Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].[NH3:23]>C(Cl)Cl.C(O)C>[NH2:23][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13]
Reactant: N
Reactant: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Solvent: CCO
Solvent: ClCCl
Product: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 g (10 mmol) of the intermediate from Step B were suspended in 40 ml CH2Cl2. 50 ml of a 2M solution of NH3 in ethanol were added and the reaction mixture was stirred for 16 h at ambient temperature. The mixture was poured into an ice/water mixture and the precipitate was separated. The precipitate was redissolved in ethyl acetate. This organic phase was washed with 2M aqueous HCl. The aqueous phase was made alkaline (pH=8-9) and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to yield 1.7 g of the intermediate.
Reaction SMILES: [N:1]1([C:10](=[O:26])/[CH:11]=[CH:12]/[C@@H:13]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[N:1]1([C:10](=[O:26])/[CH:11]=[CH:12]/[C@@H:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a solution of 1,1-dimethylethyl [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]carbamate (3.21 g, 8.95 mmol) in CH2Cl2 (10.0 mL) was added TFA (10 mL, 130 mmol). The reaction mixture was stirred for 17.5 h at RT and then concentrated under reduced pressure and dried under high vacuum to afford the title compound. LC-MS m/z 259 (M+H)+, 0.76 min (ret time).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19].O>C(Cl)Cl>[CH3:15][O:16][CH2:17][C:18]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=[O:19]
Reactant: COCC(=O)Cl
Reactant: NCc1nccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)NCc1nccs1
Reaction time: 0.25 h
Yield: 102 %

Procedure:
To a solution of 342 mg (3.0 mmol) of 2-aminomethylthiazole and 0.50 ml (3.6 mmol) of triethylamine in 5 ml of methylene chloride was added dropwise with ice-cooling a solution of 390 mg (3.6 mmol) of methoxyacetyl chloride in 2 ml of methylene chloride, and the mixture was stirred at the temperature for 15 minutes. To this was added 2 ml of water, and the mixture was stirred for 5 minutes. The organic layer was separated, and the aqueous layer was extracted two times with methylene chloride. The combined organic layers were washed with a small amount of a50% aqueous solution of potassium carbonate, dried over anhydrous potassium carbonate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 570 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[I-:19].[K+].C1(C)C=CC=CC=1.Cl>CN(C)P(N(C)C)(N(C)C)=O.[Cu]I>[I:19][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: [I-]
Reactant: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CCN(c2cccc3cc(I)cnc23)CC1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1)(1.75 g, 5.7 mmol), copper (I) iodide (5.4 g, 28.5 mmol) and potassium iodide (9.6 g, 57.8 mmol) in hexamethylphosphoramide (20 ml) was heated in an oil bath at 150° C. for 21 h under argon. To the cooled reaction mixture was added toluene (120 ml) and 1M hydrochloric acid (120 ml) and the whole was shaken vigorously for 5 minutes. The insoluble brown solid was then collected by filtration, washed with methanol (3×40 ml) and resuspended in a mixture of dichloromethane (150 ml) and 2M sodium hydroxide (150 ml). After shaking the mixture vigorously, the insoluble material was filtered, washed with dichloromethane (2×50 ml) and discarded. The filtrate and washings were transferred to a separating funnel and the layers were separated. The aqueous phase was extracted with dichloromethane (2×100 ml) and the combined organic extracts were dried (MgSO4) and concentrated to a brown oil (1.5 g) which was identified by NMR spectroscopy as a mixture of the title compound (D2) and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) in a ratio of 4:1. This mixture was used directly in the next stage (see Example 1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10]C(C)([O-])C.[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:5][C:23]1([CH3:10])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C(C)Br
Reactant: O=Cc1ccccc1Br
Agent: [K+]
Product: CCOC(=O)CC1(C)OC1c1ccccc1Br
Temperature: 25 °C
Yield: 69 %

Procedure:
A 50 g (0.27 mole) sample of 2-bromobenzaldehyde was added to 33.3 g of dry potassium t-butoxide under N2 at -78°. A 48.9 g (0.27 mole) sample of ethyl 2-bromopropionate was added slowly with stirring. The mixture was allowed to warm to room temperature and stir for 18 hr. The mixture was partitioned between ether and dilute HCl. The ether was washed with brine, dried (MgSO4) and the solvent evaporated in vacuo. The residue was distilled under vacuum to give 53.2 g (69% yield) of ethyl 3-(2-bromophenyl)-2-methyloxiraneacetate as an oil, bp 110°-120° C., 0.005 mm/Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][NH2:12].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][NH:12][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NNc1cc([N+](=O)[O-])ccc1Cl
Yield: 77.5 %

Procedure:
To a solution of 2-chloro-5-nitrophenylhydrazine (37.60 g) in dichloromethane (200 ml), triethylamine (22.27 g) and pivaloyl chloride (26.59 g) were added, and the resultant mixture was stirred at room temperature for 12 hours. The reaction mixture was combined with water. The dichloromethane layer was washed with water, dried and concentrated under reduced pressure to give 1-(2-chloro-5-nitrophenyl)-2-(2,2-dimethylpropionyl)hydrazine (42.23 g). m.p., 153.3° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][CH:18]1CCCC[CH2:19]1)=[O:16].NC1C=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:31][C:27]1[N:26]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:19]=[N:29][CH:28]=1
Reactant: CN1C(C(=O)NC2CCCCC2)=C(O)c2ccccc2S1(=O)=O
Reactant: Nc1cncc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from 4-hydroxy-2-methyl-N-cyclohexyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22].O>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:22])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A thin slurry of 4-hydroxypiperidine (50 g, 494 mmol) in THF (200 ml) was added to a stirred suspension of potassium tert-butoxide (110.9 g, 990 mmol) in THF (650 ml) at room temperature and washed in with THF (50 ml). The resultant mixture was stirred under nitrogen for 20 minutes. 1,2-Dichloro-4-fluorobenzene (98 g, 594 mmol) was added and the resultant mixture heated at reflux for 90 minutes. The reaction mixture was cooled to room temperature and water (500 ml) added. The layers were separated and the solvent removed from the organic fraction. The material was then partitioned between MTBE and 10% aqueous citric acid solution. The layers separated and the aqueous layer washed with further MTBE (2×250 ml). The aqueous phase was basified to pH>10 by addition of 10N NaOH solution and the product extracted with iso-propyl acetate (2×30 ml). The organics were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step (109.1 g, 90%).
Reaction SMILES: C([N-][CH:5]([CH3:7])C)(C)C.[Li+].[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl-].[NH4+]>O1CCCC1>[C:18]([C:17]([C:14]1[CH:15]=[N:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)([CH2:21][C:22]([O:24][CH2:5][CH3:7])=[O:23])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:19]
Reactant: CCOC(=O)CBr
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(CC#N)cn1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
10.12 ml (20.25 mmol) of lithium diisopropylamide are introduced in 22 ml of anhydrous tetrahydrofuran in a 100 ml three-necked round-bottomed flask under an argon atmosphere at −78° C. 1.00 g (6.75 mmol) of (6-methoxypyridin-3-yl)acetonitrile (WO2004/111031) in solution of 5 ml of anhydrous tetrahydrofuran is added. The reaction mixture is subsequently brought back gently to 0° C. and stirred at this temperature for one hour. The reaction medium is then cooled to −78° C. and 2.25 ml (20.25 mmol) of ethyl bromoacetate are added dropwise. The resulting mixture is subsequently brought back slowly to ambient temperature and then left stirring for 12 hours. The reaction medium is subsequently poured into a saturated aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate in the proportions of 90/10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ncc(Br)cn2)ccn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 5-bromo-2-iodopyrimidine 183-1 (114 mg, 0.4 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 183-2 (88 mg, 0.4 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), Na2CO3 (170 mg, 1.6 mmol), toluene (0.4 mL), H2O (0.4 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (3 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give 5-bromo-2-(2-methylpyridin-4-yl)pyrimidine 183-3. MS m/z 250.0 (M+1).
Reaction SMILES: C1([SiH3])C=CC=CC=1.[NH2:8][C:9]1[C:23]([C:24]([O:26]CC=C)=[O:25])=[C:12]2[N:13]=[C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][N:11]2[N:10]=1.CCOCC>C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:8][C:9]1[C:23]([C:24]([OH:26])=[O:25])=[C:12]2[N:13]=[C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: C=CCOC(=O)c1c(N)nn2ccc(OCCN(C)C)nc12
Agent: [Pd]
Agent: [SiH3]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a solution of phenylsilane (478.5 mg, 550.0 μL, 4.422 mmol) and allyl 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylate (900 mg, 2.948 mmol) in DCM (5 mL) was added palladium triphenylphosphane (170.3 mg, 0.1474 mmol). The reaction mixture was stirred at room temperature for 3 h. Ether was slowly added to the mixture and a white solid precipitated. This solid was filtered off, washed with small amount of diethyl ether and dried to afford pure 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid as off-white solid. (530 mg, 67% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:34]=[O:35])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].O.C([OH:39])C>O.O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:34]=[O:35])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([NH2:33])=[O:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccccc54)c3C=O)ncc2c1
Reactant: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3C=O)ncc2c1

Procedure:
A round bottom flask containing 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3 carbonitrile (12 mg, 0.03 mmol) was taken up in 10% water/tetrahydrofuran (1.5 ml). Next hydrido(dimethylphosphinousacid-kp)[hydrogen bis-(dimethylphosphinito-kp)]platinum(II) catalyst (2 mg, 0.005 mmol) was added and the mixture was heated to reflux (oil bath). After 1 hour the mixture was cooled to ambient and the volatiles stripped (rotary evaporator) to provide a crude product. This reaction (as described above—but using 10% H2O/ethanol as solvent) was repeated on a 61 mg scale (0.24 mmol) and worked up as described. The combined crude material from the 2 reactions was purified by preparative thin layer chromatography (3 plates, eluting with 5% MeOH/CH2Cl2 and then re-developing again with 5% MeOH/CH2Cl2). The product band was collected to provide 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carboxamide as a light yellow solid (51 mg). LC/MS calcd for C28H23FN4O3 (m/e) 482.52, obsd 483.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 6.03 (br. s, 2H) 7.20-7.36 (m, 3H) 7.44-7.59 (m, 3H) 7.66 (d, J=7.93 Hz, 1H) 7.81 (t, J=7.60 Hz, 1H) 7.91 (s, 1H) 8.19 (m, 1H) 8.23 (d, J=2.64 Hz, 1H) 9.52 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C(OCC([Cl:14])=O)C.[CH3:15][N+:16]([CH2:19][CH:20]([OH:25])[CH2:21][C:22]([O-:24])=[O:23])([CH3:18])[CH3:17]>COC(C)(C)C>[CH2:1]([O:3][CH2:4][C:5]([C:20]([CH2:21][C:22](=[O:23])[O-:24])([CH2:19][N+:16]([CH3:15])([CH3:17])[CH3:18])[OH:25])=[O:7])[CH3:2].[Cl-:14]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: CCOCC(=O)O
Reactant: CCOCC(=O)Cl
Solvent: COC(C)(C)C
Product: CCOCC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Product: [Cl-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A mixture of ethoxy acetic acid (5 ml; 0.07 moles) and ethoxyacetyl chloride (1.8 ml; 0.015 moles) which had been prepared as disclosed in step (b) of Example 5, was kept under stirring for 2 hours at 80° C. To this mixture carnitine chloride (2 g; 0.01 moles) which had been previously dried was added. The resulting mixture was first kept at 80° C. until complete dissolution of carnitine took place, then at 40° C. for eight days. A further amount of ethoxyacetyl chloride (0.9 ml; 0.007 moles) was added and the resulting mixture was kept at 40° C. for seven days. Upon addition to the mixture of tert-butyl methyl ether an oil precipitated. The oil precipitation was repeated four times with acetonitrile/tert butyl methyl ether until complete removal of the ethoxyacetic acid in excess. 1.5 grams of the title compound were thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:24])([CH3:23])[C:20](O)=[O:21])[CH:15]=3)[C:10]([CH3:25])=[N:9]2)[CH:5]=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH:51]1[CH2:54][CH:53]([OH:55])[CH2:52]1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:24])([CH3:23])[C:20]([N:51]4[CH2:54][CH:53]([OH:55])[CH2:52]4)=[O:21])[CH:15]=3)[C:10]([CH3:25])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)C(=O)O)ccc12
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)C(=O)N3CC(O)C3)ccc12
Reaction time: 18 h

Procedure:
To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoic acid (100 mg, 0.30 mmol) in DMF (3 mL) was introduced O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 18 hr at RT, the solution was re-treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 3 hr at RT, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (DCM containing a 2-10% gradient of methanol) furnished the title compound as a colorless solid: 1H NMR (500 MHz, DMSO) delta 1.64 (3H, s), 2.58 (3H, s), 3.58-3.75 (1H, m), 4.09-4.19 (1H, m), 4.19-4.28 (1H, m), 4.49 (1H, s), 4.63-4.76 (1H, m), 5.67-5.81 (1H, m), 6.14 (1H, d, J=17.5 Hz), 6.98 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.38 (1H, d, J=8.7 Hz), 7.87 (1H, dd, J=8.2, 1.8 Hz), 8.27 (1H, d, J=5.5 Hz), 8.87 (1H, s); LC-MS: m/z=+393.05 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3)CC2)c(C)c1
Yield: 85.3 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (348 mg) described in Preparation Example 133 and 1-methylimidazolidin-2-one (96 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (278 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:18]
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cccc(C)c1C(=O)N1C(=O)CN(c2ccccc2)C1=O
Yield: 6.3 %

Procedure:
In 30 ml of pyridine, were dissolved 1.1 g (6.25 mmol) of 1-phenyl-imidazolidin-2,4-dione and 1.12 g (6.65 mmol) of 2,6-dimethylbenzoyl chloride to conduct a reaction at 60° C. for 3 hours. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was then dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 122 mg (yield: 5.8%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:23]3[CH2:22][CH2:21][N:20]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[F:13])[CH2:25][CH2:24]3)[C:7]=2[CH:8]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Fc1ccccc1N1CCN(Cc2csc3ccc(Cl)cc23)CC1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 1-(2-fluorophenyl)piperazine were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.65 (m, 2H), 3.02 (m, 6H), 3.78 (s, 2H), 6.92–7.10 (m, 4H), 7.40 (dd, 1H, J=8.7,1.5), 7.67 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=1.5 Hz). MS (DCI/NH3) m/z 361.0 (M+H)+. Anal. Calcd for C19H18N2SClF: C, 63.24; H, 5.03; N, 7.76. Found: C, 63.17; H, 4.90; N, 7.67.