Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32](=[NH:35])[NH:33][OH:34])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:36].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]3[NH:35][C:37](=[O:38])[O:34][N:33]=3)=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:36]
Reactant: Cc1cc(C(=N)NO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2noc(=O)[nH]2)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-hydroxycarbamimidoyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.1 g) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (62 mg) at room temperature. To the mixture was added sodium hydride (55%, 38 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (62 mg).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N>C(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][N:6]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)ccn1
Yield: 51 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolyl methylthio)ethylamine was heated under reflux in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 177-178° in 51% yield. The latter compound was heated under reflux in 2N hydrogen chloride in ethanol for 24 hours and the mixture was evaporated to dryness. The residue was recrystallised from 2-propanol/ethanol containing hydrogen chloride to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 172-176°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][N:6]([C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][N:6]([C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([OH:24])=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 88.4 %

Procedure:
0.78 g of {[2-{2-(S)-[Benzyloxy-carbonyl]-pyrrolidin-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester were dissolved in 50 mL of methanol and hydrogenated for 3 h at room temperature using 0.4 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.58 g (89%) of the title compound as a colorless oil. (−)-APCI-MS: 477 ([M-H]−).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C>O1CCOCC1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCCCCCC>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine (0.675 g, 2.15 mmol), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.794 g, 2.30 mmol), Cs2CO3 (3.50 g, 10.7 mmol), XANTPHOS (0.053 g, 0.088 mmol) and tris(benzylideneacetone)dipalladium(0) (0.039 g, 0.043 mmol) in dioxane (5.4 mL) was heated to 55° C. for 1.5 h, analysed by HPLC, then cooled to room temperature. Heptane (2.4 mL), charcoal (0.27 g) and celite (0.27 g) were added. The suspension was stirred for 30 min at room temperature, and then filtered over celite, rinsing with toluene (13.5 mL×3). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (DCM:MeOH:NEt3 9:1:0.1) to give the title compound (0.867 g, 70%) as a red amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[CH3:18].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[CH3:18]
Reactant: CCn1ncc(C)c1-c1cc(C(=O)OC)sc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc(C)c1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (260 mg, 0.90 mmol) in THF/H2O (2 mL/2 mL) was added KOH (201 mg, 3.6 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give crude 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, which was used directly without further purification: LC-MS (ES) m/z 271 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[N:12]([O-])=[O:13].[Na+]>Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([N:12]=[O:13])[CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)OCCN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)OCCN2N=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3,4-Dihydro-7-methyl-2H-benzo[b][1,4]oxazine (280 mg, 1.87 mmol) was dissolved in 3N HCl (20 mL). Sodium nitrite (129 mg, 1.87 mmol) in water (1 mL) was added dropwise into the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain 270 mg of 7-Methyl-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (free base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O.CN(C)C=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cncc1Cl

Procedure:
Thus obtained 3,5-dichloropyridine-4-carboxylic acid (384 mg, 2 mmol) was dispersed in 1,2-dichloroethane (30 mL) to prepare a slurry, added with thionyl chloride (0.44 mL, 5 mmol), further added with dimethylformamide (0.3 mL), and the mixture was refluxed under heating for 1 hour. The solvent was evaporated under reduced pressure to thereby obtain a crude product of 3,5-dichloropyridine-4-carbonylchloride. 3-(4-aminophenyl)-2-{3-[(2,2-dimethyl propionyl)isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (2.04 g, 4.5 mmol) obtained in Example 38 was then dissolved in 1,2-dichloroethane (30 mL), and added with pyridine (0.57 mL, 7 mmol). To the mixture, the 1, 2-dichloroethane solution (10 mL) of 3,5-dichloro pyridine-4-carbonylchloride obtained in the above was added, and the mixture was stirred for 1 hour. The reaction solution was treated with water (15 mL), extracted with chloroform, dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, and the resultant residue was purified through silica gel column chromatography (hexane:ethyl acetate (v/v)=3:2) to thereby obtain 3-[4-(3,5-dichloropyridine-4-carbonylamino) phenyl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (yield: 2.77 g, yield ratio: 98%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=2)=[N:26]1.CCN(C(C)C)C(C)C.[F:48][C:49]([F:62])([F:61])[C:50]1[NH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([CH2:59][NH2:60])=[CH:54][CH:53]=2>CN(C=O)C>[NH:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:60][CH2:59][C:55]3[CH:56]=[C:57]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([C:49]([F:62])([F:48])[F:61])=[CH:58]4)=[O:36])=[CH:37][CH:38]=2)=[N:26]1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(-c2cc[nH]n2)cc1
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(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(-c2cc[nH]n2)cc1
Reaction time: 24 h

Procedure:
To a solution of HATU (0.200 mmol) in DMF (0.5 ml) was added 4-(1H-pyrazol-3-yl)benzoic acid (Apollo Scientific Ltd.) (0.12 mmol) in DMF (0.5 ml), followed by DIPEA (0.300 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 0.025 g, 100 μmol) in DMF (0.25 ml). The experiment was carried out in an array form using a Bohdan mini block. The block was shaken for 24 hours. The compound was purified using an amino propyl column which was pre-conditioned with DMF. The column was washed with DMF (×2). The washings were evaporated to dryness and the resulting residue was then purified by MDAP to give the title compound;
Reaction SMILES: I[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][CH:13]=[C:12]2[O:11][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[CH:8][S:9][C:10]=2[C:2]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc4ncsc4c3I)c2cc1OC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4ncsc4c3-c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
4-(7-Iodo-benzothiazol-6-yloxy)-6,7-dimethoxy-quinoline (compound 294) (40 mg), phenylboronic acid (40 mg), and tetrakistriphenylphosphine palladium (20 mg) were dissolved in N,N-dimethylformamide (5 ml) to prepare a solution. A 2 M aqueous potassium carbonate solution (0.3 ml) was added to the reaction system, and the mixture was stirred at 80° C. for 20 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (35 mg, yield 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([CH3:34])[CH2:31][C@H:30]([NH:35]C(=O)OC(C)(C)C)[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2.Cl>O1CCOCC1.CO>[NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([CH3:34])[CH2:31][C@H:30]([NH2:35])[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the intermediate tert-butyl {(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The resulting residue was dissolved in 4.5 mL of MeOH and treated with 0.3 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C27H36N7O [M+H]+: m/z=474.3. found: 474.4.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C[O:9][CH2:10][CH2:11]OC>>[OH:9][C@@H:10]1[C@H:2]2[C@H:1]([O:4][CH2:5][CH2:6]2)[O:3][CH2:11]1
Reactant: CC(=O)OC(C)=O
Reactant: COCCOC
Product: O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 23 °C
Yield: 42 %

Procedure:
To a stirred solution of reacemic alcohol 24 (2 g, 15.4 mmol) and acetic anhydride (4 g, 42.4 mmol) in 100 mL of DME was added 2.7 g (about 25% by weight of lipae PS30) of immobilized Amano lipase and the resulting suspension was stirred at 23° C. The reaction was monitored by TLC and 1H NMR analysis until 50% conversion was reached. The reaction mixture was filtered and the filter cake was washed repeatedly with ethyl acetate. The combined filtrate was carefully concentrated in a rotary evaporator, keeping the bath temperature below 15° C. The residue was chromatographed over silica gel to provide 843 mg (42%) of 25 (95% ee; aD23° −11.9°, MeOH); 1H-NMR (CDCl3) δ 1.85 (m, 2H), 2.3 (m, 1H), 2.9 (m, 1H), 3.65 (dd, J=7.0, 9.1, 1H), 3.85-4.0 (m, 3H), 4.45 (dd, J=6.8, 14.6, 1H), 5.7 (d, J=5.1, 1H); also, 1.21 g of 26 after washing with 5% aqueous sodium carbonate (45%, aD23° +31.8°, MeOH); 1H-NMR (CDCl3) δ 1.85-2.1 (m, 2H), 2.1 (s, 3H), 3.1 (m, 1H), 3.75 (dd, J=6.6, 9.2, 1H), 3.8-4.1 (m, 3H), 5.2 (dd, J=6.4, 14.5, 1H), 5.7 (d, J=5.2, 1H). Acetate 26 was dissolved in THF (5 mL) and 1 M aqueous LiOH solution (20 mL) was added to it. The resulting mixture was stirred at 23° C. for 3 h and the reaction was extracted with chloroform (3×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was chromatographed over silica gel to provide 733 mg of 27 (97% ee; aD23° −12.5°, MeOH).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: NCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Yield: 51.3 %

Procedure:
Method E. Reaction of oxalyl chloride (76 λL, 0.88 mmol) and benzoic acid 35 (226 mg, 0.58 mmol) with subsequent coupling to 3-pyridinylmethylamine (65 λL, 0.64 mmol) gave benzamide 36 (142 mg, 51%) as a white powder: mp (MeOH/EtOAc) 189-191° C.; 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.7Hz, 1 H, H-2′), 8.47 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 8.00 (dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.91 (dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.74 (ddd, J=8.0, 2.1, 1.4Hz, 1 H, H-4′), 7.70 (ddd, J=8.9, 3.0, 2.0Hz, 2 H, H-2″, H-6″), 7.36 (ddd, J=7.9, 4.7, 0.7Hz, 1 H, H-5′), 7.13 (ddd, J=8.9, 3.0, 2.0Hz, 2 H, H-3″, H-5″), 4.60 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 3.84 (s, 3 H, OCH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.5, 163.3, 157.9, 149.8, 148.9, 148.0, 135.3, 135.1, 134.8, 130.4 (2), 129.8, 128.8, 128.0 (2), 126.1, 125.3 (2), 123.4, 114.3 (2), 55.7, 53.0, 40.4, 9.6; MS m/z 477.6 (MH+, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06; H, 5.11; N, 8.51. Found: C, 61.85; H, 4.88; N, 8.62%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:34][CH2:35]2)=[CH:41][CH:40]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
126 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (83 mg, 0.289 mmol), DIPEA (0.076 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=O)[CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:11]1
Reactant: CC1CC(=O)CC(C)C1
Reactant: C#Cc1ccccn1
Product: CC1C=C(C#Cc2ccccn2)CC(C)C1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 3,5-dimethylcyclohexanone (6.0 mmol, 0.85 mL); yields 2-[(3,5-dimethyl-1-cyclohexen-1-yl)ethynyl]pyridine as a transparent yellow oil (500 mg, 39% overall yield) as a mixture of diastereomers. 1H NMR (CDCl3, 300 MHz) δ 8.57 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.19 (m, 1H), 6.15 (br s, 1H), 2.29 (m, 2H), 1.80 (br m, 2H), 1.00 (m, 6H), 0.88 (br m, 2H). MS (EI ionization) 211 (M+).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][NH:5][CH:4]1[CH3:11].N1C=CC=CC=1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[OH:10][CH2:9][CH:7]1[CH2:6][NH:5][CH:4]([CH3:11])[CH:3]([O:2][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:8]1
Reactant: CC1NCC(CO)CC1O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1NCC(CO)CC1OC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.9 g. of 3-hydroxy-5-hydroxymethyl-2-methylpiperidine hydrochloride in 10 ml. of pyridine was added to a solution of 0.9 g. of isonicotinoyl chloride hydrochloride in 25 ml. of dimethylformamide under cooling. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-water and extracted with chloroform. The extracted was washed with water, dried and the solvent was distilled off to give a crystalline substance. The substance was recrystallized from a mixture of ethyl acetate and hexane to give 0.7 g. of the desired product. m. p. 126° - 128°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.CCOC(C)=O>CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]1
Reactant: Clc1ccccn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Temperature: 140 °C
Yield: 0 %

Procedure:
A solution of 2-chloropyridine (0.83 ml, 8.81 mmol), tert-butyl piperidine-4-ylcarbamate (1.85 g, 9.24 mmol) and TEA (0.98 mL, 9.69 mmol) in DMSO (5 mL) was heated at 120° C. for 4 h 45 mins and then warmed to 140° C. for 2 days. EtOAc was added and the organic phase was washed with water then brine before evaporating to dryness. The residue was purified on a Biotage Horizion HPFC system eluting with 20% EtOAc in petroleum ether (40-60° C.) to give the title compound (0.65 mg, 27%). 1H NMR (500 MHz, CDCl3): 8.19 (s, 1H), 7.48 (dd, 1H), 6.67 (d, 1H), 6.61 (t, 1H), 4.49 (bs, 1H), 4.21 (d, 2H), 3.70 (bs, 1H), 2.99 (t, 2H), 2.05 (d, 2H), 1.59-1.38 (m, 11H). 13C NMR (CDCl3): 159.5, 155.4, 148.2, 137.7, 113.3, 107.5, 79.6, 48.4, 44.6, 32.3, 28.7; Mass Spectrum: M+H 278.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycine and L-phenylalanyl-L-methionine benzyl ester are reacted according to the procedure detailed in Example 12, there is obtained N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycyl-L-phenylalanyl-L-methionine benzyl ester.