Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=CC=N[CH:3]=1.C([O:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20](Cl)[C:19]([CH:23]=[CH2:24])=[N:18][CH:17]=1)(C)(C)C>>[CH2:23]([C:19]1[C:20]([CH2:1][CH:2]([CH3:7])[CH3:3])=[CH:21][C:16]([C:15]([OH:14])=[O:25])=[CH:17][N:18]=1)[CH3:24]
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Reactant: O=C(O)c1cccnc1
Product: CCc1ncc(C(=O)O)cc1CC(C)C

Procedure:
6-Ethyl-5-isobutyl-nicotinic acid is prepared in analogy to Nicotinic acid 3 from 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester and 2,4,6-tri-(2-methyl-propenyl)cycloboroxane pyridine complex, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971); LC-MS: tR=0.64 min, [M+1]+=207.98.
Reaction SMILES: [C:1]1([CH:11]([N:13]=[C:14]=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:14]([NH:13][CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:15]
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Reactant: CC(N=C=O)c1cccc2ccccc12
Product: COc1cc2c(NC(=O)NC(C)c3cccc4ccccc34)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 14, 1-(1-naphthyl)ethyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDCl3) 1.41-1.57 (m, 2H), 1.76 (m, partially obscured by water peak), 1.86-2.05 (m, 5H), 2.02 (s, 3H), 2.91 (s, 2H), 3.87 (s, 3H), 4.02 (d, 2H), 5.95 (s, 1H), 7.19 (s, 1H), 7.23 (s, 1H), 7.39-7.52 (m, 3H), 7.6 (d, 1H), 7.71 (d, 1H), 7.84 (m, 1H), 8.12 (m, 1H), 8.57 (s, 1H), 8.64 (s, 1H), 10.67 (t, 1H); Mass Spectrum: M+H+ 500.
Reaction SMILES: Br[C:2]1[C:3](=[O:26])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[C:27]([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:3](=[O:26])[C:2]=1[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(OCc2ccc(F)cc2F)ccn(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (EXAMPLE 107) (0.14 g, 0.32 mmol), K2CO3 (88 mg, 0.64 mmol) and Cs2CO3 (0.10 g, 0.32 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (18 mg, 0.12 mmol), followed by trimethylboroxine (40 mg, 0.32 mmol). The reaction mixture was degassed, purged with argon, and heated at reflux for 4 h. The reaction mixture was cooled to room temperature, and partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 97:3 methylene chloride/MeOH) afforded 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-3-methyl-1H-pyridin-2-one as a white solid (0.09 g, 79%): mp 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 7.50-7.40 (m, 1H), 7.35-7.25 (m, 1H), 7.17 (d, J=9 Hz, 1H), 7.06 (d, J=6 Hz, 1H), 7.00-6.80 (m, 4H), 6.12 (d, J=9 Hz, 1H), 5.12 (s, 4H), 2.07 (s, 3H). ES HRMS m/z 360.1180 (M+H C20H16F3NO2 requires 360.1206).
Reaction SMILES: [Na].C(O)C.[N+]([CH:8]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:20])([O-])=O.Cl>C(Cl)Cl.O.C(O)C.O>[CH2:9]([OH:20])[CH2:8][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: O=C1CCCCCCCCCCC1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCO
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
For purposes of analytical determinations, the process of Example 2 was carried out with sodium boroduteride (NaBD4) To 40 milliliters of absolute ethanol was added about 2.5 grams of NaBD4 (0.05972 mole). The suspension was stirred and about 6.78 grams (0.02986 mole) solid 2-nitro cyclododecan-1-one were added in portions maintaining the temperature at about 15° C. The addition took about 20 minutes and some foaming was evidenced (gas evolution). After the addition was complete, a white, fairly thick precipitate was evident. An additional 10 milliliters of ethanol was added to facilitate stirring. The reaction mass was allowed to warm to room temperature and stirred overnight. The acidification process of the previous examples was followed and the precipitate again disappeared at a pH of 2 after addition of about 100 milliliters of 2% HCl. The solution had a fine white appearance. The ethanol/water was stripped to about 1/2 the starting volume and the water-oil emulsion left was taken up in methylene chloride. After two washings with methylene chloride, the combined organic layers were dried over magnesium sulfate and the solvent stripped off and vacuumed. A yellow oil was recovered which solidified fairly rapidly. The material melts at 40° C. and approximately 6.95 grams of product were recovered. Using the deuterium ions supplied in place of hydride ions from the NaBD4, the nuclear magnetic resonance spectroscopy confirmed the ring opening of the cyclic compound to form a dodecanol having a nitro substituent at the opposite end of the hydroxy function. Furthermore, the analysis confirmed that the carbonyl function had been converted to the hydroxy function.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH2:15][CH:14]=[CH:13][CH:12]=1)[CH2:8]2.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>C(O)C>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[C:11]1[CH:15]=[CH:14][C:13](=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:12]=1)[CH2:10]2
Reactant: C1=CCC(C2C3CC4CC(C3)CC2C4)=C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1C1C2CC3CC(C2)CC1C3
Reaction time: 144 h
Yield: 46.8 %

Procedure:
A 500 mL round bottom flask containing 2-adamantylcyclopentadiene (30.18 g, 150.7 mmol) was added benzophenone (27.50 g, 150.9 mmol) and 300 mL absolute ethanol. Once the solids had dissolved, sodium methoxide (15.00 g, 278 mmol) was added and the reaction was stirred for six days. The orange precipitate was collected by suction filtration and the air dried product was then stirred in 100 methanol for two days before the solid was collected by suction filtration and washed with 100 mL methanol. Drying in vacuo for two days provided 25.72 grams of desired product (46.8%). And second crop was obtained: 6.08 grams (57.9% for both crops). MS (GC-MS) m/z 364.5 (M+). 1H NMR (CDCl3): δ 1.52-2.23 (m, 14H, adamantyl-H), 2.80 (s, 1H, 2-H-adamantyl), 7.30-7.40 (m, 12H, phenyl-H), 6.05 (m, 1H, fulvene-H), 6.29, 6.59 (d, 3JHH=3.4, 3.7 Hz, 2H, fulvene-H). 13C NMR (CDCl3): δ 28.14, 28.14, 31.21, 31.21, 32.72, 32.72, 38.06, 38.92, 38.92 (adamantyl-C), 45.20 (2-C-adamantyl), 118.16, 125.01, 133.10 (fulvene-CH1), 127.68, 127.68, 127.77, 127.77, 128.31, 128.31, 132.02, 132.02, 132.08, 132.08 (phenyl-CH1), 141.70, 141.70 (ipso-C), 144.39, 148.69, 152.27 (fulvene-CH0). Elemental analysis calculated for C28H28: C, 92.26; H, 7.74. Found: C, 83.42; H, 6.59.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[CH:4][CH:3]=1.Br[C:11]([F:18])([F:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[F:17][C:11]([F:18])([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CN(C)C(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)C(F)(F)Oc1ccc(Br)c(F)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of 4-bromo-5-fluoro-phenol (4.0 g, 20.7 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (4.4 g, 21.6 mmol) and K2CO3 (3.2 g, 23.2 mmol) in 20 mL of DMAC was heated to 100° C. for 120 min. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL), water and brine and dried over MgSO4. The product (5.7 g, >96% purity by NMR, 17.6 mmol, 85% yield) was obtained as a yellow oil that solidified upon standing.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:35][C:34](=[O:36])[C:33]3([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:23]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:34]([C:33]1([NH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:22]([CH3:23])[CH3:21])=[CH:26][CH:27]=2)=[O:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:36]
Reactant: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 84 mg (0.42 mmol) of L-methionine methyl ester hydrochloride and 100 mg (0.35 mmol) of 2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of toluene, and the mixture was refluxed under heating overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with saturated brine and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 93 mg (59%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2cccnc2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cccnc6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.SC1C=C[C:18]([OH:21])=[CH:17]C=1.N1C=CC=CC=1.O>C(OC(=O)C)(=O)C>[C:18]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1)(=[O:21])[CH3:17]
Reactant: Oc1ccc(S)cc1
Reactant: O=C(O)c1csc2ccc(O)cc12
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11) (1,140 mg) prepared in above (1) was dissolved in acetic anhydride (2 ml), pyridine (4 ml). After 3 hours, water was added and the mixture was continuously stirred under ice-cooling for 1.5 hours. The deposited crystals were filtered, washed with water and dried to provide 1,349 mg of the title compound (12). Yield: 97.3% mp 239-240° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][N:9]=[C:8]([Br:11])[CH:7]=1)=[O:5].[CH2:13]([Mg]Br)[CH3:14].[NH4+].[Cl-]>C1COCC1>[Br:11][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH2:13][CH3:14])[O:10][N:9]=1
Reactant: CON(C)C(=O)c1cc(Br)no1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a chilled (−78° C.) solution of 3-bromo-isoxazole-5-carboxylic acid methoxy-methyl-amide (1.20 g, 5.11 mmol) in THF (56 mL) was added a 1 M solution of ethylmagnesium bromide (13.0 mL, 13.0 mmol) in THF dropwise over a 5 minutes period. The reaction was monitored by TLC (hexanes-EtOAc 4:1). After 5 hours, the reaction was transferred via a 16 gauge cannula to a 0° C. solution of saturated aqueous NH4Cl (75 mL). The resultant heterogeneous mixture was warmed to room temperature and maintained at this temperature for 15 hours. The aqueous phase was then extracted with Et2O (2×) and EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(3-bromo-isoxazol-5-yl)-propan-1-one as an orange solid which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([OH:22])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:24][CH3:25].O>CN(C)C=O>[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:22][CH2:24][CH3:25])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCC
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Sodium hydride (60%, oily, 1.28 g) was added to a solution of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (8.78 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 30 minutes. Iodoethane (2.82 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(1-benzyl-3-ethoxy-1H-pyrazol-4-yl)propionate (8.80 g, yield: 91%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(#N)C.C(Cl)Cl>[O:41]([CH2:40][CH2:39][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4CCOc3ccccc3)n2)ccn1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.24 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine and 70 mg (0.48 mmol) potassium carbonate in 5 mL acetonitrile was treated with 0.074 mL (0.48 mmol) β-bromophenetole at 0° C. The mixture was stirred at 50° C. for 8 h before it was cooled to ambient temperature for 16 h at which time MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromotography, the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[CH:28][CH:29]=2)[CH:2]=1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Reactant: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c2c1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Copper sulfate pentahydrate (70 mg; 0.28 mmol; 0.07 eq.) was added to a solution of 3-ethynyl-5-methyl-1H-indazole (665 mg; 4.26 mmol; 1.00 eq.), 4-(4-azidobenzoyl)morpholine (987 mg; 4.25 mmol; 1.0 eq.) and D-(−)-isoascorbic acid sodium salt (283 mg; 1.43 mmol; 0.34 eq.) in DMF (15 mL) and water (0.5 mL). The reaction suspension was heated in MW at 80° C. for 40 min then poured into HCl solution (1N) and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid (1.38 g, 83%). 1H NMR (300 Mz, DMSO-d6) δ: 13.25 (s, 1H), 9.36 (s, 1H), 8.20-8.10 (m, 3H), 7.68 (d, J=108.7 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.28 (dd, J=1.4, 8.6 Hz, 1H), 3.74-3.36 (m, 8H), 2.48 (s, 3H). HPLC (Condition A): Rt 3.21 min (purity 98.6%). MS (ESI+): 389.2, MS (ESI−): 387.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([NH:22][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C(CCl)Nc1cccc2[nH]ccc12
Solvent: CS(C)=O
Solvent: O
Product: O=C(CNCc1ccccc1)Nc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A solution containing 2-chloro-N-(1H-indol-4-yl)-acetamide (3.0 g, 14.4 mmol), benzylamine (4.76 g, 43.1 mmol) in DMSO (60 mL) was stirred at ambient temperature for 16 hours. The mixture was poured into water (700 mL) and the crude product crystallized as a solid. After filtration, the solids were dissolved in ethyl acetate (600 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate and filtered. Concentration of the ethyl acetate gave the title compound as a white solid, (3.36 g, 83.6%), mp 158-161° C.; MS EI m/e 279 (M+).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Yield: 96.9 %

Procedure:
Cyclohexylamine (1.27 mL, 11.17 mmol) was added to a solution of Compound 62 (2.0 g, 5.6 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 2.23 g (96%) of white solids. M.P. 158° C. 1H NMR (DMSO-d6): δ 1.22 (m, 2H), 1.35 (m, 3H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 3.87 (m, 1H), 5.51 (s, 2H), 7.16 (m, 2H), 7.24 (m, 1H), 7.32 (m, 2H), 7.42 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 10.36 (s, 1H). EIMS m/z 411 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:27]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:35]/[C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:26][N:27]=3)=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
A solution of 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 3.0 mmol) obtained in Step 1 in methanol (10 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.99 g, 3.0 mmol) and potassium carbonate (0.82 g, 5.9 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain (E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 16%).