Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.[CH3:81][O:82][CH2:83][CH2:84][O:85][CH2:86]CN>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:81][O:82][CH2:83][CH2:84][O:85][CH3:86])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: COCCOCCN
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: COCCOCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (17A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and 2-(2-methoxyethoxy)ethanamine. MS (m/z) 716.15 [M+H]+.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH:18]2[C:19](=[CH:27]O)[C:20](=O)[CH2:21]3)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[C:1]([N:5]1[C:20]2[CH2:21][CH:22]3[N:17]([S:14]([C:11]4[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=4)(=[O:16])=[O:15])[CH:18]([CH2:25][CH2:24][CH2:23]3)[C:19]=2[CH:27]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)(C)n1ncc2c1CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using tert-butyl hydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21][S:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH:33]([CH3:36])[CH2:34][CH3:35])[CH:8]([CH3:11])[CH2:9][CH3:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[S:22][S:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH:8]([CH3:11])[CH2:9][CH3:10])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH:33]([CH3:36])[CH2:34][CH3:35])([OH:39])=[O:38]
Reactant: CCC(C)C(NC(=O)c1cccc(F)c1SSc1c(F)cccc1C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC(C)C(NC(=O)c1cccc(F)c1SSc1c(F)cccc1C(=O)NC(C(=O)O)C(C)CC)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-2-methyl-butylcarbamoyl)-6-fluorophenyldisulfanyl]-3-fluoro- benzoylamino]-3-methylpentanoic acid tert butyl ester (0.6 g ,0.8 mmol) and anisole (1 ml) in 10 mL dichloromethane at 0° C., was added dropwise 10 mL trifluoroacetic acid. The mixture was allowed to warm to ambient temperature. After 4 hours, 5 mL toluene was added and the solvents were removed in vacuo. The crude product was recrystallized from methanol/water to yield 0.2 g of the title compound, mp 188-190° C.
Reaction SMILES: Cl[Sn]Cl.O.[I:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][N:7]=1.[OH-].[Na+]>CCOC(C)=O>[I:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[CH:8][N:7]=1
Reactant: Cc1cc(I)ncc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(I)ncc1N
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of SnCl2.H2O (20.5 g, 108 mmol) in EtOAc (200 mL) was added 2-iodo-4-methyl-5-nitropyridine (5.7 g, 21.6 mmol) in EtOAc (20 mL). Heat was released, and the reaction mixture was kept at reflux for 2 hr. After cooling to rt, the reaction mixture was treated with 50% NaOH (50 mL). Solid was filtered off and washed with EtOAc. The filtrate was washed with brine, dried, and concentrated to afford 2-iodo-4-methyl-5-pyridinamine (5 g, 99%) as a yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH2:29][CH2:30]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccccn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 68.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-pyridin-2-ylpiperidin-4-amine dihydrochloride (0.173 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.175 g, 69%). 1H NMR (500 MHz, CDCl3): δ 8.08-8.03 (m, 1H), 7.50-7.44 (m, 2H), 7.41-7.32 (m, 4H), 6.55-6.47 (m, 2H), 5.28-5.20 (m, 1H), 4.02-3.93 (m, 2H), 3.11-3.00 (m, 1H), 2.41-2.30 (m, 2H), 1.73-1.60 (m, 2H), 1.67 (s, 9H), 1.36-1.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 159.1, 148.0, 137.7, 134.2, 131.9, 130.1, 128.9, 125.4, 113.5, 107.5, 107.0, 61.7, 50.7, 44.1, 41.2, 32.0, 27.8; Mass Spectrum: M−H+ 441.
Reaction SMILES: [C:1]([C:4]([C:15]1[N:23]2[C:18]([C:19](=[O:35])[NH:20][C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[N:22]2)=[C:17]([CH3:36])[N:16]=1)([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][C:21]1[NH:20][C:19](=[O:35])[C:18]2=[C:17]([CH3:36])[N:16]=[C:15]([C:4]([CH:1]([OH:3])[CH3:2])([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:23]2[N:22]=1
Reactant: COc1ccc(Cc2nn3c(C(C)(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cc2nn3c(C(C)(CCCc4ccccc4)C(C)O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
100 mg (0.20 mmol) of 7-(1-acetyl-1-methyl-4-phenylbutyl)-2-(3,4-dimethoxy-benzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one are reacted analogously to Example 12 with 23 mg (0.60 mmol) sodium borohydride to give 2-(3,4-dimethoxybenzyl)-7-[1-(1-hydroxyethyl)-1-methyl-4-phenylbutyl]-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]
Reactant: COCOCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COCOCCCCCCCCCCCCCCCCN

Procedure:
To a suspension of 0.97 g of N-(16-methoxymethoxyhexadecyl)phthalimide in 50 ml of ethanol was added 0.4 ml of hydrazine monohydrate and the mixture was heated under reflux for 2 hours. The reaction solution was distilled under reduced pressure. The residue was diluted with chloroform, washed with a 1N aqueous solution of sodium hydroxide, dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was chromatographed over a silica gel column to afford the title compound as a colorless oily substance.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]([C:11](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][N:20]=1)[C:12](OCC)=[O:13])#[N:10]>O1CCCC1>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]2[N:20]([CH:21]=1)[C:12](=[O:13])[C:11]([C:9]1[NH:10][N:7]=[N:6][N:5]=1)=[CH:17][N:18]=2)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1
Yield: 30.4 %

Procedure:
Aluminum chloride (0.89 g., 6.67 mmoles was carefully added to cold (-30°) tetrahydrofuran (42 ml.). Sodium azide (1.3 g., 20.0 mmoles was then added and the mixture heated at reflux for 40 minutes. Ethyl 2-cyano-3-(5-n-butyl-2-pyridylamino)acrylate (1.50 g., 5.49 mmoles) was added and the mixture heated under reflux for 18 hours. The cooled mixture was concentrated and the residue treated with ice water (50 ml.). The mixture was acidified to pH 3 with 6N hydrochloric acid. The mixture was filtered and the collected solid treated with boiling 3% aqueous sodium bicarbonate for 10 minutes. The mixture was filtered and the filtrate acidified to pH 4 with 6N hydrochloric acid. The precipitate was recrystallized from N,N-dimethylformamide to give the title compound (0.45 g., 30.4%), m.p. 284°-285° (decomp).
Reaction SMILES: C(OC([N:8]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([CH3:48])[CH:44]=[CH:43]2)[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N:17]([CH3:36])[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:33])[NH:31][CH3:32])=[CH:26][CH:25]=2)[C:11]=1[Cl:37])=O)(C)(C)C.[ClH:49]>C(OCC)(=O)C>[ClH:16].[ClH:49].[Cl:37][C:11]1[C:12]([N:17]([CH3:36])[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[CH:22]=[CH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30](=[O:33])[NH:31][CH3:32])=[CH:28][CH:29]=2)=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][NH:8][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([CH3:48])[CH:44]=[CH:43]2
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CN(C(=O)OC(C)(C)C)c3cccc4ccc(C)nc34)c2Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CNc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-[N-tert-butoxycarbonyl-N-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl]amino]-2-methylquinoline (32.3 mg) in ethyl acetate (0.5 ml) was added 4N solution of hydrogen chloride in ethyl acetate (0.5 ml) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was concentrated in vacuo to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzylamino]-2-methylquinoline dihydrochloride (22.0 mg) as amorphous powder.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH:12][C:13]3[C:14](=[O:29])[N:15]([CH3:28])[CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[CH:11]=[C:5]2[CH2:4]1)[CH3:2].Cl[C:31]1[C:36]([CH:37]=[O:38])=[C:35]([N:39]2[CH2:51][CH2:50][C:49]3[N:48]4[C:43]([CH2:44][CH2:45][CH2:46][CH2:47]4)=[CH:42][C:41]=3[C:40]2=[O:52])[N:34]=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH:12][C:13]3[C:14](=[O:29])[N:15]([CH3:28])[CH:16]=[C:17]([C:31]4[C:36]([CH:37]=[O:38])=[C:35]([N:39]5[CH2:51][CH2:50][C:49]6[N:48]7[C:43]([CH2:44][CH2:45][CH2:46][CH2:47]7)=[CH:42][C:41]=6[C:40]5=[O:52])[N:34]=[CH:33][CH:32]=4)[CH:18]=3)[CH:11]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Reactant: CCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 55.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 208d (120 mg, 0.30 mmol), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido-[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (99 mg, 0.30 mmol), PdCl2(dppf) (13 mg, 0.015 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate (49 mg, 0.60 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 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 30:1 dichloromethane/methanol to afford the 208e (95 mg, 56%) as a yellow solid. MS-ESI: [M+H]+ 567.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([NH2:31])[CH:23]=[C:24]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:31][C:22]2[CH:23]=[C:24]([C:26]3[NH:30][N:29]=[N:28][N:27]=3)[CH:25]=[C:20]([Br:19])[CH:21]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: Nc1cc(Br)cc(-c2nnn[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (250 mg, 1.1 mmol) in CH2Cl2 (6 mL) was added 3-bromo-5-(1H-tetrazol-5-yl)-phenylamine dihydrochloride (prepared as described in Part C, 365 mg, 1.32 mmol), HBTU (626 mg, 1.65 mmol) and DIPEA (0.576 ml, 3.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH2Cl2 and successively washed with 1M aqueous HCl solution (30 mL) and a saturated aqueous NaHCO3 solution. The organic phase was dried (phase separator) and evaporated under vacuum. The crude mixture was purified by preparative HPLC (C18 Nucleosil 100-10, flow: 40 ml/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA). After combination of the purified fractions, CH3CN was removed under vacuum and lyophilization gave the desired compound. MS (LC/MS): 447.1 [M−H]−; tR (HPLC conditions k): 4.62 min.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1([S:18]([N:21]2[CH2:24][C:23](=O)[CH2:22]2)(=[O:20])=[O:19])[CH2:17][CH2:16]1.[Na+].[Cl-]>O1CCCC1.O>[CH3:14][C:15]1([S:18]([N:21]2[CH2:24][C:23](=[CH:5][C:3]#[N:4])[CH2:22]2)(=[O:19])=[O:20])[CH2:17][CH2:16]1
Reactant: CC1(S(=O)(=O)N2CC(=O)C2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(S(=O)(=O)N2CC(=CC#N)C2)CC1
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 17 mg, 0.42 mmol) in tetrahydrofuran (2 mL) at 0° C. was added diethyl cyanomethylphosphonate (70 μL, 0.43 mmol) dropwise. The mixture was then allowed to reach room temperature and stir for a further 45 minutes. A solution of 1-[(1-methylcyclopropyl)sulfonyl]azetidin-3-one (prepared in Step 5) in tetrahydrofuran (1.0 mL) was added and the mixture was allowed to stir at ambient temperature for 16 hours. Into the reaction was added water and solid NaCl, and the product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated to afford product (71 mg, 100%), used without further purification in Step 7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][OH:22])([CH3:16])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](OCCCOC(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(C)(C)OCCCO)CC1

Procedure:
A solution of 0.245 g (0.52 mmol) of 1-t-butoxycarbonyl-4-(2-(3-triisopropylsilyloxy-1-propyl)oxy-2-methyl-1-propyl)piperidine and 0.53 mL (0.53 mmol) of tetrabutylammonium fluoride (TBAF) in 2 mL of THF was stirred at rt for 2 h. The reaction mixture was partitioned between ether and water. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:acetone, 9:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C[Al](C)C.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@@:23]([OH:49])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:24]([S:26][C@@H:27]1[CH2:32][O:31][C@@H:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37](OC)=[O:38])=[CH:35][CH:34]=2)[O:29][CH2:28]1)[CH3:25]>>[Cl:10][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[NH:1][C:37](=[O:38])[C:36]1[CH:41]=[CH:42][C:33]([C@H:30]2[O:29][CH2:28][C@H:27]([S:26][C@H:24]([CH3:25])[C@:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])([OH:49])[CH2:43][N:44]3[CH:48]=[N:47][CH:46]=[N:45]3)[CH2:32][O:31]2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: N#Cc1ccc(N)cc1Cl
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)c(Cl)c3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-amino-2-chlorobenzonitrile (182 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (167 mg, yield 90%) as a colorless oil which was recrystallized from ethyl acetate-isopropyl ether to give white powdery crystals.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: BrCc1ccccc1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.94 g) and benzyl bromide (0.285 mL) as starting materials, 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.087 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](C(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[Na+].[Cl-]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(F)cn1
Temperature: 25 °C

Procedure:
The solution of dimethyl 2-(5-fluoropyridin-2-yl)malonate (400 mg 1.76 mmol), NaCl (109.2 mg, 1.87 mmol) and H2O (56.3 g, 3.13 mmol) in DMSO (3 mL) was stirred at 130 degree for 6 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to get desired product. LC-MS: m/z (M+H)=170.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2=[N:32][C:33](=[O:35])[N:34]=[C:30]2[CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COCCC(C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
70 mg (186 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate), 27.7 mg (186 μmol, 1.0 eq.) of 5-aminobenzimidazolone, 26.4 mg (186 μmol) of Oxima and 28.9 μl (186 μmol) of DIC in 3.9 ml of dimethylformamide were reacted according to General Method 5. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/0.1% formic acid and acetonitrile/0.1% formic acid, gradient 10% acetonitrile to 90% acetonitrile) and then subjected to basic extraction (aqueous sodium hydroxide solution/ethyl acetate). Yield: 44 mg (47% of theory)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[N:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[CH:15][CH:14]=1
Reactant: Oc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccncc2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.0 g) and pyridin-4-ol (1.8 g) were mixed with THF (50 ml), and triphenylphosphine (6.23 g) was added thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was added dropwise, followed by stirring at 55° C. overnight. Triphenylphosphine (5 g) and a 1.9 M DIAD/toluene solution (10 ml) were added to the reaction mixture, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and a liquid separation operation was carried out by the addition of EtOAc and 0.5 M hydrochloric acid. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (4.2 g).