Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:4]2[N:3]=1.[CH3:24][NH2:25]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:25][CH3:24])[N:5]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:4]2[N:3]=1
Reactant: CN
Reactant: Clc1nc2nc(-c3ccccn3)nn2c(Cl)c1-c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1c(-c2ccccc2)c(Cl)nc2nc(-c3ccccn3)nn12
Temperature: 100 °C
Yield: 26.9 %

Procedure:
1 g (2.9 mmol) 5,7-dichloro-6-phenyl-2-pyridine-2-yl-[1,2,4]triazolo[1,5-a]pyrimidine are given in 8.2 mL DMF (no complete dissolution). After addition of 3.65 mL of a 2M (7.3 mmol) solution of methylamine in THF the reaction mixture is heated in a microwave oven at 100° C. for 20 minutes. From the clear brown solution the DMF is evaporated, the residue is diluted with brine and extracted three times with dichloromethane. The combined organic extracts are dried over Na2SO4 and the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane, methanol). 265 mg (26.9%) of the desired product are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:26])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C(O)(C(F)(F)F)=O>ClCCl.C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[C:9]([CH3:26])=[N:10][N:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:12]=2)[CH:4]=1
Reactant: Cc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-methyl-pyrazol-1-yl]piperidine-1-carboxylate (500 mg) in dichloromethane (3 ml) was added TFA (1 ml). The solution was stirred at 25° C. for 2 hours. The mixture was evaporated to dryness, then the residue was diluted in dichloromethane and ammonia in methanol 7N was added. After removal of solvents, the crude product was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane followed by 10 to 25% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford a solid which was stirred in acetonitrile overnight, filtered and dried to afford 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (290 mg) as a solid; NMR Spectrum: (DMSOd6) 1.77 (dd, 1H), 1.82 (dd, 1H), 1.93-1.99 (m, 2H), 2.12 (bs, 1H), 2.32 (s, 3H), 2.58 (ddd, 1H), 3.01-3.07 (m, 2H), 4.06-4.25 (m, 1H), 7.41-7.48 (m, 2H), 7.64 (bs, 2H), 7.80 (dd, 1H), 7.84 (dd, 1H), 8.04 (s, 1H), 8.28 (d, 1H), 8.35 (d, 1H); Mass spectrum: M+H+: 375
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]1([C:20](Cl)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:21])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1cccc2ccccc12
Yield: 27.9 %

Procedure:
The general procedure of Example 45 was followed using 2.00 g 5-chloro-4-hydroxy-2-pyridone, 3.93 g of α-naphthoyl chloride and 100 ml of pyridine, thereby producing 1.15 g of the title compound in a yield of 28%.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:12][CH2:11][CH2:10][CH2:9][S:8]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1>[CH3:6][C:7]1([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[S:12][CH2:11][CH2:10][CH2:9][S:8]1
Reactant: CC1SCCCS1
Reactant: BrCCCCOCCCc1ccc(N2CCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(CCCCOCCCc2ccc(N3CCCC3)cc2)SCCCS1
Reaction time: 2 h
Yield: 45.5 %

Procedure:
n-Butyllithium (1.5M in hexane, 12 ml) was added over 5 min to a stirred solution of 2-methyl-1,3-dithiane (2.4 g) in dry THF (30 ml) at 70° under nitrogen. The yellow solution was then stirred at -30° to -20° for 2 h, cooled to -78° and treated with a solution of the product of stage (iii) (6.1 g) in THF (25 ml). The solution was stirred at room temperature overnight, the solvent was evaporated and the residue was purified by FCC (hexane→System D 9:1) to give the title compound as a pale yellow oil (3.2 g) T.l.c. (System D 9:1) Rf 0.18.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1.[Br:12][C:13]1[C:14]([CH3:25])=[CH:15][C:16]2[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=2[C:23]=1[CH3:24].[C:26](Cl)(=[O:28])[CH3:27]>C(OCC)(=O)C.O>[Br:12][C:13]1[C:14]([CH3:25])=[C:15]([C:26](=[O:28])[CH3:27])[C:16]2[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=2[C:23]=1[CH3:24]
Reactant: Cc1cc2c(c(C)c1Br)CC(C)(C)O2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CC(=O)c1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Yield: 8.3 %

Procedure:
Aluminium chloride (3.56 g, 26.7 mmol) was added to a mixture of chlorobenzene (40 mL) containing 5-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (4.55 g, 17.8 mmol) synthesized in Reference Example 120 and acetyl chloride (4.20 g, 53.4 mmol) at −40° C., and the mixture was stirred at the same temperature. After stirring for 1 hour, the reaction solution was poured into water, and extraction was performed using ethyl acetate. The extract was washed with saturated sodium bicarbonate water and saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 99:1-95/5) to give 440 mg of the title compound (yield: 8%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Cl[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:8])[C:3]2([CH:7]=[CH:6][CH:5]=[CH:4]2)[CH:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCl
Reactant: CC(C)=C1C=CC=C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: CCOC(=O)C1C(C)(C)C12C=CC=C2

Procedure:
A well stirred, 10°-15° C. nitrogen blanketed mixture of 10.6 g. of 6,6-dimethylfulvene, prepared above, and 12.2 g. of ethyl chloroacetate was treated dropwise over 1.5 hr. with a solution of 11.7 g. of potassium t-butoxide in 75 ml. of dry t-butyl alcohol. The reaction was stirred an additional 1.5 hr. at 10° C. and most of the alcohol was then removed at reduced pressure. Ether extraction of an aqueous solution of the residual semisolid afforded 15.2 g. of yellow oil. Subsequent distillation afforded 2.5 g. (13%) of yellow ester, b.p. 75°-80° C. (0.25 mm.). Gas chromatographically purified ester exhibited the following spectral properties: ir (film) 5.77, 8.33, 8.69, 9.24, 12.0, 12.7 μ; nmr (CCl4) τ 3.38, 3.69, 3.99 (3m, 4, --CH=CH--CH=CH--), 5.99 (q, 2, J = 7 Hz, OCH2CH3), 7.41 (s, 1, CHCO2Et), 8.47, 8.60 (6, CH3 's), 8.80 (t, 3, J = 7 Hz, OCH2CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:10]=O>C(O)=O>[CH3:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: C=O
Reactant: O=C(O)C1CCCCN1
Solvent: O=CO
Product: CN1CCCCC1C(=O)O
Reaction time: 5 h

Procedure:
Into a 25 ml 3-necked round bottom flask, was placed piperidine-2-carboxylic acid (975 mg, 7.56 mmol), HCHO (2.0 ml) and HCOOH (2.6 ml). The resulting solution was allowed to react, with stirring, for 5 hours while the temperature was maintained at reflux. The reaction progress was monitored by LCMS. The mixture was then concentrated by evaporation under vacuum using a rotary evaporator. The residue was triturated with 30 ml of Et2O to provide 1-methylpiperidine-2-carboxylic acid of as a white solid (0.5 g, 41%).
Reaction SMILES: [NH2:1][C:2]1=[C:3]([Cl:18])[C:4](=[O:17])[C:5]([CH3:16])=[CH:6]/[C:7]/1=[N:8]/[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.[OH-].[Na+]>[NH2:1][C:2]1[C:3]([Cl:18])=[C:4]([OH:17])[C:5]([CH3:16])=[CH:6][C:7]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: CC1=C/C(=N/c2ccc(N)cc2)C(N)=C(Cl)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2ccc(N)cc2)c(N)c(Cl)c1O

Procedure:
10 mg (0.04 mol) of (4Z)-3-amino-4-[(4-aminophenyl)imino]-2-chloro-6-methylcyclohexa-2,5-dien-1-one are added to a solution comprising 16 mg of sodium hydrosulphite in 500 μl of methanol and 5 μl of an aqueous sodium hydroxide solution. The reaction medium is stirred and then the solution is treated according to the usual procedure and characterized. 3-Amino-4-[(4-aminophenyl)amino]-2-chloro-6-methylphenol) (2b) is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][C@H:24]1O[C@@H:27](N2C3N=CN=C(N)C=3N=C2C2C=CC=CC=2)[C@H:26](O)[C@@H:25]1O>CN.C(O)C>[CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: Nc1ncnc2c1nc(-c1ccccc1)n2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CN
Solvent: CCO
Product: CNC[C@H]1O[C@@H](n2c(-c3ccccc3)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 4d was prepared by the same procedure as described for the preparation of 4a using 3d (2.00 g, 5.52 mmol) and 33% methylamine/ethanol solution (40 mL). After column chromatography (elution with 4:1:0.2 chloroform:methanol:NH4OH), a yellow glassy solid was obtained: 963 mg (49%); MS m/z 357 (M+H)+; 1HNMR (DMSO-d6) δ 8.19 (s, 1H, H-2), 7.72-7.76 (m, 2H, 8-phenyl o-H's), 7.58-7.61 (m, 3H, 8-phenyl m- and p-H's), 7.40 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=6.4 Hz), 5.38 (d, 1H, 2′-OH, J2′-2′OH=6.2 Hz), 5.29 (ddd, 1H, H-2′, J1′,2′=6.4 Hz, J2′,3′=5.1 Hz, J2′-2′OH=6.2 Hz), 5.14 (bs, 1H, 3′-OH), 4.19 (bs, 1H, H-3′), 3.95-4.0 (m, 1H, H-4′), 2.82 (d, 2H, 5′-CH2, J=5.2 Hz), 2.34 (s, 3H, 5′NH—CH3).
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]Br)#[N:2].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>O>[C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)#[N:2]
Reactant: CCCCC(C#N)(CBr)c1ccc(Sc2ccccc2)cc1
Reactant: c1c[nH]cn1
Solvent: O
Product: CCCCC(C#N)(Cn1ccnc1)c1ccc(Sc2ccccc2)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 10 g (0.027 mole) of 2-cyano-2-(4-phenylthiophenyl)hexyl bromide and 8 g (0.13 mole) of imidazole is heated with stirring at 160° for four hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over Na2SO4. The drying agent is filtered and to the filtrate is bubbled dry hydrogen chloride gas until solution is strongly acidic. The hydrochloride salt is washed with ether and back neutralized with dilute ammonium hydroxide solution to give 8 g of pure product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH3:28])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[CH3:31][N:32]1[CH:36]=[C:35]([CH:37]=O)[N:34]=[CH:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>CO.ClCCCl>[F:30][C:2]([F:1])([F:29])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@@H:13]2[CH2:26][N:27]([CH3:28])[CH2:37][C:35]2[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: CNC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: Cn1cnc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: CN(Cc1cn(C)cn1)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.2 %

Procedure:
A 25-mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-((2S)-2-((methylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (50 mg, 0.108 mmol), 1-methyl-1H-imidazole-4-carbaldehyde (59.4 mg, 0.539 mmol, ASDI, Newark, Del.), sodium triacetoxyborohydride (114 mg, 0.539 mmol, Sigma-Aldrich, St. Louis, Mo.), AcOH (0.617 μl, 10.79 μmol) and DCE (5 mL). The reaction was stirred at room temperature for 12 h. MeOH (20 mL), was added and the mixture was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 5 to 10% CH2Cl2 in MeOH) to give 1,1,1-trifluoro-2-(4-((2S)-2-((methyl((1-methyl-1H-imidazol-4-yl)methyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) as a mixture of two isomers.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[Cl-]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NCCCn1ccnc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14.9 g of chloroacetyl chloride in 25 ml of methylene chloride was added to a stirred solution of 15.0 g of 1-(3-aminopropyl)imidazole in 75 ml of methylene chloride at 0° C. The rate of addition was controlled to keep the reaction temperature below 15° C. During the course of the reaction a brown gummy viscous oil separated out of solution. Approximately two-thirds of the way through the addition, 50 ml of 20% NaOH was added to the mixture, and the oil went into solution. After the addition was completed, the mixture was stirred at room temperature for 15 minutes. The water layer was removed, the organic layer was dried over MgSO4 and filtered, and the solvent was removed under vacuum to give a yellow oil. The oil was dissolved in 30 ml of water and the pH was adjusted to approximately 3.0. Analysis for organic chloride indicated dimerization and/or trimerization had occurred.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[O:10][C:9](=[O:19])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([CH2:6][N:3]([CH3:4])[CH3:2])=[CH:8][C:9](=[O:19])[O:10]2)=[CH:15][CH:14]=1
Reactant: CNC
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(CN(C)C)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
A mixture of dimethylamine hydrochloride (0.18 g), 4-bromomethyl-7-methoxycoumarin (0.30 g), potassium carbonate (0.5 g) and dichloromethane (10 ml) was stirred at room temperature for 2 days. The solid was filtered off and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluent 5% methanol in dichloromethane), then crystallised from methanol to give the title compound as a white solid (0.145 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:12]=1.C[OH:27]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]([NH2:23])=[O:27])=[CH:20][CH:19]=2)[N:12]=1
Reactant: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Reactant: CO
Solvent: O
Product: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C(N)=O)cc3)n2)c(C)c1
Yield: 56 %

Procedure:
A mixture of compound (52) (0.00303 mol) and NaBO3.4H2O (0.00911 mol) in CH3OH (30 ml) and H2O (10 ml) was stirred and refluxed for 4 days. The reaction mixture was cooled. The precipitate was filtered off and the precipitate (*) was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH gradient from 100/0 to 95/5). The desired fractions were collected and the solvent was evaporated, yielding 0.586 g (56%) of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide (compound 100). The filtrate (*) was purified by reversed-phase HPLC (eluent gradient: ((0.5% ammoniumacetate in H2O)/CH3CN 90/10)/CH3OH/CH3CN (0 minutes) 75/25/0, (44 minutes) 0/50/50, (57 minutes) 0/0/100, (61.1-70 minutes) 75/25/0). Three desired fraction groups were collected and their solvent was evaporated, yielding 0.18 g of 4-[[4-[(2,4,6-trimethylphenyl)amino]-pyrimidinyl]amino]benzamide, N3-oxide (compound 106) and 0.030 g of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide, N1-oxide (compound 107).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].C(N(CC)CC)C>C(O)C>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCC(=O)O
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c(NCC(=O)O)cc(=O)oc2c1OC1CCCC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (170 mg, 0.58 mmol), glycine (52 mg, 0.69 mmol), triethylamine (0.2 mL, 1.4 mmol), and ethanol (2 mL) was heated at 75° C. in a sealed vial. After 2 d, more glycine (136 mg, 1.8 mmol) and triethylamine (0.3 mL, 2.2 mmol) were added. The reaction was heated at 75° C. for an additional day, allowed to cool to rt, concentrated, diluted with ethyl acetate (40 mL), and then washed with 1N HCl (50 mL×3). The organic layer was dried, filtered, and concentrated to give 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.87 (t, 1H), 7.68 (d, 1H), 7.08 (d, 1H), 4.88 (s, 1H), 4.81 (m, 1H), 4.00 (d, 2H), 3.87 (s, 3H), 1.90-1.44 (m, 8H); MS (ESI): 333.9.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=1.FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=[C:18]1[O:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of sodium hydride (60 wt % in mineral oil, 0.772 g, 19.3 mmol) in tetrahydrofuran (92 ml) was added tert-butyl 4-hydroxy-piperidine-1-carboxylate (3.70 g, 18.4 mmol) at 0° C. The mixture was stirred at room temperature for one hour, then 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (4.09 g, 18.4 mmol) was added. The mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved into dichloromethane (37 ml), and trifluoroacetic acid (41.9 g, 368 mmol) was added to the solution. The mixture was stirred at room temperature for 5 hours. After concentration under reduced pressure, the residue was dissolved into water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one as a pale yellow solid (2.48 g, 8.63 mmol, 47%). This compound was used for the next reaction without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:19][N:20]([CH2:31][C:32]([O:34][CH3:35])=[O:33])S(C1C=CC(C)=CC=1)(=O)=O)C.C[O-].[Na+]>CO>[CH3:35][O:34][C:32]([C:31]1[N:20]=[CH:19][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[CH:8][C:7]=2[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:33]
Reactant: CCOC(=O)c1cccc(Oc2ccc(F)cc2)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(Oc3ccc(F)cc3)cccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
To a stirred solution of 3-(4-fluoro-phenoxy)-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-benzoic acid ethyl ester (2.66 g, 5.17 mmol) in anhydrous methanol (8 mL) was added dropwise a solution of sodium methoxide (30% wt, 2.8 mL) and methanol (2 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then 3 h at room temperature before it was concentrated in vacuo. Water was added and the pH of the slurry was adjusted with 1 N HCl to pH=10. The resulting precipitate was collected by filtration, washed with water, saturated sodium bicarbonate, and water, and was dried in vacuo to give the title compound as a white solid (1.51 g): MS: (+) m/z 314.07 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH:12]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:13][O:14]CC2C=CC(OC)=CC=2)=[CH:6][C:5]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O.CCOC(C)=O.CCCCCC>[CH:25]1([CH2:24][CH:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:38])=[C:5]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH:6]=2)[CH2:13][OH:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(COC(COCc2ccc(OC)cc2)CC2CCCCC2)cc1-c1ccccc1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COC(CO)CC2CCCCC2)cc1-c1ccccc1C
Reaction time: 0.83 h
Yield: 83.2 %

Procedure:
To a solution of N-[4-(3-cyclohexyl-1-(4-methoxybenzyloxy)prop-2-yloxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester (Example 1051B, 360 mg) in dichloromethane (2 mL) was added water (5 drops), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (190 mg). After 50 min, the reaction was diluted with EtOAc/hexane (1:1, 10 mL), dried (MgSO4), and filtered through a pad of silica gel. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluting with 20%-30% EtOAc/hexane to give the title compound (230 mg, 90%) as a colorless oil.
Reaction SMILES: [N:1]([C:4]1([CH3:25])[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH2:15][CH2:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1)=C=O.[OH-].[Na+].Cl>C1COCC1.O>[NH2:1][C:4]1([CH3:25])[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH2:15][CH2:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:8][CH2:9]1
Reactant: CC1(N=C=O)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(N)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.6 %

Procedure:
A solution of (1R)-1-[(4-isocyanato-4-methyl-1-piperidinyl)methyl]-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (561 mg, 1.638 mmol) in THF (10 ml) and water (10.00 ml) at rt was treated with sodium hydroxide (5 ml, 10.00 mmol), and stirred at rt for 1 h. Reaction was then treated with concentrated HCl (5 ml, 12M) and stirred at rt for 18 h, then evaporated. The resultant solid was treated with methanol (20 ml) and then the solvent was decanted from the solid and evaporated to give the product as an impure green solid (687 mg, 108%).