Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Oc3ccccc3F)nc2n1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4F)nc3n2)cc1
Temperature: 4 °C
Yield: 32.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (6.1 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-(2-fluorophenoxy)-1,8-naphthyridine (7.65 g). The product produced by precipitation in water (5.5 g; m.p. 200° C.) is dissolved in boiling ethanol (180 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-[7-(2-fluorophenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (3.8 g) is produced, m.p. 208° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.C1(N2CCC3C=C(OC4C=CC(C#N)=CN=4)C=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: CC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 214 (E214) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 1-(6-chloropyridin-3-yl)ethanone using the method described for Example 100 (E100); MS (ES+) m/e 337 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc([N+](=O)[O-])cc2C1=O
Yield: 16.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a: 600 mg, 3.125 mmol) was reacted with 3-iodo-4-methyl-pyridine (684.3 mg, 3.125 mmol), 1,4-dioxane (10 mL), copper iodide (59.5 mg, 0.3125 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (147.5 mL, 0.9375 mmol) and potassium phosphate (1.65 g, 7.8125 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 150 mg of the product (17% yield).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9](=[O:10])[O:11][CH3:12])=[CH:26][CH:25]=1
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.83 h
Yield: 79 %

Procedure:
0.14 ml of triethylamine and 0.08 ml of methyl chloroformate were added to a solution of 250 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in Example 3(b)] in 5 ml of methylene chloride cooled in an ice-water bath and the resulting mixture was stirred at the same temperature for 50 minutes. The temperature of the reaction mixture was then elevated to room temperature and the mixture was stirred for a further 30 minutes. At the end of this time water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was; washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate to give 243.1 mg (yield 79%) of the title compound as a solid having a melting point of 142°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(Cl)Cl.[BH4-].[Na+]>C(O)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CO>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:39][CH2:14][C:13]2[CH:16]=[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11][CH:12]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: COc1cccc(N)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(NCc2cnc(Nc3ccc(OC)nc3)c(-c3nc(C)nc4[nH]cnc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (191.7 mg, 0.4303 mmol) was suspended in ethanol (4.0 mL) and tetraisopropoxytitanium (0.26 mL, 0.878 mmol) and 3-methoxyaniline (0.080 mL, 0.716 mmol) were added. The reaction was stirred under nitrogen at room temperature overnight, and then more DCM (about 3 mL) was added, along with more Ti(OiPr4) (0.13 mL, 0.44 mmol) and 3-methoxyaniline (0.050 mL, 0.45 mmol). Stirring was continued overnight, and then sodium borohydride (32.3 mg, 0.854 mmol) was added, along with MeOH (1 mL). The reaction was stirred at room temperature for 35 minutes and then quenched with 5 N HCl (0.60 mL), which was added dropwise. Stirring was continued at room temperature over the weekend. Then, the suspension was diluted with DCM and MeOH and filtered through a pad of Celite® (diatomaceous earth). The Celite® (diatomaceous earth) pad was washed with DCM and MeOH, and the filtrate was concentrated, treated with water, and filtered again through a fritted filter (no Celite® (diatomaceous earth)). The solid was washed with water, collected, and dried under high vacuum in a water bath at 50° C., and then at room temperature overnight, to give 5-((3-methoxyphenylamino)methyl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (162.8 mg, 81% yield). MS (ESI pos. ion) m/z 469 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.53 (s, 1H), 9.74 (s, 1H), 8.62 (s, 1H), 8.51 (d, J=2.54 Hz, 1H), 8.27 (d, J=2.15 Hz, 1H), 8.13 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.00 (t, J=8.12 Hz, 1H), 6.87 (d, J=8.80 Hz, 1H), 6.38-6.17 (m, 3H), 4.29 (s, 2H), 3.85 (s, 3H), 3.66 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.CC(C)([O-])C.[K+].[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH2:35])[N:28]=3)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:2][CH2:35]2)[N:28]=3)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCCCC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCCCC4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of trimethylsulfoxonium iodide (0.385 g, 1.75 mmol) and potassium tert-butoxide (0.196 g, 1.75 mmol) in 4 mL DMSO was added 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclohexylvinyl)thiazolo[5,4-b]pyridine (0.371 g, 0.874 mmol) rapidly as a solution in THF (8 mL min volume). The reaction mixture became a light purple color. The reaction was sealed and heated to 60° C. After 4 h, the reaction mixture was cooled, quenched with ice and sat'd aq. NH4Cl, diluted with EtOAc and the organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting orange oil/solid was purified by silica gel chromatography 40 g, 0-40% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclohexylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: calculated: 438.2; Observed: 439.1 (M++1).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:20]([OH:21])=[C:19]2[C:14]([CH:15]=[C:16]([C:23]([OH:25])=O)[C:17](=[O:22])[O:18]2)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:16]3[C:17](=[O:22])[O:18][C:19]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[C:11]([OH:10])[C:20]=4[OH:21])=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2ccc(O)c(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccc(O)c(O)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (43.1 μL, 0.25 mmol) was added to 7,8-dihydroxy-3-carboxy-coumarin (50 mg, 0.23 mmol) and HATU (94.1 mg, 0.25 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (47.1 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo for final product: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)COCCO.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CNc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
26.2 g (0,137 mol) of 2,5-dichloro-1-nitrobenzene, 20.6 g (0,274 mol) of glycine and 18.9 g (0.137 mol) of potassium carbonate in 200 ml of diethylene glycol were heated at 120° C. for 1 h. After cooling, 100 ml of water were added and the solution was acidified with 1M hydrochloric acid. The precipitate was filtered off with suction to yield 17.1 g (54%) of the product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH3:12][Sn:13](Cl)([CH3:15])[CH3:14]>CCOCC>[CH3:1][N:2]1[C:6]([Sn:13]([CH3:15])([CH3:14])[CH3:12])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1nccc1[Sn](C)(C)C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
A solution of 1-methyl-1H-pyrazole (1.6 g, 20.0 mmole) in Et2O was treated with n-butyllithium (12.5 ml, 1.6 M in hexanes, 20.0 mmole) over a period of 10 minutes at room temperature. The yellow slurry was stirred for a further 90 minutes. Subsequently, trimethyltin chloride (4.0 g, 20.0 mmole) was added in one portion. The brown slurry was stirred for 30 minutes, filtered and the filtrate was concentrated, in vacuo, to a black oil (5.0 g). The product was isolated by distillation at 1.5 Torr (67–72° C.) as a clear oil (2.1 g, 42%): 1H-NMR (DMSO-d6, 400 MHz) δ 7.40 (1H, d, J=1.5 Hz), 6.27 (1H, d, J=1.7 Hz), 3.84 (3H, s), 0.34 (9H, s). ESIMS m/z 243–247 ion cluster (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][S:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.O>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)[S:11](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(/C=C/c1cccc(Cl)c1)Nc1cccc(Cl)c1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(/C=C/c1cccc(Cl)c1)N(Cc1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a well-stirred suspension of NaH (23.2 mg, 0.92 mmol, 5.6 eq.) in 4 mL of THF, a THF solution (1.5 mL) of compound 2 (53.9 mg, 0.16 mmol, 1 eq.) was added and the mixture was stirred for 1 hour at room temperature. Afterwards, the reaction mixture was cooled at 0° C. and a THF solution (1.5 mL) of 3-chlorobenzylbromide (52.2 mg, 0.25 mmol, 1.5 eq.) was added. After the reaction mixture was stirred at room temperature for 22 h, water was added and the product was extracted three times from the aqueous phase with EtOAc. The resulting organic phase was washed with brine, dried under Na2SO4 and the solvent evaporated. After the product was purified from the crude by flash column chromatography (15% EtOAc/hexanes), compound ef-rs-03-075 (26.1 mg, 0.06 mmol) was obtained in a 35% yield. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, ArH, 1H), 7.42 (dt, J=7.6, 1.7 Hz, ArH, 1H), 7.36 (m, ArH, 3H), 7.23 (m, ArH, 6H), 7.14 (m, ArH, 2H), 6.78 (d, J=15.4 Hz, C═CH, 1H), 4.76 (s, CH2, 2H). 13C NMR (100 MHz, CDCl3, δ): 141.55 (CH), 140.00 (C), 137.62 (C), 135.26 (C), 134.81 (C), 134.51 (C), 134.14 (C), 131.04 (CH), 130.45 (CH), 130.24 (CH), 129.92 (CH), 128.91 (CH), 128.56 (CH), 128.49 (CH), 128.27 (CH), 127.97 (CH), 127.03 (CH), 126.59 (CH), 126.55 (CH), 124.48 (CH), 54.36 (CH2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:33]=[CH:32][C:18]([O:19][CH2:20][C:21]3[NH:22][C:23]4[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:36](Br)[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:33]=[CH:32][C:18]([O:19][CH2:20][C:21]3[N:25]([CH2:36][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:38])[C:24]4[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:23]=4[N:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4ccc(C#N)cc4[nH]3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4cc(C#N)ccc4n3CC(=O)c3ccccc3)cc2)CC1
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)-phenoxymethyl]-5-cyanobenzimidazole (915 mg) in dimethylformamide (15 ml) was added 60% sodium hydride (90 mg) with ice-cooling, and the mixture was stirred at the same temperature for 20 min. Phenacyl bromide (426 mg) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by HPLC (hexane:ethyl acetate=2:3) to give the title compound (385 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)[C:6]#[N:7]
Reactant: OC1CCOCC1
Reactant: COc1cc(C#N)ccc1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8 g 3-Methoxy-4-hydroxy-benzonitrile, 28.1 g triphenylphosphine and 5.48 g tetrahydro-4H-pyran-4-ol was suspended in 1 L tetrahydrofuran at 0° C. before 24.7 g di-tert-butylazodicarboxylate (DBAD) was added over 30 min. The reaction was warmed to ambient temperature and stirred for 2 d. After this time, the reaction was diluted with water and ethyl acetate. The organic phase was separated and then it was washed with 1N sodium hydroxide, water and saturated sodium chloride, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel chromatography (SiO2: heptane/ethyl acetate 8:2 to 7:3) to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:59][O:60][C:61](=[O:83])[CH:62]=[CH:63][CH:64]([NH2:82])[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[CH:67]=1>C1COCC1>[CH3:59][O:60][C:61](=[O:83])[CH:62]=[CH:63][C@H:64]([NH:82][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH:67]=1
Reactant: O=C(O)CCCCCCc1ccccc1
Reactant: COC(=O)C=CC(N)Cc1cn(Cc2ccccc2)c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=C[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of 7-phenylheptanoic acid (92 mg, 0.447 mmol), BOP (217 mg, 0.491 mmol) and DIPEA (69 mg, 93 μL, 0.535 mmol) in THF (2.5 mL) was stirred for 10 min. To this was added a solution of the trifluoroacetic acid salt of 4-amino-5-(1-benzyl-1H-indol-3-yl)-pent-2-enoic acid methyl ester (200 mg, 0.446 mmol) and DIPEA (173 mg, 233 μL, 1.34 mmol) in THF (2.5 mL). The mixture was stirred overnight at room temperature. The solvent was removed and the crude material subject to column chromatography (50% EtOAc/petroleum ether, Rf 0.66) to afford the title compound (197 mg, 85%). 1H NMR (CDCl3) δ 7.59 (1H, d, J=7.26 Hz), 6.94-7.28 (15H, m), 5.81 (1H, d, J=15.81 Hz), 5.48 (1H, d, J=8.34 Hz), 3.59 (2H, s), 5.05 (1H, m), 3.12 (1H, dd, J=6.42, 14.49 Hz), 3.04 (1H, dd, J=5.85, 14.49 Hz), 2.57 (2H, t, J=7.64 Hz), 2.07 (2H, t, J=7.67 Hz), 1.9-1.2 (8H, m). 13C NMR (CDCl3) δ 172.5, 166.5, 148.1, 142.6, 137.3, 136.6, 128.7, 128.4, 128.3, 128.2, 127.6, 126.9, 126.7, 125.6, 122.1, 120.8, 119.6, 118.8, 109.9, 109.4. 51.6, 49.9, 50.2, 36.7, 35.8, 31.2, 29.9, 29.0, 28.9, 25.4. ISMS: 523 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]([CH3:15])([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].Br[C:23]#[N:24]>C1COCC1.CCOC(C)=O>[CH3:14][C:6]([CH3:15])([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:2]1[CH2:3][O:4][C:23]([NH2:24])=[N:1]1
Reactant: CC(C)(Cc1ccccc1)CC(N)CO
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1)CC1COC(N)=N1
Reaction time: 17 h
Yield: 54.3 %

Procedure:
To a stirred solution of (RS)-2-amino-4,4-dimethyl-5-phenyl-pentan-1-ol (0.97 g) at r.t. in THF (15 ml) under an argon atmosphere were added K2CO3 (0.78 g) and a solution of BrCN (0.59 g) in THF (10 ml). The mixture was stirred for 17 h. The suspension was diluted with EtOAc and washed with H2O. The aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on Isolute® Flash-NH2 silica gel from Separtis (gradient: cyclohexane→CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-4-(2,2-dimethyl-3-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine (0.59 g) as an off-white sticky solid. MS (ISP): 233.2 ([M+H]+))
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]1([C:19]#[C:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.[CH:33](=O)[CH2:34][CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[CH2:33]([N:1]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([C:20]#[C:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH2:34][CH2:35][CH3:36]
Reactant: O=Cc1ccc(C#Cc2ccccc2)cc1
Reactant: CCCC=O
Reactant: COC(=O)c1cc(N)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 75.1 %

Procedure:
A solution of methyl 5-amino-2-fluorobenzoate (500 mg, 2.96 mmol), 4-(phenylethynyl)benzaldehyde (6 10 mg, 2.96 mmol) and acetic acid (0.25 mL, 4.40 mmol) in toluene (20 mL) was heated under reflux for 3 h with azeotropic removal of water. Then the solvent was removed by distillation at atmospheric pressure and replaced by anhydrous DCE (20 mL). Butanal (Fluka, 0.66 mL, 7.39 mmol), sodium triacetoxyborohydride (1880 mg, 8.87 mmol) and acetic acid (0.25 mL, 4.40 mmol) were added and the resulting mixture was heated at 70° C. After 45 min, an additional amount of sodium triacetoxyborohydride (630 mg, 2.96 mmol) was added. After 45 min, the reaction mixture was diluted with water (40 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc): gave. 924 mg (75%) of the title compound as a colorless oil. HPLC, Rt: 5.6 min (purity: 99.8%). LC/MS, M+(ESI): 416.1. 1H NMR (CDCl3) δ: 7.51-7.44 (m, 4H), 7.32 (m, 3H), 7.17 (m, 3H), 6.92 (dd, J=9.8, 9.7 Hz, 1H), 6.73 (m, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.36 (t, J=7.2 Hz, 2H), 1.60 (m, 2H), 1.34 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:24]([CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:11][N+:12]([O-:14])=[O:13])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C(=O)c1ccc(OC)cc1)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2

Procedure:
Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate. A solution of 5.355 kg (24.1 moles) ethyl 3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.