Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:14]=1[C:34](OC)=[O:35]>O1CCCC1>[OH:35][CH2:34][C:14]1[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:18][C:13]=1[CH3:12]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CO
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (12.24 g) in a mixture of dry tetrahydrofuran (180 ml) and diethyl ether (360 ml) was dropwise added a solution of methyl 6-methyl-2-phenyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylate in dry tetrahydrofuran (180 ml) under cooling at -50°~-40° C. The excess lithium aluminum hydride was decomposed by a careful addition to ice water. The separated organic layer was washed with 15% sulfuric acid (400 ml) and extracted with ethyl acetate (1 l). The organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride successively and concentrated in vacuo. The residue was recrystallized from diethyl ether to give 5-hydroxymethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)-pyrimidine (30 g).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.B(Br)(Br)Br>C(Cl)Cl>[CH:28]1([C:34]([N:9]2[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[CH2:10]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccc(C2CNCc3cc(OC)ccc32)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1Cc2cc(O)ccc2C(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline (0.103 g, 0.382 mmol, 1.0 eq., see Preparation 64) and triethylamine (0.107 ml, 0.764 mmol, 2.0 eq.) in CH2Cl2 (2 ml) was added to a vial containing cyclohexanecarbonyl chloride (0.084 g, 0.573 mmol, 1.5 eq.). The reaction mixture was stirred overnight at RT. To this mixture was added BBr3 as a 1.0M solution in CH2Cl2 (1.15 ml, 1.15 mmol, 3.0 eq.). The reaction mixture was stirred overnight at rt, then cooled to −78° C. and quenched with MeOH (1.5 ml). The reaction mixture was evaporated under a stream of nitrogen and purified by reverse phase HPLC (gradient elution 98:2 H20:0.1% TFA, then 2:98 MeCN:H2O). The exact yield was not determined.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:20])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:20])[C:9]3[C:14]([S:15](=[O:18])(=[O:19])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)#[N:2]
Reactant: NC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
3-Carbamoylthioxanthone-10,10-dioxide (32.5 g) was dissolved in dimethyl formamide (ca. 1 liter) and cooled to -10° C. in a solid carbon dioxide ethanol bath. Thionyl chloride (80 ml) was then added dropwise over 0.5 hour, maintaining the internal temperature at -5° to -10° C. Stirring was continued at this temperature for a further 2 hours. The reaction mixture was then poured into ice-water. The precipitated solid was filtered off, washed well with water, and dried at 100° C. The resulting 3-cyanothioxanthone-10,10-dioxide had a melting point of 282°-283° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH:3]=2)=[C:28]([CH3:35])[CH:27]=1)#[N:25]
Reactant: Cc1cc(C#N)ccc1B(O)O
Reactant: Cc1cc(I)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(C#N)cc2C)cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1,3-bis(1,1-dimethylethyl) 2-(3-iodo-5-methylphenyl)propanedioate (the product of Step A, 320 mg, 0.74 mmol), 4-cyano-2-methylphenylboronic acid (178 mg, 1.11 mmol), sodium carbonate (78 mg, 0.74 mmol), bis(triphenylphosphine)palladium(II) dichloride (52 mg, 0.074 mmol), dioxane (5 mL), and water (1 mL) was heated to 80° C. and stirred for 20 minutes. The reaction mixture was then cooled to room temperature, and filtered through a plug of silica gel eluting with 20% ethyl acetate in hexanes. Concentration of the eluant under reduced pressure provided a brown oil (430 mg) containing the crude product, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].O>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCc1nnnn1C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nnnc1CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
24.9 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-methyl-1H-tetrazol-5-yl)methoxy]imino]-acetate are dissolved in 100 ml of methanol and the solution is treated with 250 ml of 1N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 12 hours and treated with 150 ml of water. The methanol is subsequently removed under reduced pressure. The aqueous solution is washed with ethyl acetate and treated with 250 ml of 1N aqueous hydrochloric acid. The acid crystallizes upon concentration. The acid is filtered off and, for the removal of water (about 16%), stirred for 6 hours in 350 ml of acetonitrile, filtered and dried. There are obtained 14.2 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-methyl-1H-tetrazol-5-yl)methoxy]imino]-acetic acid of melting point 185° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[CH3:28][NH2:29]>CO>[C:21]1([S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[C:8]([CH2:7][NH:6][CH2:5][C:4]([NH:29][CH3:28])=[O:3])=[CH:9][CH:10]=[CH:11]3)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CNCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CN
Solvent: CO
Product: CNC(=O)CNCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
[(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-acetic acid ethyl ester is added to methylamine in methanol, and the solution is stirred at room temperature, then concentrated under reduced pressure. The oil is dissolved in ethanol and 1N HCl in diethyl ether is added to precipitate 2-[(6-benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-N-methyl-acetamide as a hydrochloride salt.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([NH:21][NH2:22])=[N:16][CH:17]=[CH:18][C:19]=1[Cl:20]>C1COCC1>[Br:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:22][N:21]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1nccc(Cl)c1Br
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)c(Cl)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a stirring solution of triphosgene (5.766 g, 19.43 mmol) in anhydrous THF (50 mL) at room temperature was added 1-(3-bromo-4-chloropyridin-2-yl)hydrazine (1.438 g, 70% pure) portion-wise over 15 min. The resulting suspension was stirred under argon at room temperature overnight, then cooled at 0° C. and quenched carefully by slow addition of water (30 mL). The resulting yellowish suspension was filtered, and the solid collected was washed with water (20 mL×3), then diethyl ether (5 mL), and dried in a 60° C. vacuum oven to obtain 0.525 g of the title compound, 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as an off-white solid. HPLC/MS: retention time=1.93 min, [M+H]+=248.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[CH2:4][C:5]1[N:6]=[CH:7]O[CH:9]=1.C([NH2:17])=O>O>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[CH2:4][C:5]1[N:6]=[CH:7][NH:17][CH:9]=1
Reactant: Clc1cccc(Cl)c1Cc1cocn1
Reactant: NC=O
Solvent: O
Product: Clc1cccc(Cl)c1Cc1c[nH]cn1
Temperature: 180 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g of 4-(2',6'-dichlorobenzyl)oxazole and 30 ml of formamide is stirred at 180° C. for 4 hours. The mixture is cooled and diluted with water. The reaction product is thereafter isolated in the same manner as described in Example 49(d).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][C:6]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:7]=1[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13]Br>O1CCCC1>[CH:1]([NH:4][CH2:13][C:12]#[C:11][CH2:10][O:9][CH2:8][C:7]1[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:6]=1[F:5])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Solvent: C1CCOC1
Product: CC(C)NCC#CCOCc1cc(Br)ccc1F
Yield: 85.6 %

Procedure:
A solution of isopropylamine (0.25 ml, 2.9 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (97 mg, 0.29 mmol) in tetrahydrofuran (1.4 ml). The cloudy reaction mixture was stirred for about twenty hours, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2×5 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 78 milligrams (86%) of the title intermediate.
Reaction SMILES: N[C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.N([O-])=O.[Na+].[Cl-:27].[Na+]>C(O)C.O.Cl>[Cl:27][C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: [Cl-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled solution of t-butyl 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid and sodium nitrite (1.18 g, 0.017 mol) were added portionwise over 15-20 minutes. The reaction mixture was stirred at 0°-5° C. for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried (Na2SO4) and concentrated to give 3.1 g (73%) of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]1[N:26]=[N:27][N:28]=[C:21]1[C:20]([NH2:29])=[C:19]2[NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]1[N:26]=[N:27][N:28]=[C:21]1[C:20]1[N:29]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]2=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccc(OCc3ccccc3)cc12
Solvent: c1ccncc1
Product: CCOCc1nc2c(c3cc(OCc4ccccc4)ccc3n3nnnc23)n1CC(C)C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Ethoxyacetyl chloride (2.7 g, 22 mmol) was added dropwise to a solution of 7-(benzyloxy)-N5-(2-methylpropyl)tetraazolo[1,5-a]quinoline-4,5-diamine (7.6 g, 21 mmol) in 200 mL of pyridine. The solution was stirred for 1 hour and additional ethoxyacetyl chloride was added. The solution was refluxed overnight, after which the solvent was removed. The solid material was dissolved in 300 mL of chloroform and stirred with 150 mL of 1% aqueous sodium carbonate. The pH was adjusted to 10 with 10% sodium hydroxide. The organic fraction was washed with 2 portions of 1% sodium carbonate and once with brine solution. The organic fraction was then dried over sodium sulfate and concentrated to give 8.8 g of 8-(benzyloxy)-5-(ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-a]quinoline as a tan solid. A small portion was recrystallized from ethanol to provide an analytical sample, mp 183.5-184.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[N:7][S@](C(C)(C)C)=O)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH3:20][Mg]Br>ClCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C@H:6]([NH2:7])[CH3:20])=[C:4]([C:16]([F:17])([F:18])[F:19])[CH:3]=1
Reactant: CC(C)(C)[S@](=O)N=Cc1ccc(Cl)cc1C(F)(F)F
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a stirred solution of the crude (S)-N-(4-chloro-2-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (26.8 g, 86.0 mmol) in dichloromethane (290 mL) at −48° C. was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 63.0 mL, 189.0 mmol) dropwise. The reaction was stirred below −40° C. for 18 h, and the reaction was slowly warmed to 0° C. and quenched with 50% saturated aqueous ammonium chloride solution (100 mL). The phases were separated, and the organic layer was washed with deionized water (50 mL). The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (14.6 g, 44.5 mmol, 52%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:10][C:7]1[CH:8]=[N:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc(O)cnc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2ccccc2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a flame dried flask under N2 was placed 2-chloro-5-hydroxynicotinonitrile (2.0 g, 0.012 mol), DMF (60 mL), NaH (50% oil dispersion, 0.75 g, 0.013 mol) and the mixture cooled to 0°-4° C. A solution of benzyl bromide (1.5 mL, 0.013 mol) in DMF (2 mL) was then added and the solution allowed to stir at room temperature overnight. The mixture was poured into H2O and extracted with Et2O (3×). The organic layer was concentrated to yield 2.0 g (100%) of 5-benzyloxy-2-chloronicotinonitrile. An analytical sample of 5-benzyloxy-3-chloronicotinonitrile was prepared by trituration with C6H14, mp 114°-15° C.; 1H NMR (CDCl3) δ5.2 (2H, s) 7.4 (5H, s), 7.5 (1H, d, J=3) and 8.35 (1H, d, J=3); IR (nujol) 2220 cm-1 ; MS m/e M+ 244.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: N#Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C#N)CC1
Temperature: 120 °C
Yield: 51.6 %

Procedure:
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.5 mmol), 2-cyanophenylboronic acid (0.23 g, 1.6 mmol), tetrakis-triphenylphosphine (0.17 g, 0.15 mmol) and cesium carbonate (0.73 g, 2.26 mmol) were dissolved in a mixture of DME (3 mL), IMS (1.0 mL) and water (0.4 mL) under argon. The mixture was heated by microwave irradiation to 120° C. for 0.3 hours then diluted with water. The products were extracted into DCM, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-20% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a yellow oil (0.22 g). LCMS m/z 261.2 [M+H]+. R.T.=4.59 min (Analytical Method 4).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].C([O-])(=O)C.[Na+].[Br:44]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:44][C:22]1[CH:21]=[N:20][C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]3[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[C:23]=1[N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]1
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(Br)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (125 mg, 0.23 mmol), sodium acetate (38 mg, 0.46 mmol), and bromine (36 μL, 0.7 mmol) in acetic acid (1 mL) was stirred at ambient temperature for 1 minute. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow oil, which was used in the next step without any further purification (65 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCCCC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27])[CH2:2][CH2:3][CH3:4].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(OCCCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)ccc1-c1cc(OC)ccc1F
Reaction time: 1 h
Yield: 96.57 %

Procedure:
To a mixture of T9.3 (1.1530 g, 3.079 mmol) and THF (10 mL) at 0° C. was added LAH (1.0 M solution in THF (4.619 mL, 4.619 mmol)). The reaction was stirred for one hour and then carefully diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to provide T9.4 (0.9050 g, 96.57% yield).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:20])(C(C)(C)C)(C)C.CCN(CC)CC>CC#N>[OH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ccccc2)c(O)c1
Yield: 76.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N.HF (100 uL, 0.62 mmol) in acetonitrile for 10 minutes at 23° C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%). mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][N:24](CC5C=CC(OC)=CC=5)[C:17]=34)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.FC1C(C2C=C(NC3C4C(=CN(CC5C=CC(OC)=CC=5)N=4)N=CC=3)C=CN=2)=NC(C)=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2ncc3nccc(Nc4ccnc(-c5nc(C)ccc5F)c4)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4ccnc(-c5nc(C)ccc5F)c4)c3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)n1
Temperature: 70 °C

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and trifluoroacetic acid (20 mL) were combined and heated at 70° C. for 3 hours. The reaction mixture was then cooled, concentrated give a residue which was suspended in dichloromethane (50 mL) and added to a saturated solution of sodium bicarbonate (50 mL) with stirring. The mixture was sonicated and filtered. The solid was dried under vacuum and suspended in ethyl acetate. The solid again collected by filtration to give N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine. MS [M+H] found 321.3.
Reaction SMILES: [OH:1][C@:2]1([CH3:23])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:24][C:25]([F:37])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH2:35])=[CH:32][N:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][C:25]([F:24])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@:2]([OH:1])([CH3:23])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:32][N:31]=[CH:30][N:29]=1
Reactant: CC(F)(F)COc1ncncc1CN
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@]1(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@@](C)(O)C(C)(C)C2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 4-(((1R,4R)-4-hydroxy-3,3,4-trimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude) in THF (2.8 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg, 0.246 mmol) and DIEA (100 mg, 0.738 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 2 h. The solvent was evaporated and the residue was purified via standard methods to afford the title compound (34.2 mg, 0.074 mmol, 30% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.70 (s, 1H), 8.34-8.32 (m, 1H), 8.13 (s, 1H), 4.70 (t, J=12.0 Hz, 1H), 4.64-4.59 (m, 2H), 4.18-4.15 (m, 1H), 1.81-1.74 (m, 3H), 1.68-1.41 (m, 6H), 1.32-1.30 (s, 3H), 0.92-0.85 (s, 6H). MS (ESI) m/z 462.2 [M+H]+.