Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH3:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:15]([C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:28])[N:24]=2)[NH:19][CH:18]=1)=[O:16].[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[N:35]=1.O>O1CCCC1.C(OCC)(=O)C>[Br:33][C:34]1[N:35]=[C:36]([CH2:40][N:19]2[C:20]3[C:25](=[N:24][C:23]([CH3:28])=[CH:22][CH:21]=3)[C:26](=[O:27])[C:17]([C:15](=[O:16])[C:14]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:12]([CH3:11])[CH:13]=3)=[CH:18]2)[CH:37]=[CH:38][CH:39]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc2[nH]cc(C(=O)c3ccc(C)c(C)c3)c(=O)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(n1)c(=O)c(C(=O)c1ccc(C)c(C)c1)cn2Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium hexamethyldisilazane (0.49 mL, 0.246 mmol, 0.5 M in THF) was added to a solution of 3-(3,4-Dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one (60 mg, 0.205) in 2 mL of tetrahydrofuran. After the reaction was stirred at room temperature for 20 minutes 2-bromo-6-bromomethyl-pyridine (61.8 mg, 0.246 mmol) was added and stirred overnight at room temperature. Water and ethyl acetate were added and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude brown solid was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]: 462.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.3 min.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1>C(OCC)C>[CH2:1]([C:8]1[C:13]([C:38]2([OH:41])[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CO[C@@H]1CN(c2ccc(C3(O)CCN(C)CC3)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a mixture of 500 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 10 ml of diethyl ether was added dropwise 1.99 ml of a 2.45 M hexane solution of n-butyllithium at −78° C. After stirring at the same temperature for 30 minutes, a solution of 552 mg of 1-methyl-4-piperidone in 3 ml of diethyl ether was added dropwise thereto. After stirring at the same temperature for 30 minutes, the temperature was elevated to room temperature. The organic layer was separated by adding water and ethyl acetate to the reaction mixture, and then it was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was purified by NH-silica gel column chromatography with 5% methanol/ethyl acetate, to give 125 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:29][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: Clc1ccc(N2CCN(CCCc3[nH]nc4c3CCCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 5 and 1-(4-chlorophenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazol is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=N/C(C(C)C)C(C)C)[CH3:2].[OH-:20].[Na+]>C1COCC1.Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]=[O:20])[CH3:2]
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(OC)c1C=O
Temperature: 25 °C

Procedure:
A solution of 1.0 g (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine in 1 ml THF and 0.19 ml 4N HCl was heated to reflux for 1 hour then cooled to ambient temperature and poured onto a 1N aqueous NaOH solution. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with a heptane/ethyl acetate gradient as eluent: 0.50 g 2-ethyl-6-methoxy-benzaldehyde as colourless oil: MS (EI): 261.2 (M+.), 218.2 ((M-((CH3)2CH))+., 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>>[CH2:19]([C:10]1[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][C:6](=[O:22])[N:5]2[CH2:4][CH2:3][CH2:2][N:26]1[CH:25]=[N:24][N:23]=[CH:27]1)[CH:20]=[CH2:21]
Reactant: c1nc[nH]n1
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCl
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCn1cnnc1

Procedure:
1-(3-Chloropropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and 1H-1,2,4-triazole were reacted and treated similarly as in Example 71, there was obtained 5,7-diallyl-3,4-dihydro-6-hydroxy-1-[3-(1,2,4-triazol-4-yl)propyl]-2(1H)-quinolinone.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)=[O:2].[CH2:26]([Mg]Cl)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.Cl>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]([OH:2])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1)[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:19]
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(C=O)cc1)S(C)(=O)=O
Reactant: Cl[Mg]CCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCCCCCN(Cc1ccc(C(O)CCc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.6 %

Procedure:
A solution of ethyl 7-[(4-formyl-benzyl)-methanesulfonyl-amino]-heptanoate (200 mg, 0.54 mmol) in CH2Cl2 (2.5 mL) was cooled to 0° C. Phenethylmagnesium chloride (0.6 mL, 1M in THF, 0.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Water and HCl (1N) were added and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (10% EtOAc/hex to 40% EtOAc/hex) to afford the title compound of Step A (40 mg). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.45 (d, 1H), 7.13–7.40 (m, 7H), 4.65–4.73 (m, 1H), 4.32–4.46 (m, 2H), 4.11 (q, 2H), 3.25–3.35 (m, 1H), 3.00–3.22 (m, 2H), 2.83 (s, 3H), 2.60–2.81 (m, 1H), 1.96–2.34 (m, 4H), 1.15–1.70 (m, 12H); MS 493 (M+18).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: C1CCNCC1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCN1CCCCC1)\c1nc2ccccc2o1
Yield: 42 %

Procedure:
The title compound was prepared as described in Example 5 starting with (D) of Example 5 (2.5 g, 7.6 mmmol) and using piperidine in place of dibutylamine to produce 1.2 g (42% yield) of the title compound as the HCl salt, mp 230°-232° C. IR(KBr): 1600 cm−1. MS: 377(MH+). 1H NMR (DMSO): δ 7.91-6.95 (m, 10H), 3.99 (t, J=5.2 Hz, 2H), 3.10 (m, 6H), 1.75 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.[H-].[Na+].CC(N(C)C)=O.C([Li])CCC>O1CCCC1>[CH3:38][N:14]1[C:15]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]2[N:4]=[CH:3][CH:2]=[CH:7][N:6]=2)=[N:13]1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncccn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 5.8 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]4-(tert-butyl)benzenesulfonamide (Example 3, 100 mg) in anhydrous tetrahydrofuran (2 ml) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 18 mg), followed by dimethyl acetamide (0.5 ml). The mixture was cooled to −78° C. and n-butyl lithium (1.6M in hexanes, 0.1 ml) was added dropwise under an atmosphere of nitrogen. The yellow solution was allowed to stir at −78° C. for 20 minutes. 1.25 ml of this solution was withdrawn by syringe and added dropwise to a mixture of ether (10 m) and water (10 ml). The aqueous layer was extracted with ether (3×10 ml). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (2:1) to yield the title compound as a white solid (5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][C:17](I)=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([NH2:15])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: NC(=O)c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (51 mg, 0.07 mmol), copper (I) iodide (28 mg, 0.15 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.82 mmol) to a solution of 2-fluoro-5-iodobenzamide, (prepared as described in PREPARATION 44), (0.482 g, 1.82 mmol) in triethylamine (7 mL, 53 mmol) and heat at 70° C. After 10 minutes, add toluene (10 mL) to the solidified reaction mixture, heat at 70° C. for 1 h, cool to room temperature and stir overnight. Concentrate and purify the residue by silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes, to give the title compound as a white solid (260 mg, 32%).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.C([Li])CCC.[I:19]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[I:19][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:11]=[CH:10][N:9]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1ccnc1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1I
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 34.3 %

Procedure:
A solution of Example 191E (1.50 g, 7.56 mmol) in dry tetrahydrofuran (38 mL) at −40° C. was treated dropwise with a solution of n-butyllithium in hexanes (2.5 M, 3.93 mL, 9.83 mmol). After addition of the n-butyllithium, the solution took on a distinct light orange color. The solution was stirred at −40° C. for 45 minutes, followed by dropwise addition of a solution of iodine (2.69 g, 10.59 mmol) in dry tetrahydrofuran (18 mL) followed by warming to room temperature for 20 minutes. The solution was treated with water and with vigorous stirring, solid sodium sulfite was added to discharge the iodine color. The mixture was diluted with ethyl acetate and extracted with water and saturated sodium chloride solution. Drying (Na2SO4), filtration, and concentration in vacuo afforded an oil, which was chromatographed over a 220 g silica gel cartridge, eluting with 0-20% acetonitrile in chloroform. These procedures afforded the title compound (840 mg, 34%) as a colorless oil that crystallized upon pumping under high vacuum. MS (ESI+) m/z (rel abundance) 325 (100, M+H)+, 326 (12).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(=S)=S>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:23]1[CH:24]=[CH:25][C:20]([C:13]([CH3:12])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:21][CH:22]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To 700 ml of carbon disulfide containing 36.5 g (0.254 mole) of 4-chlorobutyryl chloride is added 74.5 g (0.56 mole) of aluminum chloride with stirring in an ice bath (about -10° C.). Stirring is continued for about 15 minutes at about 25° C. then the mixture is recooled to 5° C. and 48.4 g (0.294 mole) of ethyl α,α-dimethylphenylacetate in 100 ml of carbon disulfide is added. The reaction mixture is stirred on an ice bath for 31/2 hours then stirred for 151/2 hours at 25° C. then poured into HCl-ice water and extracted with chloroform. The extract is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated giving as a solid ethyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.Cl.[CH2:34]([N:36]([CH:39](C)C(O)=O)[CH2:37][CH3:38])[CH3:35]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:3](=[O:5])[CH2:2][CH2:39][N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCN(CC)C(C)C(=O)O
Agent: Cl
Product: CCN(CC)CCC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and diethylaminopropionic acid hydrochloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-3-diethylamino-propan-1-one. MS (M+H)+: 473.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH2:11][C:12]1([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:26])[NH:13]1)C1C=CC=CC=1.N#N>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10](=[O:31])[CH2:11][C:12]1([CH2:27][CH:28]([CH3:29])[CH3:30])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:26])[NH:13]1
Reactant: CC(C)CC1(CC(=O)NOCc2ccccc2)NC(=O)N(CCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CC1(CC(=O)NO)NC(=O)N(CCc2ccccc2)C1=O
Reaction time: 2.5 h
Yield: 104.5 %

Procedure:
A solution of N-benzyloxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide (85.0 mg, 0.201 mmol) in 25% MeOH/EtOAc is purged with N2, treated with palladium hydroxide on carbon (17 mg, 20% by weight), and placed under a H2 atmosphere (balloon). After 2.5 hours, the reaction mixture is filtered through celite and concentrated under reduced pressure to yield 70 mg of an off-white foam. The material is recrystallized from hot EtOAc/hexane to give 36 mg (54%) of the title compound as a white, powdery solid (mp 145°-147° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[K+].[C:26]1([CH:32]=[CH:33][S:34]([NH-:37])(=[O:36])=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)C>CS(C)=O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:37][S:34]([CH:33]=[CH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:35])=[O:36])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: [NH-]S(=O)(=O)C=Cc1ccccc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.6 %

Procedure:
To 4,6-dichloro-5-p-tolyl-pyrimidine (2.0 g) disolved in DMSO (35 ml) was added di-isopropyl-ethyl-amine (1.46 ml) followed by 2-phenyl-ethenesulfonamide potassium salt (2.78 g). The mixture was stirred for 48 h at rt then poured onto water (500 ml) and diethylether (250 ml) was added and the solution was stirred for 30 minutes. The layers were separated and the water layer was acidified with acetic acid (2.0 ml) and cooled to 0° C. for 1 h. The precipitated product was filtered off and washed with water and diethylether and dried to give 2-phenyl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (2.02 g). tR=5.32 (LC); M+=386.23 (ES+); M−=384.22 (ES−).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:8].O1CCCC1.ICCC>CCCCCC>[CH3:8][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH2:1][CH2:2][CH3:3])[CH3:6]
Reactant: [Li]CCCC
Reactant: COc1cccc(CN(C)C)c1
Solvent: CCCCCC
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCc1c(CN(C)C)cccc1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere, 420 ml. of a 1.6 M solution of n-butyllithium in hexane were slowly added to a solution of 105.6 g. of N,N-dimethyl-3-methoxybenzylamine in 1000 ml. of tetrahydrofuran by means of an addition funnel, keeping the temperature below 0° C. with an external ice/ethanol bath. After the addition was completed, the reaction was stirred at 0° C. for four hours. At this time, 68.3 ml. of 1-iodopropane were added dropwise to the solution keeping the temperature below 10° C. The reaction was stirred for one hour. The cooling bath was removed and the reaction was stirred an additional two hours. The reaction was then heated to reflux for about 16 hours. The reaction solution was concentrated in vacuo and the residue was taken up in diethyl ether. The ether solution was first washed with an aqueous sodium hydroxide solution and then with water. The ether layer was dried over sodium sulfate and the solvent was removed in vacuo. The residue was vacuum distilled at 3 torr. The fraction collected between 105° and 115° C. provided 104.3 g. of the desired title intermediate. NMR, IR.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([OH:10])([CH3:9])[CH3:8])(=[O:3])[CH3:2].[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][C:7]([O:10][C:11](=[O:15])[C:12]([O:10][C:7]([CH3:8])([CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[CH3:6])=[O:13])([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)OCCC(C)(C)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)(C)OC(=O)C(=O)OC(C)(C)CCOC(C)=O
Reaction time: 8 h

Procedure:
To a solution of compound (71) (0.322 g, 2.2 mmol) in 10 mL pyridine, oxalyl chloride (0.127 g, 1 mmol) was added slowly and the solution was stirred overnight. 20 mL of ethyl acetate was then added and was washed with 10% ammonium chloride (3×20 mL) followed by brine (1×20 mL). The organic layer was then dried over sodium sulfate, evaporated to dryness and the crude product was collected as an oily, white solid. (0.130 g) 1H NMR (400 MHz, CDCl3): δ 1.57 (s, 12H), 2.04 (s, 6H), 2.19 (t, J=6.8, 4H), 4.20-4.24 (t, J=6.9, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:20][O:21]C(Cl)Cl>ClCCCl>[CH:20]([C:5]1[CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:2]([CH3:1])[CH:6]=1)=[O:21]
Reactant: CCOC(=O)c1cccn1C
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C=O)cn1C
Temperature: -30 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethyl 1-methyl-1H-pyrrole-2-carboxylate (3.69 g, 28.24 mmol; see step (ii) above) and AlCl3 (8.02 g, 60.11 mmol) were added to a solution of nitromethane (40 mL), and 1,2-dichloroethane (40 mL) at −30° C. Dichloromethyl methyl ether (2.5 mL, 28 mmol) in 1,2-dichloroethane (10 mL) was added rapidly to the solution and the mixture was allowed to stir at −30° C. for 16 h. The solution was then poured onto ice (50 g) and the layers were separated. The aqueous layer was then extracted with ether (50 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed under reduced pressure, to yield the title compound as a crystalline brown/black solid (4.77 g, 94%).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:7][CH:6]=1)[CH3:2].O=S(Cl)[Cl:28]>C(Cl)Cl>[Cl:28][CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)[C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[O:23])=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc3cccnc23)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound II (2.0 g, 6.6 mmol) was dissolved in dry CH2Cl2 (25 mL) and SOCl2 (0.53 mL, 7.3 mmol) was added. The solution was stirred at 25° C. for 30 min and the solvent was evaporated in vacuo. Compound III was obtained as an oil (˜100%) and used in the next reaction without further purification.