Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol, 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichloride (842 mg, 1.2 mmol) were combined in 12 mL of 1,2-dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 h and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by flash chromatography on silica gel to yield the title compound (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3) δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][NH2:12])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][N:14]1[CH:19]=[C:18]([C:20](O)=[O:21])[C:17]([C:23](OC)=[O:24])=[C:16]([Cl:27])[C:15]1=[O:28]>>[Cl:27][C:16]1[C:15](=[O:28])[N:14]([CH3:13])[CH:19]=[C:18]2[C:20](=[O:21])[N:12]([CH2:11][CH2:10][C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[C:23](=[O:24])[C:17]=12
Reactant: NCCc1nc2ccccn2n1
Reactant: COC(=O)c1c(C(=O)O)cn(C)c(=O)c1Cl
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2=O

Procedure:
The title compound was prepared in analogy to the process described in Example c1) starting from 2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)ethanamine and compound (4).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](=[O:20])[C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1)[CH3:2].O.[C:22](O)(=[O:24])[CH3:23]>C(OC(=O)C)(=O)C.[Zn]>[C:22]([NH:18][CH:12]([C:11](=[O:20])[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=NO)C(=O)CCc1cccc(CC)c1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(CC)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the product from step (iv) (20.9 g) in acetic acid (100 ml) and acetic anhydride (25 ml) was added zinc dust (30 g) portionwise at a rate to maintain the internal temperature <40° C. The mixture was stirred for 18 hours and water (125 ml) was added at such a rate as to maintain the temperature at around 40° C. The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was extracted with dichloromethane and the extract was washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (100.2 g) in THF (400 mL) was added t-butylamine (125 mL). An exothermic reaction results with gentle refluxing of the solvent. After 30 min, the bath was removed and the mixture was allowed to warm to r.t. Isopropyl acetate (400 mL) was added and the mixture was washed twice with water. The aqueous phase was back-extracted with ethyl acetate and the combined organics were dried (sodium sulfate) and concentrated to provide the title compound as a solid (112.9 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:21])[CH2:14]2.CO>CCOCC>[OH:21][C:15]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: Brc1ccccn1
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOCC
Product: OC1(c2ccccn2)CN2CCC1CC2
Temperature: -70 °C
Yield: 27.7 %

Procedure:
n-Butyl lithium (1.6M in hexanes, 17.4 ml, 27.9 mmol) was added dropwise to a solution of 2-bromopyridine (2.66 ml, 27.9 mmol) in ether (75 ml) cooled to -70° C. After 30 min a solution of 3-quinuclidinone (3.49 g, 27.9 mmol) in ether (25 ml) was added and the reaction mixture allowed to warm to -20° C. over 1 h. Methanol (50 ml) was added and the solution concentrated. The crude product was chromatographed through silica-gel using dichloromethane/methanol/ammonia (89:10:1) as eluent to give 1.58 g of the title compound as a tan solid. The dihydrochloride salt was prepared; m.p. 210°-5° C.; Found C, 51.82; H, 6.50; N, 9.98. C12H18N2Cl2O requires C, 51.99; H, 6.55; N, 10.10; δ(360 MHz, D2O) 8.792 (1H, d, J=5.4 Hz, py-H), 8.528 (1H, dt, J=8.1, 1.5 Hz, py-H), 8.139 (1H, d, J=8.1 Hz, py-H), 7.961 (1H, t, J=6.7 Hz, py-H), 4.177 (1H, d, J=14.3 Hz, H-2ax), 3.661 (1H, d, J=14.3 Hz, H-2eq), 3.54-3.35 (4H, m, H2 -6 and H2 -7) 2.55-1.65 (5H, m, H-4, H2 -5 and H2 -8); m/e 204 (M+).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8](OC)=[O:9])[N:6]=1.CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1
Reactant: COC(=O)Cc1nc(Br)sc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1sc(Br)nc1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of ester prepared in Example 24 (3.80 g, 15.2 mmol) in CH2Cl2 (100 mL) was added DIBAL-H (33.4 mL, 33.4 mmol of a 1.0 M solution in toluene) at −78° C. After 15 minutes, the solution was warmed to 0° C. and stirred for an additional 90 minutes. An aqueous solution of 2N HCl (50 mL) was then added dropwise to quench the excess DIBAL-H. The solvent layers were separated and the aqueous layer extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (5:2 hexanes/EtOAc) to yield the title compound (2.5 g, 74%) as a yellowish oil that solidified upon standing. (C6H8BrNOS): LC-MS, RT 1.38 min, M+H 221.0; 1H NMR (CDCl3): δ 2.31 (s, 3H), 2.82 (t, 2H), 2.90-3.00 (broad s, 1H), 3.89 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:16]=2)[N:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>C1COCC1.C(Cl)Cl>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:16]=2)[N:3]=1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCN
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1OCCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a solution of methyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-(3-chloropropoxy)benzoate (200 mg, 0.439 mmol) in THF (2 mL) was added tert-butyl (8-aminooctyl)carbamate (118 mg, 0.483 mmol) and Hunig'sBase (230 μl, 1.318 mmol). The resulting mixture was stirred for 16 h. The mixture was diluted with DCM and washed with water, then brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 20-40% EtOAc/hexanes. The product fractions were collected and the solvent removed under vacuum to give 208 mg (96%) methyl 4-(4-(8-(tert-butoxycarbonylamino)octylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-(3-chloropropoxy)benzoate.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[SH:15])=O)(C)(C)C>C(O)=O>[S:15]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[CH:6]1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1S
Solvent: O=CO
Product: c1cc2scnc2cn1

Procedure:
3-(tert-Butoxycarbonylamino)-4-mercaptopyridine (Japanese Patent Application Laid-Open (kokai) No. 4-321691) (9.20 g) was dissolved in formic acid (60 mL), and the solution was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added 5N aqueous potassium hydroxide (100 mL) and diethyl ether to partition the residue. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. Diethyl ether was added to the residue, and the resultant precipitated solid was collected by filtration, to thereby give the title compound (3.97 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)=[O:45]>CN(C=O)C>[CH3:42][O:43][C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)=[O:45]
Reactant: O=C(O)c1c[nH]nn1
Reactant: COC(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester (47.8 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (18 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:19]1[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=1)=[O:15]
Reactant: COc1ccccc1
Reactant: NCCCC(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C(=O)CCCN)cc1
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 78 %

Procedure:
Trifluoromethanesulfonic acid (4 ml) was ice-cooled, and 4-aminobutyric acid (1093 mg, 10.6 mmol) was added. Then, anisole (1 ml, 9.25 mmol) was added. The mixture was heated and stirred at 80° C. for 50 min. The mixture was cooled to room temperature and added dropwise to water (17 ml) under ice-cooling. The mixture was stirred under ice-cooling for 20 min and then at −10° C. for 30 min. The crystals were filtrated, washed with ice-cooled saturated brine, and dried under reduced pressure to give 4-amino-4′-methoxybutyrophenone trifluoromethanesulfonate (2.47 g, yield 78%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].OS(O)(=O)=O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:12])[CH3:13])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)N1C(=O)C(C)(C)c2ccc(F)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-Fluoro-1-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one E-1.2′″ (17.0 g; 76.9 mmol) in acetic acid (550 ml) was added fuming HNO3 (8.5 g; 134.9 mmol) at 25° C. The reaction mixture is stirred for 15 min at 25° C. and then concentrate H2SO4 (17.0 g; 173.5 mmol) is added and the mixture is stirred for 30 min at 25° C. After completion of the reaction the reaction mixture was poured in to ice cold water. The obtained solid was filtered and dried. The solid was recrystallized with ethyl acetate to obtain pure compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2NN=[N:27][N:26]=2)=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccc(Cl)cc2)o1
Yield: 84.3 %

Procedure:
The title compound (1.65 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.26 g), 5-(4-chlorophenyl)tetrazole (1.08 g) and dicyclohexylcarbodiimide (1.15 g) according to the method of description 1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:10]1[C:11](=[O:49])[N:12]2[C:16](=[CH:17][C:18]=1[C@:19]([CH2:43][CH3:44])([O:25][C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1([O:48][CH2:47][CH2:46][O:45]1)[CH2:14][CH2:13]2)#[N:9]>[Ni].C(O)(=O)C>[C:1]([NH:9][CH2:8][C:10]1[C:11](=[O:49])[N:12]2[C:16](=[CH:17][C:18]=1[C@:19]([CH2:43][CH3:44])([O:25][C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:34])=[O:35])=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1([O:45][CH2:46][CH2:47][O:48]1)[CH2:14][CH2:13]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@@](CC)(OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)c1cc2n(c(=O)c1C#N)CCC21OCCO1
Agent: [Ni]
Solvent: CC(=O)O
Product: CCOC(=O)[C@@](CC)(OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)c1cc2n(c(=O)c1CNC(C)=O)CCC21OCCO1

Procedure:
To a mixed solvent which was composed of 20 ml of acetic acid and 50 ml of acetic anhydride and containing 6 g of Raney nickel, 2.00 g of the compound (XIII) obtained in the above procedure (3) was added. While exposing the reaction system to light from a tungsten lamp, the compound (XIII) was reduced for 2 hours under a hydrogen gas stream. After removal of Raney nickel by filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and then developed by a 50:1 mixed solvent of chloroform and methanol. A fraction containing the intended product was concentrated to drynes,s thereby obtaining 2.15 g of the title compound in an amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: CI
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.00 g, 6.8 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. To the solution was added NaH (0.300 g, 12.5 mmol) portionwise over 1 h. H2(g) was evolved during the addition. The reaction was allowed to stir for 30 minutes at 0° C. and then methyl iodide (0.422 mL, 6.8 mmol) was added and allowed to stir at room temperature for 13 h. The reaction was quenched with ice water and concentrated down. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with EtOAc (3×), the organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/90% hexane to yield the title compound (1.1 g, 52%). 1H-NMR (CDCl3): δ 1.29 (s, 3H), 1.47 (s, 9H), 2.47 (dt, 1H), 2.76 (m, 1H), 3.07 (d, 1H), 3.33 (dt, 1H), 3.71 (s, 3H), 4.11 (m, 1H), 4.50 (d, 1H)
Reaction SMILES: COCCOC[CH2:7][O:8][CH2:9][CH2:10][NH2:11].[CH3:12][C@@H:13]1[CH2:15][C@H:14]1[C:16](O)=O>>[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]1[CH2:15][CH:14]1[CH3:16]
Reactant: COCCOCCOCCN
Reactant: C[C@@H]1C[C@H]1C(=O)O
Product: COCCNCC1CC1C

Procedure:
Prepared from 2-[2-(2-methoxyethoxy)ethoxy]ethanamine and trans-2-methylcyclopropanecarboxylic acid using steps A and B in the procedure described for the synthesis of Intermediate 3.6.1. MS (ES, M+H) 232.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[CH3:22][S:23](O)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:10]([NH:9][C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:3]=1)=[N:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])#[N:11]
Reactant: CS(=O)(=O)O
Reactant: N#CNC(=NCCc1ccccc1Cl)c1cncc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.2 %

Procedure:
To a solution of 5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide (110 mg, 0.39 mmol) in pyridine (2 ml) was added anhydrous methanesulfonic acid (65 mg, 0.37 mmol), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, ice and a saturated aqueous sodium carbonate solution (20 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml×3). The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (Wako Gel C-200, 20 g) and eluted with chloroform:methanol (50:1) to give the title compound (45 mg, yield 32%) as colorless powder.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:20]2[O:30][C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:9]2[O:19][C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:3][CH:2]=1.[O:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[K]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[O:19]=[C:9]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])[C:8](=[CH:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:20]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[C:28]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])=[O:30]
Reactant: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Reactant: CC(C)(C)O[K]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
The compound 52 (1.0 g, 2.5 mmol) obtained in the same manner as in Example 21 (b) was dissolved in dry benzene (80 ml), treated with KOC(CH3)3 (684 mg, 6.1 mmol), and heated under reflux for 1 hour. After completion of the reaction, the solvent was evaporated and the residue was dried and suspended by adding a small amount of water under ice cooling. The aqueous layer was made neutral with 0.5N.HCl, and the residue was dissolved by adding chloroform. The mixed layer was removed to a separating funnel. After the solid was completely dissolved, water was added to wash the solution so as to make the chloroform layer neutral or weak acidic. The chloroform layer was separated, washed with saturated aquecus NaCl solution and dried over magnesium sulfate. The solvent was evaporated to give a white solid. The product was dissolved in chloroform and purified by silica gel column chromatography (developing solvent: benzene:ethyl acetate=4:1) to give the desired compound as white solid (801 mg, crude yield 58%). Recrystallization from the mixed solvent of methanol and water gave white crystals (654 mg, yield, 47%). m.p., 117°-118° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=C.[H-].[Na+].Cl.ClCC[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>CN(C=O)C.O>[N:20]1([CH2:3][CH2:1][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:5]2=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCN1CCCCC1
Temperature: 45 °C
Yield: 46.7 %

Procedure:
A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (35 g, 0.2 moles) in DMF (250 ml) was added dropwise to a suspension of 80% sodium hydride (6 g, 0.2 moles) in DMF (50 ml). The reaction mixture was first heated at 45° C. for 30 minutes, allowed to cool at room temperature, and an additional amount of 80% sodium hydride (7.2 g, 0.24 moles) was added. Then 1-(2-chloroethyl)piperidine hydrochloride (44.16 g, 0.24 moles) was added portionwise and the reaction mixture was heated at 80° C.-90° C. for 3 hours. The mixture was then cooled at room temperature, adjusted to pH 3 with 37% aqueous HCl, and heated to 80° C. for additional 2 hours. The reaction mixture was poured into water and washed with ethyl acetate. The aqueous phase was adjusted to pH 8-9 with a saturated sodium carbonate solution and extracted into ethyl acetate. The organic layer was taken to dryness to give an ivory solid which after crystallization from isopropyl ether afforded 22.9 g of the title compound. M.p. 123° C.-125° C.