Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[H-].[Na+].C(O[C:13](=O)[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C.O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]1[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH3:6])[N:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCC(=N)NO
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Hydroxy-butyramidine (0.425 g, 4.16 mmol) in DMF (2 ml) is added to a stirred suspension of sodium hydride (0.183 g of a 60% dispersion in oil, 4.58 mmol) in the presence of molecular sieves (0.4 g). The reaction flask is then immersed in a pre-heated oil bath at 50° C. and stirring continued for 5 min. 3-tert-Butoxycarbonylamino-propionic acid ethyl ester (0.904 g, 4.16 mmol) in DMF (2 ml) is added over 5 min followed by more DMF (2 ml). After 3 h at 50° C. the mixture is cooled to 0° C. and water (3 ml) is added. The mixture is allowed to warm to room temperature then filtered through Celite™ filter material, washing with ethyl acetate, and the solvent is removed. Purification by chromatography, eluting with DCM:MeOH (95:5 increasing to 85:15) affords the titled compound.
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:19]([CH:21]=[CH2:22])=[O:20]>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:2]=[CH:3][CH:19]([OH:20])[CH:21]=[CH2:22])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: C=CC=O
Reactant: C=C(Br)c1ccc(OC)c(OC)c1
Agent: [Li]C(C)(C)C
Product: C=CC(O)C=Cc1ccc(OC)c(OC)c1
Yield: 42.3 %

Procedure:
According to the General Procedure C, 1-Bromo-1-(3,4-dimethoxyphenyl)ethene (1.00 g, 4.11 mmol), t-BuLi (6.05 ml, 10.28 mmol) and acrolein (691 mg, 12.33 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=2:1, Rf=0.25) the title compound (382 mg, 1.74 mmol, 42%) as a yellow oil; C13H16O3 (220.26).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:3]=1.Cl[C:19](OC(Cl)(Cl)Cl)=[O:20].[CH2:26]([NH2:32])[CH:27]1[O:31][CH2:30][CH2:29][CH2:28]1>>[CH2:26]([NH:32][C:19]([N:6]1[C:2]([CH3:1])=[CH:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)=[N:5]1)=[O:20])[CH:27]1[O:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCO1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)n[nH]1
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nn1C(=O)NCC1CCCO1
Yield: 70.3 %

Procedure:
5-Methyl-3-(3-trifluoromethylphenyloxy)pyrazole reacted with trichloromethyl chloroformate in the same manner as in Example 198 and then reacted with tetrahydrofurfurylamine to give a white solid of N-tetrahydrofurfuryl-5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole-1-carboxamide (yield: 70.3%). mp: 101-102° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.56-1.67 (m, 1H), 1.84-2.05 (m, 3H), 2.60 (s, 3H), 3.29-3.39 (m, 1H), 3.55 (ddd, J=3.8, 6.1 and 13.8 Hz, 1H), 3.70-3.90 (m, 2H), 4.00-4.10 (m, 1H), 5.74 (s, 1H), 7.21 (br s, 1H), 7.33-7.37 (m, 1H), 7.40-7.51 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[F:13][CH:14]([F:20])[C:15](=O)[CH2:16][C:17]#[N:18].N1CCCCC1.[NH2:27][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][C:30]#[N:31]>ClCCl.C(O)(=O)C>[F:13][CH:14]([F:20])[C:15]1[NH:27][C:28]([C:32]([F:35])([F:34])[F:33])=[C:29]([C:30]#[N:31])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:16]=1[C:17]#[N:18]
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: N#CCC(=O)C(F)F
Reactant: N#CC=C(N)C(F)(F)F
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)(F)F)=C3C#N)cc12

Procedure:
A mixture of 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 273 mg (1.03 mmol) 4,4-difluoro-3-oxobutanenitrile (Example 14A), 0.067 ml (1.17 mmol) acetic acid and 9.3 μl (0.094 mmol) piperidine in dry dichloromethane (4 ml) containing 4 Å molecular sieve was stirred under reflux for 12 h. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-propanol (2 ml) and acetic acid (1 ml) under argon, and 510 mg (3.75 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] were added. The solution was stirred under reflux for 6 h. Upon cooling, the mixture was evaporated to dryness, and the residue was treated with toluene (4 ml) containing a small amount of p-toluenesulfonic acid. The mixture was stirred under reflux for further 12 h. Upon cooling, the mixture was evaporated to dryness again, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 39 mg (11% of th.) of the racemic title compound.
Reaction SMILES: [C:1]([C:3]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)[C:10](Cl)=[O:11].[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)[CH:18]=[N:17]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[C:1]([C:3]1([C:6]([NH:8][C:10](=[O:11])[NH:34][C:31]2[CH:30]=[CH:29][C:28]([O:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([C:19]4[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=4)[CH:26]=3)=[CH:33][N:32]=2)=[O:7])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C(N)=O)CC1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C4(C#N)CC4)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A suspension of Example B8 (0.074 g, 0.673 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.059 mL, 0.673 mmol), stirred at RT for 1 h, then heated to 80° C. for 1.5 h. The mixture was cooled to RT, added drop-wise to a solution of Example A2 (0.15 g, 0.561 mmol) and pyridine (0.226 mL, 2.81 mmol) in THF (4 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-cyano-N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropanecarboxamide (176 mg, 78%) as an off-white solid. MS (ESI) m/z: 404.1 (M+H+).
Reaction SMILES: [C:1]1([S:10]([NH:13][CH2:14][C:15]([NH2:17])=O)(=[O:12])=[O:11])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22].[OH2:25]>CN(C)C=O>[C:1]1([S:10]([NH:13][C:14](=[O:25])[CH2:15][NH:17][C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)Cl
Reactant: NC(=O)CNS(=O)(=O)c1scc2ccccc12
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)NCC(=O)NS(=O)(=O)c1scc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product obtained in Step 1 (0.45 g) in N,N-dimethylformamide (5 ml) was added slowly 60% sodium hydride (75 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Methyl chloroformate (0.14 ml) was added to the above-mentioned mixture followed by stirring for 20 minutes at room temperature. 60% sodium hydride (75 mg) was added to the solution, and the mixture was stirred for 1.5 hours at room temperature, then 15 minutes at 70° C. After cooling to room temperature, water (20 ml) was added to the resultant mixture and this aqueous solution was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water, then saturated aqueous NaCl solution. After drying over anhydrous magnesium sulfate, ethyl acetate was removed in vacuo and the residue was purified by silica-gel column chromatography to give 0.18 g of the objective compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)[CH3:2].[CH2:12]([Mg]Cl)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)[CH3:2].[CH2:12]([C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]CCc1ccccc1
Agent: CCOC1=CC(=O)CCCC1
Solvent: CCOC(C)=O
Product: O=C1C=C(CCc2ccccc2)CCCC1
Yield: 184.8 %

Procedure:
3-Ethoxycycloheptenone was synthesized following published procedures.8 The general procedure for the preparation of substrates using 3-ethoxycycloheptenone (766 mg, 4.97 mmol) and phenethymagnesium chloride (10 mmol, 1M in THF) gave, after flash chromatography (4:1 hexanes:ethyl acetate), the title compound as a colorless liquid (0.984 g, 93%). 1H NMR (300 MHz, CDCl3): δ 7.32-7.13 (m, 5H), 5.91 (br s, 1H), 2.79 (dd, J=10.5, 7.8 Hz, 2H), 2.64-2.39 (m, 6H), 1.86-1.70 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 204.0, 161.1, 140.9, 129.6, 128.5, 128.3, 126.3, 43.0, 42.4, 34.4, 33.1, 25.4, 21.5. IR (neat): 3027, 2937, 2865, 1656, 1495, 1453, 1268, 878, 747, 699 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11]1.[CH2:20]([O:22][C:23](=O)[CH:24](Br)[CH3:25])[CH3:21].C(=O)([O-])[O-:29].[K+].[K+].C(#N)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:23]([O:22][CH2:20][CH3:21])[CH:24]=[C:25]=[O:29])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1n(-c2cc(O)c(Cl)cc2Cl)nc2n1CCCC2
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(C=C=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl

Procedure:
20.1 Parts of 2-(2,4-dichloro-5-hydroxy phenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one prepared as described in Example 3, 12.1 parts of ethyl-2-bromopropionate, 9.3 parts of anhydrous potassium carbonate and 100 parts of dry acetonitrile were refluxed for 5 hours. The reaction was cooled and poured into 250 parts of H2O. The aqueous suspension of product was extracted three times with 250 parts of methylene chloride and then the solution was dried with anhydrous sulfate. The solvent was removed on a rotary evaporator at reduced pressure. The glassy residue was crystallized from ethyl acetate-ether mixture. The yield was 16.0 parts of a light brown solid with m.p. 136°-138°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([C@@H:27]3[CH2:28][C@H:26]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:30])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenyl-1-cyclopropanecarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-(trans)-2-phenylcyclopropane-1-carboxamide as an off white solid, m.p. 77.0° C. 1H NMR (300 MHz, DMSO-d6) δ 7.90 (dd, J=8.1, 1.2 Hz, 1H), 7.81 (dd, J=8.1, 1.2 Hz, 1H), 7.78 (s, 1H), 7.50 (dt, J=8.1, 1.5 Hz, 1H), 7.33-7.15 (m, 4H), 7.05-7.02(m, 2H), 5.84 (broad s, 1H), 5.51 (s, 2H), 4.52 (t, J=7.2 Hz, 2H), 3.32 (q, J=6.6 Hz, 2H), 2.49-2.43 (m, 1H), 2.07-1.95 (m, 3H), 1.64-1.51 (m, 3H), 1.25-1.18 (m, 1H); IR (KBr) 3304, 3179, 2939, 1640, 1582, 1527, 1479, 1396, 1250, 755, 735, 689 cm−1; MS (EI) m/e 399.2059 (399.2059 calcd for C24H25N5O).
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:31][CH:30]=3)[CH3:28])=[CH:18][CH:17]=2)[C:11]([O:13]C)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO>O1CCOCC1>[C:3]1([S:9][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:33][CH:34]=3)[CH3:28])=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=NOCCOc1ccc(CC(Sc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
2.00 ml of a 1N aqueous sodium hydroxide solution was added to a mixture of 350 mg of methyl 2-phenylthio-3-[4-[2-[[1-[4(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 3, 3 ml of methanol and 2 ml of dioxane, and the mixture was stirred at 50° C. for 4 hours. After the reaction, the reaction mixture was concentrated and diluted with water. Then, the pH of the reaction mixture was adjusted to a value of 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 324 mg of the desired compound as a foamy solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:28])=[C:4]([CH:10]2[N:15]([CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:29][C:30]1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)(OCC)C>CCOC(C)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:29]([CH3:30])[O:28][C:3]=2[C:4]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N)c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)(OCC)OCC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C)oc2c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(3-amino-2-hydroxy-6-methoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (100 mg; 0.26 mmol), commercially available p-TsOH (2 mg; 0.01 mmol), and commercially available triethyl orthoacetate (290 mg; 1.69 mmol) was refluxed (100° C.) for 25 min. After cooling to rt, AcOEt was added, and the obtained mixture was filtered over a pad of celite. The filtrate was then washed with water and brine, and the mixed aq. layers were further extracted with AcOEt. The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=20/1) afforded the target compound. LC-MS (conditions A): tR=0.54 min.; [M+H]+: 401.73 g/mol.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:28])[C:24](=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:1])=[CH:11][C:10]2=[O:12])[C:25](=[O:27])[CH3:26]
Reactant: COc1ccccc1C(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1C(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
250 mg (1.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 280.9 mg (1.46 mmol) of 1-(2-methoxyphenyl)butane-1,3-dione, 99.7 mg (1.66 mmol) of acetic acid and 11.3 mg (0.13 mmol) of piperidine in 5 ml of dichloromethane and, after addition of molecular sieves, heated under reflux under argon for 4 h. The solvent is removed after filtration in vacuo. 480 mg (99% of theory) of the title compound are obtained and are employed without further purification in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12].O.[NH2:18][NH2:19]>CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[NH:19][N:18]=1
Reactant: COC(=O)C(=O)CC(=O)c1ccccc1Br
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2Br)n[nH]1
Temperature: 130 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of methyl 4-(2-bromophenyl)-2,4-dioxobutanoate (540 mg, 0.0019 mol) in AcOH (4 mL) was added hydrazine monohydrate (67 mg, 0.00208 mol). The reaction mixture was allowed to stir at 130° C. overnight and then concentrated. The residue was dissolved in EtOAc, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give methyl 3-(2-bromophenyl)-1H-pyrazole-5-carboxylate (0.516 g, 97%) as a white solid. LCMS: (FA) ES+ 283.2, ES-281.2.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH:13]([OH:26])[CH2:14][N:15](CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])=[CH:11][C:10]=1[NH:29][CH:30]=[O:31])C1C=CC=CC=1.CCOCC>C(O)C.[C].[Pd]>[CH:30]([NH:29][C:10]1[CH:11]=[C:12]([CH:27]=[CH:28][C:9]=1[OH:8])[CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])=[O:31]
Reactant: CC(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)NCC(O)c1ccc(O)c(NC=O)c1

Procedure:
In 20 ml. of ethanol there was dissolved 1.4 g. of 4-benzyloxy-3-formylamino-α-(N-benzyl-N-isopropylaminomethyl)-benzyl alcohol and after adding to the solution 0.2 g. of 10% palladium carbon, the catalytic reduction was carried out at normal temperature and pressure. After 165 ml. of hydrogen was absorbed, the reaction was stopped. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and then the residue thus formed was dissolved in a small amount of ethanol. Thereafter, when a small amount of ether was added to the solution and the solution was allowed to stand, a crystalline material was formed. By recovering the crystalline material by filtration, 0.7 g. of 3-formylamino-4-hydroxy-α-(isopropylaminomethyl)benzyl alcohol was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Reaction time: 2 h
Yield: 90.4 %

Procedure:
In 300 ml of toluene was suspended 9.2 g of 60% sodium hydride in a nitrogen stream, and 21.3 g of 2pyrrolidinone was slowly added dropwise to the suspension at an inner temperature controlled at 40° C. or lower. After stirring the mixture for 2 hours, 19.7 g of 2-chloro-N(2,6-dimethylphenyl)acetamide was added thereto, and the mixture was allowed to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., followed by allowing to cool with stirring. The precipitated crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 22.2 g (90%) of the titled compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:24]([F:27])([F:26])[F:25].Cl[C:29]1[CH:39]=[C:33]2[N:34]([CH3:38])[CH2:35][CH2:36][CH2:37][N:32]2[C:31](=[O:40])[N:30]=1>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:29]3[CH:39]=[C:33]4[N:34]([CH3:38])[CH2:35][CH2:36][CH2:37][N:32]4[C:31](=[O:40])[N:30]=3)=[CH:20][CH:21]=2)=[CH:11][C:10]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: C#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCCn2c1cc(C#Cc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
A suspension of bis(triphenylphosphine)palladium(II) chloride (70.3 mg, 0.1 mmol) and copper(I) iodide (19.1 mg, 0.1 mmol) in anhydrous THF (12 mL), was purged with Ar for 10 mins at rt. The suspension was treated with triethylamine (0.42 mL, 3.0 mmol), and 1-chloro-4-(4-ethynylphenoxy)-2-(trifluoromethyl)benzene (446 mg, 1.5 mmol) was added under an Ar atmosphere, which produced a dark amber color. After 5 mins, 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (100 mg, 0.5 mmol) was added, and stirred for 2 h at 50° C. The reaction mixture was diluted with EtOAc, washed with water, and then concentrated. The residue was purified by MDAP to afford the title compound (30 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:25](=[O:26])[NH:41][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1)([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
N-Boc-O-Benzyl-tyrosine (20.0 g, 53.9 mmol) was dissolved in DMF (270 mL) and treated with diisopropylethylamine (19 mL, 108 mmol), tert-butylamine (5.7 mL. 53.9 mmol), and HBTU (13.9 g, 53.9 mmol). The reaction was stirred for 15 minutes and then diluted with EtOAc (1 L), washed with saturated bicarbonate solution (2×1 L) and brine (1 L), dried over Na2SO4 and concentrated to give 22.1 g (92%) of (S)-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3]([C:9]([OH:11])=[O:10])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[CH:2][CH:1]=2)[CH2:15][CH2:14]1.[ClH:8].[ClH:8]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.2 %

Procedure:
To a well-stirred suspension consisting of 17.1 g. (0.10 mole) of α-chloro-p-toluylic acid in 150 ml of absolute ethanol under a nitrogen atmosphere at room temperature (˜20° C.), a solution consisting of 44.1 g. (0.44 mole) of N-methylpiperazine dissolved in 50 ml. of ethanol was added dropwise. The resulting reaction mixture was refluxed for a period of 16 hours and then cooled to room temperature. The cooled reaction mixture was concentrated in vacuo and the thus obtained residue partitioned between 100 ml of diethyl ether and 100 ml of 3N aqueous sodium hydroxide. The separated aqueous layer was then washed three times with 100 ml of diethyl ether, cooled in an ice-water bath and subsequently acidified with concentrated hydrochloric acid. The resulting solids were filtered and air-dried, followed by trituration with 150 ml of boiling isopropyl alcohol and stirring for a period of two minutes. After filtering while hot and drying the product there were obtained 9.4 g (35%) of pure 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride (9) as the hemihydrate, m.p. 310°-312° C. MS: 235.1 (M+H); 1H NMR (D2O) δ 8.04 (d, J=8.21 Hz, 2H), 7.59 (d, J=8.21 Hz, 2H), 3.50 (s, 2H), 3.63 (br, 8H), 2.97 (s, 3H); 13C NMR δ 170.18, 133.13, 131.91, 130.90, 60.22, 50.61, 48.77, 43.25.