Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=[O:3])[CH3:2].Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:56]=[C:50]3[CH2:51][N:52]([CH3:55])[CH2:53][CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:56]=[C:50]5[CH2:51][N:52]([CH3:55])[CH2:53][CH2:54][N:49]5[N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:30]=[CH:29]2)([CH3:34])([CH3:33])[CH3:32]
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCCCO
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (153 mg, 0.31 mmol), 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (61 mg, 0.21 mmol), potassium phosphate (110 mg, 0.52 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (9.87 mg, 0.02 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (5.95 mg, 0.01 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×150 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane) to give acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzyl ester (56 mg, 46%) as a light yellow solid: mp. 188-193° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 2.34 (s, 3H) 2.77 (t, J=5.29 Hz, 2H) 3.50 (s, 2H) 3.63-4.06 (m, 5H) 4.17-4.67 (m, 3H) 5.98 (s, 1H) 7.33-8.05 (m, 6H) 8.50 (d, J=2.64 Hz, 1H) 9.24 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:24]([Cl:25])=[C:23]([OH:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:15])[CH:14]=[CH:19][C:18]3[CH:21]=[CH:22][C:23]([OH:26])=[C:24]([Cl:25])[C:17]=3[Cl:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2)s1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1

Procedure:
1-(5-(4-Bromophenyl)thien-2-yl)-3-(2,3-dichloro-4-hydroxyphenyl)prop-2-en-1-one is prepared from 1-(5-(4-bromophenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[CH:7][C:6]=1[NH:12]C(=O)OC(C)(C)C)#[C:2][CH2:3][CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:3]([C:2]1[NH:12][C:6]2=[CH:7][N:8]=[C:9]([Cl:11])[CH:10]=[C:5]2[CH:1]=1)[CH3:4]
Reactant: CCC#Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc2cc(Cl)ncc2[nH]1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
A mixture of tert-butyl 4-(but-1-ynyl)-6-chloropyridin-3-ylcarbamate (3.5 g, 12.5 mmol) and TBAF (6.65 g, 25 mmol) in THF (60 mL) was heated at reflux for 24 hours. After cooling, the mixture was poured into ice water and extracted with CH2Cl2 (100 mL×3). The combined organic layers was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give 2-ethyl-5-chloro-1H-pyrrolo[2,3-c]pyridine (2.0 g, 89%). 1H-NMR (CDCl3, 300 MHz) δ 8.96 (brs, H), 8.46 (s, 1H), 7.44 (s, 1H), 6.24 (s, 1H), 2.89 (q, J=7.5 Hz, 2H), 1.37 (t, J=7.5 Hz, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([N:21]1[CH2:34][CH2:33][CH2:32][C@H:22]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>CCOCC>[NH2:11][C@H:12]([C:19]([N:21]1[CH2:34][CH2:33][CH2:32][C@H:22]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 161.4 %

Procedure:
To 1.79 g of compound (95) was added 19 ml of 25% hydrobromic acid--acetic acid cooled in an ice bath followed by stirring one hour at room temperature. The reaction mixture was added to 190 ml of desiccator ether and precipitates thus formed were quickly collected by filtration and dried overnight in a desiccator containing potassium hydroxide to provide 2.05 g of L-histidyl-N-phenyl-L-prolinamide.2-hydrobromide (96).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1c[nH]c(Sc2ccc(Cl)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2ccc(Cl)c(Cl)c2)c1

Procedure:
Methyl 5-(3,4-dichlorophenylthio)pyrrole-3-carboxylate (1.7 g.) was combined with 20 ml. of methanol and 20 ml. of 1N sodium hydroxide and refluxed for 3 hours. The methanol was allowed to evaporate, and approximately one volume of water was added to the aqueous residue, which was then extracted twice with ether, cooled in an ice-water bath, acidified with conc. hydrochloric acid, and the product extracted into ethyl acetate. The three ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a gummy solid which was crystallized by trituration with hexane and recovered by filtration (1.34 g., m.p. 156°-159° C.). Recrystallization from chloroform gave purified 5-(3,4-dichlorophenylthio)pyrrole-3-carboxylic acid (850 mg., m.p. 159°-161° C.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](C(O)=O)[CH:16]=3)[CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[NH2:36][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]1=[O:1])[CH2:18]2
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21

Procedure:
A solution of (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylic acid from Step B (65.0 mg, 0.233 mmol), diphenylphosphoryl azide (0.060 mL, 0.279 mmol), and triethylamine (0.039 mL, 0.279 mmol) in t-BuOH (5 mL) was heated to reflux for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=295 (M-C4H7).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: N#Cc1cccc(I)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C#N)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (103 mg, 0.55 mmol) and 3-iodobenzonitrile (134 mg, 0.59 mmol) according to the general procedure IC to give 68 mg (58%) of an orange-brown solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.26 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.79-7.78 (m, 1H), 7.73-7.70 (m, 1H), 7.61-7.57 (m, 1H), 7.48-7.43 (m, 3H), 7.22-7.18 (m, 2H), 3.67 (s, 3H), 3.00-2.95 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.7, 135.5, 134.8, 131.9, 131.3, 129.2, 128.5, 125.0, 120.2, 118.1, 116.7, 112.8, 91.7, 86.6, 51.7, 35.3, 30.8; EI-MS m/z 289 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[H][H]>N.[Ni]>[NH3:11].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[C:5]([CH3:12])[C:4]=1[CH3:13]
Reactant: COc1ccc(CC#N)c(C)c1C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: COc1ccc(CCN)c(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (4-methoxy-2,3-dimethyl-phenyl)-acetonitrile (200 mg, 1.14 mmol) and Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was stirred under 60 psi of hydrogen gas at room temperature for 18 hours. Tlc analysis showed that not all of the starting material had been consumed and so further Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was added. The reaction mixture was stirred under 60 psi of hydrogen gas for an additional 18 hours at room temperature and was then filtered through Arbocel®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 to afford the title product as a pale brown solid, 233 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Fc1ccc(/C=C/CBr)cc1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccc(F)cc2)c(C)c(C)c1NC=O
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-fluorobenzene, the title compound was synthesized according to Reference Example 17a. Yield: 52%. Melting point: 196-198° C. (Ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:24])[C:19]([F:23])([F:22])[CH2:20]I>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][C:19]([F:23])([F:22])[CH:18]([F:24])[F:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: FC(F)C(F)(F)CI
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 105 °C
Yield: 71.1 %

Procedure:
To a solution of 4-nitro phenol (860 mg, 6.1 mmol) in DMF (10 ml) was added potassium carbonate (1.4 g, 10 mmol) and 1,1,2,2-tetrafluoro-3-iodo-propane (500 mg, 2 mmol). The reaction mixture was heated at 100-110° C. for 6 hr, then cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 ml), then washed once with 5% sodium hydroxide solution, several times with water, and finally brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 1-nitro-4-(2,2,3,3-tetrafluoro-propoxy)-benzene (360 mg, 68%) as solid.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:24])=[CH:6][CH:5]=3)[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:9][CH:10]=2)=[N:27][CH:28]=1
Reactant: Brc1ccc(I)nc1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B(O)O)cc2)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(Br)cn3)cc2)cc1
Temperature: 95 °C
Yield: 82 %

Procedure:
A mixture of (4-(di-p-tolylamino)phenyl)boronic acid (Compound 26) (3.17 g, 10 mmol), 2-iodo-5-bromo-pyridine (5.68 g, 20 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (2.76 g, 20 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 95° C. overnight. The resulting solution was diluted with ethyl acetate (200 mL), loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 4:1 to 3:2). The desired fraction was collected and concentrated to give a light yellow solid (Compound 27) (3.5 g, in 82% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH2:20][CH2:19]1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:20][CH2:19][O:18][CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(N2CCOCC2)nc1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.24 mmol) was used in general procedure 2 with 6-morpholinonicotinic acid (0.30 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-morpholinonicotinamide. MS (Q1) 437.0 (M)+
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[CH:12]2)[N:4](COCC[Si](C)(C)C)[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=[CH:12]2)[NH:4][CH:3]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2nccc(-n3cnc(-c4ccccc4)c3)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c[nH]c2nccc(-n3cnc(-c4ccccc4)c3)c12
Yield: 75.9 %

Procedure:
Compound (97b) (0.272 g) was dissolved in THF (2.3 mL), and tetrabutylammonium floride (2.0 mL, a 1.0 M solution in THF) was added to the resulting solution, followed by reflux for 24 hr. The reaction solution was concentrated and was then purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain compound (97c) (0.140 g, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22]CC5C=CC(OC)=CC=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH2:22])=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Temperature: 120 °C
Yield: 89 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (480 mg, 0.818 mmol) and TFA (2.0 mL). The mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 20 min then the solvent was removed. The crude residue was treated with 1N NaOH and the resulting precipitate was collected to give 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (340 mg, 0.728 mmol, 89%) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 466.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (1H, s), 9.01 (1H, s), 8.84 (1H, s), 8.71 (1H, s), 8.18 (1H, d, J=8.8 Hz), 8.03 (2H, m, J=8.4 Hz), 7.85-7.93 (1H, m), 7.45 (2H, m, J=8.2 Hz), 7.28 (2H, s), 2.34 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30].[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)(c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(C#C[Si](C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
4-[1-Ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (11.20 g, 24.43 mmol) in DMF (100 ml) is added trimethylsilylacetylene (6.90 ml, 48.85 mmol), dichlorobis(triphenylphosphine) palladium (1.71 g, 2.44 mmol) and triethylamine (23.84 ml, 171 mmol) and heated to 80° C. overnight. The reaction mixture is concentrated and filtered through a pad of silica gel eluted with 10% EtOAc/Hexanes. The eluent is concentrated and chromatographed (330 g SiO2, 2% EtOAc/Hexanes) to yield the title compound (8.07 g, 81%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1
Reactant: COc1cccc(Nc2cc(F)ccc2[N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: COc1cccc(Nc2cc(F)ccc2N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
(5-Fluoro-2-nitrophenyl)-(3-methoxyphenyl)amine (3.35 g, 12.7 mmol) was dissolved in EtOAc (50 mL) and the flask evacuated and flushed with nitrogen gas. 10% Pd/C (0.35 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas, at RT overnight. A further amount of 10% Pd/C (0.35 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas for a further 1 h. The resultant mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound as a red gum (2.97 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 7.15 (1H, t, J=8.08 Hz), 6.91 (1H, dd, J=9.89, 2.72 Hz), 6.76-6.62 (2H, m), 6.49-6.37 (3H, m), 5.29 (1H, s), 3.77 (3H, s), 3.52 (2H, s)
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CC(C)=O.O1CCOCC1.[Pd]>[C:28]([N:12]1[CH2:13][CH2:14][C:8]2[C:9](=[N:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[N:7]=2)[CH2:11]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c(NC(C)C)nc2C1
Temperature: 45 °C
Reaction time: 17 h
Yield: 47.5 %

Procedure:
To a pressure reactor charged with a red-orange solution of tert-butyl 4-(3-(isopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate (2.0 g, 5.37 mmol) in acetone (100 mL) and dioxane (100 mL) was added palladium, 10 wt % on activated carbon (0.229 g, 2.148 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (5.04 mL, 53.7 mmol) was added at 23° C. The mixture was stirred under hydrogen at 310 kPa for 17 hr at 45° C. The reaction mixture was filtered through Celite™, rinsed with dioxane, and concentrated via rotary evaporation. The crude material was purified via medium pressure chromatography using 10% to 100% gradient of EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (1.068 g, 47.5%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) 6 ppm 1.16-1.21 (m, 6H), 1.42 (s, 9H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.58 (t, J=5.9 Hz, 0.9H), 2.70 (t, J=5.6 Hz, 1.1H), 2.87-2.98 (m, 4H), 3.51 (br s, 4H), 3.67-3.75 (m, 2H), 4.06-4.15 (m, 1H), 4.41 (s, 1.1H), 4.44 (s, 0.9H), 5.50 (d, J=7.8 Hz, 1H), 5.53 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 419.0.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(Cl)(Cl)Cl.Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:14]
Reactant: OCCCCCCO
Reactant: C1=COCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: OCCCCCCOC1CCCCO1
Yield: 57 %

Procedure:
6-(2-Tetrahydropyranyloxy)hexanol was prepared by a modification of the method described by Bohlmann, Jeute and Reinecke, Chem. Ber., 1969, 102, 3283. 3,4-Dihydro-2-H-pyran (33.6 g., 0.4 mole) was added dropwise at 30°C. with stirring to hexane-1,6-diol (47.2 g., 0.4 mole) in chloroform (500 ml.) and concentrated hydrochloric acid (30 drops). The temperature was allowed to rise to 40°C. and maintained at this level for 3 hours. The solution was then washed with aqueous sodium bicarbonate and then water and dried over potassium carbonate. The solvent was removed in vacuo, and the residue distilled under reduced pressure to give 6-(2-tetrahydropyranyloxy)hexanol (46.1 g., 57%), b.p. 102°-120°C./0.2 mm.Hg.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]([Mg]Br)=[CH2:11].[Mg].C(Br)=C.[Cl-].[NH4+]>O.C1COCC1>[CH:1]1([CH2:7][CH:8]([OH:9])[CH:10]=[CH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCC1CCCCC1
Reactant: C=C[Mg]Br
Agent: C=CBr
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)CC1CCCCC1
Reaction time: 0.5 h

Procedure:
A solution of 60 g (0.47 mol) of cyclohexylacetaldehyde in 400 ml of abs. THF is added dropwise at -20° to a solution of vinylmagnesium bromide in abs. THF, prepared from 13.8 g (0.57 mol) of magnesium and 66.3 g (0.62 mol) of vinyl bromide in 500 ml of abs. THF. When the addition is complete, the whole is stirred for 30 minutes at -20° and then hydrolysed with 900 ml of saturated ammonium chloride solution. After diluting with 250 ml of H2O, the reaction mixture is extracted three times with 1 liter of ether each time, washed three times with 500 ml of brine each time, dried with MgSO4 and then concentrated by evaporation in a rotary evaporator. The residue is distilled at 50°/0.1 mbar.