Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:59])[C:49]2[C:29]([CH:30]=[C:31]3[CH:48]=[C:47]4[C:34]([C:35]5[C:40]([C:41]6[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=6)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][C:32]3=2)=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[CH3:59][C:25]1([CH3:24])[C:49]2[C:29]([CH:30]=[C:31]3[CH:48]=[C:47]4[C:34]([C:35]5[C:40]([C:41]6[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=6)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][C:32]3=2)=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:21]4[C:22]5=[C:23]6[C:18](=[CH:19][CH:20]=4)[CH:17]=[CH:16][CH:15]=[C:14]6[CH:13]=[CH:12][C:11]5=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:26]1
Reactant: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)C=C(c2ccc(-c3ccc4ccc5cccc6ccc3c4c56)cc2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 57 %

Procedure:
A mixture of 5 g (14 mmol) of 1-(4-bromophenyl)pyrene, of 7.53 (16 mmol) 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of Tetrakis(triphenylphosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 4.95 g (yield 57%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 620.2; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.06 (s, 1H), 8.86 (d, J=8.00 Hz, 1H), 8.80 (d, J=8.00 Hz, 1H), 8.75 (s, 1H), 8.71 (d, J=8.00 Hz, 2H), 8.33˜8.27 (m, 2H), 8.22˜8.20 (m, 2H), 8.14˜8.05 (m, 6H), 7.94 (d, J=8.00 Hz, 2H), 7.89 (s, 1H), 7.85˜7.69 (m, 7H), 1.77 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]2[CH:46]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]4[CH:46]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1cccc2nc(CCl)cn12
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5c(C)cccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 77 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.8 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.22 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes upon which 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (218 mg, 1.2 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC) upon which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (280 mg, 77.7%,) as a light yellow solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H), 2.6 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=455.6. HPLC: (97.3%, Condition-A).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([CH:22]=[N:23][CH:24]=2)[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])=[O:6])[CH3:2].Cl.[CH:26]1(CON)C[CH2:27]1>>[CH:2]1([CH2:1][O:3][NH:4][C:5]([C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH:22]=[N:23][CH:24]=3)[C:12]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[O:6])[CH2:27][CH2:26]1
Reactant: NOCC1CC1
Reactant: CCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: Cl
Product: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(I)cc1F

Procedure:
The title compound was prepared in an analogous fashion to N-ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide, using O-(cyclopropylmethyl)-hydroxylamine hydrochloride as the starting material. 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.82 (s, 1H), 10.36 (s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.73 (dd, J=10.4 Hz, 1.8 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.58 (t, J=8.4 Hz, 1H), 3.67 (d, J=7.2 Hz, 2H), 1.12 to 1.01 (m, 1H), 0.54-0.48 (m, 2H), 0.28-0.23 (m, 2H); LCMS (method D2): RT=1.33 min, [M+H]+=468.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]([OH:30])=[C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]3[CH:17]=2)[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([C:24]1[CH:23]=[N:22][N:19]2[CH:20]=[CH:21][C:16]([N:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]3[CH:10]=[C:5]([F:4])[CH:6]=[CH:7][C:8]=3[O:30][CH2:2][CH3:3])=[CH:17][C:18]=12)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCC)cc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Iodoethane (0.17 g, 1.08 mmol) was added to a mixture of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Int-76) (0.2 g, 0.54 mmol) and K2CO3 (0.23 g, 1.62 mmol) in CH3CN (10 mL) and continued stirring at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in hexane as eluent) to afford the desired compound (Int-77). MS (ESI): m/z 398.1 (M+H).
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1)(C)(C)C.Cl[C:36]1[N:37]=[C:38]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[C:39]2[CH:44]=[C:43]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]3)[S:42][C:40]=2[N:41]=1>>[CH3:55][S:52]([N:49]1[CH2:50][CH2:51][N:46]([CH2:45][C:43]2[S:42][C:40]3[N:41]=[C:36]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][OH:6])=[N:9][CH:10]=4)[N:37]=[C:38]([N:56]4[CH2:57][CH2:58][O:59][CH2:60][CH2:61]4)[C:39]=3[CH:44]=2)[CH2:47][CH2:48]1)(=[O:54])=[O:53]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(CO)nc4)nc3s2)CC1

Procedure:
2-(tert-Butyl-diphenyl-silanyloxymethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 362. NMR: (CDCl3): 2.58-2.60 (4H, m), 2.73 (3H, s, Me), 3.20-3.22 (4H, m), 3.75 (2 μl, s), 3.81-3.84 (4H, m), 3.90-3.92 (4H, m), 4.76 (2H, s, NH2), 6.92 (1H, s, Ar), 7.25 (1H, d, J 8.3, Ar), 8.61 (1H, d, J 8.3, Ar) and 9.51 (1H, s, Ar). MS: (ESI+): MH+=505.14
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[F:12][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:19]=[O:20])[CH:21]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: O=Cc1cncc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1F
Temperature: 95 °C
Yield: 25.1 %

Procedure:
A mixture of 4-cyano-3-fluorophenylboronic acid (0.495 g, 3 mmol), 5-bromonicotinaldehyde (0.558 g, 3.00 mmol), sodium carbonate (2M in water, 3.00 mL, 6.00 mmol), bis(triphenylphosphine)palladium(II) chloride (0.053 g, 0.075 mmol) in DMF (10 mL) was heated to 95° C. for 3 h. After concentration, the residue was dissolved into CH2Cl2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH—CH2Cl2, v/v, 0.5%-1%) yielded a colorless solid (170 mg) ESI-MS m/z: 227 [M+1]+.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1)(=O)C.[S].N1[CH2:19][CH2:18][O:17]CC1.[OH:20]CC[NH-]>>[OH:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([CH2:19][C:18]([OH:17])=[O:20])=[CH:5][C:6]=1[CH3:12]
Reactant: [NH-]CCO
Reactant: C1COCCN1
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Agent: [S]
Product: Cc1cc(CC(=O)O)cc(C)c1O

Procedure:
2-(4-Hydroxy-3,5-dimethylphenyl)acetic acid is prepared in a known way (cf. J. Org. Chem. 11, 798 (1946)) from 4-acetyl-2,6-dimethylphenol, sulfur, and morpholine (Willgeroth-Kindler Reaction) and has a melting point of 147° C. The acid is converted into the 2-hydroxyethylamide (yellow-brown oil) through the methyl ester (melting point 95° C.) by the method of Example 1.1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1C(=O)N([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][C@@H:57]2[S:61][CH2:60][C@@H:59]3[NH:62][C:63]([NH:65][C@H:58]23)=[O:64])=O)C(=O)C1.O>CN(C)C=O>[O:64]=[C:63]1[NH:62][C@H:59]2[CH2:60][S:61][C@@H:57]([CH2:56][CH2:55][CH2:54][CH2:53][C:51]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]3[N:16]4[N:15]=[C:14]([C:28]5[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=5)[C:13]([C:11]5[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[N:12]=5)=[C:17]4[CH:18]=[CH:19][CH:20]=3)=[O:50])[C@H:58]2[NH:65]1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)CCCC[C@@H]4SC[C@@H]5NC(=O)N[C@@H]54)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (33 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL) was added triethylamine (0.03 mL, 0.21 mmol) and d-biotin-N-hydroxysuccinimide ester (27 mg, 0.08 mmol). The resultant mixture was warmed to room temperature and stirred for 30 minutes. A subsequent 5 mg of d-biotin-N-hydroxysuccinimide ester was added and the mixture was stirred an additional 30 minutes. Water was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and then brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% to 8% methanol in dichloromethane) provided 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-pentanamide (25 mg, 51%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.80 (d, 1 H), 7.58 (d, 2 H), 7.32 (m, 1 H), 7.00 (d, 2 H), 6.60 (s,1 H), 6.39 (m, 1 H), 6.33 (d, 1 H), 6.18 (m, 1 H), 6.02 (m, 1 H), 5.72 (s, 1 H), 5.62 (broad, 1 H), 4.44–4.31 (m, 2 H), 4.19 (m, 1 H), 3.89 (s, 3 H), 3.39 (m, 2 H), 3.28 (m, 2 H), 3.06 (m, 1 H), 2.95 (m, 2 H), 2.77 (dd, 1 H), 2.58 (d, 1 H), 2.20–2.05 (m, 4 H), 1.82–1.54 (m, 12 H), 1.39 (m, 2 H); MS m/z 698 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[N+]([O-])=O.[N:16](OCCC(C)C)=[O:17].[CH3:24]C[O-].[Na+].Cl>C(O)C>[CH2:1]([O:2][C:3]([C:4]1[C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[O:17][N:16]=1)=[O:15])[CH3:24]
Reactant: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC[O-]
Reactant: CC(C)CCON=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1noc2cc(Br)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A solution of (4-bromo-2-nitro-phenyl)-acetic acid methyl ester (0.99 g, 3.61 mmol) in ethanol (8 mL) at room temperature is treated with isoamyl nitrite (0.60 mL, 4.47 mmol). A solution of NaOEt in ethanol (1.9 M, 2.0 mL) is added, and the mixture is stirred at 60° C. for 2 hours and at room temperature for 16 hours. The mixture is neutralized with HCl (1.0 M, 4.0 mL) and concentrated under reduced pressure. The residue is extracted with ethyl acetate (20 mL×2) and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25% ethyl acetate in hexanes to give the title compound (0.36 g, 37%). ES/MS m/e 269.8; 271.8 (M+1).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.Cl>CCOCC>[C:10]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])(=[O:15])[CH3:9]
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1nc2ccccc2c(=O)o1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
Cyclohexylmagnesium bromide (240 ml of a 2M solution in ether, 0.48 mol) in ether (200 ml) was added dropwise to a solution of 2-methyl-4H-3,1-benzoxazin-4-one (100 g, 0.62 mol) in ether (1100 ml) at -10° C. over 2 h. The mixture was stirred at this temperature for 2 h, then at ambient temperature for 30 min. After cooling to -10° C. the suspension was treated with 2M HCl (600 ml), keeping the temperature below 0° C. After stirring for 15 min the layers were separated, and the ethereal layer washed sequentially with water (500 ml), 5% sodium hydroxide solution (2×500 ml) and finally water (2×500 ml). The organic layer was separated, dried (MgSO4), evaporated in vacuo and chromatographed on silica gel using petrol:ethyl acetate (2:1) to give (2-acetamidophenyl) cyclohexyl methanone (28 g, 24%) as a pale yellow solid. mp 66° C. 1H NMR (CDCl3, 360 MHz) δ 1.25-1.89 (10H, m), 2.23 (3H, s), 3.33 (1H, m), 7.13 (1H, d of t, J=6 and 1 Hz), 7.53 (1H, d of t, J=6 and 1 Hz), 7.92 (1H, d, J=6 Hz), 8.76 (1H,d, J=6 Hz), 11.73 (1H, brs).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH2:24]([O:20][C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
At 0° C., diethyl azodicarboxylate (3.4 mL) was added to a THF solution (13 mL) of 4-amino-3-nitrophenol (1.0 g), benzyl alcohol (1.0 g) and triphenyl phosphine (1.9 g), and stirred at room temperature for 5 hours. The reaction liquid was diluted with ethyl acetate, and the organic layer was washed with aqueous 1 N sodium hydroxide solution, aqueous saturated sodium hydrogencarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/8 to 3/7) to obtain 4-(benzyloxy)-2-nitroaniline (1.2 g) as a red solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C[C@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: C[C@H](c1ccccc1)n1c(O)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol (3.87 g, 11.9 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:4.8:95). The cliromatographed product was triturated sequentially with hot acetonitrile, hot isopropanol, and hot ethanol and washed with diethyl ether after each trituration and filtration. The filtrates were combined, concentrated under reduced pressure, washed with diethyl ether, and dried in a vacuum oven overnight to provide 214 mg of 4-amino-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol as tan needles, mp greater than 250° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>CN(C=O)C.C(Cl)Cl>[CH3:21][C:22]1[CH:26]=[CH:25][N:24]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[N:23]=1
Reactant: Cc1cc[nH]n1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)n1
Temperature: 110 °C
Yield: 42.1 %

Procedure:
To a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2CO3 (496 mg, 3.59 mmol) in DMF (10 mL) was added 3-methyl-1H-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110° C. and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo and the residue obtained was dissolved in DCM (40 mL) and washed with H2O (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a residue which was purified by silica column chromatography (PE/EA=8/1 to 3/1) to afford pure product 3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg, 1.007 mmol, 42.1% yield). 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 6.42 (d, J=2.4 Hz, 1H), 2.36 (s, 3H). ES-LCMS: m/z 272.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.O1CCCC1.C([Li])CCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CCCCCC>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[C:6]=1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cc1cnn(C2CCCCO2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)cnn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 73.8 %

Procedure:
To a solution of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.258 g, 1.55 mmol) in tetrahydrofuran (6 mL, 70 mmol) at −78° C. was added 2.5 M of n-butyllithium in hexane (0.80 mL). The reaction was stirred at −78° C. for 50 minutes, and then tributyltin chloride (0.60 mL, 2.2 mmol) was added. The reaction was kept at −78° C. for 2 hours and then quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture was diluted with more water and extracted with ethyl acetate. The organic portion was dried with MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 520.6 mg (74%) of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-1H-pyrazole. LCMS (ESI): M+H=457.2; 1H NMR (400 MHz, DMSO-d6) δ 7.31 (s, 1H), 5.11 (d, J=8.3 Hz, 1H), 3.81 (d, J=11.4 Hz, 1H), 3.59-3.48 (m, 1H), 2.23 (dd, J=20.7, 9.4 Hz, 1H), 2.04 (s, 3H), 1.97 (d, J=12.8 Hz, 1H), 1.90 (d, J=13.3 Hz, 1H), 1.48 (m, 9H), 1.30 (dd, J=14.5, 7.3 Hz, 6H), 1.20-0.97 (m, 6H), 0.86 (t, J=7.3 Hz, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:20])[CH3:19])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:22]Br>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:20])[CH2:19][Br:22])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(Oc1cccc(C(C)=O)c1)c1ccccc1
Reactant: BrBr
Product: COC(=O)C(Oc1cccc(C(=O)CBr)c1)c1ccccc1

Procedure:
[3-(2-Bromo-acetyl)-phenoxy]-phenyl-acetic acid methyl ester was synthesized from (3-acetyl-phenoxy)-phenyl-acetic acid methyl ester and bromine as described in example 31.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:42]=[C:43]([OH:47])[CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[N:10]=[C:9]1[O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:40][C:39]([F:38])([F:48])[F:49])[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (4.7 g, 8.58 mmol, intermediate 18) in DMF (15 mL) was added 3-(trifluoromethoxy)phenol (1.83 g, 10.28 mmol) and potassium carbonate (2.4 g, 17.39 mmol). The mixture was stirred at 80° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5.3 g, 89.3% yield) as yellow oil. LCMS retention time 3.974 min; LCMS M+Na 713.