Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=3)[CH:7]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1C(=O)OC(C)(C)C
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cc(Oc3ccc(N)cc3)ccn2)cn1C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
A 100 ml flask was charged with 4-((2-chloropyridin-4-yl)oxy)aniline (150 mg, 0.68 mmol), 1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate (260 mg, 0.81 mmol), 2M Na2CO3 solution (0.5 ml, 1.0 mmol), PdCl2(PPh3)2 (5 mg, 0.007 mmol), 10 ml of 1,4-dioxane and 3 ml of water. The mixture was flushed with nitrogen and heated at 70° C. for 30 minutes. The mixture was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered and dried to give the crude, which was further purified by silica gel chromatography eluting with 2-3% MeOH/CHCl3 to give 1-tert-butyl 2-methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate as light brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].O1CCOCC1.Cl>O>[S:12]1[C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[N:11]1
Reactant: COC(=O)c1cccc2nnsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc2nnsc12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
100 g (0.51 mol) of 7-methoxycarbonylbenzo-1,2,3-thiadiazole are suspended in 1000 ml of water, and then 310 ml of 2N sodium hydroxide solution and 5 ml of dioxane are added. The reaction mixture is heated to 40° C., is stirred for 4 hours at that temperature and is then cooled to 10° C. A further 1000 ml of water are added and the batch is neutralised with 310 ml of 2N hydrochloric acid. The resulting precipitate is isolated by filtration, lightly dried in a current of air and then dissolved in tetrahydrofuran and the solution is dried over magnesium sulfate, filtered and concentrated. The crystals are suspended in hexane, isolated by filtration and dried.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[Br:15]Br.C(=O)(O)[O-].[Na+]>CCOCC>[Br:15][CH2:13][C:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:7]=1)=[O:14]
Reactant: BrBr
Reactant: CC(=O)c1cccc(OCCCCl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1cccc(OCCCCl)c1
Reaction time: 26 h

Procedure:
A solution of the product of Step A (2.1 g) in ether (11 mL) was treated with bromine (0.53 mL) and the mixture stirred for 26 hours. The mixture was poured into saturated sodium bicarbonate solution (50 mL) and the organic layer was separated. The aqueous layer was washed with a fresh portion of ether (50 mL) and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated to yield the title compound (2.8 g).
Reaction SMILES: [OH-].[Na+].C([S:6][CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)C>CO>[SH:6][CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)CSC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(C)CS
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
At -20° C., 3N NaOH (150 mL, 450 mmol) was added dropwise to a solution of ethyl 3-(acetylthio)-2-methylpropanoate (66.47 g, 349 mmol, Step 5) in 700 mL of MeOH and the mixture was stirred at that temperature for 30 min. 25% Aq NH4OAc was then added and the title thiol was extracted with EtOAc, dried over MgSO4, concentrated and distilled to yield 42.52 g (82%) of the title compound as an oil; bp: 96°-98° C./15 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Product: CCOC(=O)c1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
This compound is synthesized following an analogous procedure as described in Example 1, step 1.1 starting from 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) and 3-chloro-benzylamine; m.p. 305-306° C.; MS-ES+: (M+H)+=407.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[C:3]=1[NH2:11].Cl[C:13]1[S:14][CH:15]=[CH:16]N=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[N:11]=[C:13]1[S:14][CH:15]=[CH:16][N:7]1[C:5]2=[O:6]
Reactant: NC(=O)c1cccc(F)c1N
Reactant: Clc1nccs1
Product: O=c1c2cccc(F)c2nc2sccn12
Yield: 78.6 %

Procedure:
15.4 g of 3-fluoroanthranilamide and 13.1 g of 2-chlorothiazole were stirred for 7 hours at 150° C. After working up in the conventional manner there was obtained 17.3 g (79%) of the above compound; m.p. 187°-189° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:9]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:15][CH2:16][S:17]C(=O)C.[OH-].[K+]>CCO>[C:11]([CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:15][CH2:16][SH:17])[C:4]=1[C:3]([OH:21])=[O:2])([OH:13])=[O:12]
Reactant: COC(=O)Cc1cccc(CCSC(C)=O)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(CCS)c1C(=O)O
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A deoxygenated mixture of 2-(2-acetylsulfanyl-ethyl)-6-methoxycarbonylmethyl-benzoic acid methyl ester (0.555 g, 1.77 mmol) and 6 N KOH (3 mL) in EtOH (7 mL) was heated at reflux for 18 h. After allowing to cool to rt, the mixture was partitioned between 1 N HCl (75 mL) and EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in ether (100 mL), filtered to remove some unidentified solid material, and concentrated to give 2-carboxymethyl-6-(2-mercapto-ethyl)-benzoic acid as a white solid (0.310 g, 73%): 1H NMR (CDCl3) δ1.37 (t, J=8.2 Hz, 1H), 2.76 (m, 2H), 3.06 (m, 2H), 3.90 (s, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.21 (d, J=6.9 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H): 13C NMR (CDCl3) δ27.25, 40.43, 41.83, 131.58, 131.64, 132.45, 132.55, 134.66, 141.41, 176.14, 179.40. Anal. Calcd for C, H11H12O4S: C, 54.99; H, 5.03; S, 13.35. Found: C, 55.20; H, 5.26; S, 13.32.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8].Cl>O>[N:1]([N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]([O:6][CH3:5])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3]
Reactant: O=N[O-]
Reactant: COC(=O)CCCCCNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCCCN(N=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g of sodium nitrite in 5 ml of water is added dropwise at 0°-10° to a mixture of 4.42 g of N-(5-methoxycarbonylpentyl)-aniline, 2.9 ml of concentrated hydrochloric acid, and ice as needed to maintain the desired temperature. The mixture is then allowed to stir at ambient temperature for 1 hour and is then extracted with ether. The extract is washed with water, dried over magnesium sulfate, and evaporated in vacuo to give N-nitroso-N-(5-methoxycarbonylpentyl)-aniline as an oil.
Reaction SMILES: CCCCC.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[Cl:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][N:26]1[CH2:25][CH2:24][N:23]([CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Pentane (10 mL) was added to sodium hydride (0.50 g, 11 mmol of 50% suspension in mineral oil) and the mixture was stirred under nitrogen. The pentane was decanted. Anhydrous DMF (12 mL) was added and the suspension was cooled to 0° C. [Bis(4-fluorophenyl)methylpiperazine (2.9 g, 10 mmol) in anhydrous DMF (14 mL) was added at 0° C. within 10 min. The reaction mixture was allowed to warm to room temperature. After 1 h, the mixture was cooled to 0° C. and to the light green solution 1-chloro-3-bromopropane (5 mL, 50 mmol) in anhydrous DMF (5 mL) was added over a period of 10 min. The mixture was stirred under nitrogen at room temperature for 72 h. The solvents were evaporated in vacuo (1 mm Hg) at 50° C. The residue was triturated in methylene chloride and filtered through celite. The filtrate was washed with water (2× 100 mL), dried (sodium sulfate), filtered, and the filtrate was evaporated in vacuo to give crude chloro-propyl compound (3.65 g). Pentane (50 mL) was added, and on the next day the pentane insoluble solid was removed by filtration. The filtrate was evaporated in vacuo to give the title compound (2.3 g, 75%) as a clear, colorless oil. 100 MHz 1H NMR (CDCl3) δ: 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.57 (m, 2H), 2.2-2.6 (m, 10H), 1.9 (m, 2H). DCI/MS (M+1) 361.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]([NH:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][C:38](=[O:39])[NH:40][C:41]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH3:36])[CH3:32]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 38 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[CH:5]=O.Cl.[NH2:15]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[C:5]#[N:15]
Reactant: COc1cc(C=O)c(OC)cc1C
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C#N)c(OC)cc1C
Temperature: 105 °C
Reaction time: 2 h

Procedure:
By analogy to steps outlined in J. Med. Chem. 1976, 19(12), 1400-1404. 2,5-dimethoxy-4-methylbenzaldehyde (14.8 g, 82.2 mmol) is dissolved in pyridine (300 mL) and to it, is added hydroxylamine hydrochloride (6.8 g, 98.6 mmol). The suspension is heated at 105° C. for 2 h. Acetic anhydride (15.5 mL, 164 mmol) is then added to the reaction and stirring is continued for another 2 h. The solution is evaporated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic fraction is dried (Na2SO4) and evaporated to give a yellow solid which is taken up in hexanes and filtered to give 2,5-dimethoxy-4-methylbenzonitrile as a white solid. (cas #51267-09-5) MS (ESI) m/z 178.2 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[Na].[CH3:11]O>>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:11])=[O:8])[N:3]=[CH:2]1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: [Na]
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-Imidazoleacetic acid, sodium salt, hydrate (compound ix, where R2 is H) (3.0 g, 18.1 mmol) in MeOH (50 ml) was cooled to about 0° C. and anhydrous HCl gas was bubbled into the mixture for about 15 minutes while maintaining reaction temperature below about 5° C. The reaction was stirred for about 12 hour at room temperature and then solvents were removed under reduced pressure to yield an oil which solidifies on standing. Mass spec 141.0 MH+, NMR (300 MHZ, DMSO-d6, 30° C.), 9.0-9.2 (1H, s), 7.47.6 (1H, s), 3.85-3.95 (2H, 3), 3.6-3.7 (3H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:15])[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19]([O:35][CH2:36][CH3:37])[CH2:20]O[C@H](CC=C)COCC1C=CC=CC=1)[CH3:17]>>[CH2:16]([O:18][CH:19]([O:35][CH2:36][CH3:37])[CH2:20][O:15][C@H:10]([CH2:11][CH:12]=[CH:13][CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Reactant: CC=CC[C@@H](O)COCc1ccccc1
Product: CC=CC[C@H](COCc1ccccc1)OCC(OCC)OCC

Procedure:
(2R)-1-(Benzyloxy)hex-4-en-2-ol (C9) (150 g, 0.73 mol) was converted to the product according to the method used for synthesis of ({[(2R)-2-(2,2-diethoxyethoxy)pent-4-en-1-yl]oxy}methyl)benzene (C2) in Preparation P1, except that the initial combination of reagents was carried out at 0° C. The product was obtained as a brown oil (400 g, ≦0.73 mol), which was used for the next step without further purification. By 1H NMR analysis, this material contained a roughly 1:1 mixture of geometric isomers. 1H NMR (400 MHz, CDCl3), characteristic peaks for product: δ 7.25-7.38 (m, 5H), 5.38-5.60 (m, 2H), 4.55 and 4.55 (2 s, total 2H), 2.22-2.37 (m, 2H), 1.60-1.68 (m, 3H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:29][C:30]([O:32][CH:33](I)[CH3:34])=[O:31])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:27]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:28])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCOC(=O)OC(C)I
Agent: [Na+]
Product: CCOC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 93.4 %

Procedure:
In the same manner as in Example 81, 167 mg of the title compound was prepared from 145 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 148 mg of 1-(ethoxycarbonyloxy)ethyl iodide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: IC1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
This compound was synthesized from the commercially available piperidin-4-yl-carbamic acid tert-butyl ester (2) (5 g, 25 mmol, 1 equiv) which was dissolved in acetonitrile (150 mL), followed by the addition of iodo-cyclopentane (9.79 g, 50 mmol, 2 equiv) and K2CO3 (3.45 g, 25 mmol, 1 equiv). The solution was stirred at room temperature for 48 hours. Due to the incompleteness of the reaction, iodocyclo-pentane (1.70 g, 8.69 mmol, 0.35 equiv) and K2CO3 (1 g, 7.25 mmol, 0.29 equiv) were added to the solution. The solution was stirred at room temperature for several hours. The solution was filtered over a bed of dicalite and the filtrate was evaporated under reduced pressure to obtain 3 (6.70 g, 25 mmol, quantitative). LRMS (ES+): m/z 269.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[C:19]([CH2:24]O)=[N:20][CH:21]=[CH:22][CH:23]=1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:17][C:18]1[C:19]([CH2:24][O:1][C:2]2[C:3]3[N:4]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Reactant: OCc1ncccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cccn12
Temperature: 110 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 2 g of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate, 2 g of (3-fluoropyridin-2-yl)methanol, 4 g of (tributylphosphoranyliden)acetonitrile, and 40 ml of toluene was stirred at 110° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration. The obtained residue was purified by silica gel column chromatography to obtain 2.15 g of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Yield: 86.2 %

Procedure:
A solution of 4,5-dichloropyridazin-3(2H)-one (10 g, 60.6 mmol) in tetrahydrofuran (60 mL, 1.0M) was treated with pyridinium para-toluene sulfonate (3.03 g, 12.1 mmol) and 3,4-dihydro-2H-pyran (8.5 mL, 93.2 mmol). The reaction was heated at reflux for 5 h and was then treated with a second aliquot of 3,4-dihydro-2H-pyran (5.5 mL, 60.3 mmol). The reaction was stirred at reflux overnight. After this time, the reaction was concentrated in vacuo, taken up in ethyl acetate (250 mL), and washed with a 2N aqueous sodium hydroxide solution (2×250 mL). The organics were then washed with a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (Biotage, 330 g, 10% ethyl acetate/hexanes) afforded 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (13.01 g, 86%) as an off-white solid; ES+-HRMS m/e calcd for C9H10N2O2Cl2 [M+Na+] 271.0011, found 271.0012.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[C:21]2[CH:37]=[CH:38][CH:39]=[CH:40][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[C:21]3[CH:37]=[CH:38][CH:39]=[CH:40][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(C2CCCCC2)c2ccccc2-c2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(C2CCCCC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-N), the title compound was prepared. The reaction was monitored by tlc (Rf=0.35, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=2)[CH:5]=1.[CH2:21]([NH2:23])[CH3:22].[BH4-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:23][CH2:21][CH3:22])[CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc(C=O)c2)c1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCNCc1cncc(-c2cc(C(=O)OC)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
4-Cyano-3-(5-formyl-pyridin-3-yl)-benzoic acid methyl ester (0.445 g, 1.67 mmol) was suspended in MeOH/dichloromethane (1:1; 8 mL) and a solution of ethylamine (2M in MeOH, 1.25 mL, 2.51 mmol) was added. The mixture was stirred for 16 hours at room temperature. The mixture was then was cooled to 0° C. and NaBH4 (76 mg, 2.01 mmol) was added in portions over 10 minutes. After allowing the mixture to warm to room temperature over 2 h, the reaction was quenched with 1 mL of water. The solution was concentrated in vacuo to ⅓ of its original volume and then it was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined organics were dried (Na2SO4) filtered and the solvent removed in vacuo to give 4-cyano-3-(5-ethylaminomethyl-pyridin-3-yl)benzoic acid methyl ester as a yellow oil (0.353 g, 72%). MS(ESI) m/z 296.0 (M+H)+.
Reaction SMILES: N[CH:2]1C2(CC2)CN[CH2:3]1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].BrCCBr>>[C:11]([C:10]1([C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1)(=[O:12])[CH3:13]
Reactant: NC1CNCC12CC2
Reactant: CCOC(=O)CC(C)=O
Solvent: BrCCBr
Product: CCOC(=O)C1(C(C)=O)CC1

Procedure:
Taking 7-amino-5-azaspiro[2.4]heptane as an example, ethyl acetoacetate is first reacted with 1,2-dibromoethane in the presence of a base to give ethyl 1-acetyl-1-cyclopropanecarboxylate. Then, using bromine, the acetyl group of this compound is brominated to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. This bromoacetyl compound is then cyclized with benzylamine to give 5-benzyl-4,7-dioxo-5-azaspiro[2.4]heptane. When this compound is reacted with hydroxylamine hydrochloride, the ketone in the 7-position is converted to an oxime to give 5-benzyl-7-(hydroxyimino)-4-oxo-5-azaspiro[2.4]heptane. This oxime is reduced with lithium aluminum hydride to give a spiro ring-containing aminopyrrolidine compound, viz., 7-amino-5-benzyl-5-azaspiro[2.4]heptane. When the benzyl group of this compound is eliminated by an ordinary procedure, such as catalytic hydrogenolysis, 7-amino-5-azaspiro[2.4]heptane, which is a racemic compound, is obtained. When this cleavage of the benzyl group after the amino group is protected by the reaction of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile (hereinafter referred to briefly as BOC-ON), 7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane is obtained.