Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[C:23]#[N:24])[CH2:3]1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].C(NC(C)C)(C)C>ClCCl>[C:25]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[C:23]#[N:24])[CH2:3]1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: CCOCCn1c(=O)c(C#N)c(NC2CNC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C=CC(=O)N1CC(Nc2c(C#N)c(=O)n(CCOCC)c3ccccc23)C1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(Azetidin-3-ylamino)-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.050 g, 0.16 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.005 g, 0.055 mmole) followed by the addition of diisopropylamine (1.5 eq, 0.031 g, 0.075 mmole, 0.05mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was, evaporated and the residue was purified by flash chromatography to afford 4-(1-Acryloyl-azetidin-3-ylamino)-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.008 g, 28% calc M+H 367, obs M+H 367).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]([CH3:19])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C1COCC1>[Br:22][C:16]1[C:15]([OH:18])=[CH:14][CH:13]=[C:12]2[C:17]=1[N:9]([CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:21])[CH3:20])[CH3:19])[N:10]=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 65.5 %

Procedure:
To a solution of the product from Step B (6.00 g, 19.6 mmol) in anhydrous THF (300 mL) at 0° C. was added N-bromosuccinimide (3.49 g, 19.6 mmol) in 10 portions over 20 min. The mixture was poured into a saturated aqueous solution of sodium bisulfite (300 mL) and extracted with EtOAc (3×100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue (6.39 g). Chromatography (silica, 10% EtOAc/hexane) gave a solid (4.95 g, 66%): LC/MS (+APCI) m/z 385, 387 (M+H).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:6]([O:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:5]=1)=[N+]=[N-]>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:6]([O:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:5]=1
Reactant: CC(C)(O)COc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)COc1cc(N)nc(N2CCOCC2)n1
Reaction time: 24 h

Procedure:
1-(6-azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol was dissolved in a mixture of tetrahydrofuran (200 mL) and methanol (20 mL). To the solution was added 10% palladium on carbon (2 g) and the reaction was stirred under an atmosphere of hydrogen for 24 hours. The reaction was then filtered through celite and evaporated to give 1-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (2.0 g).
Reaction SMILES: [C:1]([C:3]1([CH2:8][CH2:9][CH3:10])[CH2:7][CH:6]=[CH:5][CH2:4]1)#[N:2].[CH2:11]([Mg]Br)[CH3:12].[BH4-].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:2][CH:1]([C:3]1([CH2:8][CH2:9][CH3:10])[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH2:11][CH3:12]
Reactant: CCCC1(C#N)CC=CC1
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCC1(C(N)CC)CC=CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 134.4 %

Procedure:
1-cyano-1-propylcyclopent-3-ene (62, 2.3 g, 16.9 mmol) was dissolved in toluene (15 mL) and ethyl magnesium bromide (11.2 mL, 33.7 mmol, 3M in ether) added. After stirring for 30 minutes at 90° C., the reaction mixture was cooled and added dropwise to ice cold methanol (66 mL), followed by sodium borohydride (638 mg, 17 mmol). The mixture was warmed to room temperature and stirred overnight. The white suspension was treated with sodium hydroxide solution (aqueous, 1M), filtered through celite and then extracted with dichloromethane/isopropanol (3:1). The filtrate was washed with dichloromethane. The organic phase was washed with brine, dried over sodium sulphate and evaporated to give 3.8 g of a yellow oil. This was taken up in dichloromethane and extracted twice with hydrochloric acid (2M). The aqueous layer was made basic with sodium hydroxide solution (6M) and extracted with dichloromethane. Evaporation gave 1.38 g of desired product as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C)C=O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzoic acid (500 g) was added to a mixed solvent of dimethylformamide (500 ml) and toluene (1.5 Liters). Thionyl chloride (217 ml) was added thereto at room temperature with stirring and the mixture was stirred at a refluxing temperature for 3 h. The reaction mixture was then ice-cooled and added dropwise to 28% aqueous amonia (750 ml). The mixture was stirred further for 1 h. The precipitated crystals were collected by filtration, and the crystals were recrystallized from hydrous ethanol to give 2-chloro-5-nitrobenzamide (346 g), melting point: 177–179° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C[N:20](C=O)C>>[NH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)[C:7]([CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])=[CH:8]1
Reactant: CC(C)(O)CCc1c[nH]c2ccc(F)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (8.1 g, 204 mmol, 60% in mineral oil) in DMF (100 mL) at 0° C. is treated with 4-(5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (3 g, 13.6 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (7.7 g, 68 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by filtration through a short plug of silica gel to afford 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol, which is used in the next step without further purification. MS: 237 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 7.22 (m, 1H), 6.98 (m, 2H), 4.71 (s, NH2, 2H), 2.75 (m, 2H), 1.86 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]([CH3:13])[CH3:12])=[C:4]([NH2:14])[CH:3]=1.CC(C)([O-])C.[K+].[H][H]>[Ru].C(O)(C)(C)C>[NH2:1][CH:2]1[CH:7]([CH:8]([CH3:9])[CH3:10])[CH2:6][CH:5]([CH:11]([CH3:13])[CH3:12])[CH:4]([NH2:14])[CH2:3]1
Reactant: [H][H]
Reactant: CC(C)c1cc(C(C)C)c(N)cc1N
Agent: [Ru]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)C1CC(C(C)C)C(N)CC1N
Yield: 27.5 %

Procedure:
A suitable autoclave was charged with 20.7 g (0.108 mol) of purified 1,3-diamino-4,6-diisopropylbenzene, 0.3 g (2.7 mmol) of potassium t-butoxide, 2.0 g of 5% Ru on alumina, and 100 mL of t-butanol. The autoclave was heated to 190° C. at 25.5 MPa hydrogen for 24 hours. It was then cooled and its contents filtered. The solvent was removed from the filtrate in vacuo and the resulting liquid distilled through a 20.3 cm Vigreaux column at about 4 mm Hg/115°-118° C. to give 5.9 g (28%) of 1,3-diamino-4,6-diisopropylcyclohexane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([O:22]CC)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7]
Reactant: CCOC(=O)c1cn(C(COC)COC)c2ccc(I)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
Ethyl 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 22, 270 mg, 0.60 mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL). Lithium hydroxide (56 mg, 2.42 mmol) was added and the mixture was stirred for 10 min at room temperature. The reaction mixture was then refluxed at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added. The pH was adjusted to 2 with hydrochloric acid (2N) and the solid that precipitated was collected by filtration and dried to afford 185 mg (75%) of 1-(1,3-dimethoxypropan -2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:11][C:10]=2[CH3:25])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:32]=[C:31](O)[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:26][C:27]1[CH:32]=[C:31]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[C:10]([CH3:25])=[CH:11][C:12]([O:16][CH2:17][C:18]4([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]4)=[CH:13][C:14]=3[CH3:15])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(CO)c1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)cc1F
Yield: 89.4 %

Procedure:
To a solution of 4-({[3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (0.90 g, 2.51 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.56 g, 2.64 mmol) and tributylphosphine (0.86 mL, 3.26 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.85 g, 3.26 mmol) at room temperature with stirring, and the mixture was stirred for 10 hrs. The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.24 g, yield 89%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(N(CC)CC)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: C#CCCCCl
Reactant: COc1cc(Br)ccc1-c1cnc(C)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C#CCCCCl)ccc1-c1cnc(C)o1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-bromo-2-methoxyphenyl)-2-methyl-1,3-oxazole (6.00 g), 5-chloropent-1-yne (4.74 mL), dichlorobis(triphenylphosphine)palladium(II) (1.57 g), copper(I) iodide (426 mg) and triethylamine (60 mL) was stirred at 70° C. for 3 hr, and diluted with ethyl acetate, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.85 g).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[NH:9][C:10](=O)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:8]=2[N:9]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(=O)[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1ncc2c(C(=O)O)cc(Cl)nc21
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
To a 75 mL pressure vessel was added 1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4.12 g, 18.62 mmol), followed by phosphorous oxychloride (26.0 ml, 279 mmol). The flask was sealed and the stirring mixture heated at ca. 105° C. for ca. 18 h. After cooling to room temperature, the contents were concentrated in vacuo to remove most of volatiles. The residual contents were poured into a mixture of ice and 3M NaOH (60 mL), followed by additional 3M NaOH to ensure the pH stayed basic. The mixture was stirred for 30 min., and then cooled in an ice bath. The heterogenous mixture was slowly acidified to pH=3-4 with 6M HCl. The resulting suspension was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow solid which was dried in a hi-vac oven overnight. The title compound was collected as 4.11 g (90%), and used without further purification. LCMS E-S (M+H)=240.2/242.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.57 Hz, 6 H) 5.17 (quin, J=6.63 Hz, 1 H) 7.65 (s, 1 H) 8.41 (s, 1 H) 14.25 (br. s., 1 H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:2]2[CH2:3][O:1]2)=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(CC2CO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC2CO2)cc1
Reaction time: 22 h
Yield: 81.8 %

Procedure:
(RS)-4-Oxiranylmethyl-phenol (1 g, 6.66 mmol) was dissolved in CH2Cl2 (50 ml) and stirred at room temperature in the presence of tert-butyldimethylsilyl chloride (1.3 g, 8.66 mmol), 4-dimethyl-aminopyridine (0.018 g, 0.15 mmol) and triethylamine (1.2 ml, 8.66 mmol). After 22 hours at room temperature, the reaction mixture was washed with H2O (2×100 ml) and the resulting aqueous phases were extracted with CH2Cl2 (100 ml). The combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (RS)-tert-Butyl-dimethyl-(4-oxiranylmethyl-phenoxy)-silane (1.44 g, 82%) as yellow oil, MS: m/e=264 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(SCCN(C)C)[nH]c2c1
Yield: 64.8 %

Procedure:
4.11 g (25 mmoles) of 5-methyl-benzimidazoline-2-thione, 4.32 g (30 mmoles) of 2-(dimethylamino)-ethylchloride hydrochloride and 2.55 g of sodium hydrogencarbonate are refluxed in 50 ml of ethanol for 6 hours. The reaction mixture is filtered off, concentrated and the residue is worked up according to the method of Example 2. The dichloromethane extracts are concentrated and the residue is crystallized from petrolether. 3.81 g of 2-(2-dimethylamino-ethylthio)-5-methyl-benzimidazole are obtained, which melting point does not change after recrystallizaton from acetonitrile. M.p.: 103° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:27]#[N:28]>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:28]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1
Reactant: N#Cc1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3-chloro-4-(3,4-dichlorobenzyl)benzonitrile (0.93 g), anhydrous iron (III) chloride (0.50 g) and o-dichtorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (300 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.64 g of desired compound (melting point: 179.0°-185.0° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](O)(=O)C>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:34])=[N:18][N:17]=3)[C:11]=2[N:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Reactant: CC(=O)O
Product: Cc1nc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Temperature: 180 °C
Yield: 59 %

Procedure:
di-tert-Butyl 1-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (0.075 g, 0.16 mmol, from Step 3) was dissolved in acetic acid (3 mL) and was heated in the microwave to 180° C. for 5 minutes. Solvent was removed in vacuo, the crude product was reconstituted in MeCN and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (27 mg, 59%).
Reaction SMILES: CS(O)(=O)=O.CS(O[CH2:11][CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][C:16]=2[CH:17]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].ClCCl>CN(C=O)C>[N:30]([CH2:11][CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[CH:18][C:16]=2[CH:17]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc3oc(CCN=[N+]=[N-])cc3c2)cc1
Yield: 71 %

Procedure:
Methanesulfonic acid (109 mg, 0.32 mmol), the product from Example 1C and sodium azide (83 mg, 1.28 mmol) was stirred in DMF for 4 days, then poured into dichloromethane and washed with water. The crude product was purified by flash chromatography, eluting with 2:1 dichloromethane/hexane to provide the title compound as a clear syrup (65 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:15][CH2:16][C:17]2[C:25]3[C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=[N:21][C:20]=3[NH:19][CH:18]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH3:14][C:11]1([N:15]2[CH2:16][C:17]3=[CH:18][NH:19][C:20]4[C:25]3=[C:24]([CH:23]=[CH:22][N:21]=4)[C:26]2=[O:27])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC1(NCc2c[nH]c3nccc(C(=O)O)c23)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(N2Cc3c[nH]c4nccc(c34)C2=O)CC1

Procedure:
3-((1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (34 mg, 0.088 mmol), HATU (67 mg, 0.175 mmol), and pyridine (0.021 mL, 0.263 mmol) were stirred in DMF (3 mL) at room temperature for 2 h. The solution was concentrated in vacuo to give the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:15])[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1.[CH3:20][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:15])[NH:13][C:12]([C:16]([O:18][CH3:20])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=S)[nH]c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(=S)c(Nc2cc(N)ncn2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylic acid (5, 0.5 g, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol is added (trimethylsilyl)diazomethane (2 M in hexanes, 1.29 mL, 2.58 mmol). The reaction is stirred at room temperature for 1 h. The resulting mixture is concentrated and purified via column chromatography to afford methyl 5-(6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylate (6).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[CH:1]=[O:10]
Reactant: COc1cccc(C=O)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of m-anisaldehyde (25.2 g) and anhydrous sodium acetate (37.6 g) in acetic acid (150 ml) is added bromine (30.8 g) and the resulting solution stirred 45° C. overnight, then at room temperature for about 4 hours. The reaction mixture is poured into water (300 ml), stirred for 15 minutes, then filtered and the solid residue dissolved in toluene. The toluene solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is recrystallized from hexanes to give the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[S:16][C:17]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:18][CH:19]=1)=[O:14])(C)(C)C>C(Cl)Cl>[CH2:36]([S:35][CH2:34][CH2:33][N:23]([S:24]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH2:22][CH2:21][CH2:20][C:17]1[S:16][C:15]([C:13]([OH:14])=[O:12])=[CH:19][CH:18]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN(CCSCc2ccccc2)S(=O)(=O)c2cccnc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCCN(CCSCc2ccccc2)S(=O)(=O)c2cccnc2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
TFA. A solution of 5-(3-((2-benzylsulfanyl-ethyl)-(pyridine-3-sulfonyl)-amino)-propyl)-thiophene-2-carboxylic acid tert-butyl ester prepared of Example 3, Step B (0.038 g) in 1 mL CH2Cl2 was cooled to 0° C. and 1 mL TFA was added. The mixture was warmed to room temperature and was stirred for 1 h. The CH2Cl2 and TFA were removed by evaporation, azeotroping with added CH2Cl2 to yield the title compound (46.3 mg). MS 475 (M−1).