Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:25][CH3:26])=[N:4][C:5]([N:22]([CH3:24])[CH3:23])=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH3:21].[Li]CCCC.C[O:33]B(OC)OC.OO.[OH-].[Na+].Cl>C1COCC1.O>[CH3:23][N:22]([CH3:24])[C:5]1[N:4]=[C:3]([O:25][CH3:26])[C:2]([OH:33])=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH3:21])[N:6]=1
Reactant: COB(OC)OC
Reactant: COCOCCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1nc(N(C)C)nc(OC)c1O
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution at −5° C. containing 120 mg (0.25 mmol) of 5-bromo-4-methoxy-6-(10-(methoxymethoxy)decyl)-N,N-dimethylpyrimidin-2-amine in 3 mL of anhydrous THF were added 390 μL (0.62 mmol) of 1.6 M solution of n-BuLi in hexanes. The reaction mixture was stirred at −5° C. for 20 min. Then to the mixture were added 84 μL (0.75 mmol) of trimethoxy boron and the reaction mixture was stirred for 1 h. Then to reaction mixture were added 0.55 mL of 30% aq. H2O2 followed by 0.18 mL of 3N aq. NaOH. The reaction mixture was stirred for 30 min and poured into 50-mL of water. The mixture was neutralized with diluted aq. HCl and extracted with two 50-mL portions of ethyl acetate. The combined organic solution was washed with a 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 2:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 47 mg (51%); silica gel TLC Rf 0.50 (2:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.29-1.21 (br m, 10H), 1.64-1.54 (m, 4H), 2.58 (br s, 2H), 3.07 (s, 6H), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.92 (s, 3H) and 4.59 (s, 2H); 13C NMR (CDCl3) δ 26.14, 27.65, 29.29, 29.37, 29.42, 29.45, 29.52, 29.69, 31.19, 37.21, 37.21, 53.24, 55.03, 67.86, 96.32, 126.92, 154.98, 155.94 and 158.04; mass spectrum (APCI+), m/z 370.2700 (M+H) (C19H36N3O3 requires 370.2706).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][S:9][C:10]2[S:14][C:13]([NH:15]C(=O)C)=[N:12][CH:11]=2)=[N:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:15][C:13]1[S:14][C:10]([S:9][CH2:8][C:6]2[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=2)=[CH:11][N:12]=1
Reactant: CCc1cnc(CSc2cnc(NC(C)=O)s2)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cnc(CSc2cnc(N)s2)o1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (1.3 g, 4.6 mmol) in 1 N hydrochloric acid (15 mL) was stirred at 80-90° C. for 3 h. It was cooled to rt and the pH of the solution was adjusted to 7 with sodium carbonate. The product was extracted with methylene chloride (3×10 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was triturated with ethyl ether and the precipitated solid was collected to afford 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (610 mg, 55%) as a solid, mp 119-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (0.30 g, 1.91 mmol), benzyl bromide (0.36 g, 2.10 mmol, 1.1 eq), potassium carbonate (0.792 g, 5.73 mmol, 3.0 eq) and tetrabutylammonium iodide (5.0 mg, 0.014 mmol, 0.007 eq) in dimethylformamide (5 mL) was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction mixture and the resulting solid precipitate was isolated by vacuum filtration and dried to provide the title compound (0.455 g, 96%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[N:21]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1oc(-n2ncc3ccccc32)nc1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (1.50 g), 1H-indazole (1.18 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were collected by filtration, dried and dissolved in a mixed solvent of tetrahydrofuran (20 mL) and ethanol (20 mL). A 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was acidified with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were collected by filtration using isopropyl ether and dried to give 3-[4-(4-chlorophenyl)-2-(1H-indazol-1-yl)-5-oxazolyl]propionic acid (824 mg, yield 45%) as pale-yellow prism crystal. melting point: 204–205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][N:8]([CH2:18][C:19]#[N:20])[C:7]=2[CH:21]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+]>C(OC(=O)C)(=O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][N:8]([CH2:18][CH2:19][NH:20][C:22](=[O:24])[CH3:23])[C:7]=2[CH:21]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)N(CC#N)CC(c1ccccc1)O2
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)N(CCNC(C)=O)CC(c1ccccc1)O2
Reaction time: 16 h

Procedure:
The compound obtained in Step D (350 mg; 1.25 mmol) is dissolved in a Parr reactor with acetic anhydride. Raney nickel (30% by weight, 115 mg) and sodium acetate (1.5 eq.; 1.87 mmol; 154 mg) are then added. The mixture is left at 50° C. for 16 hours under a hydrogen pressure of 40 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (1/9)). The title product is obtained in the form of white crystals and is recrystallised from an Et2O/i-PrOH (6/4) mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.ClCCl>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[C:14]([CH3:28])[O:13][N:12]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of 4,6-dimethylpyrimidin-2-amine (84 mg, 0.682 mmol) in pyridine (8 mL), stirred under nitrogen at room temperature, was added 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (346 mg, 1.147 mmol). The reaction mixture was stirred at room temperature overnight. 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.142 mL, 0.682 mmol) was then added to the mixture and the reaction heated by microwaves to 150° C. for 15 minutes. Dichloromethane (DCM) (15 mL) was added to the mixture and the organic phase washed with water (2×25 mL), then dried using a hydrophobic frit. Solvent was removed in vacuo to give the crude product (100 mg) as an orange oil. This was used directly in the next step without further purification. LCMS (2 min, formic) Rt 0.81 min, m/z (ES+) 389 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(O)C>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Solvent: CCO
Product: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 235a (55 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.59-1.83 (m, 2H) 2.02 (s, 3H) 2.75 (s, 3H) 3.97 (t, J=6.43 Hz, 2H) 6.31 (d, J=7.35 Hz, 1H) 7.04-7.18 (m, 4H) 7.25-7.45 (m, J=8.64, 3.86 Hz, 3H) 7.77 (d, J=8.46 Hz, 1H) 8.35 (d, J=7.35 Hz, 1H) 8.94 (d, J=8.82 Hz, 1H) 9.96 (s, 1H) 10.99 (s, 1H) 14.31 (s, 1H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1.CN(C=O)C.[Sn](Cl)Cl.O.[OH-].[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1cnc(Oc2ccccc2Br)nc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cnc(Oc2ccccc2Br)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(2-bromophenoxy)-5-nitropyrimidine (5.30 g, 17.9 mmol) in DMF (35.8 ml, 17.9 mmol) was added tin (II) chloride (17.0 g, 89.5 mmol) and water (4.48 ml, 17.9 mmol). The reaction was sonicated for 15 min and became deep red and exothermic in nature. The reaction was stirred at RT. After 4 h, the reaction was diluted with EtOAc, cooled to 0° C. and neutralized with 10% NaOH. Tin residue precipitated out of the solution. The reaction was diluted with EtOAc. The suspension was allowed to settle. The organic layer was decanted and passed through a fritted funnel. This procedure was repeated two more times to extract product into the organic layer. The organic layer, containing the product, was washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel using 90:10 DCM:(90:10:1 DCM:MeOH:NH4OH). Upon concentration of the product fractions, the resulting brown solid was dissolved/suspended in DCM, washed with water to remove the DMF, washed with brine, dried over MgSO4, filtered, and concentrated. Yellow solid, 2-(2-bromophenoxy)pyrimidin-5-amine was obtained. MS Calc'd for C10H8BrN3O: [M]+=265. Found: [M+H]+=266; [M+2H]+=267.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]2[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=2)[C@@H:14]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CO>[CH:1]1([CH:7]=[CH:8][C:9]2[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=2)[C@@H:14]2[O:21][C@H:18]([CH2:19][O:20][C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:54][CH:53]=3)[C@@H:16]([OH:17])[CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C=CC1CCCCC1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C=CC4CCCCC4)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 54.7 %

Procedure:
Compound (2b) (320 mg, 0.95 mmol) was azeotroped three times with anhydrous pyridine. The mixture was added with anhydrous pyridine (1.5 ml) and 4,4′-dimethoxytrityl chloride (380 mg, 1.12 mmol), and subsequently with DMAP (41 mg, 0.34 mmol). Finally, triethylamine (160 μl, 1.14 mmol) was added and the mixture was stirred for 21 hours at room temperature. After characterization by TLC (CHCl3:MeOH=9:1), the product was purified using a silica gel column with the development solvent of CHCl3 and MeOH while varying the ratio of CHCl3:MeOH from 98:2 to 95:5 to obtain the target Compound (3b) as a pale yellow solid (329 mg, 0.52 mmol, yield 54%). The target compound was determined by 1H NMR for identification. Further, mass analysis was carried out by MALDI-TOF MS and it was identified as the target compound (calcd. for C38H43N2O7 [M+H]+ 639.306, found 639.496).
Reaction SMILES: [C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=O)[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][OH:41]>CO>[C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=[N:40][OH:41])[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=O)CO3)C(C)(C)C)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=NO)CO3)C(C)(C)C)c1
Yield: 82.1 %

Procedure:
To a 100 mL round bottom flask, containing 100 mg (0.24 mm) of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-formyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide, added 0.50 g of triethylamine, 70 mg (1 mm) of hydroxylamine hydrochloride and 25 mL of methanol. The reaction mixture was refluxed for 1 hour. The methanol was removed on a rotary evaporator and the residue was dissolved with chloroform and dilute HCl and transferred to a separatory funnel. The chloroform extract was dried and evaporated to dryness. The residue was chromatographed on silica and the product eluted with 40% ethyl acetate in hexane. Evaporation of solvent yielded 85 mg of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-[3-(hydroxyimino-methyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl]-hydrazide. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.7 (s, 1H), 7.4 (d, 1H), 7.05 (s, 2H), 6.95 (s, 1H), 6.55 (d, 1H), 6.15 (m, 1H), 4.8 (m, 1H), 4.0-4.4 (m, 4H), 2.248 (s, 6H), 1.915 (s, 3H), 1.574 (s, 9H); TLC: Rf=0.40 (1:1 ethyl acetate:hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[C:24]([C:26]([NH2:28])=[O:27])[O:23][N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:25]=[C:24]([C:26]([NH2:28])=[O:27])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1ccn2Cc1ccc(-c2cc(C(N)=O)on2)cc1
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
To a mixture of 4-methylindole (20 mg, 0.15 mmol) in THF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 30 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 35 mg, 0.125 mmol) in THF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The THF was evaporated and the residue was taken up in DMF (2 mL). The reaction mixture was stirred at room temperature for 8 days, then H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (16-20% acetone/CH2Cl2) to give 3-[4-(4-methyl-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (6 mg, 14%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (br. s., 1H), 7.97 (br. s., 1H), 7.81 (d, J=8.2 Hz, 2H), 7.43-7.56 (m, 2H), 7.17-7.34 (m, 3H), 6.91-7.03 (m, 1H), 6.80 (d, J=6.9 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.47 (s, 2H), 2.45 (s, 2H).
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:21]1([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][N:7]=[C:6]3[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: Cc1cccc(Nc2ncnc3ccc(F)cc23)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ncnc3ccc(-n4cnc5ccccc54)cc23)c1
Temperature: 150 °C
Yield: 47.5 %

Procedure:
A mixture of 6-fluoro-4-(3-methylanilino)quinazoline hydrochloride salt (0.347 g), benzimidazole (0.33 g), potassium carbonate (0.78 g) and DMF (7 ml) was stirred and heated at 150° C. for 24 hours. The mixture was evaporated and the residue was suspended in a mixture of methylene chloride and methanol. The suspension was filtered and the filtrate was evaporated to give a solid which was washed with ethyl acetate and purified by column chromatography using a 24:1 mixture of methylene chloride and methanol as eluent. The resultant solid was triturated with methylene chloride, filtered and dried to give 6-(1-benzimidazolyl)-4-(3-methylanilino)quinazoline (0.2 g), m.p. 245-246° C.; NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 6.96-6.99 (d, 1H), 7.27-7.33 (t, 1H), 7.35-7.42 (m, 2H), 7.64-7.77 (m, 3H), 7.82-7.86 (m, 1H), 7.99-8.03 (d, 1H), 8.15-8.20 (m, 1H), 8.66 (s, 2H), 8.90 (d, 1H), 9.80 (s, 1H);
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH2:22][CH3:23])/[C:17](=[N:24]/[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2F)/[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH2:22][CH3:23])/[C:17](=[N:24]/[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:27]=2[O:3][CH2:4][C@@H:5]2[CH2:6][CH2:7][C:8](=[O:10])[NH:9]2)/[CH:16]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCC(=O)N2)cc(C(C)(C)C)n1C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
Sodium hydride (50 mg, 60% dispersion in mineral oil, 1.25 mmol) was added to a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (72 mg, 0.62 mmol) in dimethylformamide (0.5 mL). After 10 minutes a solution of Example 125A (0.12 g, 0.31 mmol) in dimethylformamide (1.0 mL) was added and the mixture stirred for 3 hours. The reaction mixture was partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (hexanes:EtOAc:MeOH:Et3N (4:4:1:0.2) to afford the title compound (50 mg, 0.10 mmol, 33% yield). 1H NMR (500 MHz, Pyridine-d5) δ ppm 0.76 (t, J=7.5 Hz, 3H), 1.16 (s, 9H), 1.57-1.64 (m, 2H), 1.64-1.69 (m, 1H), 1.95-2.03 (m, 1H), 2.27 (ddd, J=16.9, 9.7, 7.3 Hz, 1H), 2.37-2.45 (m, 1H), 3.71 (s, 3H), 3.88 (t, J=9.3 Hz, 1H), 4.05-4.12 (m, 1H), 4.31 (t, J=7.3 Hz, 2H), 4.38 (dd, J=9.6, 3.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.64 (dd, J=8.5, 2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 9.25 (s, 1H); MS (ESI+) m/z 481.2 [M+H]−. Anal. calculated for C24H31F3N4O3: C, 59.99; H, 6.50; N, 11.66. Found: C, 59.81; H, 6.45; N, 11.52.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>COCCO>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(F)ccc12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was dissolved in 2-methoxyethanol (97 ml). Formamidine acetate (20.13 g, 193.4 mmol) was added and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 N, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4(3H)-one as an off-white solid (10.35 g, 65% yield):
Reaction SMILES: IC1C=CC([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14](C(=O)C)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].[OH-].[K+]>C(O)CC(C)C.[Cu].O>[C:36]1([C:35]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:41]=[CH:40][C:39]([N:14]([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[CH:16]=[CH:17][C:18]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=4)=[CH:16][CH:17]=3)=[CH:19][CH:20]=2)=[CH:38][CH:37]=1
Reactant: CC(=O)N(c1ccccc1)c1ccccc1-c1ccc(I)cc1
Reactant: CCCCCCCCCCCC
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)CCO
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4ccc(-c5ccccc5)cc4)cc3)cc2)cc1
Yield: 77.8 %

Procedure:
There were mixed 16.5 g (0.040 mole) of N-(4′-iodobiphenylyl)acetanilide, 11.8 g (0.048 mole) of N-(4-biphenyl)aniline, 8.3 g (0.060 mole) of anhydrous potassium carbonate, 0.1 g (0.002 mole) of copper powder and 10 ml of n-dodecane, followed by reaction at 200 to 212° C. for 15 hours. The reaction product was extracted with 200 ml of toluene, and the insoluble matter was removed by filtration. Then, the filtrate was concentrated to obtain oily matter. The oily matter was dissolved in 60 ml of isoamyl alcohol, and 4 ml of water and 4.00 g (0.060 mole) of 85% potassium hydroxide were added, followed by hydrolysis at 130° C. After isoamyl alcohol was removed by steam distillation, extraction with 250 ml of toluene was performed, followed by washing with water, drying and concentration. The concentrate was purified by column chromatography (carrier: silica gel, eluate: toluene/n-hexane=1/2) to obtain 15.2 g (yield: 77.8%, HPLC purity: 97.0%) of N-(4-biphenylyl)-N,N′-diphenyl-4,4′-diaminobiphenyl. The melting point was 126.6 to 127.4° C.