Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.Cl.CN.[CH:17]([N:20](C(C)C)CC)(C)C>C(#N)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:20][CH3:17])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: CN
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 70 °C
Yield: 96.5 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (5.0 g, 22.7 mmol) in acetonitrile (50 mL) was added methylamine hydrochloride salt (1.84 g, 27.2 mmol) and diisopropylethylamine (14.6 g, 113.6 mmol), and the reaction mixture was heated at 70° C. overnight. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were separated, combined, washed with water (50 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (4.7 g, crude), which was directly used in the next step without further purification. MS (ES+) C9H11ClN2O2 requires: 214, 216. found: 215, 217 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1.C([O:26][CH2:27][CH:28]([CH3:44])[CH2:29][N:30]1[CH:34]=[C:33]([B:35]2[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]2)[CH:32]=[N:31]1)C1C=CC=CC=1>>[CH3:44][CH:28]([CH2:29][N:30]1[CH:34]=[C:33]([B:35]2[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:42])([CH3:43])[O:36]2)[CH:32]=[N:31]1)[CH2:27][OH:26]
Reactant: CC(COCc1ccccc1)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CC(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 91 %

Procedure:
Prepared analogously to Compound 3E using 1-[3-(Benzyloxy)-2-methylpropyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford 376 mg of the title compound (91%). 1H NMR (CDCl3, 400 MHz): δ=7.81 (s, 1H) 7.70 (s, 1H) 4.22-4.29 (m, 1H) 4.13-4.20 (m, 1H) 3.51-3.55 (m, 1H) 3.50 (s, 1H) 3.36 (dd, J=11.37, 6.57 Hz, 1H) 2.16-2.26 (m, 1H) 1.33 (s, 12H) 0.93 (d, J=6.82 Hz, 3H). MS (ESI): m/z=267.18 [M+H]+. UPLC: tR=1.18 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[N:5].[ClH:6].[CH2:7]([OH:9])[CH3:8]>>[ClH:6].[CH3:1][O:2][CH2:3][C:4](=[NH:5])[O:9][CH2:7][CH3:8]
Reactant: CCO
Reactant: COCC#N
Agent: Cl
Product: CCOC(=N)COC
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
2-Methoxyacetonitrile (1.0 g, 14.1 mmol) was dissolved in anhydrous ethanol (28.1 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-methoxyacetimidate hydrochloride (1.0 g, 44.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.42 (q, J=7.0 Hz, 2H), 4.31 (s, 2H), 3.36 (s, 3H), 1.32 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:11])[S:8][C:7]=1[Cl:12])=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:12][C:7]1[S:8][C:9]([Cl:11])=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
3-Thiophenecarboxylic acid ethyl ester (1.56 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (5.36 g) was added. The mixture was stirred at room temperature for 4 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred for 15 minutes and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dichloro-3-thiophenecarboxylic acid ethyl ester (2.3 g). 2,5-Dichloro-3-thiophenecarboxylic acid ethyl ester (2.25 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dichloro-3-thiophenecarboxylic acid (1.89 g) as crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].CCCCCC>COCCOC.[Cu]I.C(OCC)(=O)C>[Cl:13][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:12]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
5-Chloro-3-pyridinyl trifluoromethanesulfonate (4.0 g, 15 mmol) and CuI (580 mg, 3.0 mmol) were combined in DME (100 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (10.6 mL, 76.5 mmol), and PdCl2(PPh3).su-b.2 (1.1 g, 1.5 mmol) were added, then trimethylsilyl-acetylene (3.3 ml, 23 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 h at which time GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™., and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 99:1 hexane:ethyl acetate to afford 3-chloro-5-[(trimethylsilyl)ethynyl]pyridi-ne (2.8 g, 87% yield) as a brown solid. 1H NMR (CDCl3, 300 MHz) Δ8.51 (s, 1H), 8.44 (s, 1H), 7.70(s, 1H), 0.22 (s, 9H). MS (EI ionization) 209 (M+).
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:17]=2)=[CH:13][CH:12]=1.Br[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[CH:37][CH:36]=1>O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=[CH:37][CH:36]=3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:32])[CH3:33])[N:17]=2)=[CH:13][CH:12]=1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)s2)n1
Reactant: Brc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Cn1cc(-c2ccnc3ccccc23)c(-c2ccc(Cl)s2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
To a degassed solution of acetonitrile (4 mL) and water (1 mL) were added potassium carbonate (4 eq, 2.8 mmol), 3-(5-chloro-2-thienyl)-1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq, 0.7 mmol), 4-bromoquinoline (1 eq, 0.7 mmol) and 1,1′-bis(diphenylphosphinoferrocene)palladium(II)dichloride (0.1 eq, 0.07 mmol). The mixture was stirred at 130° C. in the microwave for 60 min. The solvent was evaporated and water and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 1:0 to 9:1) to afford 45 mg of 4-[3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazol-4-yl]quino line (15% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([CH:10]=2)[O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: COc1ccc(Oc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)cc1Oc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 4-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-2-(p-methoxyphenoxy)-1-nitrobenzene (12.4 g, 0.027 mol) in methylene chloride is cooled to -78° C., treated with boron tribromide (68 mL of a 1M solution in methylene chloride, 0.068 mol), stirred at -78° C. for two hours, warmed to room temperature and poured onto cracked ice. After the ice has melted, the phases are separated and the aqueous phase is extracted with methylene chloride. The organic phase is combined with the organic extracts and the resultant organic solution is washed with brine and dried over anhydrous sodium sulfate. Silica gel (5 g) is added to the dried organic solution and the mixture is concentrated in vacuo to obtain a brown powder. The powder is placed on top of silica gel in a flash chromatography column and eluted with a (1:1) ether/hexanes solution to give the title product as a brown oil (7.5 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: O[Li].O.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12].C1COCC1.Cl>C(OCC)(=O)C.O>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
LiOH.H2O (181 mg, 4.31 mmol) was added to a stirred solution of phenylmethyl 5-(methyloxy)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 6; 500 mg, 1.44 mmol) in a 3:1 mixture of THF:H2O (40 ml). The mixture was refluxed for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a yellow solid. 280 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[F:16][C:12]1[N:11]=[C:10]([CH2:9][O:8][C:4]2[N:3]=[C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cccc(COc2cncc(Cl)n2)n1
Reactant: C1CNCCN1
Product: Fc1cccc(COc2cncc(N3CCNCC3)n2)n1

Procedure:
Following the general procedure for the preparation of I-3b above, 2-chloro-6-(6-fluoro-pyridin-2-ylmethoxy)-pyrazine (100 mg, 0.42 mmol) and piperazine (360 mg, 4.17 mmol) were reacted to give the title compound (3-B). The crude material was purified by preparative TLC using 5% methanol/methylene chloride with 1% NH4OH as the eluant to yield 23 mg of the title product (3-B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4)cc3)sc2c1
Yield: 85.8 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methylbenzothiazole (1.0 g, 4.16 mmol) and benzoyl chloride (0.58 g, 4.16 mmol) in dry THF (10 ml) containing triethylamine (0.46 g, 4.58 mmol) to give the title compound (1.23 g, 86%) as a colourless solid after work-up.
Reaction SMILES: [N+:1]([C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34])([O-])=O.C(O)C.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:22][CH:21]=4)[CH2:18][CH2:19]3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34]
Reactant: CC1=C2OC(C)(CN3CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=C(N)C(C)C2CC(C)(CN3CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Yield: 41.1 %

Procedure:
To 1.3 g of 4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)piperazine, 30 ml of ethanol was added and 4.4 g of stannous chloride-dihydrate and 15 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 6 hours. The reaction solution was poured into water, neutralized with a 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol=30:1) to obtain 0.5 g of the objective product (melting point: 165-167° C.).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([NH2:27])[CH:18]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:27][C:19]1[CH:18]=[C:17]([O:16][CH3:15])[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:9])(=[O:3])[CH3:2]
Reactant: COc1cc(N)cc2ccccc12
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Product: COc1cc(NC(=O)c2cc(Cl)ccc2OC(C)=O)cc2ccccc12
Yield: 39.9 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 4-methoxy-2-naphthylamine as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [OH:1][OH:2].C1COCC1.[C:8]1([C:14](Br)([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>FC(F)(F)C([O-])=O.[Ag+].C([O-])(O)=O.[Na+]>[CH3:15][C:14]([O:1][OH:2])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCC(C)(Br)c1ccccc1
Reactant: OO
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(C)(OO)c1ccccc1

Procedure:
10.50 g (0.04 mol) of 1-methyl-1-phenylundecyl alcohol was dissolved in 50 ml of dichloromethane, cooled in ice bath, 10.6 ml (12.29 g, 0.08 mol) of trimethylsilyl bromide was added and the mixture stirred for 1 h under protection from moisture. The solution was diluted with 100 ml ether and washed four times with 50 ml water, brine, dried and evaporated to give crude 2-phenyl-2-bromododecane. 35 ml of 2.3 M hydrogen peroxide in THF (0.08 mol) was added to the 2-phenyl-2-dodecyl bromide and the mixture was cooled on ice bath. 8.84 g (0.04 mol) of silver trifluoroacetate was added. 70 ml of conc. NaHCO3 was added and the mixture filtered. The reaction flask and the filter cake was rinsed with diethyl ether. The aqueous phase was separated and the organic phase washed with conc. NaHCO3, 50 ml water, brine, dried and evaporated to give an oil. The oil was purified by flash chromatography using 2:8 ether:pentane as eluent. The yield of 1-methyl-1-phenylundecyl hydroperoxide was 30%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.Cl[CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:20][CH2:19]2)=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.7 %

Procedure:
Into a 50 milliliter three-necked round-bottom reaction flask equipped with a mechanical stirrer, thermometer and nitrogen inlet and outlet was added 5.0 grams (17.0 mmol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate, 3.91 grams (16.7 mmol) of 2-chloroethyl-paratoluenesulfonate, 5.74 grams (41.6 mmol) of anhydrous potassium carbonate and 17 milliliters of anhydrous dimethylformamide. The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for a period of 4 days. The product was then isolated by diluting with methylene chloride, filtering off the solids and concentrating under reduced pressure to give a solid material. Chromatography on silica gel with a 3:1 volume/volume hexane-ethyl acetate eluent provided 1.89 grams (5.8 mmol) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate as a white solid having a melting point of 87.5° C.-89.0° C. The total yield was 35 percent based on a 96.7 weight percent assay of the staring ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. NMR analysis of the product indicated the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](O)=[N:8][C:7]([C:12]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)=[N:6]2.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1CN>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH:32][CH2:33][C:38]1[CH:37]=[CH:36][CH:35]=[CH:34][N:30]=1)=[N:8][C:7]([C:12]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)=[N:6]2
Reactant: CC(C)(C)OC(=O)NC1(c2nc(O)c3c(Cl)ccn3n2)CC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC1(c2nc(NCc3ccccn3)c3c(Cl)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a stirred solution of tert-butyl (1-(5-chloro-4-hydroxypyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (500 mg, 1.54 mmol) in acetonitrile (50 mL) was added BOP (1.02 g, 2.31 mmol), DBU (0.464 mL, 3.08 mmol) and the reaction mixture was stirred at RT for 1 h. Pyridin-2-ylmethanamine (166 mg, 1.54 mmol) was added to the reaction mixture and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash ISCO (REDISEP®, SiO2, 12 g, 10% MeOH/CHCl3) to give tert-butyl (1-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (320 mg, 50.1%) as a pale yellow solid. LCMS Condition B-16: retention time 1.06 min, [M+1]=415.2. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89-0.92 (m, 2H), 1.15-1.17 (m, 2H), 1.38 (s, 9H), 4.75 (d, J=5.7 Hz, 2H), 6.69 (d, J=2.7 Hz, 1H), 7.25-7.33 (m, 3H), 7.52-7.56 (m, 1H), 7.73-7.76 (m, 1H), 7.96-7.98 (m, 1H), 8.53 (d, J=5.2 Hz, 1H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][CH3:15])[C:5]1=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C(O)(=O)C>[CH3:15][O:14][C:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[C:5]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1CCC(CC=O)C2=O
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: COc1cccc2c1CCc1ccn(CCNC(C)=O)c1-2
Yield: 39.9 %

Procedure:
175 mg of 2-(2-oxoethyl)-5-methoxy-1-tetralone and 144 mg of N-acetylethylenediamine were heated to reflux under argon in 4 ml of acetic acid for 1.5 hours. The solvent was removed in a vacuum. The residue was taken up in 25 ml of water and extracted several times with dichloromethane. Chromatography on 20 g of silica gel with ethyl acetate gave a greenish coloured oil. This was crystallized from toluene for purification. 91 mg (46%) of N-[2-(4,5-dihydro-6-methoxy-1H-benz[g]indol-1-yl)ethyl]-acetamide with m.p. 133° were obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]4=[N:17][CH:18]=[C:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:45][C:46]([CH3:48])=[CH2:47].CCOC(C)=O>CN(C=O)C.O>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:47][C:46]([CH3:48])=[CH2:45])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: C=C(C)CBr
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Temperature: 65 °C
Yield: 105.8 %

Procedure:
tert-Butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.50 g, 0.95 mmol) and Cs2CO3 (1.55 g, 4.75 mmol) were combined in DMF (19 mL). 3-Bromo-2-methylpropene (0.191 mL, 1.90 mmol) was added and the mixture was heated at about 65° C. for about 3 h. EtOAc (50 mL) and water (50 mL) were added and the layers separated. The organic layer was washed with 5% aqueous LiCl (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-methylallyl)carbamate (0.584 g, 106%): LC/MS (Table 2, Method h) Rt=2.43 min.; MS m/z: 581 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[CH:12]=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:13][CH:12]=[CH2:11])[CH:8]=[O:9]
Reactant: C=CCO
Reactant: CC(C=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCC(C)(C=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-phenylpropionaldehyde (9.90 mL, 74.5 mmol), allyl alcohol (20.4 mL, 300 mmol) and p-toluene sulfonic acid (0.8560 g, 4.5 mmol) in benzene (37 mL) was heated to reflux for 19 hours and a Dean-Stark trap was used to collect the water formed. The mixture was cooled to room temperature and saturated aqueous NaHCO3 (5 mL) and H2O (5 mL) were added. The phases were separated and the organic layer was washed a second time with saturated aqueous NaHCO3 (5 mL) and H2O (5 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. A solution of the resultant yellow residue in p-xylene (150 mL) was heated to reflux for 24 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The resultant aldehyde (13.0 g) was used in the next reaction without further purification.