Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>CS(C)=O.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:26]2[N:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])=[CH:14][CH:13]=1
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Reactant: N#Cc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3C#N)cc2)nc2ccccc21
Temperature: 80 °C

Procedure:
To a solution of 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (120 mg, 0.5 mmol) in DMSO (1 mL) was added cesium carbonate (196 mg, 0.6 mmol) and 2-fluoronicotinonitrile (61 mg, 0.5 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 5% of MeOH in CH2Cl2, followed by trituration with ether, to provide 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinonitrile as off-white solid. MS (ESI, pos. ion) m/z: 342.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]P(=O)(OCC)OCC)[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=O)[CH2:22]2>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:21]2[CH2:22][CH:23]3[N:18]([CH3:17])[CH:19]([CH2:25][CH2:24]3)[CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(Cc1cccc(Br)c1)OCC
Reactant: CN1C2CCC1CC(=O)C2
Solvent: C1CCOC1
Product: CN1C2CCC1CC(=Cc1cccc(Br)c1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
To a solution of diethyl [(3-bromophenyl)methyl]phosphonate (3.07 g, 10 mmol) in THF (20 mL) was added 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.67 g, 12 mmol) then KOBu-t (1.234 g, 11 mmol). The reaction mixture was stirred at room temperature for 5 h before it was quenched with NH4Cl (5 mL, saturated aqueous). The organic layer of the reaction mixture was separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layers were loaded onto a Combiflash Redisep silica gel column (40 g) and purified by Combiflash chromatograph to afford 2.48 g (85%) of the title compound. LC-MS m/z 292 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18]C)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1.C(=O)C>>[F:22][C:2]([F:1])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: CCCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21
Agent: CC=O
Product: CCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1=H, n=1) and acetaldehyde. 1H NMR (400 MHz, CDCl3) 11.23 (br. s, 1H), 7.07 (s, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 3.39 (q, 2H, J=7.1), 3.31 (t, 2H, J=5.6), 2.88 (t, 2H, J=6.4), 1.98 (m, 2H), 1.18 (t, 3H, J=7.1).
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=1[C:32]([OH:34])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([N:21]1[C:22](=[O:23])[C:24]2[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=2[C:32]1=[O:34])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1nsc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)c1nsc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 95.1 %

Procedure:
7.5 g (74.1 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 17.4 g of a 50% strength solution of propanephosphonic anhydride (27.3 mmol) in dichloromethane were added dropwise in succession to 5.4 g (20 mmol) of 5-tert-butylaminocarbonyl-3-isopropylisothiazole-4-carboxylic acid in 200 ml of dichloromethane at -5° C. and the mixture was then refluxed for 6 hours. Working up was carried out as described above for Example No. 1.003. 4.8 g (95%) of N-tert-butyl-3-isopropylisothiazole-4,5-dicarboximide were obtained as a solid of melting point 52°-53° C. (Example No. 3.001).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)cncc1Br
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
3-bromo-5-chloropyridine (25 g, 130 mmol) in THF (50 mL) was added slowly to a solution of LDA (140 mmol) in THF (250 mL) at −78° C. over 10 minutes. After stirring for 30 minutes, ethyl chloroformate (26 mL, 260 mmol) in THF (30 mL) was added in portions over 5 minutes. After 10 more minutes, the reaction mixture was poured into cold 10% aqueous NaHCO3 (500 mL). The mixture was extracted with ethyl acetate (2×250 mL). The organic layer was dried over MgSO4 and evaporated. The crude solid was filtered through a silica pad with hexane (500 mL). The filtrate was evaporated to provide pure ethyl 3-bromo-5-chloropyridine-4-carboxylate (28 g, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]([CH3:17])[CH2:12][CH2:13][CH2:14][C:15]#[N:16].O.Cl>C(OCC)C>[OH:10][C:11]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:17])[CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: CC(=O)CCCC#N
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(O)(CCCC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One hundred mL (0.1 mole) of a 1.0 molar solution of 4-chlorophenylmagnesium bromide in diethyl ether is stirred, and a solution of 11.4 mL (0.1 mole) of 5-oxohexanenitrile in 125 mL of diethyl ether is added dropwise. The exothermic reaction causes the reaction mixture temperature to rise to about 31° C. The reaction mixture is then cooled in an ice-bath, and the dropwise addition of the nitrile solution is continued. The complete addition requires about 30 minutes. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for two hours. The reaction mixture is then poured into 500 mL of water and made acidic with aqueous 2N hydrochloric acid. The organic layer is separated, and the aqueous layer is extracted with one 250 mL portion of diethyl ether. The organic layers are combined and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residual oil. The oil is subjected to column chromatography on silica gel, using methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 15.0 grams of 5-hydroxy-5-(4-chlorophenyl)hexanenitrile. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]#[N:6]
Reactant: ClCCCBr
Reactant: N#Cc1ccc(-c2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccccc2)c(OCCCCl)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 3-hydroxy-4-phenylbenzonitrile (3.0 g) in N,N-dimethylformamide (30.7 mL) was added potassium carbonate (6.37 g). Then 1-bromo-3-chloropropane (3.6 mL) was added, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was partitioned between diethyl ether (45 mL) and water (10 mL). The organic layer was washed with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=15/1) to give the title compound (4.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([CH:36]=O)=[C:31]([Cl:38])[CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([C:36]2[NH:20][C:15]3[CH:14]=[C:13]([C:11]4[O:12][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][N:10]=4)[CH:18]=[CH:17][C:16]=3[N:19]=2)=[C:31]([Cl:38])[CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Reaction time: 72 h

Procedure:
To a 20 ml scint. vial was added 0.3783 g (1.32 mmol) 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine, 0.4000 g (1.32 mmol) of 3-(3,5-Dichloro-4-formyl-phenyl)-propionic acid tert-butyl ester (step A), and 6 mL of DMSO. To this dark brown solution was added 0.0321 g (0.198 mmol) of FeCl3. Allowed to stir open to air for 72 h. Extracted with EtOAc, and washed with water, brine and dried with Na2SO4. Purified on silica gel (ACN/DCM, 1:9 to 4:6) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (9H) 2.64 (t, J=7.33 Hz, 2H) 2.92 (t, J=7.26 Hz, 2H) 7.60 (s, 2H) 7.72 (d, 2H) 7.78 (d, J=8.59 Hz, 0.5H) 7.92 (d, J=8.46 Hz, 0.5H) 8.00-8.09 (m, 1H) 8.17-8.22 (m, 2H) 8.31 (s, 0.5H) 8.50 (s, 0.5H) 13.32 (d, J=11.24 Hz, 1H). MS (m/z) 571.1 M (+1), tR=1.59, Meth 10
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][S:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>C1(C)C=CC=CC=1.CN1CCCC1=O.O.C(OCC)(=O)C.[Cu](I)I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:19][CH3:18])[CH:21]=1
Reactant: CSc1cccc(O)c1
Reactant: COC(=O)c1cccnc1Cl
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1Oc1cccc(SC)c1
Temperature: 110 °C

Procedure:
2-Chloronicotinic acid methyl ester (WO 02/085358, pg. 21, example 1) (8.00 g, 47 mmol), caesium carbonate (21.30 g, 65 mmol) and copper iodide (890 mg, 4.7 mmol) were dissolved in a toluene:1-methyl-2-pyrrolidinone 4:1 mixture (155 mL) and the reaction mixture treated with 3-methylsulphanyl-phenol (6.21 g, 44 mmol) (WO 98/45268, pg. 68, preparation 61). The reaction mixture was heated td 110° C. for 18 hours. The reaction mixture was diluted with water (250 mL), and ethyl acetate (250 mL) and filtered through Arbocel®. The organic layer was separated and the aqueous extracted with ethyl acetate (2×250 mL). The organics were combined, washed with water and brine and dried over magnesium sulphate. The organics were concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with toluene:ethyl acetate 100:0 to 98:2. The crude product was triturated with hexane:ether 66:33 to yield the title product, 4.90 g.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:35][CH2:34]2)[CH:30]=[N:29][CH:28]=1)CCC>CN(C=O)C.[Cu]I.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>[C:42]([O:41][C:40]([NH:39][CH:36]1[CH2:37][CH2:38][N:33]([C:31]2[N:32]=[C:27]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=4)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=3)[CH:28]=[N:29][CH:30]=2)[CH2:34][CH2:35]1)=[O:46])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)c1ccc2c(c1)c(I)cn2C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A mixture of 1-tert-butyl 5-methyl 3-iodo-1H-indole-1,5-dicarboxylate (6 g, 14.96 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate (1d) (10.2 g, 17.95 mmol) in DMF (60 mL) was purged with argon gas for 5 min, added CuI (4.27 g, 22.44 mmol), palladium tetrakis (1.7 g, 1.5 mmol) and again purged with argon gas for 5 min. The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 1 h. The reaction mixture was then poured into water. The resulting precipitate was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was concentrated and combined with the above precipitate to give the crude product. Purification was carried out by column chromatography to obtain the title compound as a brown solid (2.5 g, 30%). MS (ESI, pos. ion) m/z: 552.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Solvent: CC(=O)N(C)C
Product: O=C(O)c1nc(N2CCOCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
3,6 Dichloropyridine-2-carboxylic acid (0.55 g, 2.86 mmol), morpholine (1.37 g, 15.7 mmol) and N,N dimethylacetamide (1.37 mL) were combined and stirred for 24 h at 80° C. An additional volume of morpholine (1.39 g, 15.7 mmol) was added and heating continued for 40 hours more. After cooling the DMA was removed in the presence of toluene. The residue was dissolved in water and extracted with ether to remove excess morpholine. The aqueous was acidified to pH=2 and the product extracted into ether. Crystallization from water gave a white solid, 369 mg (53% yield). 1H NMR (CD3OD): δ 3.52 (t, 4H), 3.78 (t, 4H), 6.97 (d, 1H), 7.65 (d, 1H). LC-MS, M+H: 243.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.O.[NH2:21][NH2:22]>C(O)C>[C:8]1([C:6]2[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:2]([SH:1])[NH:22][N:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C(=C1SCS1)c1ccccc1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Sc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a suspension of 2-(1,3-dithietan-2-ylidene)-1,2-diphenylethanone (1.88 g, 6.61 mmol) in ethanol (50 mL) was added hydrazine hydrate (0.496 g, 9.92 mmol). The reaction was refluxed for 16 h, cooled to room temperature and concentrated. The residue was neutralized with HCl (1.0 M) to pH 6-7 and extracted with EtOAc/H2O. The organic extract was dried over MgSO4 and concentrated to give the title compound (1.5 g). LCMS m/z=253.4 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 4.01-4.19 (m, 1H), 6.92-7.58 (m, 10H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C)C=O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCCCCCCBr
Reactant: COC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)OCCCCCCBr
Yield: 22.2 %

Procedure:
To 120 ml of dry N,N-dimethylformamide, 4.0 g of 60% sodium hydride was added. To the mixture was added dropwise 11.81 g of methyl 2-hydroxyisobutyrate with stirring under ice-cooling, and stirred for 10 minutes. Then, 122 g of 1,6-dibromohexane was added and stirred for 15 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=20:1) to provide 6.25 g of the objective compound as yellowish oil.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]5[CH2:32][O:31][CH2:30]5)[CH2:25][C@@H:24]4[CH3:33])=[CH:19][N:18]=3)[C:13](=[O:34])[N:12]([CH3:35])[CH:11]=2)[C:3]=1[CH:4]=[O:5].[CH2:36]1[C:41]2=[CH:42][C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[N:40]2[CH2:39][CH2:38][NH:37]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:36]1[C:41]2=[CH:42][C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[N:40]2[CH2:39][CH2:38][N:37]1[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]5[CH2:32][O:31][CH2:30]5)[CH2:25][C@@H:24]4[CH3:33])=[CH:19][N:18]=3)[C:13](=[O:34])[N:12]([CH3:35])[CH:11]=2)[C:3]=1[CH:4]=[O:5]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(Cl)c3C=O)cn(C)c2=O)nc1
Reactant: c1c2c(n3c1CNCC3)CCCC2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 220a (300 mg, 1.0 eq., 0.61 mmol), 1,2,3,4,6,7,8,9-octahydropyrazino[1,2-a]indole (128 mg, 1.2 eq., 0.73 mmol), Pd2(dba)3 (55 mg, 0.1 eq., 0.060 mmol), X-Phos (30 mg, 0.1 eq., 0.060 mmol), Cs2CO3 (390 mg, 2.0 eq., 1.22 mmol), and dioxane (15.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/EtOH to afford 220b (100 mg, 26%) as yellow solid. MS-ESI: [M+H]+ 635.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Yield: 186.3 %

Procedure:
(S)-2-Ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (8.1 g, 34 mmol) was dissolved in benzylic alcohol (14.7 g, 135 mmol) and freshly washed sodium hydride (1.63 g, 41 mmol) was caustiosuly added under nitrogen atmosphere. The resulting mixture was warmed up to 50° C. under vacuum and after 6 h toluene was added and the mixture was extracted with aq. KHSO4 (2N). The combined organic layers were dried and evaporated under high vacuum at 70° C. to afford title compound as an oil (9.51 g, 93.1%). 1H NMR (400 MHz, CDCl3): δ 7.19-7.40 (m, 5H), 7.03-7.06 (d, 2H), 6.68-6.71 (d, 2H), 5.14 (s, 2H), 4.03-4.06 (t, 1H), 3.57-3.61 (m, 1H), 3.36-3.40 (m, 1H), 2.97 (s, 1H), 1.14-1.18 (t, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[C:11][CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([N:16]1[CH2:17][CH2:18][N:13]([C:10]#[C:11][CH3:12])[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#CN1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CN1CCN(C(=O)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
A solution of 5.6 g. of benzoyl chloride was added to a stirred solution of 1.96 g. of N-propynyl piperazine, 4.04 g. of triethylamine and 100 ml. of chloroform. The mixture was stirred 4 hours, filtered and the filtrate washed in sequence with 100 ml. of water, 100 ml. of 5% aqueous potassium carbonate and 100 ml. of water. The chloroform solution was then evaporated in vacuo to produce a white solid. Crystallization from cyclohexane produced the expected white crystals of N'-benzoyl-N-propynyl piperazine, m.p. 94°-5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][O:20]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:37]1(O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>CC#N>[O:20]([CH2:19][C:15]1[O:16][CH:17]=[CH:18][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OCc2occc2C2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)furan-3-yl]piperidine-1-carboxylic acid t-butyl ester (65 mg, 0.15 mmol, 1.0 eq.) was dissolved in MeCN (770 μL) and added to a mixture of potassium carbonate (32 mg, 230 mmol, 1.6 eq.) and phenol (21.1 mg, 224 μmol, 1.5 eq.). The resulting mixture was shaken at 50° C. overnight. The mixture was then cooled and the solids removed. The supernatant was combined with TFA (12 μL, 160 mmol, 1.0 eq.) and the resulting mixture was shaken overnight at room temperature. The solution was concentrated using an evaporator, then dissolved in 1:1 AcOH:H2O (5.0 mL) then an additional 2.0 ml AcOH, filtered, and purified by preparative HPLC to yield the title compound as a TFA salt (1.4 mg, 88% purity). MS m/z: [M+H]+ calcd for C16H19NO2, 258.14. found 258.2.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=O)[O:3]1.Cl.[CH2:13]([O:15][C:16]([C:18]1([NH2:23])[CH2:20][CH:19]1[CH:21]=[CH2:22])=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1([NH:23][C:9]([CH:6]2[CH2:5][CH:4]3[CH2:8][CH:7]2[C:2](=[O:1])[O:3]3)=[O:11])[CH2:20][CH:19]1[CH:21]=[CH2:22])=[O:17])[CH3:14]
Reactant: O=C(O)C1CC2CC1C(=O)O2
Reactant: C=CC1CC1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 13 (857 mg, 5.5 mmol), in DMF (14 mL) and DCM (25 mL) at room temperature, was added the hydrochloride of 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester, prepared as described in WO03/099274, (1.15 g, 6.0 mmol), HATU (2.29 g, 6.0 mmol) and DIPEA (3.82 mL, 22 mmol). The reaction was stirred under N2-atmosphere at ambient temperature for 1 h. LC/MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was redissolved in DCM (100 mL) and 0.1 M HCl (aq) and the phases were separated. The organic phase was washed with NaHCO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo afforded the target compound (1.6 g, 99%). LC/MS>95%, m/z (ESI+)=294 (MH+)