Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N1(C2CCCCCCCC2)CCCCCCCC1>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2sccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C1CCCCC(N2CCCCCCCC2)CCC1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccsc1-c1ccc(CBr)cc1
Yield: 67.1 %

Procedure:
A mixture of 2-(4-methylphenyl)-3-cyanothiophene (1.5 g, 7.5 mmol), N-bromosuccinimide (1.34 g, 7.5 mmol), and azabicyclononane (20 mg) in carbon tetrachloride was irradiated with UV light for one hour. The reaction mixture was cooled, and the solid filtered off. The filtrate was concentrated, and the residue purified by flash chromatography, eluting with 5% ethyl acetate/hexane, to yield 2-(4-bromomethylphenyl)-3-cyanothiophene 1.4 g, m.p. 68-75 (slightly impure, used as such).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[Br:17])(=O)=O.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC.[Li+].[Cl-].[OH-].[Na+]>CN(C=O)C>[Br:17][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[C:12]([CH3:13])[C:7]=1[CH:20]=[CH2:21]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc([N+](=O)[O-])cc1Br
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 28.3 %

Procedure:
The reaction mixture of 2-bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (65B) (10.1 g, 27.7 mmol), tributylvinyltin (8.18 ml, 27.7 mmol), LiCl (1.4 g, 33.2 mmol), PdCl2dppf (607 mg, 0.83 mmol) in DMF (50 ml) was reacted at 70° C. for 3 h. Then 2N NaOH was added and stirred at 70° C. for 5 min. The reaction mixture was cooled down, washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65C (1.9 g, 30%). 1H-NMR: 400 MHz, (CDCl3) δ: 8.30 (d, J=0.8 Hz, 1H), 8.03 (d, J=1 Hz, 1H), 6.71-6.64 (dd, J=18, 12 Hz, 1H), 5.77-5.74 (d, J=12 Hz, 1H), 5.51-5.46 (d, J=18 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]12([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=5)=[CH:24]4)=[CH:19][C:18]=3[O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.O>C1COCC1>[C:7]12([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[O:32])=[CH:29][CH:28]=5)=[CH:24]4)=[CH:19][C:18]=3[O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)Cl)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)N4CCOCC4)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 ml (20.6 mmol) of morpholine and 40 ml of THF were introduced into a round-bottomed flask. A solution of 3.5 g (6.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid chloride in THF was added dropwise and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The solid obtained was triturated in hexane, filtered and dried. 2.8 g (74%) of the expected amide were collected, which amide had a melting point of 86°-7° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH3:18][C:19]1[N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]3)=[CH:5][CH:4]=2)[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Yield: 35.4 %

Procedure:
To a solution of 4-bromomethylphenylboronic acid pinacol ester (564 mg, 1.90 mmol) in acetone (19 mL) was added 2-methylbenzimidazole (377 mg, 2.85 mmol), potassium iodide (16 mg, 0.095 mmol) and K2CO3 (394 mg, 2.85 mmol) and the reaction mixture heated at 60° C. for 3.25 h. The reaction mixture was diluted with H2O and extracted with EtOAc (×2). The organic layers were combined, dried (phase separation cartridge) and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC-MS to afford 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]1H-benzoimidazole as an off-white solid (234 mg, 35%).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[C:5]([O:11][CH3:12])(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].C(Br)C=C>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[C:5]([CH:6]([C:7](=[O:8])[CH3:9])[CH2:3][CH:2]=[CH2:1])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(C)=O
Reactant: C=CCCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: C=CCBr
Product: C=CCC(C(C)=O)C(=O)OC
Yield: 30 %

Procedure:
In J. Org. Chem., Vol. 39, No. 22, 1974 at page 3271, an article by Durst & Liebeskind entitled, "Phase Transfer Catalysis. The Acetoacetic Ester Condensation" indicates that reaction of allyl chloride with methyl acetoacetate gives rise to a 30% yield of 4-carbomethoxy-1-hexen-5-one and reaction of methyl acetoacetate with allyl bromide in the presence of an Aliquat 336® catalyst gives rise to a 94.7% yield of 4-carbomethoxy-1-hexen-5-one. The reaction is carried out however in the presence of anhydrous benzene which gives rise to the danger of causing minute traces of benzene to exist in the final desired product which is to be used for its organoleptic properties in perfumery. The potential presence of such solvent is unacceptable in the perfumery field.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[OH:9])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc(Cl)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2O)CC1
Reaction time: 18 h
Yield: 82 %

Procedure:
2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231 mmol) were set stirring in dichloromethane (600 mL). Sodium triacetoxyborohydride (58.0 g, 274 mmol) was added in portions over 10 min. Acetic acid (12 mL, 210 mmol) was then added and the mixture left to stir for 18 h. Saturated NaHCO3 was added and the organics seperated. The organics were dried (MgSO4) and evaporated to give 56 g (82%) of a light beige solid. TLC (silica, 50% EtOAc/hexanes): Rf=0.66. MS (electrospray): exact mass calculated for C16H23ClN2O3, 326.14. m/z found, 349.1 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 6.70 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.55-3.50 (m, 1H), 2.93 (br s, 2H), 1.93 (d, J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35 (d, J=11.2 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11])(=O)[CH3:2].Cl.[CH3:17][O:18][NH2:19].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11])[CH3:2]
Reactant: COC(=O)NCc1cccc(C(C)=O)c1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CON=C(C)c1cccc(CNC(=O)OC)c1
Yield: 87.7 %

Procedure:
0.40 g of methyl N-(3-acetylbenzyl)carbamate was dissolved in 10 ml of ethanol, and 0.36 g of methoxyamine hydrochloride and 5 ml of an aqueous solution of 0.54 g of sodium acetate were added thereto, followed by reflux under heating for 8 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane to obtain 0.40 g of methyl N-[3-(1-methoxyiminoethyl)benzyl]carbamate as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 90 °C

Procedure:
The mixture of 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (11.2 mg, 0.027 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (5.2 mg, 0.027 mmol) in 1 mL of isopropanol was heated to 90° C. for 1 hour. The solvent was evaporated and the residue was re-dissolved in a mixture of methanol and CH2Cl2 (1:1, v/v) and applied onto a prep-TLC plate (2000 micro). The plate was developed in NH4OH/MeOH/CH2Cl2 (1:9:90, v/v). 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 1) was obtained as a yellow solid (8.6 mg, 61%). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.52 (s, 1H), 7.44 (m, 2H), 7.28 (s, 1H), 7.19 (m, 3H), 6.66 (m, 2H), 4.40 (q, 2H), 3.00-3.18 (m, 8H), 2.60 (m, 4H), 2.35 (s, 3H), 2.22 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N6O3: 525.25 (M+H), Found: 525.4.
Reaction SMILES: [N:1]([CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[CH:15]=[CH:16][CH:17]=[N:18][C:7]=2[N:6]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:5]1=[O:29])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[CH:15]=[CH:16][CH:17]=[N:18][C:7]=2[N:6]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[C:5]1=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N=[N+]=[N-])c2ccccc2-c2cccnc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N)c2ccccc2-c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Add palladium/carbon (2.2 g, 1.0 mmol, 5% on carbon) to a nitrogen purged solution of 7-azido-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (39.8 g, 92.3 mmol) in ethanol (923 mL). Evacuate/fill with hydrogen three times and stir under hydrogen (one atmosphere) at ambient temperature overnight. Filter over Celite®, rinse with ethanol and ethyl acetate and concentrate to obtain the title compound as a transparent oil (36.6 g, 89.9 mmol, 97%). MS (m/z): 384 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].CN(C1C=CC=CN=1)C>CN(C)C=O.O>[CH3:28][S:29]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3cc(O)ccc3c12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)Oc1ccc2c(c1)[nH]c(=O)c1c3ccc(OS(C)(=O)=O)cc3oc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dry N,N-dimethylformamide was dissolved 500 mg of 3,9-dihydroxy-5H-benzofuro[3,2-c]quinolin-6-one. To the solution were added successively 1.3 ml of triethylamine, 0.72 ml of methylsulfonyl chloride and 10 mg of -dimethylaminopyridine, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the precipitates were collected by filtration, washed with water and ether, and dried to obtain 725 mg of 3,9-bis(methylsulfonyloxy)-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>C(O)C>[C:3]([CH:4]([CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[NH:2])[NH2:10]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCC(C(=N)N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-amino-3-iminopropionoate hydrochloride (10 g) and triethylamine (18.4 mL) in ethanol (100 mL) was added ethyl acrylate (7.15 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=1)[CH3:13]
Reactant: Cc1cc(Br)cnc1N
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cnc1N
Temperature: 140 °C
Yield: 123.5 %

Procedure:
A mixture of 2-amino-5-bromo-3-methylpyridine (1.41 g, 7.53 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.50 g, 7.53 mmol), palladium(II) acetate (33.8 mg, 0.15 mmol), tri-o-tolylphosphine (183.2 mg, 0.60 mmol), triethylamine (4.50 mL, 32.3 mmol), and anhydrous acetonitrile (8 mL) was stirred and heated at 130–132° C. in a sealed glass tube for 18 h. The mixture was further heated at 140° C. for 84 h. The resulting dark-brown solution was cooled to ambient temperature and concentrated by rotary evaporation. The residue was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). the combined CH2Cl2 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried producing a dark-brown oil (2.84 g). The crude product was purified by column chromatography on silica gel (135 g), eluting with ethyl acetate-hexane (3:1, v/v) to remove impurities, followed by elution with CH3OH-Et3N (98:2, v/v) to collect the product. Fractions containing the product (Rf 0.70) were combined and dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried to give 1.11 g (48.4%) of an amber-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([O:21][CH2:22][CH2:23]O)[CH2:17][CH2:18][S:19][CH3:20])=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CSOC(I)=O>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[C:12]([CH:16]([CH2:17][CH2:18][S:19][CH3:20])[O:21][CH2:22][CH2:23]2)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C(CCSC)OCCO)[nH]c(=O)c1OCc1ccccc1
Agent: CSOC(=O)I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2CCSC
Reaction time: 20 h
Yield: 52.4 %

Procedure:
To a solution of intermediate 20, ethyl 5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (527 mg, 1.25 mmol) and Et3N (505 mg, 5 mmol) dissolved in 10 mL of CH2Cl2 was added a solution of CH3SO2CI (288 mg, 2.5 mmol) dissolved in 2 mL of CH2Cl2. This was stirred for 20 hrs then concentrated. The crude product was purified by chromatography on silica gel, using 10:1 CH2Cl2:ether as eluent, to give the title compound 265 mg (52% yield). (500 MHz, CDCl3) δ ppm: 7.31-7.55 (5 H, m) 5.30 (2 H, s) 4.75 (1 H, dd, J=3.66 Hz) 4.32-4.40 (2 H, q, J=7.17 Hz) 4.13-4.30 (2 H, m) 3.75-3.97 (2 H, m) 2.20-2.84 (4 H, m) 2.06 (3 H, s)1.32 (3 H, t, J=7.17 Hz); LC/MS m/z 405 (M+H).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][C:3]2[S:4][CH2:5][C:6](=[O:8])[N:7]=2)[CH2:12][CH2:11]1
Reactant: CN1CCN(CCN)CC1
Reactant: CSC1=NC(=O)CS1
Product: CN1CCN(CCNC2=NC(=O)CS2)CC1

Procedure:
2-[2-(4-Methyl-piperazin-1-yl)ethylamino]-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and 2-(4-Methyl-piperazin-1-yl)-ethylamine following general procedure E.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8](=[O:31])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:32]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42]Br)[CH3:33]>CS(C)=O>[CH2:32]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][N:9]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[CH3:33]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)c1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccccc1CN(C(=O)OC(C)(C)C)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a suspension of 3.41 g of powdered KOH in 110 ml of DMSO was added at 22° C. 6.00 g of {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-carbamic acid tert-butyl ester and the suspension was stirred for 25 min. A solution of 7.40 g of 2-bromomethyl-benzoic acid ethyl ester in 10 ml of DMSO was added slowly keeping the temperature at 15-20° C. and stirring was continued at 22° C. for 2.5 h. The dark mixture was partitioned between 500 ml of a saturated aqueous NH4Cl and 200 ml of AcOEt, the organic layer was washed with saturated aqueous NH4Cl and water, dried and evaporated. The residue was purified by chromatography (SiO2, n-hexane/AcOEt 4:1) to give 7.96 g of the title compound as a pale yellow oil. MS: (M+H)+ 557.3.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.Cl>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
880 mg (5 mmol) of 1-acetyl-2-indolinone and 610 mg (5 mmol) of benzoic acid are dissolved in 15 ml of DMF and after the addition of 1.8 g (5.5 mmol) of TBTU, 840 mg (5.5 mmol) of HOBt and 3.2 g (25 mmol) of N-ethyl-N,N-diisopropyl-amine are stirred for 16 hours at ambient temperature. The solution is stirred into dilute hydrochloric acid, the precipitate is suction filtered and dried at 60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9](O)=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2].B.C1COCC1.Cl>>[N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)[nH]n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 3-nitro-1H-pyrazole-5-carboxylic acid (4.71 g, 30 mmol), BH3/THF (75 mL, 1 mol/L, 75 mmol) was stirred at 60° C. for 2 h. The mixture was cooled to room temperature and 4M HCl (19 mL, 75 mmol) was added. It was stirred at 70° C. for 2 h. After cooling down to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine (100:100 mL). The aqueous phase was extract with ethyl acetate (4×50 mL). The combined organic layer was dried on Na2SO4 and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford 139a (3.5 g, 79%) as a white solid. MS-ESI: [M+H]+ 144.2
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][CH3:25])[C:21]([CH2:26][C:27](Cl)=[O:28])=[C:20]([CH2:30][CH3:31])[CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][CH3:25])[C:21]([CH2:26][C:27]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:28])=[C:20]([CH2:30][CH3:31])[CH:19]=1
Reactant: CCc1cc(Cl)cc(CC)c1CC(=O)Cl
Reactant: CCOC(=O)C(C)=NNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(Cl)cc1CC
Yield: 66.2 %

Procedure:
To a solution of 1.1 g of ethyl 2-(methylhydrazono)propanoate in 20 mL of acetonitrile was added 0.68 g of potassium carbonate. The mixture was stirred under ice cooling. To the mixture was added dropwise a solution of 1.26 g of 4-chloro-2,6-diethylphenylacetyl chloride in 8 mL of acetonitrile over about 10 minutes. The mixture was further stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated under reduced pressure. To the residue was added 20 mL of ice water, followed by extraction with ethyl acetate (20 mL, 10 mL×2). The extracts were combined, washed with an aqueous saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to basic alumina column chromatography (ethyl acetate:hexane=1:6) to give 1.2 g of a light yellow solid. The solid was washed with cold hexane and air dried to give 0.79 g of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:15])[N:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=1.[CH3:16]C1NNC(=O)C=1.BrCCCC1C=CC=CC=1>>[CH3:1][C:2]1[CH2:3][C:4](=[O:15])[N:5]([CH2:7][CH2:8][CH2:9][C:10]2[CH:16]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1
Reactant: Cc1cc(=O)[nH][nH]1
Reactant: CCCCCCCCN1N=C(C)CC1=O
Agent: BrCCCc1ccccc1
Product: CC1=NN(CCCc2ccccc2)C(=O)C1
Yield: 69 %

Procedure:
By a procedure similar to that for 2,4-dihydro-5-methyl-2-octyl-3H-pyrazol-3-one, starting from 3-methyl-3-pyrazoline-5-one (19.63 g, 0.20 mol) and 1-bromo-3-phenylpropane (39.80 g, 0.20 mol), 2,4-dihydro-5-methyl-2-(3-phenylpropyl)-3H-pyrazol-3-one (29.40 g, 69%) was obtained as colorless needles, m.p. 103°-105° C.