Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:28]=[CH:29][C:30]([NH:31][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 76 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-(trifluoromethyl)aniline gave the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 6.54 (d, J=8.3 Hz, 2H), 4.40 (s, 2H), 2.71 (t, J=7.5 Hz, 2H), 1.80-1.65 (m, 2H), 1.40-1.07 (m, 16H), 0.80 (t, J=6.8 Hz, 3H). M−(LC/MS(ESI)): 472.5; M+(LC/MS(ESI)): 474.2. HPLC (Condition A), Rt: 6.78 min (HPLC purity: 97.5%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[C:17]([O:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].O.C(O)(=O)C.CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:10]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([O:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Yield: 75.3 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 1.7 g.), 10% palladium carbon (1 g.), water (3 ml.), acetic acid (0.3 ml.), methanol (20 ml.) and tetrahydrofuran (35 ml.) was treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1 g.), yellow powder.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2
Reactant: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(O)ccc12
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(OCCCCCC)ccc12

Procedure:
From 9-fluoro-7-octylphenanthren-2-ol by reaction with 1-bromohexane and sodium hydride in abs. DMF.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(F)c1F
Yield: 93.5 %

Procedure:
Prepared according to Method A step A from 2,3-difluorobenzoic acid (4.0 g, 25 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35 mmol), oxalyl chloride (2.2 mL, 25 mmol) and 6 mL of pyridine to give the title compound (4.7 g) as an oil. Used as is in the next preparation.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[H-].[Na+].CS(C)=O>CO>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:2]([CH3:1])([CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:3])=[CH:10][CH:11]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: CC(C)(C)CC(C)(C)c1ccc(Nc2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
First, 76.20 mmol of Bis-(4-(2,4,4-trimethylpentan-2-yl)phenyl)amine, 91.45 mmol of 4-Fluoronitrobenzene, 114.31 mmol of sodium hydride, 2.74 g of NaH, and 120 ml of dimethyl sulfoxide (DMSO) were added into a bottle. After stirring at 120° C. for 48 hrs, the reaction mixture was cooled and then poured into 1 L of methanol. The yellow precipitate was collected by filtration and dried under vacuum. The product was purified by silica gel column chromatography (dichloromethane:n-hexane=1:3) and recrystallized from ethyl acetate to afford 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline as a yellow crystal with a yield of 60%. The 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline had a melt point of 167° C. The synthesis pathway was as follows:
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[N:16]([CH2:21][C:22](OCC)=[O:23])[CH:15]=[CH:14]2.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOCC>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[N:16]([CH2:21][CH2:22][OH:23])[CH:15]=[CH:14]2
Reactant: CCOC(=O)Cn1ccc2cc(Br)c(F)cc21
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCn1ccc2cc(Br)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIBAL-H (1 M in hexanes) (4 mL, 4 mmol) was added to a 0° C. solution of ethyl (5-bromo-6-fluoro-1H-indol-1-yl)acetate (0.480 g, 1.60 mmol) in anhydrous THF (10 mL). The reaction was stirred at rt for 1 h, then treated with saturated aqueous Rochelle's salt and Et2O. The mixture was stirred vigorously for 30 min. The layers were separated and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 60% EtOAc/hexanes afforded the desired compound as an oil.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[C:23]([O:22][C:21](=[O:27])[NH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:2]2[C:10]3[O:9][CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)[CH2:15][CH2:16]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)NC1CCN(c2cc([N+](=O)[O-])cc3ccoc23)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 29.7 %

Procedure:
Xylene (200 mL) was added to 7-iodo-5-nitro-1-benzofuran (2.78 g, 9.61 mmol), tert-butyl piperidin-4-ylcarbamate (2.31 g, 12.0 mmol), Pd2(dba)3 (0.22 g, 0.24 mmol), Xantphos (0.56 g, 0.96 mmol) and sodium tert-butoxide (1.29 g, 13.0 mmol). The mixture was heated at 120° C. with stirring for 16 h. The reaction mixture was allowed to reach room temperature, filtered through a pad of Celite, and concentrated in vacuo. The crude product was purified by flash chromatography, using DCM as eluent, to afford 1.03 g (84%) of the title product. HPLC 94%, RT: 2.770 (System B; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 1.45 (s, 9H) 1.62-1.72 (m, 2H) 1.75-2.03 (m, 2H) 2.94-3.02 (m, 2H) 3.55-3.57 (m, 1H) 3.88-3.93 (m, 2H) 7.01 (d, J=2.23 Hz, 1H) 7.64 (d, J=2.23 Hz, 1H) 7.93 (d, J=2.23 Hz, 1H) 8.13 (d, J=2.23 Hz, 1H). LC-MS 362 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].N(OC(C)(C)C)=O.N[C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>C(O)(=O)C>[C:1]([O:4][C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC[C@H](N)C(=O)O
Reactant: CC(=O)[O-]
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@H](OC(C)=O)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Sodium acetate (11.9 g, 146 mmol) and tert-butyl nitrite (15.0 g, 146 mmol) were added to an acetic acid (300 mL) solution of (2S)-2-aminobutyric acid (10.0 g, 97.0 mmol) under ice cooling, and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, then water was added to the reaction mixture, and the resulting mixture was extracted twice with ethyl acetate. The organic layer thus obtained was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and further, the resulting residue was azeotropically boiled twice with 1,4-dioxane (50 mL) to give the title compound (8.4 g, yield: 60%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]12([CH3:18])[C:14]([CH3:16])([CH3:15])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[OH:17].[Al].N.COC1C=CC(C=O)=CC=1.S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.O.C(O)(=O)C.CO.C(OCC)(=O)C.N1C=CC=CC=1>[C:1]([OH:6])(=[O:7])[CH2:2][CH2:3][C:4]([OH:17])=[O:5].[C:8]12([CH3:18])[C:14]([CH3:15])([CH3:16])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[OH:17].[C:8]12([CH3:18])[C:14]([CH3:15])([CH3:16])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[OH:17]
Reactant: O=C1CCC(=O)O1
Agent: CC1(C)C2CCC1(C)C(O)C2
Agent: CN(C)c1ccncc1
Agent: COc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Temperature: 65 °C
Reaction time: 53 h

Procedure:
First, 4-(dimethyl amino) pyridine (31.1 mg) was added to 9.1 ml pyridine, before adding succinic anhydride (487.7 mg). Borneol (168.4 mg) was added last, and the reaction mixture was heated under reflux with stirring for 53 hr at 65° C. The reaction was monitored by thin layer chromatography (“TLC”). The TLC assay used silica gel 60 F264 aluminum sheets (0.2 mm thick) from E. Merck (Darmstadt, Germany) with a mobile phase of 100 % ethyl acetate, 100% methanol, and 1% aqueous ammonia in a ratio of 80:20:1. The resulting bands were visualized by adding a mixture of 100% anisaldehyde, 100% acetic acid, and 100% sulfuric acid in a ratio of 0.5:50:1. The reaction was stopped with 20 ml H2O. The resultant product was extracted three times, each time with 25 ml methylene chloride. The organic layer was collected from each extract, pooled, rotaevaporated to dryness, and then dried under vacuum in the presence of phosphorous pentoxide. The product produced was boreol-hemisuccinate.
Reaction SMILES: FC1C=CC=CC=1C#N.OCCN1CCNCC1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]#[N:35])[CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C.[C:45]12([C:55](Cl)=[O:56])[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH2:46]1)[CH2:52]2>CN(C)C=O.C(Cl)Cl>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][O:19][C:55]([C:45]23[CH2:54][CH:49]4[CH2:48][CH:47]([CH2:53][CH:51]([CH2:50]4)[CH2:52]2)[CH2:46]3)=[O:56])[CH2:23][CH2:24]1)#[N:35]
Reactant: N#Cc1ccccc1N1CCN(CCO)CC1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: N#Cc1ccccc1F
Agent: OCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCN(CCOC(=O)C23CC4CC(CC(C4)C2)C3)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
2-Fluorobenzonitrile (6.0 g, 50 mmoles) and 1-(2-hydroxyethyl)-piperazine (6.5 g, 50 mmoles) were combined in 500 mL of dimethylformamide and heated at 80° C. under N2 for 24 hours. After cooling, the solvent was removed in vacuum and the crude 1-(2-hydroxyethyl)-4-(2-cyanophenyl)piperazine thus produced was used without purification. 2.3 Grams (10 mmole) of the crude 1-(2-hydroxyethyl)-4-(2-cyanophenyl)piperazine was dissolved in 100 mL of CH2Cl2 and 1.3 g (10 mmole) of diisopropyl ethylamine was added, followed by addition of 2.0 g (10 mmole) of 1-adamantanecarbonyl chloride. The mixture was stirred at room temperature for 3 hours, washed with saturated NaHCO3 solution, saturated brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel with CHCl3 and the product thus obtained was crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 1.1 g of title compound as the monohydrochloride salt, mp. 230°-231° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH-].[K+].[I:22]I>CN(C=O)C>[I:22][C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([CH:8]3[CH2:7][CH2:6][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:10][CH2:9]3)[CH:12]=2)[NH:17][CH:18]=1
Reactant: II
Reactant: c1cc2cc(C3CCC4(CC3)OCCO4)cnc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ncc(C3CCC4(CC3)OCCO4)cc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of the azaindole (XIb-19) (2.51 g, 9.72 mmol) in DMF (40 mL), was added crushed KOH pellets (2.05 g, 36.6 mmol) followed by I2 (2.22 g, 8.7 mmol). The mixture was stirred at room temperature for 3.5 h and concentrated in vacuum. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 solution (40 mL). The aqueous layer was extracted with EtOAc (3×60 mL). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residue consisting of crude iodide (XIIb-19) was used for the preparation of (IXb-19) without any additional purification.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[CH:32]([F:34])[F:33])[N:12]=1.COCCOCCN(CCOCCOC)CCOCCOC>O.O1CCOCC1>[F:34][CH:32]([F:33])[C:24]1[N:23]([C:13]2[N:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:12]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: Sc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(Sc2ccccc2)nc(N2CCOCC2)n1
Yield: 75.8 %

Procedure:
Thiophenol (230 mg, 2.1 mmol) and NaOH (85 mg, 2.1 mmol) were combined in water to give a clear solution, which was then evaporated to dryness. 1-[4-Chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (184 mg, 0.5 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1; 16 mg, 0.05 mmol) were added and the mixture was heated under reflux in dioxane (10 mL) for 2 hr. After cooling, the mixture was diluted with water to give a solid, which was recrystallised from EtOH to give 167 mg (76% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(phenylsulfanyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 245-248° C.; 1H NMR (CDCl3) δ 7.83 (t, J=8.6 Hz, 2H), 7.67 (dd, J=8.1, 1.3 Hz, 2H), 7.58 (br t, J=7.4 Hz, 1H), 7.52 (br t, J=7.3 Hz, 2H), 7.34 (dt, J=7.9, 1.2 Hz, 1H), 7.25 (dd, J=7.8, 1.2 Hz, 1H), 6.91 (t, JHF=53.5 Hz, 1H), 3.89 (m, 4H), 3.82-3.77 (m, 4H); Anal. Calc. for C21H18F2N6OS: C, 57.3; H, 4.1; N, 19.1. Found: C, 57.2; H, 4.1; N, 19.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Br)cc21
Yield: 90.2 %

Procedure:
With 56.3 g of 3-bromo-4-methoxy toluene and 45.2 g of 5-bromoisatin as starting materials, 62.8 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
1-Fluoro-4-nitrobenzene (10.6 g) and 2,2,2-trifluoroethanol (12.0 g) were dissolved in N,N-dimethylformamide (80 ml), and potassium carbonate (15.5 g) was added thereto. The mixture was stirred at 80° C. for 2 hr, and allowed to be cooled. To the reaction mixture was added ethyl acetate (100 ml), and the white precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give an orange residue. The obtained residue was again dissolved in ethyl acetate (400 ml), and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an orange crude solid. The obtained solid was washed with a mixed solvent of 10% diethyl ether/hexane to give the title compound (15.8 g) as yellow-white needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][NH2:23])=[CH:26][CH:27]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(CN)cc3)c3cc(Br)cnc32)cc1
Yield: 71.1 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.419 mmol), 4-aminomethylphenylboronic acid hydrochloride (95 mg, 0.503 mmol) and dichlorobis(triphenylphosphine)palladium (II) (29 mg, 0.042 mmol) were combined in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) and stirred at 60° C. for 3 hrs. EtOAc was added, the organic phase was washed with water, dried and evaporated. to yield 136 mg (71%) of the title compound. MS ESI (m/z): 455.9/458.1 (M+1)+, calc. 455/457.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([O:12]C)[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([OH:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CCCc1c(OC)cccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1c(O)cccc1O
Temperature: -70 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2,4,-Dimethoxy-3-propylbenzene (7.2 g, 39.94 mmol) was dissolved in 50 ml methylene chloride and the solution was cooled to -70° C. then 87.0 ml of 1 M boron tribromide in methylene chloride was added over a period of 1 hour. The reaction mixture was stirred at -70° C. for 1 hour, then at room temperature for 2 hours. The reaction mixture was poured into 250 ml of ice water very slowly. This mixture was extracted 3 times with 100 ml methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to give the product as a white solid (4.9 g, 81.7%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1.[Li+].[OH-]>C1COCC1.CO>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of methyl 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate ((5.0 g, 12.9 mmol) in THF: MeOH (70:30) (50 mL) was added LiOH (3.10 g, 129.0 mmol) in one lot and the reaction was stirred at RT for 12 h. The solvent were removed in vacuo and the residue was diluted with water and quenched with 1N HCl (50 mL) to obtain off white precipitate. The suspension was stirred for 10 min and filtered and dried to give 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid (4.2 g, 87%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 8.03-8.06 (m, 2H), 7.84-7.86 (m, 1H), 5.93 (dd, 1 H, J=9.7, 2.3 Hz), 3.90 (d, 1 H, J=11.9 Hz), 3.74-3.76 (m, 1H), 2.35-2.41 (m, 1H), 1.97-2.00 (m, 2H), 1.69-1.80 (m, 1H), 1.41-1.58 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=[CH:7][C:6]=1[O:5]2.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:18][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[O:5][C:4]3[C:13](=[CH:14][CH:15]=[C:2]([OH:1])[CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=1)=[O:19]
Reactant: CO
Reactant: O=C(O)c1ccc2oc3cc(O)ccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2oc3cc(O)ccc3c(=O)c2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 6-hydroxy-9-oxo-9H-xanthene-2-carboxylic acid (Gapinski, D. M. "Leukotriene Antagonists", U.S. Pat. No. 4,996,230, which is incorporated herein by reference, 1991; 10.6 g, 41.4 mmol) and concentrated sulfuric acid (1 mL) in methanol (100 mL) was refluxed for 48 hours. The mixture was cooled to room temperature and the resulting precipitate collected by vacuum filtration. The filtrate was concentrated in vacuo and diluted with water, which resulted in additional precipitate. This was collected and combined with the first fraction to provide 10.8 g (97%) of the title product: 1H-NMR (DMSO-d6) 11.03 (s, 1H, --OH), 8.56 (d, J=2 Hz, 1H), 8.18 (dd, J=9, 2 Hz, 1H), 7.96 (d, J=9 Hz, 1H), 7.59 (d, J=9 Hz, 1H), 6.88 (dd, J=9, 2 Hz, 1H), 6.81 (d, J=2 Hz, 1H), 3.86 (s, 3H); MS-FAB (m/e) 271 (p+1, 6); IR (KBr, cm-1) 3093 (b), 1727, 1604, 1459, 1282, 1120, 767. Anal. (C15H10O5 :
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[CH3:25][NH2:26]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[NH:26][CH3:25]
Reactant: CN
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Reaction time: 20 h

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) and a solution of methylamine in THF (2.0M, 1.0 ml) was heated at 100° C. with stirring for 20 hours in a sealed tube. After cooling, the solvent was removed under reduced pressure and the residue was recrystallized from MeOH-IPE to give 5-[5-amino-6-(methylamino)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (13 mg). The filtrate was concentrated in vacuo, and the residue was rinsed with MeOH-IPE to give the desired product (60 mg).