Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:11][C:12]([C:14]1([O:18]/[N:19]=[C:20](/[C:53]2[N:54]=[C:55]([NH:58]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:56][CH:57]=2)\[C:21]([NH:23][CH:24]2[C:51](=[O:52])[N:26]3[C:27]([C:35]([O:37]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:36])=[C:28]([CH:31]=[CH:32][CH2:33]I)[CH2:29][S:30][C@H:25]23)=[O:22])[CH2:17][CH2:16][CH2:15]1)=[O:13])(C)(C)C>ClCCl.C(OC(C)C)(C)C>[NH2:58][C:55]1[S:56][CH:57]=[C:53](/[C:20](=[N:19]/[O:18][C:14]2([C:12]([OH:13])=[O:11])[CH2:17][CH2:16][CH2:15]2)/[C:21]([NH:23][CH:24]2[C:51](=[O:52])[N:26]3[C:27]([C:35]([O-:37])=[O:36])=[C:28](/[CH:31]=[CH:32]/[CH2:33][N+:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:29][S:30][C@H:25]23)=[O:22])[N:54]=1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=CCI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C/C[n+]4ccccc4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Pyridine (0.1 ml, 1.2 mmole) was added to a solution of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-5', 659 mg, 9.6 mmole) in dichloromethane (7 ml). The mixture was stirred at room temperature for 2.5 hours and diluted with diisopropyl ether. The resulting solid (383 mg) was collected by filtration and treated with 90% trifluoroacetic acid (5 ml) and anisole (1 ml) at room temperature for 1 hour. The resulting mixture was concentrated and the residue was triturated with ether to give 237 mg of crude I-5B, which was purified by HP-20 column chromatography [eluted with water (150 ml), 10% methanol (200 ml) and 30% methanol (500 ml)]. The eluate of 30% methanol was concentrated to a small volume, adjusted to pH 7 with sodium bicarbonate and lyophilized to afford 72 mg (21%) of I-5B. M.P. >160° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[CH3:11])[C:6]=2[CH:20]=1.C(O[C:26]([N:28]1[CH2:33][CH:32]=[C:31](B(O)O)[CH2:30][CH2:29]1)=[O:27])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C@H:10]([N:7]1[C:6]2[CH:20]=[C:2]([C:31]3[CH2:30][CH2:29][N:28]([C:26]([C@H:29]4[CH2:30][CH2:31][CH2:32][CH2:33][NH:28]4)=[O:27])[CH2:33][CH:32]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1)[CH3:11]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 100 °C

Procedure:
A mixture of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazole (1.3 g, 3.5 mmol), (N-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pincol ester (1.2 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 0.20 g, 0.18 mmol), and 2 M aqueous potassium carbonate (5.3 mL, 10.5 mmol) in toluene (10 mL) and ethanol (5 mL). The mixture was purged with nitrogen for 5 min, and then heated at 100° C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the desired product in 90% purity (1.6 g, 3.4 mmol, 97%). MS: (ES) m/z calculated for C25H28Cl2N3O [M+H]+ 472.2. found 472.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:14][CH:13]2[C:35]([O:37]C(C)(C)C)=[O:36])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[CH2:14][CH:13]2[C:35]([OH:37])=[O:36])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cccc(C(F)(F)F)c3)CC2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cccc(C(F)(F)F)c3)CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of 0.36 g (0.61 mmol) of 4-(4-methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2Cl2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2Cl2. The CH2Cl2 was washed with 1 N NaHCO3 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl acetate. The extract was dried (Na2SO4). The original CH2Cl2 extract was washed with 2 N citric acid, H2O, brine and dried with Na2SO4. The CH2Cl2 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p. 105-110° C. Anal. for C25H21F3N2O6S: Calc'd: C, 56.2; H, 4.0; N, 5.2; Found: C, 55.1; H, 3.7; N, 5.0.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:2][CH:3]=3)[O:8][C:9]=2[CH3:25])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c1

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethyl ester (24 g, 66.9 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (Columbia University WO 9731530) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester. Rf=0.63 in 35% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.03-8.00 (m, 2H), 7.65-7.60 (m, 4H), 7.43 (t, J=7.2 Hz, 2H), 7.34 (tt, J=7.2, 1.2 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 6.52 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 6.43 (t, J=2.4 Hz, 1H), 6.36 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 6H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]([CH3:14])[CH3:13])[C:7]([CH2:16][C:17](O)=[O:18])([OH:15])[CH2:6][CH2:5]2.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][CH2:31][NH:32][CH3:33]>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[C:17](=[O:18])[CH2:16][C@@:7]1([OH:15])[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C@@H:8]1[CH:12]([CH3:13])[CH3:14]
Reactant: CNCCCc1nc2ccccc2[nH]1
Reactant: CC(C)C1c2ccc(F)cc2CCC1(O)CC(=O)O
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1

Procedure:
An "activated derivative" of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl) acetic acid is a derivative that renders the acid more active in the reaction with [3-(1H-benzimidazol-2-yl)propyl]methylamine to form (1S,2S)-N-[3-(1H-benzimidazol-2-yl) propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide. Typical such derivatives include the corresponding acyl halides and anhydrides, and a preferred activated derivative is the mixed anhydride of(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid with trimethylacetic acid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:7]=2[C:8](=[O:11])[C:9]=1[CH3:10])(=[O:3])C.CC1C(=O)C2C=CC=C(C=CC)C=2OC=1[C:34](=O)[NH:35]C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[C:16]([C:15]1[C:6]2[O:5][C:4]([C:1]([NH:35][CH3:34])=[O:3])=[C:9]([CH3:10])[C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][CH:14]=1)([OH:18])=[O:17]
Reactant: CC(=O)c1oc2c(C(=O)O)cccc2c(=O)c1C
Reactant: CC=Cc1cccc2c(=O)c(C)c(C(=O)NC)oc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CNC(=O)c1oc2c(C(=O)O)cccc2c(=O)c1C
Yield: 60 %

Procedure:
The title compound was prepared following the method described for Compound 2C but using Compound 5A instead of Compound 2B. The reaction mixture was poured into an 1% aqueous solution of sodium dithionite and filtered after overnight resting to give Compound 5B (60%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14]>>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH3:9]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(C(C)=O)C(=O)COC

Procedure:
In analogy to the procedure described in Intermediate 11A], ethyl acetoacetate and methoxyacetylchloride gave the crude title compound in quantitative yield as yellow oil. MS: 202.9 (MH+).
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].NC1[CH:12]=[C:13](C)[C:14]([Cl:17])=[N:15][CH:16]=1.N(OC(C)(C)C)=O.CCCCC>COCCOC>[Cl:17][C:14]1[C:13]([CH3:12])=[CH:9][C:8]([OH:7])=[CH:16][N:15]=1
Reactant: Cc1cc(N)cnc1Cl
Reactant: CCOCC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: CCCCC
Product: Cc1cc(O)cnc1Cl
Reaction time: 0.25 h
Yield: 151.6 %

Procedure:
To a solution of boron trifluoride diethyl etherate (5.8 mL, 47.5 mmol) in DME (18 mL) at −14° C. was added dropwise a solution of 5-amino-2-chloro-3-methylpyridine (4.5 g, 31.7 mmol) in DME (60 mL). The mixture was stirred for 15 minutes and then a solution of t-butyl nitrite (4.5 mL, 38 mmol) in DME (60 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C., then pentane (100 mL) was added to give a solid. The solid was collected by filtration and dried to give the title compound (6.9 g): 1H NMR (MeOH-d4, 300 MHz) δ2.58 (s, 3H), 8.86 (d, J=2.1 Hz, 1H), 9.41 (d, J=2.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])=[CH:20][CH:19]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[O:30])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([N+:14]([O-])=[O:15])([CH3:13])[CH3:12].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[N+:14]([C:11]([CH3:13])([CH3:12])[CH3:10])[O-:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1cccc(F)c1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1cccc(F)c1

Procedure:
To a suspension of 3-fluorobenzaldehyde (327.5 mg, 2.64 mmol), 1,1-dimethylnitroethane (542.3 mg, 5.26 mmol) and zinc (517.9 mg, 7.92 mmol) in ethanol (3.0 ml) was added acetic acid (946.2 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH:33](O)=[O:34]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH:33]=[O:34])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=CO
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Product: O=CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1

Procedure:
In a similar manner to Example 4 except for the use of 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride and formic acid as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: ClC([N:4]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=O.O>O1CCCC1>[C:23]1([C@H:21]([NH:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6]2)[CH3:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Yield: 51.7 %

Procedure:
To a solution containing 54.6 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 700 ml of tetrahydrofuran was added 350 ml of water, and the mixture was stirred under reflux for 15 hours. After tetrahydrofuran was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 24.3 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+ (6) To a solution containing 24.2 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue was washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine (the following Reference example Table, Reference example 3.001(a)). MS•APCI (m/z): 255 [M+H]+ (7) By using 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10]>O.C(O)(=O)C>[Cl:14][C:13]1[CH:12]=[CH:11][C:9]([NH:10][C:2]([NH2:3])=[O:1])=[CH:8][C:7]=1[C:6]([F:5])([F:15])[F:16]
Reactant: N#C[O-]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 121.5 %

Procedure:
Sodium cyanate (1.7 g, 0.02 mol) was dissolved in water (17 ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3-trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40° C.-45° C. within 1-2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50° C. to afford the desired product (5.8 g), i.e., 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](N1C=NC=N1)=[O:7])([O-:3])=[O:2].[C:21]1(=[O:28])[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6]([CH:22]1[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]1=[O:28])=[O:7])([O-:3])=[O:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)n2cncn2)c([N+](=O)[O-])c1
Reactant: O=C1CCCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 103.4 %

Procedure:
1-(2-Nitro-4-methanesulphonylbenzoyl)-1,2,4-triazole (666 mg), cyclohexan-1,3-dione (254 mg) and potassium carbonate (419 mg, 1.8 mmol, 1.4 equiv) were suspended in acetonitrile (30 ml) and stirred overnight. The acetonitrile was removed under reduced pressure, the residue dissolved in water (100 ml) and acidified with 1 M hydrogen chloride solution to pH 1.5. The solution was extracted with dichloromethane, dried (magnesium sulfate), filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellow solid (0.789g, quant).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2ncccc2c(=O)o1

Procedure:
2-Aminonicotinic acid (5 g, 36 mmole) was suspended in acetic anhydride (25 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum. The resulting residue was slurried with ethyl acetate and hexane then filtered to provide 5 g of 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](O)=O)[CH2:12]1)=O)C1C=CC=CC=1.Cl[C:21]1[N:22]=[N:23][C:24]([NH:27][NH2:28])=[CH:25][CH:26]=1.Cl>C(Cl)Cl>[N:11]1([C:21]2[CH:26]=[CH:25][C:24]3[N:23]([C:17]([CH:13]4[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]4)=[N:28][N:27]=3)[N:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Product: c1cc2nnc(C3CCCNC3)n2nc1N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of 1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid (2.44 g), 3-chloro-6-hydrazinopyridazine (1.34 g), WSCD hydrochloride (2.13 g) and methylene chloride (60 ml) was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant reside was combined with acetic acid (80 ml), stirred at 100° C. for 2 days, and then the solvent was distilled off under reduced pressure. The resultant crude crystals were washed with ethanol, and stirred with heating under reflux in piperidine (10 ml) for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: chloroform:methanol=97:3). The resultant colorless solids were combined with ethanol (40 ml) and 10% palladium-carbon (150 mg), and stirred under hydrogen atmosphere at room temperature for 6 hours, and then the catalyst was filtered off. The resultant filtrate was concentrated under reduced pressure to obtain 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo[4,3-b]pyridazine (1.18 g) as a colorless amorphous.
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1([O:28][CH3:29])[CH2:22][N:21]([S:23]([O-:26])(=[O:25])=[O:24])[C:20]1=[O:27].N1C=CC=CC=1.[N:36]([CH:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:40](Cl)=[O:41])=[N+:37]=[N-:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[N:36]([CH:39]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:40]([NH:18][C:19]1([O:28][CH3:29])[CH2:22][N:21]([S:23]([O-:26])(=[O:24])=[O:25])[C:20]1=[O:27])=[O:41])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1
Reactant: COC1(N)CN(S(=O)(=O)[O-])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COC1(NC(=O)C(N=[N+]=[N-])c2ccccc2)CN(S(=O)(=O)[O-])C1=O
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
3-Amino-3-methoxy-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt (202 mgs; see Example 74A) is dissolved in 20 ml of dry acetonitrile. To the well stirred solution at -20° C. under dry nitrogen are added dry pyridine (167 μl) and α-azidophenylacetyl chloride (96 μl). After 20 minutes, 0.5M pH 5.5 monobasic potassium phosphate buffer (12 ml) is added and the acetonitrile removed in vacuo. The aqueous residue is extracted three times with methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to give 281 mg of crude product as a gum. This is purified by chromatography through a column of silica gel (30 g) using methylene chloride and mixtures of methylene chloride-methanol up to 6% methanol, and yielding 231 mg of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH3:13])[CH2:7][O:8][CH2:9][C:10](O)=[O:11]>C(Cl)(Cl)Cl>[CH3:5][CH:6]([CH3:13])[CH2:7][O:8][CH2:9][C:10]([Cl:3])=[O:11]
Reactant: CC(C)COCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)COCC(=O)Cl

Procedure:
2-Methylpropoxyacetyl chloride may be obtained in the following manner: thionyl chloride (5 cc) is added in the course of 15 minutes to a solution of 2-methylpropoxyacetic acid (8.3 g) in chloroform (50 cc). The mixture is heated for 5 hours under reflux and then evaporated to dryness under reduced pressure (2.7 kPa). 2-Methylpropoxyacetyl chloride (7.5 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:19])([CH3:18])[C@@H:15]4[O:17][C@@H:16]4[C:6]3=[CH:5][C:4]=2[N:3]=1.O.[NH3:21]>C(O)C>[NH2:21][C@H:16]1[C:6]2[C:7](=[CH:8][C:9]3[C:10]([CH3:12])=[CH:11][C:2]([Cl:1])=[N:3][C:4]=3[CH:5]=2)[O:13][C:14]([CH3:19])([CH3:18])[C@@H:15]1[OH:17]
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@@H]1O[C@H]31
Reactant: N
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Temperature: 90 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of (3R*,4R*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (2.0 g, 7.25 mmol) in ethanol (20 mL), ammonia water (10 mL) was added, and the resulting mixture was stirred in a sealed tube at 90° C. for 3 hours. Upon the completion of the reaction, the reaction solution was concentrated, and ethyl acetate was added thereto, The resulting solution was washed with water and then with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/2) to obtain the aimed product (yield: 86%).