Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Yield: 81.7 %

Procedure:
4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (8.0 g, 26.0 mmol) synthesized according to the method described in WO95/18125, diethyl malonate (4.79 g, 29.9 mmol), acetic acid (1.04 ml) and piperidine (1.03 ml) were mixed. While removing water through Dean-Stark trap, the mixture was refluxed under heating. Three and a half hours later, toluene was evaporated and the obtained residue was recrystallized from ethyl acetate-hexane to give the title compound (9.55 g, yield 82%) as pale-brown white crystals.
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[C:3]=1[CH3:49].[C:50](O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)([CH3:52])[CH3:51]>>[C:45]([O:44][C@@H:39]([C:4]1[C:3]([CH3:49])=[C:2]([C:50]([CH3:52])=[CH2:51])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7]1)[C:40]([O:42][CH3:43])=[O:41])([CH3:47])([CH3:48])[CH3:46]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Product: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 80 %

Procedure:
Prepared in 80% yield from methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 698.4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:31])=[C:25]([CH2:27][CH2:28][CH2:29][OH:30])[N:26]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(N(CC)CC)C>ClCCl>[CH3:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]([CH3:31])=[C:25]([CH2:27][CH2:28][CH2:29][O:30][S:2]([CH3:1])(=[O:4])=[O:3])[N:26]=3)=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Add methanesulfonyl chloride (0.086 g, 0.60 mmol) to a cool (0° C.) solution of 3-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propan-1-ol (0.170 g, 0.458 mmol) and triethylamine (0.070 g, 0.69 mmol) in dichloromethane (3 mL). Warm the reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash the crude organic material with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate to give crude methanesulfonic acid 3-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propyl ester (0.206 g, 100%): MS (m/e): 450(M+1).
Reaction SMILES: C(=[N:14][C:15]1[C:16]2[C:17]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:25][CH2:24][C:18]=3[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>O1CCCC1>[CH2:29]([N:26]1[CH2:27][CH2:28][C:17]2[C:16]3[C:15]([NH2:14])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:24][CH2:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CN2CCc3[nH]c4cccc(N=C(c5ccccc5)c5ccccc5)c4c3CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of benzhydrylidene-(3-benzyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indol-10-yl)amine (0.794 g, 1.74 mmol) in tetrahydrofuran was added 1 M hydrochloric acid (10.0 mL). The mixture was stirred at room temperature for 10 min, and then tetrahydrofuran was removed in vacuo. The aqueous mixture was extracted with ethyl acetate (2×). The acidic residue was basified with ammonia and extracted with dichloromethane (3×). The combined dichloromethane solution was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness to give 0.416 g (82%) of the title compound: mp 164-165° C.; 1H NMR (300 MHz, CDCl3) δ 7.76, 7.45-7.26, 6.88, 6.74, 6.29, 3.86, 3.27-3.23, 3.06-2.97; MS (ESI+) m/z 292 (M++H).
Reaction SMILES: C([N:4]1[CH2:26][CH2:25][C:7]2[N:8]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[OH:18])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].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>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[OH:18])[C:7]3[CH2:25][CH2:26][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
2-(2-Allyl-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (740 mg, 2.132 mmol) was dissolved in 40 mL DCM, and purged with nitrogen for 5 min. Pd(PPh3)4 (50 mg, 0.0432 mmol) and 1,3-dimethylbarbituric acid (998 mg, 6.397 mmol) were added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with saturated aqueous potassium carbonate (20 mL) solution and extracted with DCM (2×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography over neutral alumina (eluent 50% MeOH in DCM) to obtain 400 mg of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CD3OD, freebase) δ (ppm): 8.71 (d, 2H), 8.04 (d, 2H), 7.22 (s, 1H), 7.13 (d, 1H), 6.94 (d, 1H), 5.33 (t, 1H), 4.42 (m, 4H), 3.63 (t, 2H), 3.28 d (t, 1H), 3.22 (m 1H), 2.38 (s, 3H). This racemate was separated by chiral semi-preparative HPLC to obtain enantiomers 39a and 39b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11](#[N:14])[CH:12]=[CH2:13].C1N2CCN(CC2)C1>CCOCC>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][CH2:13][C:12]([C:11]#[N:14])=[CH:7]2
Reactant: C=CC#N
Reactant: O=Cc1cc(Cl)ccc1O
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: N#CC1=Cc2cc(Cl)ccc2OC1
Temperature: 25 °C

Procedure:
5-chloro-2-hydroxy-benzaldehyde Compound 15a (10.0 mmol, 1.7 g), acrylonitrile (50.0 mmol, 2.14 mL) and DABCO (2.33 mmol, 0.26 g) were mixed together and heated to reflux overnight using an oil bath. After the flask was cooled to room temperature, Et2O (100 mL) was added and the Et2O layer was washed with 10% NaOH solution followed by 1N HCl and brine. The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo to obtain 6-chloro-2H-chromene-3-carbonitrile Compound 15b as a yellow solid (1.42 g, 74%), which was used in the next step without further purification (the preceding was described in Wise, L. et al. J. Med. Chem., 1988, 31, 688).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 363.36 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([Cl:13])[N:10]=[CH:9]2)[N:5]=[CH:4][N:3]=1.[NH3:14]>C(O)(C)C>[Cl:13][C:11]1[N:10]=[CH:9][N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:14])[CH:7]=2)[CH:12]=1
Reactant: Clc1cc(-n2cnc(Cl)c2)ncn1
Reactant: N
Solvent: CC(C)O
Product: Nc1cc(-n2cnc(Cl)c2)ncn1
Yield: 98.2 %

Procedure:
A solution of 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (0.99 g, 4.60 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in a sealed vial for 18 h. After cooling the solid precipitate was filtered and dried to give 6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-amine (884 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, d, J=1.51 Hz), 8.32 (1H, d, J=0.76 Hz), 7.96 (1H, d, J=1.51 Hz), 7.30 (2H, br. s.), 6.58 (1H, d, J=1.01 Hz). LCMS: RT=0.57 min, MH+=196.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)=[N:15][N:14](COC(=O)C(C)(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:35](=[O:39])[N:36]([CH3:38])[CH3:37].[OH-].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([N:24]([CH3:25])[CH3:26])=[CH:22][CH:23]=4)=[N:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:35]([N:36]([CH3:37])[CH3:38])=[O:39]
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2ccc(N(C)C)cc2)nn3COC(=O)C(C)(C)C)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]nc(Cc4ccc(N(C)C)cc4)c3c2)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(4-dimethylamino-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester was dissolved in tetrahydrofuran. 1 M sodium hydroxide in methanol was added to the mixture, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered, and concentrated. The crude material was purified by mass-triggered reverse-phase HPLC to give 2-amino-5-[3-(4-dimethylamino-benzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.43 (dd, J=8.5, 2.3 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.5 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 5.34 (s, 2H), 4.17 (s, 2H), 2.96 (s, 6H), 2.81 (s, 6H). MS: m/z 415.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:24]#[N:25])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1O
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccccc3C#N)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (110 mg, 0.337 mmol) and 2-cyanophenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (121.4 mg, 88.1%). Melting point: 197.7-201.1° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[C:39]2[C:40]3[CH:53]=[CH:52][S:51][C:41]=3[C:42](=[O:50])[NH:43][C:44]=2[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]>>[CH3:49][O:48][C:47]1[CH:46]=[CH:45][C:44]2[NH:43][C:42](=[O:50])[C:41]3[S:51][CH:52]=[CH:53][C:40]=3[C:39]=2[C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Br)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Yield: 52.6 %

Procedure:
Following General Procedure E, tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate (160 mg, 0.50 mmol) was reacted with bis(pinacolato)diboron (140 mg, 0.55 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (140 mg, 0.45 mmol) to afford the desired product (110 mg, 47%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[CH:17][CH:16]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 4-(1-phenylethyl)benzoic acid (150 mg, 0.66 mol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (303 mg, 0.797 mmol), triethylamine (2 mL) in dichloromethane (25 mL) was stirred at 25° C. for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (101 mg, 0.66 mmol) was added. After stirring at 25° C. for 12 hours, water (15 mL) was added to the reaction mixture. And the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated to give a residue in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenylethyl)benzamide (100 mg, 42%). LRMS (M+H+) m/z: calcd 360.02. found 360. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.25 (t, J=4.5 Hz, 1H), 7.83 (d, J=7.2 Hz, 2H), 7.32-7.26 (m, 7H), 5.85 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 4.28-4.26 (m, 1H), 2.15 (s, 3H), 2.10 (s, 3H), 1.57 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=O)[CH2:2][CH3:3].C[O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=1>>[CH2:8]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13]([OH:23])=[O:12])=[CH:17][CH:18]=1)=[O:7])[CH2:9][CH3:10]
Reactant: CCCC(CCC)C(=O)O
Reactant: COC(=O)C=Cc1ccc(N)cc1
Product: CCCC(CCC)C(=O)c1ccc(C=CC(=O)O)cc1

Procedure:
This compound, a precursor to compounds 9 and 10, was synthesized from 2-propyl-pentanoic acid (0.78 mL, 4.9 mmol) and 3-(4-amino-phenyl)-acrylic acid methyl ester (0.86 g, 4.9 mmol) according to Methods a and b aforementioned. Total yield, 1.05 g (70% for 2 steps); 1 H NMR (CDCl3, 10% DMSO-d6) δ 9.49 (s, 1 H), 7.71 (d, J=8.5 Hz, 2 H), 7.55 (d, J=15.9 Hz, 1 H), 7.45 (d, J=8.4 Hz, 2 H), 6.31 (d, J=15.9 Hz, 1 H), 2.40 (m, 1 H), 1.7-1.1 (m, 8 H), 0.87 (t, 6 H).
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][OH:28].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:10][C:5]2[N:6]([C:2]([O:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[N:3][N:4]=2)[N:7]=1
Reactant: OCC(F)(F)F
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: FC(F)(F)COc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A mixture 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (38 mg, 0.1 mmol), 2,2,2-trifluoroethanol (22 μL, 0.2 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (60 μL, 0.3 mmol) and anhydrous THF (0.5 mL) in a sealed tube was stirred at 70° C. for 3 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 10 min gradient, 100% B hold for 5 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to yield 30 mg of the desired product with 90% purity. The impure product was further purified using a silica gel cartridge (4 g) eluting with a gradient of EtOAc (30-100%) in hexanes to afford 24 mg (55%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.81 min, (M+H)+=439.1. 1H NMR (CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.40-7.49 (m, 1H), 7.29-7.33 (m, 2H), 7.14-7.30 (m, 3H), 7.09 (d, J=8.56 Hz, 2H), 5.05-5.07 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[CH3:17][C:18]1[N:22]([CH2:23][C:24](=[O:32])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=[C:20]([C:33](O)=O)[CH:19]=1.CCN=C=NCCCN(C)C.Cl>CO>[O:6]=[C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:11]2[N:12]=[C:33]([C:20]3[CH:19]=[C:18]([CH3:17])[N:22]([CH2:23][C:24]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:32])[N:21]=3)[NH:13][C:10]=2[C:8](=[O:9])[N:7]1[CH2:14][CH2:15][CH3:16]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: Cc1cc(C(=O)O)nn1CC(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(C)n(CC(=O)Nc4ccccc4)n3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dipropyl-5,6-diaminouracil (2.20 mmol), in MeOH (10 mL), is added an equimolar amount of the title C compound, 5-methyl-1-phenylcarbamoylmethyl-1H-pyrazole-3-carboxylic acid, and EDCl (2.21 mmol). The reaction mixture is stirred at RT for 4-5 h while being monitored by TLC. The solvent is concentrated in vacuo and the amide intermediate is precipitated by the addition of water. After filtration, the solid is dissolved in MeOH (10 mL) and aqueous NaOH (2.5 N, 15 mL) and the mixture is stirred at 50-60° C. for 1 h. The MeOH is distilled off, and the residue is taken up in H2O and acidified with HCl to pH 4-5. The precipitate is collected by filtration, washed with water, and purified by flash chromatography (ethyl acetate-petroleum ether) to afford 2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-phenyl-acetamide: m.p. 255-257° C.; 1H-NMR (DMSO-d6) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.32 (s, 3H), 3.84 (m, 2H), 3.98 (m, 2H), δ0.08 (s, 2H), 6.74 (s, 1H), 7.08 (m, 1H), 7.33 (m, 2H), 7.59 (m, 2H), 10.41 (s, 1H), 13.85 (s, 1H).
Reaction SMILES: [F:1][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6]1.O.NN.Cl>C1COCC1.C(O)C>[F:1][CH:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(F)c2ccccc2)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N[C@H]1CC[C@H](OCC(F)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 0.7 g of racemic trans-2-[4-(2-fluoro-2-phenyl-ethoxy)-cyclohexyl]-isoindole-1,3-dione in 15 mL of THF and 15 mL of ethanol was added 0.3 mL of hydrazine hydrate and the mixture heated to reflux for 4 h, then 5 mL of 6N HCl was added and the reflux was continued for 1 h. The cooled mixture was concentrated under reduced pressure to remove ethanol and filtered. The filter pad was washed with 2×10 mL of dilute HCl and the combined filtrates basified to pH 10 with 20% sodium hydroxide and extracted with 3×25 mL portions of chloroform. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Further drying under vacuum gave 0.4 g of product as an oil. MS (m+1)=238.3.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][B:15]([OH:17])[OH:16])=[C:4](Cl)[N:3]=1.Cl.[OH-:20].[Na+]>>[OH:16][B:15]([OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(Cl)c2ncn(CCCCB(O)O)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCCCB(O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
The compound prepared in Example 3, 2-amino-6-chloro-9-(4-dihydroxyborylbutyl)purine, (0.5 g, 1.85 mmol) was added to aqueous HCl (5 mL, 2N), and the reaction mixture was heated to reflux for 5 hours. After cooling to room temperature, aqueous NaOH (10%) was added to neutralize the reaction mixture to pH 7. Water was evaporated under high vacuum, and methanol was added to the residue to remove the unreacted starting material. The remaining solid was washed with water (3×20 mL), then stirred in water overnight. After filtration, the product was air-dried for 2 days. Yield 81%; Wt. 0.38 g; mp 202°-205° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.20-1.32 (m, B CH2 CH2), 1.62-1.75 (m, B CH2 CH2 CH2), 3.88-3.98 (t, CH2 CH2 N), 6.33-6.50 (s, H2N C2 guanine), 7.40-7.45 (s, (HO)2 B), 7.68-7.71 (s, H C8 guanine), 10.47-10.53 (H N3 guanine). Electrospray Mass Spectrum (MH)+ (low resolution); Calcd. 252.12 (C9H14O3N5B); Found 252.10 (79 ppm).