Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([CH3:15])=[N:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ncc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 22 h
Yield: 70.7 %

Procedure:
1-Methylpiperazine (1.79 mL, 16.1 mmol) was added to a suspension of 5-bromo-2-methyl-3-nitropyridine (1.00 g, 4.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (267 mg, 0.461 mmol), tris(dibenzylideneacetone)dipalladium(0) (170 mg, 0.180 mmol) and cesium carbonate (3.00 g, 9.22 mmol) in 1,4-dioxane (20.0 mL) under argon in a sealed reaction vessel. The reaction mixture was allowed to stir for 22 h, at 150° C. The reaction mixture was next partitioned between EtOAc (50 mL) and water (50 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (3×50 mL). The organic solutions were combined, washed with brine (twice), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 1-methyl-4-(6-methyl-5-nitropyridin-3-yl)piperazine (0.77 g, 71%) as a brown solid, LCMS (FA): Rt=1.07 min, m/z=237.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[OH:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: OCCCO
Reactant: CNC(=O)c1ccc(O)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OCCCO)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a mixture of 5-hydroxy-N-methylpyridine-2-carboxamide (400 mg, 3.0 mmol), 1,3-propanediol (230 mg, 3.0 mmol), triphenylphosphine (786 mg, 3.0 mmol) and N,N-dimethylformamide (4.5 ml, 60 mmol) was added diisopropyl azodicarboxylate (606 mg, 3.0 mmol) while stirring at ambient temperature. After 18 hours, the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (40 mL) and filtered. The filtrate was concentrated and purified by column chromatography over silica gel using methanol/ethyl acetate (3-4%) to give 488 mg (80%) of 5-(3-hydroxypropoxy)-N-methylpyridine-2-carboxamide as a colorless gum. MS [M+H] 211.2, 1H NMR (CDCl3) δ (ppm) 8.19 (d, J=3.0 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 7.83 (b, 1H), 7.28 (m, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.88 (m, 2H), 3.02 (d, J=5.1 Hz), 2.08 (m, 2H).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([CH:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[CH2:13][CH2:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CO>[ClH:1].[ClH:1].[ClH:1].[N:2]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH2:13][CH2:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(CN4CCCCC4)ccc3C2)C1
Agent: Cl
Solvent: CO
Product: c1cc2c(cc1CN1CCCCC1)CCN(C1CCNC1)C2

Procedure:
1.25 M hydrogen chloride in methanol (11 ml) was added to tert-butyl 3-(6-(piperidin-1-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylate (0.55 g, 1.38 mmol), and the mixture was refluxed for 3 h. The solvent was removed under vacuum and the residue was taken up in ethanol/acetone (5 ml). Diethyl ether (20 ml) was then added, and the resulting precipitate was filtered out and dried under vacuum. Yield: 0.41 g (73%)
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[CH3:21])[NH:17][CH:16]=[C:15]4[CH:22]=[O:23])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.CC(=CC)C.O>[OH:1][CH2:2][C:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[CH3:21])[NH:17][CH:16]=[C:15]4[C:22]([OH:25])=[O:23])=[CH:10][CH:11]=2)[CH2:4][CH2:5]1
Reactant: Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(CO)CC2)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc2[nH]cc(C(=O)O)c2cc1-c1ccc(C2(CO)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
To a solution of 5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-6-methyl-1H-indole-3-carbaldehyde (50 mg, 0.164 mmol) in acetonitrile (3.3 mL), t-butanol (3.3 mL) and 2-methyl-2-butene (2.2 mL) was added a solution of sodium chlorite (221 mg, 3.28 mmol) and sodium dihydrogen phosphate (452 mg, 3.28 mol) in water (3.3 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h. TLC (petroleum ether/EtOAc=1:1) showed most of the starting material was consumed. The reaction was quenched with a solution of sodium sulfite (455 mg, 3.61 mmol) in water (3.0 mL), and extracted with ethyl acetate (20 mL×3). The organic layers were washed with brine (20 mL) and dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by reverse phase HPLC to give the title compound (9.3 mg, 18%) as a white solid. MS (AP+) 322.1 (M+1)+. 1H NMR (400 MHz, CD3OD) 7.89 (s, 1 H), 7.82 (s, 1 H), 7.40 (d, 2 H), 7.30 (s, 1 H), 7.28 (d, 2 H), 3.69 (s, 2 H), 2.30 (s, 3 H), 0.89 (m, 4 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:21][CH2:22]O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH2:21][CH3:22])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
To a solution of 3-nitronaphthalene-1-carboxylic acid (4.34 g, 20 mmol) in EtOH (50 mL) was added SOCl2 (3.70 mL, 30 mmol) at 0° C. The mixture was heated at reflux for 2 h and then concentrated. The residue was recrystallized from EtOH to yield ethyl 3-nitronaphthalene-1-carboxylate (4.2 g). 1H NMR (300 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.77 (d, J=8.7 Hz, 1H), 8.62 (s, 1H), 8.34 (d, J=8.1 Hz, 1H), 7.87 (t, J=7.2 Hz, 1H), 7.75 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.CC(C)=CCC/C(/C)=C/CC/C(/C)=C/C[OH:55]>ClCCl>[NH2:12][C@H:11]([C:10]([OH:17])=[O:55])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 114.4 %

Procedure:
A solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (67 mg, 0.18 mmol), 4-N,N-dimethylaminopyridine (6.1 mg, 0.05 mmol, 0.3 eq), 1,3-dicyclohexylcarbodiimide (64 mg, 0.31 mmol, 1.8 eq) in dichloromethane (2.0 mL) was treated with trans,trans farnesol (55 uL, 0.22 mmol, 1.2 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 27 mg (26%) of L-isoleucine, N-[1-(2-[1-(3,7,11-trimethyldodeca-2,6,10-trien-1-ol)]-2-oxoethyl)-L-proline] benzylamide.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:12]2[CH2:13][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonyl chloride (3.43 g) in dichloromethane (30 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (5.2 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (3.03 g, 0.03 ml) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 6.06 g (m.p. 85°-86° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:46]=[CH:47][CH:48]=1)[C:34]([NH:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=1)=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:39]2[CH:38]=[C:37]([NH:36][C:34](=[O:35])[C:33]3[CH:46]=[CH:47][CH:48]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:42]=[N:41][CH:40]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1cccc(C(=O)Nc2cncc(B(O)O)c2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)Nc2cncc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (5-(3-methoxybenzamido)pyridin-3-yl)boronic acid (120 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 148 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (50 to 100%, hexane-ethyl acetate) phase using SP1® Purification System to give 113 mg (85% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:21][N:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:31].[Na+].OO>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:21][N:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]([NH2:26])=[O:31])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C#N)c3)C2)c(OCc2ccccc2)c1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(OCc2ccccc2)c1
Temperature: 45 °C

Procedure:
3-[4-(2-Benzyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (2 g) was dissolved in 30 mL EtOH. A solution of 25% NaOH (0.23 mL) was added followed by 2.3 mL H2O2 (30%). The mixture was heated to 45° C. for 5 h and cooled to r.t. After concentration the residue was dissolved in CH3Cl (100 mL), washed with NH4Cl, water, and brine, dried over MgSO4, and concentrated to give 1.83 g of crude product which was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-3-fluoro-phenylboronic acid. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[CH:22]([C:11]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[N:8]=[N:9][CH:10]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nncc1C=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a stirred solution of 1-[2-(trimethylsilanyl)ethoxy]methyl-1 H-1,2,3-triazole (Holzer, W.; Ruso, K, J. Heterocycl. Chem., 1992, 29, 1203-7) (2.0344 g, 10.2 mmol) in anhydrous THF (30 ml), cooled to <−75° C. under nitrogen, was added dropwise, over 11 min, a 1.6 M solution of butyllithium in hexanes (6.70 ml, 10.7 mmol). The mixture was stirred at this temperature for 30 min, then allowed to warm to −20° C. over 13 min. The mixture was then recooled to <−75° C., and anhydrous DMF (0.87 ml, 11.3 mmol) was added dropwise over 8 min. The mixture was stirred at <−75° C. for 1.75 h, then at 0° C. for 75 min. Saturated aqueous NH4CI (50 ml) was then added and the mixture was extracted with diethyl ether (75 ml) then ethyl acetate (2×75 ml). The organic extracts were dried (Na2SO4) and evaporated int vacuo. The residue was purified by flash chromatography (silica gel, 40% EtOAc/hexane) to give 1.7256 g (74%) of the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) δ−0.03 (9 H, s), 0.91 (2 H, m), 3.63 (2 H, m), 6.01 (2 , s), 8.28 (1 H, s), 10.08 (1 H, s); MS (ES+) m/e 170 [M—SiMe2+H]+.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH2:30][O:31][CH3:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH2:30][O:31][CH3:32])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCNS(=O)(=O)c1ccc(N)cc1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(C)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-N-(2-methoxyethyl)benzenesulfonamide (Intermediate 15), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:55]1([C:61]2[CH:68]=[CH:67][CH:66]=[CH:65][C:62]=2[C:63]#[N:64])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.FC(F)(F)C(O)=O>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30]([N:58]1[CH2:59][CH2:60][N:55]([C:61]2[CH:68]=[CH:67][CH:66]=[CH:65][C:62]=2[C:63]#[N:64])[CH2:56][CH2:57]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
The mixture of 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (50.0 mg, 0.268 mmol), N-hydroxybenzotriazole (19.0 mg, 0.134 mmol), and 2-piperazin-1-yl-benzonitrile (46.7 mg, 0.25 mmol), triethylamine (0.05 ml) in dry dichloromethane (2 ml) was stirred overnight at rt, and then treated with trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for another 5 h and concentrated. The residue was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient to afford the title compound (6.7 mg, 9.7%) as a light yellow oil. MS m/e=516.4 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].Cl[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:12]#[N:13].O>COCCOC>[NH2:13][C:12]1[CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:5][C:4]=1[C:3]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CO
Reactant: CC(C)(C)C(Cl)=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1oc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a slurry of NaH (5.98 g, 0.24 mol, 2.6 equiv) in anh. DME (800 mL) at 0° C. was added methyl glycolate (23.0 g, 0.26 mol, 2.8 equiv) over 20 min. The mixture was stirred for 1 h at room temp. and a solution of 3-chloro-4,4-dimethyl-2-pentenenitrile (13.1 g, 0.091 mol) in DME (100 mL) was added. The resulting solution was heated to 85° C. for 42 h, cooled to room temp., and treated with H2O (100 mL). The resulting mixture was separated between H2O (200 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The residual oil was purified by flash chromatography (300 g SiO2, gradient from 50% CH2Cl2/hexane to 20% EtOAc/CH2Cl2) to give methyl 3-amino-5-tert-butylfuran-2-carboxylate as a yellow solid (2.98 g, 17%): mp 91-2° C.; TLC (20% EtOAc/hexane) Rf0.36; 1H NMR (CDCl3) δ1.26 (s, 9H), 3.84 (s, 3H), 4.54 (br s, 2H), 5.75 (s, 1H); 13C NMR (CDCl3) δ28.5 (3C), 33.0, 50.7, 98.5, 128.8, 131.0, 160.7, 168.3.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:16])[C:6]([C:17]#[N:18])=[C:5]([Cl:19])[CH:4]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+].O>CC(C)=O>[C:20]([O:23][CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:16])[C:6]([C:17]#[N:18])=[C:5]([Cl:19])[CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: N#Cc1c(Cl)cc(CBr)n(-c2ccccc2Cl)c1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 6-(bromomethyl)-4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (1.53 g) in acetone (42.7 mL) was added sodium acetate (1.75 g) at room temperature. The reaction mixture was stirred at 70° C. for 8 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (670 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1.[CH:21]([O:23][CH2:24][CH3:25])=[CH2:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([O:16][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])[CH3:15])=[CH:17][CH:18]=2)[CH:19]=1
Reactant: C=COCC
Reactant: CC(O)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 1-(4-(5-bromo-2-chlorobenzyl)phenoxy)propan-2-ol (857 mg, 2.4 mmol) in dichloromethane (20 mL) was added ethyl vinyl ether (1.2 mL, 12 mmol) and pyridinium p-toluenesulfonate (24 mg), and the mixture was stirred at room temperature for 2 h, whereupon starting material had been completely consumed as determined by TLC (eluent PE:EA=1:1). Solid sodium bicarbonate (5 g) was added, and the mixture was stirred for 10 min. Water (25 mL) was added, and the mixture was extracted with ethyl acetate, washed with sodium chloride, and dried over sodium sulfate. The residue was concentrated and purified by column chromatography to obtain intermediate CZ (900 mg, yield 87%) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 7.23-7.30 (m, 3H), 7.09-7.11 (m, 2H), 6.85-6.87 (m, 2H), 4.86-4.94 (m, 1H), 4.10-4.13 (m, 1H), 4.00 (s, 2H), 3.84-3.99 (m, 1H), 3.69-3.72 (m, 1H), 3.50-3.59 (m, 1H), 1.19-1.37 (m, 9H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:11]1([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:6][CH2:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: O=C(CBr)N1CCN(C2CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(C2CCN(CC(=O)N3CCN(C4CCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(4-cyclopentyl-piperazin-1-yl)-ethanone (1.2 mmol), 4-piperidin-4-yl-benzonitrile (1.2 mmol) and potassium carbonate (2.4 mmol) in acetonitrile (10 mL) is stirred at rt overnight. The solvent is removed in vacuo and to the residue is added DCM (40 mL) and aqueous sodium bicarbonate (15 mL). The layers are separated and aqueous layer is extracted with DCM (15 mL). The combined organic layers are dried (MgSO4) and solvent removed in vacuo to give the crude product, which is purified by PTLC (5% MeOH in DCM) to give the title compound. 1H NMR (CDCl3) δ 7.59 (2H, d), 7.32 (2H, d), 3.64 (4H, br,), 3.22 (2H, s), 3.01 (2H, br), 2.40˜2.62 (6H, m), 2.21 (2H, dt), 0.80˜1.95 (12H, m); LC-MS (M+1) 381.