved in glacial acetic acid (150 mL). The solution was cooled in an ice-bath (ca. 15° C.) while dry hydrogen bromide was passed into the solution for 8 h. The reaction mixture was poured into ice-water (250 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product (18 g) was purified by column chromatography (silica gel, ethyl acetate/heptane=1/20 to 1/10) to provide 6-bromo-6-(2-chlorophenyl)-2,2-dimethylhexanoic acid ethyl ester (15.5 g, 80.14%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.58 (d, 1H, J=7.8 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.27 (d, 1H, J=7.2 Hz), 7.21 (t, 1H, J=7.2 Hz), 5.45 (t, 1H, J=8.1 Hz), 4.09 (q, 2H, J=6.9 Hz), 2.19 (m, 2H), 1.55 (m, 2H), 1.24 (t, 3H, J=6.9 Hz), 1.14 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.45, 139.25, 132.64, 129.64, 129.27, 128.75, 127.43, 60.36, 49.97, 42.17, 39.84, 39.51, 25.41, 25.20, 23.67, 14.43. MS (GC-CI): Calculated for C16H22BrClO2 (MH)+: 361.0564; found 361.0547.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]([N:13]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[NH:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1.[CH:37](=O)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CO.O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][NH:1][CH2:2][CH2:3][N:4]2[C:8]3=[N:9][C:10]([N:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:11][CH:12]=[C:7]3[N:6]=[C:5]2[NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[CH:39][CH:40]=1
Reactant: COc1cc(Nc2nc3ccc(N(CCC(C)C)CCC(C)C)nc3n2CCN)cc(OC)c1OC
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(CNCCn2c(Nc3cc(OC)c(OC)c(OC)c3)nc3ccc(N(CCC(C)C)CCC(C)C)nc32)cc1
Yield: 68 %

Procedure:
A solution of 3-(2-aminoethyl)-N5,N5-bis(3-methylbutyl)-N2-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine-2,5-diamine (83 mg, 1 eq) and p-anisaldehyde (25 mg, 1 eq) in dichloromethane (1.5 ml) is stirred for 6 hours at a temperature of approximately 20° C. The mixture is diluted with methanol (2 ml) then sodium triacetoxyborohydride (70 mg, 2 eq) is added. After stirring for 0.5 hour at a temperature of approximately 20° C., dichloromethane (20 ml) and water saturated with sodium hydrogen carbonate (10 ml) are added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1 to 2:8) produces the expected compound (70 mg, 68% yield).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]2C)(=[O:15])=[O:14])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:20]1[CH2:18][CH2:17][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:30][CH3:31])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:2]=3[F:1])[N:11]=2)(=[O:15])=[O:14])[CH2:21]1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CC[C@@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R)-4-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-amino)sulfonyl]-3-methylpiperazine-1-carboxylate (0.75 g) in DCM (10 ml) was added TFA (10 ml) slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield: 0.27 g