Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[O:26][C:25](=[O:27])[C:9]3[CH2:10][N:11]([CH2:14][CH2:15][N:16]4[CH2:22][CH:21]5[CH2:23][CH2:24][CH:18]([CH2:19][CH2:20]5)[CH2:17]4)[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[CH:21]12[CH2:23][CH2:24][CH:18]([CH2:19][CH2:20]1)[CH2:17][N:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][C:8]3[C:6]4[CH:7]=[C:2]([NH:1][C:35](=[O:42])[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:3]([CH3:28])=[CH:4][C:5]=4[O:26][C:25](=[O:27])[C:9]=3[CH2:10]1)[CH2:22]2
Reactant: Cc1cc2oc(=O)c3c(c2cc1N)CCN(CCN1CC2CCC(CC2)C1)C3
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(=O)c3c(c2cc1NC(=O)c1ccccc1)CCN(CCN1CC2CCC(CC2)C1)C3
Temperature: 0 °C
Yield: 38.2 %

Procedure:
A mixture of 9-amino-3-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-8-methyl-5H-benzopyrano[3,4-c]pyridin-5-one (2.5 g, 0.007 moles), potassium carbonate (2.4 g, 0.017 moles), and benzoyl chloride (1.0 ml, 0.009 moles) is stirred in chloroform (50 ml) at room temperature. After 24 hours the mixture is poured into ice water. The layers are separated, and the aqueous phase is extracted with chloroform (2×60 ml). The combined organic extracts are washed with brine and dried (magnesium sulfate). The solvent is removed under reduced pressure to leave a syrup, which crystallized from ethyl acetate. Recrystallization gave the product (1.3 g), mp 174°-176° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:28]([N:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1)[CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCCCCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(n-hexyl)-N-methyl-aminomethyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=10:1) C31H35N3O3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[N:36]=[N:37][NH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:38]4[CH:39]=[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:36]=[N:37]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: c1ccc(-c2c[nH]nn2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(-c5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-phenyl-1H-1,2,3-triazole.
Reaction SMILES: [Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH:18]([OH:32])[CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=O)=[CH:23][CH:22]=4)[CH2:12]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[NH3:36]>CO>[Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH:18]([OH:32])[CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:36])=[O:30])=[CH:23][CH:22]=4)[CH2:12]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: N
Reactant: COC(=O)Cc1ccc(OCC(O)CN2CCCC(Cn3c(=O)[nH]c4cc(Cl)c(Cl)cc43)C2)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CN2CCCC(Cn3c(=O)[nH]c4cc(Cl)c(Cl)cc43)C2)cc1
Temperature: 110 °C
Yield: 25 %

Procedure:
A mixture of 11 parts of methyl 4-{3-[3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl)-1-piperidinyl]-2-hydroxypropoxy}benzeneacetate and 800 parts of methanol saturated with ammonia is stirred and heated in an autoclave at 110° C. and at a pressure of 85.7 lbs/sq. inch. The reaction mixture is cooled and evaporated. The residue is stirred in 4-methyl-2-pentanone. The product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone and a small amount of 2-propanol. The product is filtered off and dried, yielding 2.7 parts (25%) of 4-{3-[3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl)-1-piperidinyl]-2-hydroxypropoxy}benzeneacetamide; mp. 147.9° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([NH2:28])[CH:25]=[C:24]2[CH3:29].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([NH:28][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:25]=[C:24]2[CH3:29]
Reactant: Cc1cn(N)c2c(F)cccc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cccc(F)c21
Temperature: 50 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34 mmol) and 7-fluoro-3-methyl-indol-1-ylamine (342 mg, 1.47 mmol) in DMF (15 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (407 mg, 1.47 mmol) and stirred at 50° C. for 4 h. The mixture is concentrated in vacuo, diluted with Et2O (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-100% DCM in EtOAc to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (7-fluoro-3-methyl-indol-1-yl)-amide (241 mg, 48%). MS: 379 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.32 (d, 1H), 8.18 (d, 1H), 7.64 (m, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.31 (s, 1H), 7.05 (m, 2H), 2.74 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [Li][CH3:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]=[O:16].O>CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]([OH:16])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])ccc1CC(C)O
Temperature: -10 °C
Yield: 83.8 %

Procedure:
To a stirred −78° C. solution of TiCl4 (1.0 M in CH2Cl2, 1.43 mL, 1.43 mmol) in anhydrous Et2O (7 mL) was added MeLi (1.6 M in Et2O, 0.9 mL, 1.43 mmol) dropwise over a period of 20 min. The reaction mixture was allowed to slowly warm to −30° C. at which point a solution of 2-(2-methoxy-4-nitrophenyl)acetaldehyde (275 mg, 1.43 mmol) (prepared as described in PCT WO 2000/73288 A1) in anhydrous Et2O (0.750 mL) was added dropwise and allowed slowly warm to −10° C. The reaction mixture was poured into cold water and extracted with Et2O (3×50 mL). The combined ether extracts were washed with water (1×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford 0.253 g (85%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J=6.0 Hz, 3 H), 1.62 (br. s., 1 H), 2.81 (dd, J=13.2, 7.7 Hz, 1 H), 2.89-2.94 (m, 1 H), 3.93 (s, 3 H), 4.06-4.15 (m, 1 H), 7.32 (d, J=8.2 Hz, 1 H), 7.72 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=8.2, 2.2 Hz, 1 H); HPLC (Method #1): 2.68 min retention time, (89%); LCMS (ES): m/z 194 [M−H2O+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([N+:19]([O-])=O)=[C:17]([OH:22])[C:16]([Cl:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25].O>C(O)(=O)C.[Fe]>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:22])[C:16]([Cl:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2[N+](=O)[O-])c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Yield: 70.7 %

Procedure:
This compound was prepared in the manner of Step B of Example 1, using 1.5 grams (0.004 mole) 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 3.0 grams (0.054 mole) of iron dust, and 5 mL of water in 50 mL of glacial acetic acid, yielding 1.0 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7]O[C:5](=O)[CH:4]=1.[C:16]1(=[O:23])C=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>ClC1C=CC=CC=1Cl.C(Cl)(Cl)Cl.O=[Mn]=O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:20](=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[C:19](=[O:22])[CH:18]=[CH:17][C:16]2=[O:23]
Reactant: O=c1cc(C(F)(F)F)c(C(F)(F)F)co1
Reactant: O=C1C=CC(=O)C=C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=C1C=CC(=O)c2cc(C(F)(F)F)c(C(F)(F)F)cc21

Procedure:
23.47 g (0.1011 mol) of 4,5-bis-trifluoromethyl-2-oxo-2H-pyran, 54.62 g (0.5053 mol) of 1,4-benzoquinone and 26.30 g (0.3026 mol) of MnO2 in 225 ml of 1,2-dichlorobenzene are heated at 180° C. for 12 hours. The reaction mixture is then diluted with 200 ml of CHCl3 and filtered through Hyflo®. After the chloroform has been removed by distillation, the distillation residue is chromatographed over a column packed with 1300 g of SiO2 (mobile phase: first cyclohexane and then CHCl3 ; 0.3 bar excess pressure). Yield 17.94 g (60.3%), melting point: 91°-94° C.
Reaction SMILES: O[C@H:2]([CH3:40])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[O:26])=[CH:21]N=3)[CH:15]=[C:14]([O:34][C@@H:35]([CH3:39])[CH2:36][O:37][CH3:38])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+:54]>O1CCCC1>[CH3:38][O:37][CH2:36][C@H:35]([CH3:39])[O:34][C:14]1[CH:15]=[C:16]([CH:17]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH3:40])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:13]=1)[O:18][C:19]1[CH:24]=[N:23][C:22]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[CH:21][N:54]=1
Reactant: [NH4+]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
N-[(2R)-2-Hydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrole-2-carboxamide (447 mg, 0.81 mmol) synthesized in Example (131c) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (282 mg, 1.62 mmol) and triethylamine (0.34 mL, 2.43 mmol) were added, followed by stirring at 50° C. for 4 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out twice with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (279 mg, yield 65%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O>N>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 90 %

Procedure:
256 g of a 99% 1-nitro-anthraquinone are reacted in 2500 g of 35% aqueous ammonia solution at 190°-200° C for 4 hours in an autoclave. After release of pressure, the reaction product is isolated by removal of the water by distillation under vacuum and dried. Yield: 226 g of a 90% 1-amino-anthraquinone (91% of the theoretical yield) which contains 5 by weight, of 1-amino-anthraquinone imine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of the ester 25-4 (170 mg, 0.51 mmol), CH3OH (10 mL), and 1N NaOH (5 mL) was stirred for 20 hours at ambient temperature. The cooled reaction mixture was acidified with 1N HCl (5 mL) and extracted with EtOAc. The EtOAc portion was concentrated to give 25-5 as a gelataneous solid.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17])(=O)C.[OH-].[Na+].Cl>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[O:16][CH3:17]
Reactant: COc1c(OC(C)=O)ccc(C=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(O)ccc(C=O)c1[N+](=O)[O-]

Procedure:
10 g of compound 2 (0.042 mole) are added to a solution of 40 ml of sodium hydroxide 33% (m/m). The reaction mixture is heated at reflux for 10 minutes. The reaction mixture is diluted with 40 ml of water and acidified with concentrated hydrochloric acid (HCl 6N) to neutral pH. After cooling, the product is precipitated and compound 3 is isolated by vacuum filtration and by several washings with water (yield 85%-7.2 g of compound 3).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([N:21]([CH3:22])[CH3:20])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Product: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1.84 g of 1-acetyl-4-(4-fluorobenzoylmethyl)piperidine and 6 ml of a 50% aqueous solution of dimethylamine was stirred at room temperature for 3 days and the reaction mixture was worked up as in Example 1 to give 1.8 g of colorless crystals melting at 136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:4][N:3]=1.ClC1C=CC=[C:25]([C:29]([O:31]O)=[O:30])C=1>O1CCCC1>[C:29]([O:31][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:4][N:3]=1)(=[O:30])[CH3:25]
Reactant: Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 2-methyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (18.04 g), 3-chloroperbenzoic acid (18.85 g) and tetrahydrofuran (100 mL) was stirred overnight at room temperature and concentrated. The residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with tetrahydrofuran. A solution of the obtained colorless oil in acetic anhydride (100 mL) was slowly added to acetic anhydride (200 mL) heated to 130° C. and the mixture was stirred for 2 hrs. and concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and then with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl] acetate (18.09 g, yield 83%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].Cl>CN1C(=O)CCC1>[CH2:50]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH3:33]
Reactant: O=C(NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a mixture of 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid (400 g), potassium carbonate (192.5 g) in NMP (1460 ml) maintained at 20° C., was added dropwise 1-Bromo octadecane (425 g). The reaction mixture was allowed to slowly come to room temperature and further stirred for 24 hours. The reaction mixture was then poured onto ice water and the pH was adjusted to 7 with dilute HCl. The solid was filtered, dried and purified by column chromatography using hexane:ethyl acetate (95:5) as an eluant to yield pure 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid stearyl ester (430 g) as a white powder with a melting point of 56-59° C. The product was further characterized by IH NMR (CDCl3) δ 0.90 (t, 3H, CH3), 1.30 (m, 30H, 15×CH2), 1.60 (m, 2H, CH2), 3.05-3.25 (m, 2H, CH2), 4.20 (m, 2H, CH2), 4.65 (m, 1H, CH), 5.15 (m, 2H, CH2), 5.40 (d, 1H, NH), 7.30 (m, 54H, Ar), 7.45 (d, 2H, Ar), 8.15 (d, 2H, Ar)
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[C:26]1([CH:4]2[C:3](=[O:2])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1C(c2ccccc2)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester (100 mg, 0.24 mmol) (from Example 5b supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 60° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6,8-diphenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as a light brown solid. (Yield 61.2 mg, 66.2%). HRMS m/z Calcd for C25H20N4O [(M+H)+]: 393.1710. Found: 393.1714.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C)C=O.[H-].[Na+].CI>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH3:28])[C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)S/C(=C\c2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione (1.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.15 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.58 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (1.30 g, yield 98%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 226-227° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Br)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Br)cn1
Temperature: 210 °C
Yield: 87.2 %

Procedure:
Two capped microwave reaction vials each containing a solution of N-(5-bromo-4-chloropyridin-2-yl)pivalamide (0.55 g, 1.89 mmol), benzyl 4-(aminomethyl)piperidine-1-carboxylate (1.07 g, 2 eq.) and triethylamine (0.80 mL, 3 eq.) in NMP (3.8 mL) were heated at 210° C. by microwave irradiation for 1.5 hr and then allowed to cool. The contents of the two vials were combined and partitioned between EtOAc (15 mL) and sat. NaHCO3 (150 mL). The organic layer was retained whilst the aqueous was further extracted with EtOAc (15 mL). The organic extracts were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The crude material was purified by chromatography on a 40+M Biotage silica column, eluting with a gradient of EtOAc in dichloromethane, to give the title compound as a clear oil (0.83 g, 43%)