Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[C:52]([O:51][C:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:18]3[CH:19]=[C:14]([NH:13][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])[N:12]=4)[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[N:17]=3)[CH:21]=2)[CH2:44][CH2:45]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 32.4 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (50 mg, 0.129 mmol) and K2CO3 (36 mg, 0.258 mmol) in DMF (5 mL) was added tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperazine-1-carboxylate (48 mg, 0.155 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration, the residue was washed by petroleum ether to give tert-butyl-4-(2-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate (25 mg, 33%) as crude oil. LC-MS: 599.4 [M+H]+, tR=1.53 min.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2Cl)(=[O:4])[CH3:3].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:26][C:27]1[C:28]([CH3:34])=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[C:28]([CH3:34])[CH:29]=1)(=[O:4])[CH3:3]
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OC(C)=O
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloro-7-methoxyquinazoline, hydrochloride salt, was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 6-acetoxy-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 60% yield;
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[CH3:27][O:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:27][O:28][CH2:29][CH2:30][S:31]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:33])=[O:32]
Reactant: COCCS(=O)(=O)Cl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Product: COCCS(=O)(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was treated with 2-methoxyethylsulfonyl chloride essentially as in Example 79. Chromatography gave the desired product (65 mg).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CBr
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccccc21
Reaction time: 1 h

Procedure:
3-azido-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one (see example 1, 5.0 kg) was added portionwise under nitrogen to potassium tert-butoxide (3.03 kg) in dry tetrahydrofuran (50 liters) at such a rate that the temperature is is maintained below 5°, and the reaction mixture was stirred for 1 hour after the addition is completed. A solution of ethyl bromoacetate (4.38 kg) in tetrahydrofuran (5 liters) was then added slowly so as to maintain the temperature below 5°. The reaction mixture was then stored at room temperature overnight. Filteraid (1.5 kg of Hiflo) was added, and the reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the combined tetrahydrofuran solution was evaporated to dryness to give 3-azido-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one which is used without further purification in the next step.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[N:13]=[C:12]2[CH:22]([CH3:24])[CH3:23])=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:21])[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[N:13]=[C:12]2[CH:22]([CH3:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCCC2
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium borohydride (100 mg) was added to a stirred solution of Intermediate 3 (420 mg) in dichloromethane (3 ml) and methanol (3.00 ml). The reaction mixture was stirred for 1 hour. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (376 mg). LC/MS MH+ 319, Rt 0.77 min (2 minute run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cccc(CN2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82.8 %

Procedure:
A mixture of 3-methoxybenzaldehyde (10.0 g, 73.4 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (21.0 g, 146.9 mmol), sodium triacetoxyborohydride (31.1 g, 146.9 mmol), and acetic acid (4.4 mL, 73.45 mmol) in 1,2-dichloroethane (100 mL), was stirred at ambient temperature. After 19 h, a 2 N aqueous sodium carbonate solution (220 mL) was added portionwise. After stirring for 15 min, the aqueous layer was separated and extracted with methylene chloride (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to provide 8-(3-methoxybenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (16.0 g, 82%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.27-7.20 (m, 1H), 6.93-6.88 (m, 2H), 6.79 (dd, J=2.4, 8.2 Hz, 1H), 3.94 (s, 4H), 3.82-3.78 (m, 3H), 3.50 (s, 2H), 2.56-2.47 (m, 4H), 1.74 (t, J=5.6 Hz, 4H); ESI MS (m/z) 264 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:14]2[C:20]([F:21])=[C:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=[CH:17][C:15]=2[N:16]=1.CCCCCC.C(OCC)(=O)C.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:14]2[C:20]([F:21])=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccc(F)cc34)oc2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2nc3ccc(CC(=O)O)c(F)c3o2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To methyl (2-(5-fluoro-1-methyl-3-indolyl)-7-fluoro-6-benzoxazolyl)acetate (279 mg, 0.78 mmol) were added THF/methanol (1/1, 20 ml) and 0.25N NaOH (9.4 ml, 2.35 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured in 1N HCl to acidify the mixture therewith, followed by extraction with chloroform/methanol (10/1). The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The crystals thus obtained were collected by filtration under reduced pressure, washed with hexane, and dried under reduced pressure to give (2-(5-fluoro-1-methyl-3-indolyl)-7-fluoro-6-benzoxazolyl)acetic acid (208 mg, 78%) as a brown crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:20][C:21]([C:23]3[O:27][C:26]([C:28](C)=[CH2:29])=[N:25][CH:24]=3)=[O:22])[CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:31]=[O+][O-]>C(Cl)Cl.CO>[C:28]([C:26]1[O:27][C:23]([C:21]([NH:20][C@H:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:22])=[CH:24][N:25]=1)(=[O:31])[CH3:29]
Reactant: O=[O+][O-]
Reactant: C=C(C)c1ncc(C(=O)N[C@@H](CC(=O)O)Cc2ccc(-c3cccc(Cl)c3)cc2)o1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ncc(C(=O)N[C@@H](CC(=O)O)Cc2ccc(-c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-4-(3′-chlorobiphenyl-4-yl)-3-(2-(prop-1-en-2-yl)oxazole-5-carboxamido)butanoic acid (60 mg, 0.14 mmol) in DCM (2 mL) and MeOH (2 mL) at −78° C. is bubbled ozone for 30 seconds. After 30 seconds ozone is removed and oxygen is bubbled for 10 minutes. After bubbling oxygen for 10 minutes the −78° C. bath is removed and the reaction is quenched with polymer supported triphenylphosphine and the reaction is stirred at room temperature for 2 hours. After 2 hours the reaction is filtered to remove triphenylphosphineoxide on supported polymer and the filtrate is collected and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-3-(2-acetyloxazole-5-carboxamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (13 mg). HPLC retention time=1.67 minutes (condition D); MS (m+1)=427.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.59 (m, 2H) 2.60 (s, 3H) 2.87 (dd, J=10.9, 3.3 Hz, 1H) 2.94 (dd, J=10.9, 5.1 Hz, 1H) 4.46-4.60 (m, 1H) 7.31 (d, J=8.1 Hz, 2H) 7.36-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.62 (d, J=8.3 Hz, 3H) 7.69 (t, J=1.9 Hz, 1H) 7.94 (s, 1H) 8.86 (d, J=8.6 Hz, 1H) 12.31 (br. s., 1H).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].F[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].Cl>CN(C=O)C.O>[C:11]([O:10][C:8]([NH:1][C@@H:2]([CH2:3][O:4][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1c([N+](=O)[O-])cccc1C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of BOC-Ser-OH (981 mg, 4.78 mmol) in DMF (5.00 mL) was added to a suspension of NaH (60% in mineral oil, 402 mg, 10.0 mmol) in DMF (5 mL). The mixture was stirred at 0° C. for 1 h and a solution of 2-fluoro-1-nitro-3-(trifluoromethyl)benzene (1 g, 4.78 mmol) in DMF (5 mL) was added. After 2 h the mixture was diluted with H2O and acidified to pH 3 with 1 N HCl. The mixture was extracted with EtOAc, the combined extracts dried over MgSO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-6-(trifluoromethyl)phenoxy)propanoic acid (1.53 g, 81%) as a light yellow solid. MS m/z 417 (M+Na)′
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]3[CH:17]1[CH2:25][C:26]([OH:28])=O)(=[O:15])=[O:14])[CH:7]=[CH:6]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]([NH:66][CH2:67][C:68]1[CH:69]=[C:70]2[C:75](=[CH:76][CH:77]=1)[CH2:74][CH:73]([NH2:78])[CH2:72][CH2:71]2)([CH3:65])([CH3:64])[CH3:63]>C(Cl)Cl>[C:62]([NH:66][CH2:67][C:68]1[CH:69]=[C:70]2[C:75](=[CH:76][CH:77]=1)[CH2:74][CH:73]([NH:78][C:26](=[O:28])[CH2:25][CH:17]1[N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)(=[O:14])=[O:15])[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]13)[CH2:72][CH2:71]2)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)NCc1ccc2c(c1)CCC(N)C2
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NC3CCc4cc(CNC(C)(C)C)ccc4C3)ccc2c1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a cooled (0° C.) suspension of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S2) (310 mg, 0.77 mmol, 1.0 eq.) in DCM (20 ml) was added HATU (600 mg, 1.54 mmol, 2 eq.) and DIPEA (0.4 ml, 2.31 mmol, 3 eq.) and the reaction mixture was allowed to stir for 30 min. Finally, 6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-amine (A15) (180 mg, 0.77 mmol, 1.0 eq.) was added and the reaction mixture and it was stirred at RT for 16 h. The mixture was diluted with DCM (100 ml) and successively washed with ammonium chloride solution (50 ml), sodium bicarbonate solution (50 ml), water (10 ml) and brine (10 ml). The organics were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 6% MeOH/DCM) to yield the pure title compound as a white solid. Yield: 34% (160 mg, 0.26 mmol); MS, Rt=3.6 min; m/z=615.1 [MH]+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1.O>C(O)C>[CH:15]1([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:16]1
Reactant: NCC1CC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Following general procedure 2B: To a solution of N-(4-fluoro-3-nitrophenyl)acetamide (15.4 g, 77.7 mmol) in 80% aqueous ethanol (150 mL) was added cyclopropanemethylamine (10 mL) at room temperature. The reaction mixture was heated to reflux overnight. After cooling to room temperature, H2O (300 mL) was added and the desired product precipitated out as an orange solid (18 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][C:12]([OH:15])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:12]([O:15][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:9])([CH3:14])([CH3:13])[CH3:11]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Yield: 49.2 %

Procedure:
A solution of 4-chloro-pyridine-2-carbonyl chloride (150 g, 0.857 mol) in DCM (750 ml) was slowly added to a solution of 2-methyl-propan-2-ol (158.8 g, 2.14 mol) and DMAP (21 g, 0.171 mol) in DCM (750 mL) and pyridine (750 mL). The resultant mixture was stirred at 30° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography to give 4-chloro-pyridine-2-carboxylic acid t-butyl ester (90 g, 49% yield) as a yellow solid. 1H NMR (CDCl3): δ 8.63 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.44 (d, J=8.0 Hz 1H), 1.63 (s, 9H); MS (ESI) m/z: 214 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=O)C.O.[NH2:17][NH2:18]>C(O)C>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]([NH:17][NH2:18])=[O:3]
Reactant: CCOC(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2ccccc2c1
Yield: 48.4 %

Procedure:
To a solution of 2-naphthyl carboxylic acid ethyl ester (2.0 g, 9.99 mmol) in absolute ethanol (30 ml) was added hydrazine hydrate (4.85 ml, 99.9 mmol) and the reaction mixture was heated at reflux temperature for 72 h. The reaction mixture was cooled and the precipitate was filtered off, washed with 96% ethanol (2×10 ml) and diethyl ether (3×10 ml), dried in vacuo at 50° C. which afforded 0.9 g (48%) of naphthalene-2-carboxylic acid hydrazide as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]([O-])=O.[Na+]>CC(O)=O.O>[NH:1]1[C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:12]=[N:13]1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-amino-4-methylbenzoate D-1 (5.0 g, 30 mmol) in AcOH (140 mL) at 0° C. was added a solution of sodium nitrite (2.1 g, 30 mmol) in H2O (3.5 mL). After addition, the mixture was stirred at rt for 24 h. Then half of the solvent was removed under reduced pressure and the resulting mixture was diluted with H2O, and extracted with EtOAc. The combined organics were washed H2O and brine, and concentrated to give the title compound. LCMS (ESI) calc'd for C9H9N2O2 [M+H]+: 177. found 177.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:20])[CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:20])[CH2:16][C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: COc1cc(NC(=O)CC(=O)O)ccc1-c1cnco1
Reactant: Cc1cccc(N)c1
Product: COc1cc(NC(=O)CC(=O)Nc2cccc(C)c2)ccc1-c1cnco1

Procedure:
56 was prepared from 56A by a route analogous to that used for the preparation of 5, replacing aniline with m-toluidine. LC/MS: ret. timeA=3.783 min., MS (M+H)+=366.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.Cl.[CH3:30][N:31]([CH3:38])[C:32]([CH:34]1[CH2:37][NH:36][CH2:35]1)=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][N:31]([CH3:38])[C:32]([CH:34]1[CH2:37][N:36]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:35]1)=[O:33]
Reactant: CN(C)C(=O)C1CNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N(C)C)C3)n(C)c2n1
Reaction time: 18 h
Yield: 62.8 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidine-3-carboxylic acid dimethylamide hydrochloride salt (53 mg, 0.32 mmol) in DCE (4 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 363 as a white solid (83 mg, 64%). LCMS (Method G): RT=5.23 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.08 (m, 1 H); 7.70 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 9 H); 3.69-3.62 (m, 2 H); 3.57-3.46 (m, 3 H); 2.96 (s, 3 H); 2.93 (s, 3 H) and 2.90 (s, 3H)
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]([CH3:10])([O-])[CH3:8].[K+].[C:12]([C:16]1[CH:17]=[C:18]([CH:45]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1)[CH:19]=[CH:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH:29]=[CH:30][C:31]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=2)[CH:28]=1)[CH:24]=O)([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([C:16]1[CH:17]=[C:18]([CH:45]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1)[CH:19]=[CH:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH:29]=[CH:30][C:31]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=2)[CH:28]=1)[CH:24]=[CH:6][C:7]1[C:10]2[C:8]([C:7]([CH:6]=[CH:24][C:23]3[CH:26]=[C:27]([CH:29]=[CH:30][C:31]4[CH:32]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:34]=[C:35]([C:37]([CH3:38])([CH3:39])[CH3:40])[CH:36]=4)[CH:28]=[C:21]([CH:20]=[CH:19][C:18]4[CH:45]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=[C:16]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:17]=4)[CH:22]=3)=[C:10]3[C:8]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:47][CH:16]=[CH:12][CH:13]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(C=Cc3c4ccccc4c(C=Cc4cc(C=Cc5cc(C(C)(C)C)cc(C(C)(C)C)c5)cc(C=Cc5cc(C(C)(C)C)cc(C(C)(C)C)c5)c4)c4ccccc34)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.7 %

Procedure:
Dry N,N-dimethylformamide (10 ml) was added to a rapidly stirred mixture of 9,10-bis(dimethylmethylphosphonate)anthracene (395 mg, 0.935 mmoles), potassium t-butoxide (220 mg, 1.963 mmoles) and 3,5-bis(3′,5′-di-t-butylstyryl)benzaldehyde (1.000 g, 1.87 mmoles) under nitrogen and stirred at room temperature for 90 minutes. Distilled methanol (60 ml) was then added and the precipitate filtered and dried under suction. The crude product (925 mg) was recrystallized from dichloromethane-methanol and then chromatographed on flash silica using dichloromethane-pet. ether (40-60) (1:3) as the eluent. The solvent was removed to give 9,10-bis[3′,5′-bis(3″,5″-di-t-butylstyryl)styryl]anthracene (206 mg, 18%). lamdamax(film)/nm 308, 420.
Reaction SMILES: O[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:15]O)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.CCOC(C)=O.[H][H]>[Pd].CC(O)=O>[CH3:15][C:10]1[C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: OCc1cccc2c1-c1ccccc1C2O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1-c1ccccc1C2
Yield: 77.3 %

Procedure:
A solution of 9-hydroxyfluoren-4-methanol (2.6 g, 12.2 mmol) in 1.1 EtOAc:AcOH was charged with catalytic amount of 10% palladium on charcoal. The mixture was treated with hydrogen under 1600 psi, at room temperature for three days. The catalyst was removed and the solvent was evaporated under reduced pressure. Recrystalyzation from MeOH afforded 1.7 g (77.0%) of the product as a light yellow solid.