Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].Br[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>CN(C=O)C.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>[F:35][C:33]1[CH:34]=[C:29]([C:16]#[C:15][CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cc(F)cc(F)c3)CC2)n1
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a suspension of Compound 274c (70 mg, 0.27 mmol), sodium acetate trihydrate (74.2 mg, 0.55 mmol) and 1-bromo-3,5-difluorobenzene (33.5 μl, 0.27 mmol) in 2.05 mL of DMF flushed with nitrogen was added tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.014 mmol) and the reaction mixture was put into a microwave oven (Biotage) at 120° C. for 10 min. Dilution with EtOAc, washing with H2O and drying over Na2SO4 followed by evaporation and purification of the residue by automated flash liquid chromatography (Horizon™-Biotage) (PE-CH2Cl2 6:4) afforded 74 mg (73.7%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[K+:21].O.C(O)(C)C>CO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2].[K+:21]
Reactant: CCOC(=O)c1ccc(N2CCN(CC)CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Yield: 97.5 %

Procedure:
To a solution of 69.81 g of ethyl 6-(4-ethyl-1-piperazinyl)pyridine-3-carboxylate in 280 ml of methanol were added 37 g of potassium hydroxide and a small volume of water and the mixture was heated under reflux for one hour. To the reaction solution were added methanol and isopropyl alcohol, the crystal thus precipitated out was recovered by filtration and then dried under reduced pressure to afford 70.65 g of the title compound as a colorless crystal.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[C:14]1([C:11]2[S:10][C:9]([NH:8][CH2:7][C:6]([OH:20])=[O:5])=[N:13][N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CNc1nnc(-c2ccccc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1nnc(-c2ccccc2)s1

Procedure:
290 mg (0.99 mmol) of (5-phenyl-[1,3,4]thiadiazol-2-ylamino)-acetic acid tert-butyl ester in 5 ml of TFA and 5 ml of dichloromethane at room temperature for 16 h. The volatiles were removed under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:14]([O:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Formation of compound (c): A mixture of 3,5-dimethyl-4-nitrophenol (b) (2 g, 12 mmol), bromobutane (1.6 mL, 15 mmol), K2CO3 (2.1g, 15mmol) in DMF (6 mL) was stirred at 60° C. for 6 hours. The reaction mixture was poured into 50 mL of H2O and extracted with ether (3×50 mL). The combined ether layer was washed with H2O and subsequently with brine, dried over Na2SO4, filtered and concentrated to give compound (c), 4-butoxy-2,6-dimethyl-nitrobenzene (2.6 g, 97% yield) as a dark brown oil. 1H-NMR in CDCl3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[F:29])=[O:27]
Reactant: NCc1ccccc1F
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: O=C(Br)CBr
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2F)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 2-fluoro-benzylamine
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][C:17]#[N:18].C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][CH2:16][C:17]#[N:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCNc1ccc(Oc2ccccc2)cc1
Temperature: 85 °C
Yield: 44.8 %

Procedure:
A mixture of 4-phenoxyaniline (7.0 g, 37.8 mmol), bromoacetonitrile (4.5 g, 37.8 mmol) and triethylamine (4.2 g, 41.6 mmol) in tetrahydrofuran (50 mL) was heated at 85° C. for 5.25 hours then cooled and another portion of bromoacetonitrile (6.5 g, 5.46 mmol) was added. The mixture was heated at 85° C. for 18 hours then cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (30 mL) then the combined organic solutions were extracted with 5 N aqueous sodium hydroxide (30 mL), dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (98:2) as an eluent to provide 3.8 g (45%) of the title compound as a dark brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 7.32 (t, 2H), 7.03 (t, 1H), 6.87–6.94 (m, 4H), 6.76 (d, 2H), 6.26 (bs, 2H), 4.25 (s, 2H);RP-HPLC (Hypersil HS-C18, 5 μm, 100 A, 4.6×250 mm; 25%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 18.4 min.; MS: MH+ 225.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F.C(#N)C.O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OCCOC)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: COCCOc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 69A in analogy to the synthesis of the compound of Example 71A and with purification by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid). 46 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:19]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:19]1([CH2:23][S:1][C:2]2[CH:9]=[C:8]([C:10]3[C:11]([C:15]([F:16])([F:18])[F:17])=[N:12][NH:13][CH:14]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC1CCC1
Yield: 21.6 %

Procedure:
0.9 g (3.3 mmol) of 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile, 0.5 g (3.3 mmol) of cyclobutylmethyl bromide and 0.55 g (4.0 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at room temperature overnight. The resulting reaction mixture was poured into 50 ml of water and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, then washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.24 g of 2-cyclobutylmethylthio-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 21.2%) as a pale yellow powder (m.p. 102-103° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:23])(=[O:22])[CH2:18]C(O)=O.C([O-])(=O)C.[NH4+:28]>C(O)(C)C>[NH2:28][CH:8]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)[CH2:18][C:17]([OH:23])=[O:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(C(N)CC(=O)O)cc(C(C)(C)C)c1
Yield: 26.9 %

Procedure:
A mixture 3,5-di-tert-butylbenzaldehyde (0.996 g, 4.56 mmol), malonic acid (0.572 g, 5.50 mmol) and ammonium acetate (0.710 g, 9.21 mmol) in isopropanol (30 mL) was heated at reflux under nitrogen for 5 h to afford a colorless solid. The solid was filtered and washed with hot isopropanol (30 mL). The residue was dried in vacuo to give the desired racemic product as a colorless solid (0.340 g).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[C:25]([Si:12]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CC=CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cyclopent-3-enol (500 mg, 6.0 mmol) in CH2Cl2 (30 mL) at 0° C. was added imidazole (1.06 g, 15.6 mmol) and TBDPS-Cl (2.1 g, 7.8 mmol). The reaction was gradually warmed to room temperature and stirred for 16 hours. The reaction was then diluted with water (40 mL) and extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 5% EtOAc/Hexanes afforded tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane, which was then dissolved in CH2Cl2 (30 mL). 70% m-CPBA (830 mg, 6.9 mmol) was added at 0° C. The reaction was gradually warmed to room temperature while stirring for 16 hours. The reaction was then diluted with a saturated aqueous solution of NaHCO3 (40 mL) and extracted using CH2Cl2 (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded (6-oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)diphenylsilane.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([OH:23])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.C(O[C:36](=[O:38])[CH3:37])(=O)C.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:50]([NH:53][CH:54]([CH3:56])[CH3:55])([CH3:52])[CH3:51]>ClCCl>[C:36]([O:23][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[CH:22]=[CH:21][C:17]=1[C:18]([N:53]([CH:54]([CH3:56])[CH3:55])[CH:50]([CH3:52])[CH3:51])=[O:20])(=[O:38])[CH3:37]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccc(OCCCCCOc2ccc(C(=O)O)c(O)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-benzoic acid (28 g, 82 mmol) in 300 mL of dichloromethane is treated with pyridine (13.3 mL, 164 mmol) and acetic anhydride (9.3 mL, 98.4 retool) and stirred at room temperature for 30 minutes. The reaction is concentrated in vacuo and the residue is partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting 2-acetoxy-4-[5-(4-cyanophenoxy)pentyloxy]-benzoic acid is then dissolved in 300 mL of dichloromethane and treated at 0° C. with oxalyl chloride (8.6 mL, 98.4 mmol) and N,N-dimethylformamide (7.6 mL, 98.4 mmol). This solution is stirred at room temperature for 30 minutes and treated with 30 mL of diisopropylamine at 0° C. After stirring at room temperature for 30 minutes, the reaction is filtered and the filtrate is concentrated in vacuo. The resulting material is partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2-acetoxy-4-[ 5-(4-cyanophenoxy)pentyloxy]-N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]([N:13]=[C:14]([NH:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:19])[S:15][CH3:16])=O)(=[O:8])[CH3:7]>C(Cl)(Cl)Cl>[C:6]([O:9][CH2:10][C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:18](=[O:19])[N:17]=[C:14]([S:15][CH3:16])[N:13]=1)(=[O:8])[CH3:7]
Reactant: CSC(=NC(=O)COC(C)=O)NC(=O)NCc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(COC(C)=O)n(Cc2ccc(Cl)cc2)c(=O)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A phosphorus oxychloride solution (3.0 mL) of 2-({[3-(4-chlorobenzyl)ureido](methylthio)methylene}amino)-2-oxoethyl acetate (201 mg, 0.616 mmol) synthesized in Reference Synthesis Example 327 was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was added to chloroform-saturated sodium bicarbonate aqueous solution and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→0/1) to obtain the title compound (219 mg, quantitative).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH3:6].[NH:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:8]([C:13](N(C)OC)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11].Cl>C1(C)C=CC=CC=1.C1COCC1.C(OC(=O)C)C>[NH:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:8]([C:13]([CH2:3][CH2:4][CH2:5][CH3:6])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CCCCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Magnesium (0.330 g, 13.6 mmol) was activated by suspending in toluene for 30 min under N2. The toluene was removed and the Mg was dried under N2. To the suspension of Mg in THF (20 mL) was added bromobutane (1.46 mL, 13.6 mmol) dropwise and the mixture was heated at reflux. When all the magnesium was dissolved, Boc-Leu-N(OCH3)CH3 in THF was added dropwise and the reaction was stirred for 2 h at 0° C. 1M HCl (150 mL) was added followed by ethylacetate (100 mL). The organic layer was washed with 1M potassium hydrogen sulfate, water, dried (Na2SO4) and concentrated in vacuum. The expected product was purified by silica gel column chromatography. The product was characterized by 1H-NMR and 13C-NMR. ESI-MS: calcd. 271. found 293.3 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([N:2]([CH3:1])[CH3:21])=[O:20])=[CH:9][CH:8]=1)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCc1ccc(NCc2ccc(C(=O)N(C)C)cc2)cc1
Product: CCc1ccc(N(Cc2ccc(C(=O)N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using N,N-dimethyl-4-[(4-ethylphenyl)aminomethyl]benzamide (0.6 g) and 2,6-diisopropylphenyl isocyanate (0.46 mL) as starting materials, 4-[3-(2,6-diisopropylphenyl)-1-(4-ethylphenyl)ureidomethyl]-N,N-dimethylbenzamide (0.34 g) was obtained. melting point: 170–172° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([OH:22])=[C:14]([C:23]([N:25]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1.[NH2:62][NH2:63].CO>C(Cl)Cl.CC(C)=O>[NH:62]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([OH:22])=[C:14]([C:23]([N:25]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1)[NH2:63]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2ccc(Cl)nc2)c2ccccc2c1O
Reactant: NN
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2ccc(NN)nc2)c2ccccc2c1O

Procedure:
A mixture of 12.7 g (0.0144 mole) 4-(2-chloro-5-pyridinesulfonamido)-1-hydroxy-N,N-dioctadecyl-2-naphthamide, 4.7 g 95% hydrazine, and 413 ml methanol was heated under reflux for 17 hours. The hot mixture was filtered and then chilled. The product was filtered off, washed first with cold methanol, then with water, and air dried, yielding 11.7 g (93%), mp 96°-8° C. after softening. A thin-layer chromatogram using 85/15 methylene chloride/acetone to elute, showed traces of impurities.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[C:9]=1[CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C.O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[N:15]=2)[NH:10][C:9]=1[CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(-c2cnc3[nH]c(C)c(C(=O)NC(C)(C)C)c3n2)cc(OC)c1OC
Temperature: 60 °C
Yield: 24.9 %

Procedure:
To a solution of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (64 mg) in 0.5 mL of THF was added 400 uL of 1.0 M TBAF in THF. Heated the mixture to 60° C. for 14 h. Diluted with diethyl ether and water and partitioned. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Flash purification (95:5 methylene chloride:Methanol) afforded 12 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.CCOC(C)=O>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a suspension of 4-amino-benzamide (1.00 g, 7.34 mmol) in 50 mL of 1:4 CH3CN/DCM at 0° C. was added N-bromosuccinimide (NBS) (1.31 g, 7.34 mmol) in 20 mL of 1:1 CH3CN/DCM. The mixture was warmed to RT and stirred for 16 h under Ar. Treated with 100 mL of EtOAc, the mixture was washed with H2O (2×30 mL), brine (20 mL) and dried (Na2SO4). The organic solvent was evaporated in vacuo and the residue was triturated with DCM to give 1.45 g (92%) of the title compound as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C7H7BrN2O, 215.0 (M+H), found 215.1.