Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9]([O:11]CC)=O)[CH2:2]2.[OH-].[K+].Cl.Cl.[O:18]([NH2:20])[CH3:19].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(#N)C.C(Cl)(Cl)Cl>[N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9]([NH:20][O:18][CH3:19])=[O:11])[CH2:2]2
Reactant: CCOC(=O)C1=CC2CCN(C1)C2
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CONC(=O)C1=CC2CCN(C1)C2
Temperature: -30 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A solution of (±) ethyl 1-azabicyclo[3.2.1]-oct-3-en-3-ylcarboxylate (D6) (0.52 g, 2.9 mmole) in ethanol (6 ml) was treated with 85% potassium hydroxide (0.38 g, 5.7 mmole) then heated under reflux for 9h. The reaction mixture was concentrated in vacuo, treated with 5N hydrochloric acid (1.72 ml, 8.6 mole) then concentrated in vacuo and co-distilled with toluene to remove the last traces of water. The residue was treated with thionyl chloride (10 ml), heated at reflux under nitrogen for 25 minutes then concentrated in vacuo and co-distilled with toluene to afford the crude acid chloride. A solution of this material in a mixture of dry acetonitrile (12 ml) and dry chloroform (10 ml), under nitrogen, was treated with methoxylamine hydrochloride (0.48 g, 5.8 mmole) then cooled to -30° C. and treated in a single rapid addition with pyridine (1.09 g, 29 mmole) in acetonitrile (2 ml). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. It was then treated with saturated aqueous potassium carbonate (25 ml), the organic phase was separated, and the aqueous phase extracted with chloroform (8×25 ml). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on neutral alumina in a gradient of 0-10% methanol in chloroform to afford the title compound (D7) as a brown gum (0.17 g, 34%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=O)[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:16].S(=O)(=O)(O)O>>[Cl:16][C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=1
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: Clc1cnc(-c2ccccc2)cn1

Procedure:
A mixture of 0.01 mol. of 5-phenylpyrazin-2(1H)one 8.0 ml. of POCl3 and a drop of concentrated sulfuric acid is refluxed for 4-5 hr. The solution is poured into 100 g. of ice. The title compound is isolated by filtration and recrystallized.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(=O)OCC>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (1226 mg, 3.43 mmol) in THF (15 mL) was added n-BuLi (2.145 mL, 3.43 mmol), stirred for 10 min. then 3-fluoro-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (0.691 mL, 3.12 mmol) was added. The mixture was stirred at 0° C. for 1 h, then at room temperature for another 2 h. The reaction mixture was diluted with EA, washed with water, brine (50 mL), and concentrated. The residue was purified via flash chromatography to afford the title compound (449 mg, 49.8% yield) as colorless oil. LCMS: rt=3.13 min
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[CH:13]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:11]=2)=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:30])[C:10]2[CH:11]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:13]=[C:14]([OH:16])[CH:15]=2)=[N:3]1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cc(C)n(C)n2)c1
Agent: [Pd]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cc(C)n(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide (2.57 mmol) in ethanol (40 mL), under argon was treated with 10% palladium on carbon (100 mg, wetted with 0.1 mL water and 1 mL ethanol). The flask was evacuated and filled with hydrogen, this procedure was repeated 4 times. The mixture was left to stir at RT overnight under an atmosphere of hydrogen then the reaction filtered through Celite® and the cake washed with ethanol (50 mL) and ethyl acetate (50 mL). The combined organic layers were evaporated in vacuo to give the desired compound as a white foam (597 mg). 1H NMR δ (d6-DMSO): 1.23 (d, 3H), 2.25 (s, 3H), 3.31 (s, 3H), 3.47 (m, 2H), 3.66 (s, 3H), 4.66 (m, 1H), 6.40 (s, 1H), 6.46 (t, 1H), 6.95 (t, 1H), 7.06 (t, 1H), 9.60 (s, 1H), 10.49 (s, 1H); m/z 320 (M+H)+
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15])[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1C=CC=CC=1>[CH2:14]([O:13][P:12]([Cl:27])([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]2[C:1]1=[O:25])=[O:16])[CH3:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCC
Solvent: c1ccccc1
Product: CCOP(=O)(Cl)CCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of (6-phthalimidohexyl)phosphonic acid, diethyl ester, benzene, and phosphorus pentachloride is refluxed according to the procedure of Example 1(f) to give ethoxy(6-phthalimidohexyl)phosphinyl chloride.
Reaction SMILES: C[O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.C(Cl)(=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([C:3](=[O:2])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:36])([CH3:38])[CH3:37]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
A solution containing amine 50 (258 mg, 0.5 mmol) in DCM (8 mL) was cooled to 0° C. TEA (73 mg, 0.72 mmol) was added followed by benzoyl chloride (85 mg, 0.61 mmol) and the reaction mixture was warmed to ambient temperature. After 20 min, the reaction mixture was diluted with DCM and the resulting organic solution was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (hexanes/EtOAc, 1:1) to afford 278 mg (94%) of 55 as an off-white-colored foam. Mass spectrum, m/z [589.4] (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCCO
Solvent: O
Product: OCCCNc1ccnc2cc(Cl)ccc12
Temperature: 135 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
A mixture of 4,7-dichloroquinoline (25.35 g, 0.128 mol) and 3-aminopropanol (120 mL, 1.57 mol) were heated with stirring at 130-140° C. for 24 hours. After cooling, the reaction mixture was poured into water (500 mL) and filtered, and the solid residue was dried then boiled in ethyl acetate (250 mL) to give the title compound (27.3 g, 90%) as an off-white solid.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:40].C(OCC)(=O)C>>[ClH:40].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)c1cccc2ccccc12

Procedure:
The thus obtained 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid was subjected to Boc-elimination with 4 M hydrogen chloride/ethyl acetate to obtain 4-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid hydrochloride.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Cl>CN(C)C=O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH3:10]
Reactant: CCOC(=O)CN
Reactant: CCOC(CBr)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNCC(OCC)OCC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a suspension of the glycine ethyl ester hydrochloride (1.00 g) and bromoacetaldehyde diethyl acetal (1.08 ml) in N,N-dimethylformamide (30 ml), were added cesium carbonate (4.67 g) and sodium iodide (107 mg) and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was adjusted to pH 2 with 1N hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 11 with 1N aqueous solution of sodium hydroxide and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure to obtain the title compound (860 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:15][C:13]3[O:14][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[O:3][C:2]([F:1])([F:17])[F:18])=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: O=Cc1ccc(-c2ccccc2OC(F)(F)F)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccc4OC(F)(F)F)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]4[N:35]([CH2:45][CH3:46])[C:36]5[C:41]([CH:42]=4)=[C:40]([O:43][CH3:44])[CH:39]=[CH:38][CH:37]=5)=[O:33])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH2:45]([N:35]1[C:36]2[C:41](=[C:40]([O:43][CH3:44])[CH:39]=[CH:38][CH:37]=2)[CH:42]=[C:34]1[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C@H:14]3[CH2:13][CH2:12][C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][CH2:15]3)=[O:18])[CH2:20][CH2:21]2)=[N:26][CH:27]=1)=[O:33])[CH3:46]
Reactant: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)[C@H]4CC[C@H](C(=O)OCc5ccccc5)CC4)CC3)nc2)cc2c(OC)cccc21
Agent: [Pd]
Solvent: CO
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)[C@H]4CC[C@H](C(=O)O)CC4)CC3)nc2)cc2c(OC)cccc21
Reaction time: 2 h

Procedure:
A mixture of trans-4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (30 mg, 0.05 mmol), 10% Pd/C (50 mg) in methanol (20 mL) was hydrogenated at 50 psi for 2 hr. The solution was filtered and the solvent was removed to afford the product, trans-4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexane carboxylic acid, as a green solid (10 mg, 40% yield). LCMS for C29H35N5O5 calcd. (m/e) 533, observed 534 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH2:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=2)=[C:12]([Cl:28])[CH:11]=1)C.C(CC(NC(OCC)=O)=O)#N>>[Cl:28][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[CH2:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Cc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CCOC(=O)NC(=O)CC#N
Product: CC(C)c1cc(Cc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Yield: 39 %

Procedure:
This compound was prepared by a similar method to that described in Example 8, Step 2 except that (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (47) was used in place of 2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (30) to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (48) as an off-white solid (1.21 g, 39%); EI(+)-HRMS m/z calcd for C18H14Cl2N6O3 (M+H)1+ 433.0577, found 433.0577. Molecular Weight=433.2567; Exact Mass=432.0504
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH2:27][C:26]2=[O:42])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH:40]=[O:41])=[CH:38][CH:39]=3)(=[O:32])=[O:33])[CH2:27][C:26]2=[O:42])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CO)cc3)CC2=O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C=O)cc3)CC2=O)CC1
Temperature: -65 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
To a solution of oxalyl chloride (0.70 ml) in dichloromethane (60 ml) was added dropwise at −70° C. a solution of dimethylsulfoxide (0.85 ml) in dichloromethane (10 ml). Ten minutes later, to the mixture was added dropwise a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-(hydroxymethyl)benzenesulfonyl]-2-piperazinone (1.87 g) in dichloromethane (20 ml), and the mixture was stirred at about −65° C. for 1 hour. To the mixture was added triethylamine (2.79 ml), and the mixture was stirred at −60° C. to −30° C. for 2 hours. The reaction solution was diluted with dichloromethane, washed with water and saturated brine, dried and concentrated, and the the residue was purified with silica gel column chromatography (ethyl acetate). Precipitated crystals were washed with ether to give colorless crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-formylbenzenesulfonyl]-2-piperazinone (2.02 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]2=[O:34])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]5[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]5=[O:34])[CH:23]=[CH:24][CH:25]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(C5C(=O)N(C)CCN5C)c4)nn23)cn1

Procedure:
3-{3-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a brown foam (56 mg, 42%). LCMS (m/e) 444 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.80-8.74 (m, 1H), 8.69 (s, 1H), 8.43 (dd, 1H, J=2.2 and 8.7 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.51 (s, 1H), 7.35-7.27 (m, 1H), 7.06 (d, 1H, J=7.6 Hz), 6.96-6.89 (m, 2H), 6.87 (d, 1H, J=8.7 Hz), 6.82 (d, 1H, J=4.78 Hz), 4.01 (s, 3H), 3.75-3.63 (m, 2H), 3.25-3.16 (m, 1H), 3.07-2.96 (m, 1H), 2.98 (s, 3H), 2.74-2.63 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C=O)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26]2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CC1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(C)C2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 56.5 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.100 g; 0.300 mmol), 3-methylpiperidine (0.106 mL; 0.901 mmol) and triethylamine (0.211 mL; 1.50 mmol) in a mixture of tetrahydrofuran (2 mL) and DMF (0.4 mL) was heated at 110° C. in a sealed tube for 18 h. After cooling, the reaction mixture was diluted in a saturated solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.067 g (57%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.[OH:38][CH:39]([C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44])[CH3:40]>CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]=[C:13]([NH:44][C:43]4[CH:45]=[CH:46][CH:47]=[C:41]([CH:39]([OH:38])[CH3:40])[CH:42]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1
Reactant: CC(O)c1cccc(N)c1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc(NC(=O)c3cccc(C(F)(F)F)c3)c2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(Nc2ncc3cc(-c4c(Cl)ccc(NC(=O)c5cccc(C(F)(F)F)c5)c4Cl)c(=O)n(C)c3n2)c1
Temperature: 120 °C

Procedure:
A mixture of N-[2,4-dichloro-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-phenyl]-3-trifluoromethyl-benzamide (20 mg, 0.035 mmol) and 3-(1-hydroxyethyl)-aniline (50 mg, 0.364 mmol) is heated at 120° C. for ten minutes. The mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by prep-HPLC to give N-(2,4-dichloro-3-{2-[3-(1-hydroxy-ethyl)-phenylamino]-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide as a white solid. (17.9 mg, 81.4%). 1H NMR (CD3OD): δ 10.50 (s, 1H), 8.57 (d, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.86 (d, 1H), 7.68 (t, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.52 (d, 1H), 7.41 (t, 1H), 7.21 (s, 1H), 7.20 (d, 1H), 4.98 (q, 1H), 3.83 (s, 3H), 1.54 (d, 2H); MS m/z 629.10 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.[CH3:22][O-:23].[Na+]>COCCOCCO>[CH3:22][O:23][CH2:4][CH2:3][O:2][CH2:1][CH2:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOCCO
Product: CCCCCCCCCCOc1ccc(C(=O)OCCOCCOC)cc1

Procedure:
A mixture of 25 g (0.09 mol) of p-decyloxybenzoic acid methyl ester and 100 ml of diethylene glycol monomethyl ether was heated for 6 hours to 150° C. with a spatula tip of sodium methanolate. After the excess diethylene glycol monomethyl ether had been distilled off, the residue was taken up in methylene chloride, the solution was washed with water, treated with active carbon and concentrated by evaporation. 24.5 g (72%) of slightly contaminated p-decyloxybenzoic acid 2-(2-methoxyethoxy)-ethyl ester were obtained. Purification by column chromatography (SiO2, Merck/methylene chloride+5% of methanol) produced pure ester having a refractive index nD20 of 1.4945.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][CH:5]([CH2:10][C:11]2[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([OH:18])[CH:14]=[C:15]([OH:17])[CH:16]=2)[O:4]1.[Cl:25]([O-])=O.[Na+].S(=O)(=O)(O)N.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][CH:5]([CH2:10][C:11]2[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([OH:18])[CH:14]=[C:15]([OH:17])[C:16]=2[Cl:25])[O:4]1
Reactant: OC[C@H]1OC(Cc2cc(O)cc(O)c2-c2ccccc2)O[C@@H]1CO
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: OC[C@H]1OC(Cc2c(Cl)c(O)cc(O)c2-c2ccccc2)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
Compound 230 (79.6 mg, 0.240 mmol) obtained in Example 230 was dissolved in tetrahydrofuran (10 mL), and sodium chlorite (48.7 mg, 0.538 mmol) and sulfamic acid (102 mg, 1.05 mmol) were added thereto and stirred at room temperature for 2 hours. Aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium thiosulfate were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (chloroform/methanol/water=100/10/1) to obtain Compound 280 (22.7 mg, 26%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[NH2:37][C:23]1[N:24]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:34]3)=[CH:29][CH:28]=2)[CH:26]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[N:22]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(C#N)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from (4-cyanophenyl)acetic acid (Aldrich, Cat. #633453) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=468.1.