Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: NC(=O)c1c(N)sc2ccccc12
Yield: 72.8 %

Procedure:
1.96 grams (10 mmol) of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide was slowly treated with 9.0 grams (40 mmol) DDQ in toluene at room temperature. The reaction was mixed at 40° C. for 15 hours, and monitored by GLC. The solvent was then removed under reduced pressure, and the residue was transferred to 10 ml of dichloromethane and filtered via Celite. The filtrate was purified by chromatography on silica gel, using dichloromethane and ethyl acetate (at an 8:2 ratio), yielding 1.4 grams (70% yield) of 2-aminobenzo[b]thiophene-3-carboxamide as yellow powder.
Reaction SMILES: CO[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)[N:4]=1.[NH3:17]>>[N+:9]([C:8]1[C:3]([NH2:17])=[N:4][C:5]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: COc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Reactant: N
Product: Nc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 2-methoxy-3-nitro-6-(1,3-oxazol-2-yl)pyridine (0.187 g, 0.85 mmol) in aqueous ammonia (32%, 5 mL) was heated in a sealed tube to 100° C. with stirring. After 2.5 hours the mixture was cooled and the precipitate was filtered and washed with water and then dried in vacuo to give the title compound (0.134 g, 77%) as a yellow solid.
Reaction SMILES: C(N(C)C(=O)[C@@H](N[C:18]([C:20]1[N:21]([CH3:43])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37]CCCC)=[CH:24][CH:23]=2)=[O:19])C1C=CC=CC=1)C1C=CC=CC=1.C[OH:47].O.[OH-].[Li+]>C1COCC1>[OH:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:30]([NH:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:43])[C:20]([C:18]([OH:47])=[O:19])=[CH:28]2)=[O:42]
Reactant: CCCCOc1ccccc1C(=O)Nc1ccc2c(c1)cc(C(=O)N[C@H](C(=O)N(C)Cc1ccccc1)c1ccccc1)n2C
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of step (a) (2.0 g, 5.26 mM) was dissolved in THF (30 mL), methanol (10 mL), and water (10 mL). The mixture was treated with lithium hydroxide (882 mg, 21.04 mM) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to 15 mL and the pH was adjusted to about 3.0 with 1 N HCl. The mixture was extracted 3 times with ethyl acetate (25 mL). The ethyl acetate fractions were combined, dried over MgSO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:12])[N:9]=2)[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c2[nH]ncc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: Cc1ccc(Br)c2nn(C)cc12
Temperature: 80 °C

Procedure:
To a solution of 7-bromo-4-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[C:17]([CH2:18]3)=[N:16][N:15]([C:23](=[O:25])[CH3:24])[CH:14]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Product: CC(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene using acetyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[F:20][C:21]([F:28])([F:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[F:20][C:21]([F:28])([F:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: FC(F)(F)[C@@H]1CCCN1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@H]3C(F)(F)F)n2)c1

Procedure:
B16 was prepared following the general procedure reported for B10 using A1 and (S)-2-(trifluoromethyl)pyrrolidine. The title compound (B16) was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and MeOH (0.1% TFA) as eluents. Yield: 58.7 mg (15%), colorless amorphous solid. MS (ES) C15H17F3N6O2S requires: 402. found: 403 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:11]([CH3:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:21][N:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:14]=[C:10]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccccc2)nc1Cl
Reactant: Nc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cn1cc(-c2ccccc2)nc1Nc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A slurry of 4-aminophenol (0.227 g, 2.08 mmol), 2-chloro-1-methyl-4-phenyl-1H-imidazole (0.400 g, 2.08 mmol), and p-toluenesulfonic acid monohydrate (0.395 g, 2.08 mmol) was heated in 2.5 mL 2-BuOH in a sealed tube to about 110° C. for 24 h. The temperature was increased to about 120° C. and the solution was heated for 24 h. The reaction was cooled and partitioned between 50 mL pH7 buffer and DCM. The aqueous layer was extracted with DCM (3×), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting brown oil was purified by silica gel chromatography (0-100% 90/10 DCM/MeOH in DCM) to give 4-(1-methyl-4-phenyl-1H-imidazol-2-ylamino)phenol as a tan solid. MS m/z=266 [M+H]+. Calc'd for C16H15N3O: 265.3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14].[H][H]>CO>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)/C=C/c1cccc([N+](=O)[O-])c1C
Reactant: [H][H]
Solvent: CO
Product: COC(=O)CCc1cccc(N)c1C

Procedure:
48.7 g (220.1 mmol) of methyl (2E)-3-(2-methyl-3-nitrophenyl)acrylate were dissolved in 2.2 liters of methanol, and the solution was hydrogenated in a continuous-flow hydrogenation reactor (“H-Cube midi” from Thales Nano, Budapest) at a flow rate of 6-10 ml/min and at a reaction temperature of 35-40° C. and at maximum hydrogen pressure. After the reaction had ended, the product-containing solution was concentrated under reduced pressure. This gave 40.0 g of the target product as a solid (92.1% of theory).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH3:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH3:32])=[CH:26][C:23]=1[CH:24]([OH:25])[C:9]#[C:8][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(OC)c(C=O)cc1C
Product: COc1cc(OC)c(C(O)C#Cc2ccccc2)cc1C
Yield: 89 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,4-dimethoxy-5-methyl-benzaldehyde (1.00 g, 5.55 mmol) was reacted to give the title compound (1.39 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.30 (m, 6H), 6.61 (s, 1H), 5.79-5.70 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([NH:44][C:42](=[O:43])[C@H:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:33])=[O:18])[CH2:14][CH2:15]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of trans-4-(t-butoxycarbonylaminomethyl)cyclohexyl carboxylic acid (3.86 g) dissolved in dry tetrahydrofuran (150.00 ml), triethylamine (2.25 ml) was added under ice-cooling and the mixture was stirred for 5 minutes. A solution of ethyl chlorocarbonate (1.63 g) in dry tetrahydrofuran (10.00 ml) was added to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. L-phenylalanine amide hydrochloride and triethylamine (2.25 ml) were added to the mixture, and the mixture was stirred under ice-cooling for 2 hours and under room temperature for one hour, followed by concentration under a reduced pressure. Water was added to the residue, and the insolubles therein were filtered, thoroughly washed with water, and further washed with 50% aqueous ethyl alcohol and 50% ethyl alcohol-ethyl ether, followed by drying, to give N-[trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine amide (I) (4.82 g) as a white powder. This structure was confirmed by NMR spectrum.
Reaction SMILES: Cl[C:2]1[C:3]([CH:28]=[O:29])=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])=[N:16][CH:17]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:30]B(O)O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:28]([C:3]1[C:2]([CH3:30])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])=[N:16][CH:17]=1)=[O:29]
Reactant: CB(O)O
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C)c2C=O)cn1
Temperature: 90 °C

Procedure:
Ethyl 3-(5-(3-chloro-2-formyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (150 mg, 0.35 mmol), methylboronic acid (31 mg, 0.53 mmol), Pd(dppf)Cl2 (34 mg, 0.05 mmol) and K3Pa4hydrate (322 mg, 1.40 mmol) were dissolved in 1,4-dioxane (2 mL) and the resulting mixture was heated to 90° C. After 10 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl.[C:2]([CH2:10][N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH2:18][C:19]#[N:20])[CH2:13][CH2:12]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:21]([O-])=[O:22].[Na+]>O>[C:2]([CH2:10][N:11]1[CH2:12][CH2:13][N:14]([N:17]([CH2:18][C:19]#[N:20])[N:21]=[O:22])[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCNN1CCN(CC(=O)c2ccccc2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CCN(N=O)N1CCN(CC(=O)c2ccccc2)CC1

Procedure:
A solution prepared by adding 10 ml of water and 19 ml of 1N hydrochloric acid to 1.6 g of 4-(benzoylmethyl)-1-(cyanomethylamino)piperazine was cooled to 4° to 5° C., and with stirring, 1.7 g of sodium nitrite was added. The mixture was reacted at 4° to 5° C. for 1.5 hours with stirring. The reaction mixture was extracted with chloroform. The extract was washed with water and dried, and chloroform was distilled off to give 4-(benzoylmethyl)-1-(N-nitrosocyanomethylamino)piperazine as a red oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]1[O:17][C:16]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[O:9]1.C(N(CC)CC)C.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C(Cl)Cl.CCOCC>[O:17]1[C:16]2[CH:15]=[CH:14][C:12]([N:13]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:11][C:10]=2[O:9][CH2:8]1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc2c(c1)OCO2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-Chlorobutyryl chloride (1095.5 g, 7.77 mole) was added at 10°-25° C. to a mixture of 3,4-(methylenedioxy)aniline (1000.0 g, 7.29 mole), triethylamine (749.0 g, 7.40 mole) and methylene chloride (25000 mL). After stirring for 18 hours at ambient temperature ether was added and the butyramide intermediate was filtered then reslurried in water. The damp butyramide was combined with methylene chloride (10 L), 50% w/w aqueous sodium hydroxide (2000.0 g, 25.0 mole) and benzyltriethylammonium chloride (50.0 g, 0.22 mole). After stirring for 2.5 hours at ambient temperature the mixture was diluted with water and the aqueous layer was then separated. The methylene chloride layer was washed with water, decolorized with Darco G-60 and Filtrol #19, then vacuum concentrated. Ether was added to the concentrate. The mixture was chilled and the solids were collected and recrystallized from methylene chloride/ether giving 2245.0 g (75), m.p. 89°-91° which was one spot on tlc analysis.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][OH:24]>CN(C=O)C.C(OCC)(=O)C>[C:4]([Si:1]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OCCCc1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccccc1F
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylsilyl chloride (3.19 g) was added to a solution of imidazole (3.6 g) and 3-(2-fluorophenyl)propan-1-ol (example 88, step a) (2.72 g) in dry DMF (30 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×100 mL) and evaporated. The resulting gum was purified by silica gel chromatography eluting with isohexane. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 4.4 g.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:30][CH2:29][C:26]3([CH2:28][CH2:27]3)[C@H:25]([OH:31])[CH2:24]2)=[O:22])[C:13](=[O:32])[C@@H:12]1[CH3:33])=O)C1C=CC=CC=1.Cl>>[OH:31][C@@H:25]1[CH2:24][N:23]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][NH:11][C@@H:12]([CH3:33])[C:13]2=[O:32])[CH2:30][CH2:29][C:26]21[CH2:28][CH2:27]2
Reactant: C[C@H]1C(=O)N(CCCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Product: C[C@@H]1NCCN(CCCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Yield: 83 %

Procedure:
In analogy to intermediate 12E, (S)-4-[5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was hydrogenated without aqueous HCl to give the titled compound in 83% yield as light yellow oil. MS: 324.23 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[Cl:21][C:22]1[C:23]([NH2:30])=[N:24][C:25]([NH2:29])=[N:26][C:27]=1Cl.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:21][C:22]1[C:27]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)[CH3:19])=[N:26][C:25]([NH2:29])=[N:24][C:23]=1[NH2:30]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 14.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (95 mg, 0.372 mmol), 5,6-dichloropyrimidine-2,4-diamine (100 mg, 0.559 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.20 mL, 1.1 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then at 160° C. for 1.5 hours. The mixture was concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30% ACN in water. The fractions containing the desired compound were combined and extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (21 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 1.38 (d, J=6.35 Hz, 3 H), 3.65 (s, 3 H), 3.83-3.89 (m, 3 H), 5.38 (q, J=6.67 Hz, 1 H), 6.40-6.46 (m, 1 H), 6.65-6.70 (m, 1 H), 7.58-7.64 (m, 2 H), 7.80 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H20ClN9, 398; found 398.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][O:20][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccc(Cl)cc3Cl)c21
Yield: 76.5 %

Procedure:
The title compound was prepared as white crystals in 76.5% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-dichlorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29](Cl)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:20]=2[O:19][CH2:18]1>ClCCl>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[N:7]=4)=[O:30])[CH2:27][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of 6-chloro-5-methylpyridin-2-amine (71 mg, 0.50 mmol) and Et3N (140 μL, 1.0 mmol) in dichloromethane (2 mL) was added a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (110 mg, 0.50 mmol) in dichloromethane (2 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N aqueous HCl (1×5 mL) and saturated aqueous NaHCO3 (1×5 mL). The organic layer was dried over sodium sulfate and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide (120 mg, 71% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.94-7.91 (m, 1H), 7.79-7.77 (m, 1H), 7.09 (m, 1H), 7.00-6.88 (m, 2H), 6.06 (s, 2H), 2.25 (s, 3H), 1.47-1.44 (m, 2H), 1.13-1.10 (m, 2H) ESI-MS m/z calc. 330.1. found 331.5 (M+1)+. Retention time 1.99 minutes.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].[OH-].[Na+].CO>C(O)C.O>[F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (5 g, 29.36 mmol) in ethanol (30 ml) was slowly added aqueous sodium hydroxide ((2.35 g, 58.72 mmol, dissolved in water (30 ml)), and stirred for 20 h at room temperature until the starting material was consumed. The reaction mixture was concentrated and the resulting white solid was dissolved in water (100 ml). The aqueous layer was extracted by ethyl acetate (50 ml×2), and then the aqueous layer was adjusted PH to 1˜2 with concentrated HCl, and concentrated to give a white solid. The solid was added to methanol (200 ml) and stirred for overnight, filtered, and the filtrate was concentrated and dried to give the crude product (4.13 g, 99%) as a white solid, used in next step without further purification.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH2:27][NH:28][CH3:29].C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:28]([CH3:29])[CH2:27][C:19]2[N:18]([CH3:17])[C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
EDC (0.70 g, 3.7 mmole) was added to a solution of (E)3-(6-aminopyridin-3-yl)acrylic acid (0.61 g, 3.7 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (0.65 g, 3.7 mmole), HOBt.H2O (0.50 g, 3.7 mmole), and triethylamine (0.52 mL, 3.7 mmole) in DMF (30 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave a colorless semisolid which was triturated with Et2O and dried. The title compound (1.0 g, 83%) was obtained as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1 H), 7.45-7.70 (m, 3 H), 7.00-7.30 (m, 3 H), 6.69 (d, J=15.4 Hz, 1 H), 6.30-6.50 (m, 2 H), 4.89 (s, 2 H), 4.67 (br s, 2 H), 3.68 (s, 3 H), 3.01 (s, 3 H); MS (ES) m/e 321 (M+H)+. Anal. Calcd for C19H20N4O.0.40 H2O: C, 69.66; H, 6.40; N, 17.10. Found: C, 69.99; H, 6.27; N, 16.84.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=2)[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:26][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[O:14][N:13]=2)[CH:20]=[CH:19][C:18]=1[O:21][C:22]([F:23])([F:24])[F:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(OC(F)(F)F)c(Cl)c2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](N)c1nc(-c2ccc(OC(F)(F)F)c(Cl)c2)no1

Procedure:
(S)-tert-butyl(1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (2.0 g, 4.90 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 1.4 g waxy off-white solid. HRMS m/z 307.0335