Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1[CH2:31][O:30][CH2:29][CH2:28]1.BrCCOC>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:28][CH2:29][O:30][CH3:31])[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: C1CCOC1
Agent: COCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCn1c(-c2cnn(C)c2)cc2cnc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.36 mmole) was azeotroped with toluene (3 mL) and dissolved in DMF (1 mL). To the solution was added sodium hexamethyldisilazide, 1M in THF (0.4 mL, 0.4 mmole) and the reaction was stirred at room temperature for 20 minutes. Bromoethylmethyl ether (65 uL, 100 mg, 0.8 mmole) was added and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and the solution washed with water (3×8 mL) and with brine, dried and evaporated to afford the title compound. 1H-NMR (CDCl3, 500 MHz): δ 3.31 (s, 3H), 3.72 (t, J=5.68 Hz, 2H), 4.01 (s, 3H), 4.28 (t, J=5.68 Hz, 2H), 6.54 (d, J=0.95 Hz, 1H), 7.48 (t, J=0.95 Hz, 1H), 7.71 (s, 1H), 7.74 (d, J=0.95 Hz, 1H), 8.60 (d, J=0.95 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][NH:28][CH2:29][CH2:30][NH:31][CH3:32]>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:28]([CH3:27])[CH2:29][CH2:30][NH:31][CH3:32])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CNCCNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq), is dissolved in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1 ml; 7.42 mmol; 5.00 eq) followed by N,N′-dimethylethylenediamine (0.79 ml; 7.42 mmol; 5.00 eq) are added. After 30 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (19) as a beige solid (457 mg; 79%).
Reaction SMILES: FC(F)(F)C([O-])=O.O1CCCCC1[O:14][N:15]=[C:16]([C:53]1[N:54]=[C:55]([NH:58]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:56][CH:57]=1)[C:17]([NH:19][CH:20]1[C:51](=[O:52])[N:22]2[C:23]([C:35]([O:37]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:36])=[C:24]([CH2:27][N+:28]3([CH2:33][CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:25][S:26][C@H:21]12)=[O:18].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[NH2:58][C:55]1[S:56][CH:57]=[C:53]([C:16](=[N:15][OH:14])[C:17]([NH:19][CH:20]2[C:51](=[O:52])[N:22]3[C:23]([C:35]([O-:37])=[O:36])=[C:24]([CH2:27][N+:28]4([CH2:33][CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:54]=1
Reactant: CC[N+]1(CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CCCC1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NO)c4csc(N)n4)[C@H]3SC2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-ethyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (4.0 g) in dichloromethane (12 ml) were added anisole (4 ml) and trifluoroacetic acid (8 ml) under ice-cooling. After stirring for 4 hours at room temperature, the mixture was poured into diisopropyl ether (250 ml). The resulting precipitate was collected by filtration, washed with diisopropyl ether, and dissolved in 5% sodium bicarbonate solution. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid, andsubjected to column chromatography on non-ionic adsorption resin "HP-20". The desired product was eluted with 5% isopropyl alcohol and the eluate was concentrated and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-ethyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate (syn isomer) (0.30 g).
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[NH2:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].O>C(O)C>[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1].[NH2:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: NCCCC[C@H](N)C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.6 %

Procedure:
167 grams of racemic ibuprofen and 118 grams of (S)-lysine were charged into 180 cc of water and 5.82 liters of ethanol were added. The resulting slurry was agitated and aged at 30° C. for 24 hours. A clear liquor was drawn off through a filter and the liquor cooled to 25° C. The resulting supersaturated liquor was then added to a slurry of 50 grams of 99.4% (S)-ibuprofen-(S)-lysine. The precipitated solid was separated by filtration and the mother liquor recycled to the slurry mixture of racemic ibuprofen and (S)-lysine. The procedure was continued until essentially all the (S)-ibuprofen in the original charge was depleted. This procedure resulted in the formation of 144 grams of 98.1-98.8% pure (S)-ibuprofen-(S)-lysine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1>CN(C)C(=O)C.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc2cccc(Oc3ccc(OCc4ccccc4)cc3)c12
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2cccc(Oc3ccc(O)cc3)c12
Yield: 26.9 %

Procedure:
4-Amino-5-(4-benzyloxyphenoxy)quinazoline (1.5 g, 4.4 mmol) was hydrogenated under 5 atm of H2 in the presence of 0.5 g of 10% Pd/C in 80 ml of N,N-dimethylacetamide at 50-60° C. After 4 hours the reaction mixture was filtered through a glass filter of silica gel, concentrated, dissolved in 80 ml of ethanol/water 4:1 (v/v) and crystallized at 4° C. The precipitate was collected by filtration, washed with ethanol and dried at 50° C. in vacuo to give 4-amino-5-(4-hydroxyphenoxy)quinazoline (0.3 g, 27.3%, m.p. 300-302° C. (dec)).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ncc(Br)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Yield: 21.2 %

Procedure:
To a 10 ml round bottom flask, 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.450 g, 0.00199 mol) and NaH (0.143 g, 0.00597 mol) were taken in DMF (5 ml) and stirred in cooling for 15 min. SEM-Cl (0.497 g, 0.00298 mol) was added dropwise and stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was poured in to water and extracted with ethyl acetate. The combined organics were washed with brine solution. The organic layer was separated and dried over sodium sulphate, concentrated to give the crude product which was purified using column purification by eluting the compound with 10% ethyl acetate in hexanes to yield 150 mg of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22](CC3C=CC=CC=3)[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17]([CH3:40])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17]([CH3:40])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
4-[7-Benzyl-1-(2,2-dimethylpropionyloxymethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (2.227 g) was dissolved in acetic acid (100 ml), and 10% palladium on carbon (1 g) was added thereto. The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, filtered, and the filtrate was concentrated to give 1.89 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:28]=[O:29])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCc2cc(C=O)ccc2C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (Step C) (1.080 g, 3.311 mmol) was dissolved in THF (30 mL) and cooled to −78° C. n-Butyllithium (2.5 M) (3.311 mL, 8.276 mmol) was added drop-wise to the stirred solution. The reaction was stirred at −78° C. for 30 min and DMF (1.282 mL, 16.55 mmol) was added drop-wise and the mixture was slowly warmed to RT overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated in vacuo to afford the crude material, which was purified by flash column chromatography to furnish the pure title compound. MS (APCI pos) 217 (M-t-Bu).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:43][NH2:44]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:43][NH:44]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 150 °C
Yield: 11.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[4-(methyloxy)phenyl]-3-piperidinecarboxamide (190 mg, 0.426 mmol), 3 mL of EtOH, Hunig's base (0.223 mL, 1.28 mmol), and hydrazine anhydrous (0.053 ml, 1.702 mmol) were added, and the yellow mixture was heated to 150° C. for 180 minutes in microwave. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH at 50° C., and EtOAc was used to triturate. When the solution turned slightly cloudy, it was cooled to room temperature to get pure crystallized light yellow title compound (22 mg). LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (m, 1H), 1.65-1.84 (m, 2H), 1.98 (m, 1H), 2.79-3.06 (m, 2H), 3.72 (s, 3H), 4.49 (m, 1H), 4.68 (m, 1H), 5.37 (s, 2H), 6.10 (s, 2H), 6.68 (s, 1H), 6.88 (d, J=9.1 Hz, 2H), 7.53 (d, J=9.1 Hz, 2H), 7.58-7.65 (m, 1H), 7.66-7.78 (m, 1H), 7.97 (s, 1H), 9.87 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:17](=[O:19])(=[O:18])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([O:28]CC5CCCCC5)=[O:27])=[CH:22][CH:21]=4)[C:15](=[O:36])[N:14]([CH3:37])[C:13]=3[CH:38]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCOCC1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:16]2[C:15](=[O:36])[N:14]([CH3:37])[C:13]3[CH:38]=[C:9]([O:8][CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:10]=[CH:11][C:12]=3[S:17]2(=[O:18])=[O:19])=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: CN1C(=O)N(c2ccc(C(=O)OCC3CCCCC3)cc2)S(=O)(=O)c2ccc(OCC3CCCCC3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)N(c2ccc(C(=O)O)cc2)S(=O)(=O)c2ccc(OCC3CCCCC3)cc21

Procedure:
A solution of 6-cyclohexylmethoxy-2-(4-cyclohexylmethoxycarbonylphenyl)-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (0.12 g) in a mixture of conc. hydrochloric acid (1 ml), water (2 ml) and 1,4-dioxane (8 ml) was refluxed overnight. The mixture was concentrated in vacuo. The residue was treated with a mixture of ethyl acetate and aqueous 1N sodium hydroxide solution. The precipitates were collected by filtration, washed with ethyl acetate and then dissolved in a mixture of ethyl acetate and aqueous 1N hydrochloric acid. The organic layer was washed with water, dried, and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2 -(4-carboxyphenyl)-6-cyclohexylmethoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide as colorless crystals.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC(N(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.6 %

Procedure:
To a solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) (Example D) in 3 mL of DMF is added dimethyl-piperidin-4-yl-amine (33 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). Alter 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Preparative HPLC to give 7-cyclopentyl-2-[5-(4-dimethylamino-piperidine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 46%). MS(ESI) m/z 505.5 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:11]=[C:12]([NH2:13])[C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH:11]=[C:12]([NH:13][C:25](=[O:27])[CH3:26])[C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1nnc2c(N)cc(-c3ccc(OC(F)(F)F)cc3)cn12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)cn2c(C(C)C)nnc12

Procedure:
In a heavy-wall pressure tube was added 3-isopropyl-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-8-amine prepared in 9A in toluene. To this suspension was added the acetic anhydride (0.1 mL) followed my triethylamine (0.1 mL). The mixture was heated in a 110 C oil bath for 12 hours. The reaction mixture was evaporated in vacuo and purified by preparative HPLC to afford N-(3-isopropyl-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([S:16][CH3:17])[C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Cl.[OH:19][NH2:20].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([S:16][CH3:17])[C:9](=[N:20][OH:19])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)C(SC)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C)(C)C(=NO)C(SC)C2
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-3-methylsulfanyl-3,4-dihydro-1H-naphthalen-2-one (0.265 g, 1.05 mmol) in pyridine (5 ml) was added hydroxyamine hydrochloride (1.09 g, 15.7 mmol). The mixture was stirred under nitrogen at 85° C. overnight. The solution was cooled to room temperature, poured into water, extracted with ethylacetate, washed with 10% KHSO4 aqueous solution, brine, dried over MgSO4, filtered. The filtrate was evaporated under vacuo. The crude product was purified by flash column chromatography using ethylacetate:Hexane (1:9) as eluant to give the desired product as white solid (0.177 g, 63%). 1H NMR (CDCl3) δ: 8.80(br, 1H), 7.05(d, 1H, J=8.2 Hz), 6.93(d, 1H, J=2.5 Hz), 6.73(dd, 1H, J=8.2 and 2.5 Hz), 4.91(t, 1H, J=3.0 Hz), 3.81(s, 3H), 3.26(dd, 1H, J=15.6 and 5.0 Hz), 2.96(dd, 1H, J=15.6and 3.0 Hz), 2.15(s, 3H), 176(s, 3H), 1.48(s, 3H). 13C NMR (CDCl3) δ: 164.5, 159.1, 145.0, 129.6, 129.4, 111.8, 111.0, 55.3, 39.8, 35.9, 32.9, 32.4, 30.8, 15.1.
Reaction SMILES: CS(O[CH:6]([CH3:29])[CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:20]=[CH:21]3)=[N:16]2)[CH2:11][CH2:10]1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[N:30]([CH:6]([CH3:29])[CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:20]=[CH:21]3)=[N:16]2)[CH2:11][CH2:10]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexyl}-1-methylpropyl methanesulfonate (2.95 g), sodium azide (1.37 g) and DMF (100 mL) was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.50 g).
Reaction SMILES: [Li].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]#[N:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(-c2ccccc2)c(OCc2ccccc2)c1
Agent: [Li]
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccccc2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a suspension of lithium alminiumhydride (0.399 g) in tetrahydrofuran (45 mL) was added dropwise a solution of 3-benzyloxy-4-phenylbenzonitrile (2.00 g) in tetrahydrofuran (25 mL) at room temperature, and the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and then quenched by sequential addition of water (0.399 mL), 15% aqueous sodium hydroxide (0.399 mL) and water (0.399 mL). After addition of anhydrous sodium sulfate (20 g), the mixture was stirred at room temperature for 4 hours and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure to give the title compound (1.97 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C@H:9]1[CH2:14][N:13]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)[CH:34]=[C:33]([C:47]([O:49][CH3:50])=[O:48])[C:20]=4[N:21](CC4C=CC(OC)=CC=4)[C:22]=3[CH:23]=2)[CH2:12][C@@H:11]([CH3:51])[O:10]1.C1(OC)C=CC=CC=1>>[CH3:51][C@H:11]1[CH2:12][N:13]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)[CH:34]=[C:33]([C:47]([O:49][CH3:50])=[O:48])[C:20]=4[NH:21][C:22]=3[CH:23]=2)[CH2:14][C@@H:9]([CH3:8])[O:10]1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3n(Cc3ccc(OC)cc3)c12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3C[C@@H](C)O[C@@H](C)C3)ccc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
TFA (3 mL) was added to a mixture of methyl 7-((2S,6R)-2,6-dimethylmorpholino)-5-(4-methoxybenzyl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (27 mg, 0.045 mmol) and anisole (0.049 mL, 0.45 mmol) in a vial. The vial was sealed and heated at 60° C. for 3 hr and then 70° C. for an additional 4 hr. The solvent was removed and the residue was dissolved in EtOAc. This was washed with saturated aqueous NaHCO3 solution, brine, and then dried with sodium sulfate. Removal of the solvents followed by radial chromatography (step gradient elution with DCM containing 50 to 0% hexane followed by 10% EtOAc) to afforded methyl 7-((2S,6R)-2,6-dimethylmorpholino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (16 mg, 0.034 mmol, 75% yield) as a yellow oil. MS (ESI) m/z 484.1 (M+H). 1H NMR (400 MHz, chloroform-d) d ppm 9.41 (1H, s), 8.42 (1H, s), 8.32 (1H, d, J=7.30 Hz), 8.27 (1H, d, J=8.56 Hz), 8.16 (1H, s), 7.55-7.66 (2H, m), 7.00 (1H, dd, J=8.81, 2.01 Hz), 6.92 (1H, d, J=2.01 Hz), 4.08 (3H, s), 3.85 (2H, ddd, J=10.45, 6.30, 2.39 Hz), 3.63 (2H, d, J=10.58 Hz), 2.51-2.61 (2H, m), 1.30 (6H, d, J=6.04 Hz).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)=[CH:6][C:5]=1[F:19].[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:19][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH3:21])=[O:20]
Reactant: COC(=O)c1ccc(OCc2cccc(C)n2)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: Cc1cccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)c(F)c2)n1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 2-Fluoro-4-(6-methyl-pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 412.3