Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3nnc(-c4ccc(CC(C)C)c(C#N)c4)s3)c2CC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a solution of ethyl 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-4-piperidinecarboxylate (D33) (64 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 1 M HCl solution. The solvent was removed in vacuo. The residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-4-piperidinecarboxylic acid (E11) (15 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.93 (6H, d), 1.12 (3H, t), 1.57 (2H, m), 1.79 (2H, m), 2.03 (3H, m), 2.20 (1H, m), 2.81 (8H, m), 3.25 (2H, m), 7.32 (1H, t), 7.44 (2H, d), 7.67 (1H, d), 8.31 (1H, dd), 8.45 (1H, s), 12.06 (1H, br s). MS (ES): C29H34N4O2S requires 502. found 503.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:26]=[CH:27][C:21]=2[N:20]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:26]=[CH:27][C:21]3[NH:20][C:19]([C:7]4[C:6]5[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=5)[N:9]([CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)[N:8]=4)=[N:23][C:22]=3[CH:24]=2)[CH2:33][CH2:32]1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(N4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Yield: 53.8 %

Procedure:
4-(2-(5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine (50 mg, 0.111 mmol) was added to the 10% Pd/C (10 mg) in ethanol (20 mL) and then hydrogen gas (60 psi) was applied for overnight at room temperature. Upon The reaction mixture was filtered through Celite, and the solvent was removed in vacuum. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (25 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 7.66 (d, 1H, J=2.4 Hz), 7.56-7.51 (m, 2H), 7.15 (m, 1H), 7.06-7.01 (m, 2H), 5.81 (dd, 1H, J=2.4 and 9.6 Hz), 4.01 (m, 1H), 3.87 (m, 4H), 3.81 (m, 1H), 3.65 (t, 1H, J=6.8 Hz), 3.16 (m, 4H), 2.67-2.58 (m, 1H), 2.16 (m, 1H), 2.08 (m, 1H), 1.84 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17](O)(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12](=[C:17]([OH:19])[CH3:18])[C:13](=[O:15])[CH2:14]1
Reactant: O=C1CC(=O)CC(c2cc(Cl)ccc2Cl)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2cc(Cl)ccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 80.2 %

Procedure:
To a solution of 5-(2,5-dichlorophenyl)cyclohexane-1,3-dione (1.5 g), 4-dimethylaminopyridine (1.1 g) and acetic acid (0.63 g) in dimethylformamide (60 ml) was added dicyclohexylcarbodiimide (1.3 g), and the mixture was stirred at room temperature for 36 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was extracted with 1N sodium hydroxide solution, and the aqueous layer was filtered. Insoluble materials were filtered off, and the filtrate was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 5-(2,5-dichlorophenyl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (1.4 g), which was dissolved in ethanol (30 ml). To the solution was added hydrazine hydrate (0.26 g), and the mixture was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate-hexane) to give 6-(2,5-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.2 g) as colorless crystals.
Reaction SMILES: C(OC([S:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=S)C.[OH-].[Na+].Cl>>[SH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: CCOC(=S)Sc1cccc(C(=O)O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(S)cccc1C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
3-{[(ethyloxy)carbonothioyl]thio}-2-methylbenzoic acid (270 mg, 1.05 mmol) in a 1N aqueous sodium hydroxide solution (3 mL) was stirred at reflux for 15 hours. The mixture was cooled to room temperature and the pH was adjusted to 2 using concentrated aqueous hydrochloric acid. The aqueous mixture was extracted twice using dichloromethane and the combined organic solutions were washed with brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded 180 mg, 1.05 mmol (99%) of 3-mercapto-2-methylbenzoic acid. 1H NMR (400 MHz, CDCl3): 7.87 (d, 1H), 7.47 (d, 1H), 7.16-7.11 (m, 1H), 3.43 (s, 1H), 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:33]=[CH:32][C:28]2=[N:29][S:30][N:31]=[C:27]2[CH:26]=1.O>CN(C=O)C>[N:29]1[S:30][N:31]=[C:27]2[CH:26]=[C:25]([CH2:24][N:14]3[C:13](=[O:16])[CH:12]=[CH:11][C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:15]3)[CH:33]=[CH:32][C:28]=12
Reactant: O=c1ccc(-c2cc(F)c(F)c(F)c2)n[nH]1
Reactant: BrCc1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(-c2cc(F)c(F)c(F)c2)nn1Cc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.0 g (13.3 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one and 4.8 g (14.4 mmol) of caesium carbonate are suspended in 250 ml of DMF, 3.0 g (13.3 mmol) of 5-(bromomethyl)2,1,3-benzothiadiazole are added, and the mixture is stirred at room temperature. After 15 h, 110 ml of water are added to the reaction mixture, which is then stirred at room temperature for 2 h. The resultant precipitate is filtered off with suction and washed with water and dried in vacuo.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:5]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2)=[C:1]=[O:2]
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C=Nc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of phosgene (20% in toluene, 5.8 ml, 11 mmol) was added to 50 ml methylene chloride and cooled to 0° C. 4-Dimethylaminopyridine (2.86 g, 23.4 mmol) in 30 ml methylene chloride was added dropwise. A thick white suspension formed. A solution of 5-aminoisoquinoline (1.44 g, 10 mmol) in 30 ml methylene chloride was then added dropwise to this suspension. The reaction was allowed to warm to ambient temperature and stirred overnight. At the end of this time, a solution formed, and the solvent was removed under reduced pressure. The residue was triturated with 50 ml diethyl ether to give an approximately 0.1 M solution of 5-isocyanato-isoquinoline.
Reaction SMILES: [CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].[O:32]=[C:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([N:25]2[CH2:26][CH2:27][CH:28]([N:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:32])[CH2:38]3)[CH2:29][CH2:30]2)=[CH:23][C:6]2[C:7]([CH3:21])([CH3:22])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: O=C1CNCCN1
Reactant: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1N1CCC(N3CCNC(=O)C3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 30 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (30 mg) and 2-ketopiperazine (10 mg) were dissolved in THF (2 ml), added with sodium triacetoxy borohydride (30 mg), and the mixture was stirred at 30° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (20 ml). The organic layer was washed with 10% brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (11.5 mg, yield 32%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1C[C@@H](O)C[C@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3S,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp, S234-S237 (1996), 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the sample manner as in Example 1b (e) and using 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[C:4](=[O:17])[N:3]1[CH3:18].[Cl:19]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[Cl:19][C:5]1([C:8]2[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])[C:6](=[O:7])[N:2]([CH3:1])[N:3]([CH3:18])[C:4]1=[O:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)c(C2C(=O)N(C)N(C)C2=O)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)c(C2(Cl)C(=O)N(C)N(C)C2=O)c(C)c1
Yield: 78.4 %

Procedure:
There was refluxed with heating a mixture of 0.50 g (2.0 mmols) of 1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3, 5-dione, 0.32 g (2.4 mmols) of N-chlorosuccinic acid imide, 19 mg (0.08 mmol) of benzoyl peroxide and 20 ml of carbon tetrachloride for 30 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with an aqueous solution of saturated sodium hydrogencarbonate and a saturated solution of sodium chloride and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was washed with hexane, thereby obtaining 0.44 g (yield 78%) of 4-chloro-1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in the form of yellowish white crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:30]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C21H25FN6O2, 412.2
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[CH:5]=[CH:4][N:3]=1.[CH:14]([Zn]C(C)C)([CH3:16])[CH3:15].O.Cl>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:14]([CH3:16])[CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccnc1Br
Reactant: CC(C)[Zn]C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(Cl)ccnc1C(C)C
Temperature: 40 °C
Yield: 49.7 %

Procedure:
Ethyl 2-bromo-4-chloropyridine-3-carboxylate (1 g, 3.78 mmol) was dissolved in anhydrous dioxane (30 mL). A solution of diisopropyl zinc (4.5 mL, 4.54 mmol, 1.0 M in toluene) was added dropwise, followed with (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (44 mg, 60 μmol). The mixture was heated at 40° C. overnight, and water followed with 1 N HCl was added. The reaction mixture was extracted 3 times with ethyl acetate, and the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-15% hexane/ethyl acetate to afford ethyl 4-chloro-2-(propan-2-yl)pyridine-3-carboxylate (428 mg, 50% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10](#[N:12])[CH3:11]>>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)[CH2:11][C:10]#[N:12]
Reactant: CC#N
Reactant: O=Cc1cccc(I)c1
Product: N#CCC(O)c1cccc(I)c1

Procedure:
Acetonitrile addition to 3-iodobenzaldehyde (103) yielded 3-hydroxy-3-(3-iodophenyl)propanenitrile (104) as yellow oil. Yield (2.58 g, 55%): 1H NMR (400 MHz, CDCl3) 7.82 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 5.01 (m, 1H), 2.80 (d, J=6.4, 2H), 2.40 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:12]=2[CH:26]=[O:27])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2coc(-c3ccccc3)n2)cc1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-phenyloxazole (14.43 g), phosphorus oxychloride (12.97 g), N,N-dimethylformamide (100 mL) was stirred at 90° C. for 1.5 hrs. The reaction mixture was poured into iced water, and the precipitated solid was collected by filtration, washed successively with aqueous sodium hydrogen carbonate solution and water and dried. The obtained crystals were recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-2-phenyl-5-oxazolecarbaldehyde (7.90 g, 49%) as yellow prism crystals.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:35].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]([NH2:31])=[O:35])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C#N)CC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C(N)=O)CC3)ccc1-2
Reaction time: 5.5 h
Yield: 19 %

Procedure:
2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (346 mg, ˜50% pure, ˜0.40 mmol) was treated with concentrated sulphuric acid (5 mL) and the mixture was stirred for 5.5 hours then diluted with ice chips (˜50 mL) and made basic with solid sodium carbonate. The mixture was extracted with 10% MeOH in DCM (×4) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM first time then 0-100% EtOAc in DCM) to give 483 as a white solid (36 mg, 19%). LCMS: RT=3.28 min, [M+H]+=481. 1H NMR δ (ppm) (DMSO-d6): 9.54 (1H, s), 8.27 (1H, d, J=8.13 Hz), 8.05 (1H, s), 7.98 (1H, s), 7.86 (1H, s), 7.05 (1H, d, J=8.29 Hz), 6.90 (1H, s), 5.81-5.73 (1H, m), 4.32 (2H, s), 3.41-3.30 (4H, m), 3.12 (1H, m), 2.83 (1H, m), 2.13 (2H, d, J=13.80 Hz), 1.99 (1H, d, J=13.56 Hz), 1.72 (1H, s), 1.50 (12H, d, J=6.50 Hz). 1 Proton obscured by water peak
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:13].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C>[Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:8][C@@H:9]2[CH2:10][O:11][C:15]([CH3:20])([CH3:16])[O:12]2)=[CH:6][N:7]=1
Reactant: Cc1cc(C[C@@H](O)CO)cnc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: Cc1cc(C[C@@H]2COC(C)(C)O2)cnc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 970.4 %

Procedure:
A suspension of 52 (3.2 g, 16.2 mmol) in dimethoxypropane (33 mL) was cooled with an ice bath and treated with paratoluene sulfonic acid monohydrate (0.31 g, 1.62 mmol). The ice bath was removed and the solution was stirred at room temperature for 16 hrs, cooled to 5° C. and treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to afford 3.80 g (97%) of 53 as an oil. 1HNMR (CDCl3) δ 1.34 (3 H, s), 1.41 (3 H, s), 2.37 (3 H, s), 2.81 (2 H, m), 3.61 (1 H, t, J=7.0 Hz), 4.03 (1 H, m, J=6.0 Hz), 4.27 (1 H, m, J=6.0 Hz), 7.44 (1 H, s), 8.10 (1 H, s). LC/MS (M+1) 258.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]=[N:6][C:7]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1.O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:4]1[N:5]=[N:6][C:7]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCNc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCNc1ccc(OCc2ccccc2)nn1
Temperature: 180 °C
Yield: 47 %

Procedure:
Sodium hydride (22.0 mmol, 0.88 g) was dissolved in benzyl alcohol (10 mL). To the resulting solution was added N-(3-chloropyridazin-6-yl)-3-aminopropionic acid (10.0 mmol, 2.01 g), and the mixture was heated to about 165° C. (oil bath 180° C.) for 3 hours. After cooling to room temperature, water (120 mL) was added, and the aqueous phase was extracted with dichloromethane (3×50 mL). The pH was adjusted to 4.0 with 2M aqueous hydrochloric acid. The light brown precipitate was filtered, washed with water (2×1 mL) and dried over phosphorus pentoxide. The resulting solid was dried to give 1.36 g (47%) of the title compound. The product was pure according to TLC Rf 0.16 (dichloromethane/methanol/acetic acid, 85:10:5).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)[O:3]1.[CH2:21]=O.[BH4-].[Na+]>CO>[CH3:21][N:17]1[CH2:18][CH2:19][CH:14]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:20])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (0.500 g, 1.80 mmol) and 37% aqueous formaldehyde solution (0.269 mL, 3.61 mmol) in MeOH (10.0 mL) were combined and stirred at 40° C. for 2 h. Then sodium borohydride (205 mg, 5.41 mmol) was carefully added to the reaction mixture left to stir for 16 h. The reaction was concentrated in vacuo to a solid. The crude product was dissolved in EtOAc and washed with water several times. The organic layer was collected, dried with sodium sulfate, filtered and concentrated in vacuo to a solid to yield the desired product. 1H NMR (400 MHz, CD3OD): δ 7.90 (s, 1H), 7.67 (s, 1H), 4.16-4.26 (m, 1H), 3.00 (d, J=12.13 Hz, 2H), 2.34 (s, 3H), 2.25 (td, J=11.75, 3.28 Hz, 2H), 2.03-2.15 (m, 4H), 1.31 (s, 12H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[CH3:15][C:16]([CH3:46])([CH3:45])[CH2:17][N:18]([CH3:44])[C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]=[C:21]([NH:29][C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:33]([NH:35][CH3:36])=[O:34])[C:20]=1[N+:41]([O-:43])=[O:42]>CS(C)=O>[CH3:15][C:16]([CH3:46])([CH3:45])[CH2:17][N:18]([CH3:44])[C:19]1[N:24]=[C:23]([O:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:22]=[C:21]([NH:29][C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:33]([NH:35][CH3:36])=[O:34])[C:20]=1[N+:41]([O-:43])=[O:42]
Reactant: CNC(=O)c1ccc(C)c(Nc2nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(C)c(Nc2nc(OC3CCN(C)CC3)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
1-Methyl-piperidin-4-ol (56 mg, 0.5 mmol) was dissolved in 2 mL of DMSO. To the solution was added potassium tert-butoxide (56 mg, 0.5 mmol). The solution was stirred at room temperature for 1 h. The solution was then added to a solution of 3-{6-[(2,2-Dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-5-nitro-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (4 mg, 0.01 mmol) in 0.5 mL of DMSO. The solution was stirred at 80° C. for 3 h, and extracted with ethyl acetate and water. The organic layer was washed with water, brine, dried over MgSO4, and evaporated under vacuum. The residue was purified by semi-preparative hplc column to afford 0.7 mg of the product (Yield: 16%). MS (m/z) calcd for C25H37N7O4 (MH+), 500.2, found, 500.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:31][CH2:30][C:27]4[CH:28]=[CH:29][N:24]5[CH:23]=[CH:22][N:21]=[C:25]5[CH:26]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: NCc1ccn2ccnc2c1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3ccn4ccnc4c3)c2C1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (250 mg, 0.82 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (270 mg, 1.83 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was subjected to microwave irradiation at 185° C. for 4 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.