Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=[C:10]([NH2:17])[C:9]=2[N:8]=[C:7]1[CH2:18][CH2:19][CH3:20].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[CH3:22].Cl.N1C=CC=CC=1>CO>[NH2:17][C:10]1[C:9]2[N:8]=[C:7]([CH2:18][CH2:19][CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][O:2]/[N:1]=[C:21](/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)\[CH3:22])[C:14]=2[C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCO/N=C(\C)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of 1-[3-(aminooxy)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (0.64 g, 2.3 mmol) and acetophenone (325 μL, 2.76 mmol) in methanol (23 mL) was stirred overnight at room temperature, then heated at 50° C. for 4 hours. Pyridine hydrochloride (100 mg) was added to the solution and stirring was continued at 50° C. overnight. Additional pyridine hydrochloride was added and the solution was heated at reflux for 5 hours. The solvent was removed under reduced pressure and the resulting off-white solid was partitioned between chloroform (100 mL) and saturated aqueous sodium carbonate (30 mL). The aqueous layer was extracted with chloroform (3×30 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 5-30% CMA in chloroform) to yield a solid that was triturated with acetonitrile and dried under vacuum at 70° C. overnight to provide 105 mg of (1E)-1-phenylethanone O-[3-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]oxime as a white powder, mp 125.0-127.0° C. Anal. Calcd for C22H29N5O: C, 69.63; H, 7.70; N, 18.45. Found: C, 69.41; H, 7.73; N, 18.36.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[N+]=[N-].C(C1C=NC=C(CCC(C)C)C=1)#N>>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])cc(N(C)S(C)(=O)=O)c1
Agent: CC(C)CCc1cncc(C#N)c1
Product: COC(=O)c1cc(CN)cc(N(C)S(C)(=O)=O)c1

Procedure:
The desired product was synthesized from methyl 3-(azidomethyl)-5-(N-methylmethylsulfonamido)benzoate following the general procedure as described for 3-cyano-5-isopentylpyridine.
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].C1OCCOCCOCCOCCOC1.[Br:28][C:29]1[CH:30]=[CH:31][C:32](F)=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1.[Cl-].[NH4+]>O1CCCC1>[Br:28][C:29]1[CH:30]=[CH:31][C:32]([O:1][C:2]([CH3:10])([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1
Reactant: CCOC(=O)C(C)(O)CC
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC)Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-hydroxy-2-methylbutyrate (3.5 g) in tetrahydrofuran (80 ml) was added under ice-cooling sodium hydride (1.2 g), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a drop of 15-crown-5, and further thereto was added dropwise 5-bromo-2-fluoronitrobenzene (2.8 ml), and the mixture was stirred at room temperature for 14 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the title compound (5.5 g).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][NH2:18]>C(O)C>[NH2:10][C:6]1[NH:18][N:17]([CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cccc(F)c1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(F)c2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 13 g of 3-fluorobenzylhydrazine, on stirring for 5 hours in ethanol at 60° and working up as described in Example 1, yield 11.3 g, corresponding to 55% of theory, of the compound identified above as colorless crystals of melting point 129°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(CC(=O)O)c(Br)cc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Cl)c(Br)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid (149.4 mg) in dichloromethane (1.8 mL) was added oxalyl chloride (0.055 mL) followed by DMF (1 drop) uder argon. Mixture was stirred at rt for 3 h. Mixture was concentrated to dryness. Dichloroethane (ca. 10 mL) was added, and the mixture was back concentrated to dryness to obtain crude (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid chloride (151 mg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:36]2[CH:35]=[C:34]([F:37])[CH:33]=[CH:32][C:31]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
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: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-methyl-5-fluorobenzene boronic acid (73 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc×3. The combined extracts were dried and evaporated. The residue was purified on a 12+M column eluting with Pet Et2O to 60% EtOAc/Pet Et2O to afford the title compound in a 27% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]2=[NH:19])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][N:10]3[C:11]([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=43)=[N:19]2)=[CH:4][CH:3]=1
Reactant: N=c1sc2ccccc2n1CC(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc(C2CN3C(=N2)Sc2ccccc23)cc1
Reaction time: 1 h

Procedure:
A mixture of 4 parts of α-(4-chlorophenyl)-2-imino-3-benzothiazolineethanol and 23 parts of concentrated sulfuric acid is stirred first for 30 minutes in an ice-bath and further for 1 h. 30 at room temperature. The reaction mixture is poured onto crushed ice, alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The solid residue is crystallized from 2-propanol, yielding 1.6 parts of 2-(4-chlorophenyl)-2,3-dihydroimidazo[2,1-b]benzothiazole; mp. 143.3° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH:19]=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[OH:29]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+]>CC(O)(C)C.CC#N.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]([OH:29])=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 5, 608 mg, 1.98 mmol) in t-BuOH (15 ml), CH3CN (15 ml), and 2-methyl-2-butene (10 ml) was added a solution of KH2PO4 (5.4 g, 39.6 mmol) and NaClO2 (80%, 4.5 g, 39.6 mmol) in H2O (50 ml). The mixture was stirred at room temperature and additional 2-methyl-2-butene, KH2PO4, and NaClO2 were added at the above ratio every 16-24 h until the starting material was consumed. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][C@H:10]([CH3:44])[O:11][C:12]1[CH:13]=[C:14]([C:29]2[NH:33][C:32]([C:34]3[S:35][C:36]([C:39](OCC)=[O:40])=[CH:37][N:38]=3)=[CH:31][CH:30]=2)[CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:17]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][C@H:10]([CH3:44])[O:11][C:12]1[CH:13]=[C:14]([C:29]2[NH:33][C:32]([C:34]3[S:35][C:36]([CH2:39][OH:40])=[CH:37][N:38]=3)=[CH:31][CH:30]=2)[CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(CO)s3)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
Lithium aluminum hydride (22 mg, 0.580 mmol) was suspended in tetrahydrofuran (2 mL). Ethyl 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylate (106 mg, 0.190 mmol) synthesized in Example (5c) was dissolved in tetrahydrofuran (2 mL), followed by dropwise addition at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 30 minutes, water (22 μL) and an aqueous sodium hydroxide solution (5M, 88 μL) were added dropwise sequentially and slowly. After filtration through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired compound (48 mg, yield 49%) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=C(F)C=3)[C:19]=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.C(N1CCNCC1)C1C=CC=CC=1>>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:45][C:42]2[C:43](=[O:44])[N:38]([CH2:37][CH:34]3[CH2:35][CH2:36]3)[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)[CH:41]=2)[CH2:13][CH2:12]1)[C:19]1[CH:18]=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: c1ccc(CN2CCNCC2)cc1
Product: COc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 97.7 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a yellow oil (yield: 97.7%).
Reaction SMILES: [OH:1][C@@:2]1([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][C@H:6]2[CH2:8][CH2:9][C@@H:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>CCN(C(C)C)C(C)C>[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][CH2:40][N:41]([CH3:42])[CH2:17][CH2:16][C:2]1([OH:1])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNCCCc1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2C=C3c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 110 °C
Yield: 28.4 %

Procedure:
A mixture of 115 mg of rac-toluene-4-sulfonic acid (1R*,2R*,4R*)-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl ester and 55 mg of [3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amine in 2 mL of DIPEA was heated to 110° C. for 30 min. The reaction mixture was cooled to rt, quenched with MeOH-water and extracted with EtOAc. The organic phase was separated, dried and evaporated and the residue was purified by CC with EtOAc-MeOH (3:1) to give 34 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as beige foam.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH:11]([CH3:13])[NH:10][CH:9]([CH3:14])[CH2:8]2)=[N:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][O:16][C:17](=[O:20])[CH2:18][N:10]1[CH:11]([CH3:13])[CH2:12][N:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][N:4]=2)[CH2:8][CH:9]1[CH3:14]
Reactant: CC1CN(c2ncc(Br)s2)CC(C)N1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(C)CN(c2ncc(Br)s2)CC1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 74 %

Procedure:
A mixture of 1-(5-bromothiazole-2-yl)-3,5-dimethyl piperazine (21.5 g), bromo acetic acid methyl ester (8.8 mL), potassium carbonate (12.9 g) and dimethylformamide (150 mL) was stirred at 60° C. for 2.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (20.1 g). Yield: 74%.
Reaction SMILES: [CH2:1]([N:5]([CH3:11])[C:6](=O)[N:7]([CH3:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:5]([CH3:11])[C:6]([N:7]([CH3:9])[CH3:8])=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-n-butyl-1,1,3-trimethylurea (7 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (7.2 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4 ml) for 18 hours at 80°-85° C. gave 1-n-butyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (bp. 162°-163° C. at 0.7 mm Hg).
Reaction SMILES: Cl.BrC1SC2=NC(N)=CN2C=1.[C:12]([O:16][C:17](=[O:45])[NH:18][C@@H:19]([C:39]1[CH:44]=CC=C[CH:40]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27](=[O:38])[NH:28][C:29]1[N:30]=[C:31]2[N:35]([CH:36]=1)[CH:34]=[C:33]([Br:37])[S:32]2)=[O:21])(C)(C)C>>[CH3:12][O:16][C:17](=[O:45])[NH:18][C@H:19]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27](=[O:38])[NH:28][C:29]1[N:30]=[C:31]2[N:35]([CH:36]=1)[CH:34]=[C:33]([Br:37])[S:32]2)=[O:21])[CH:39]([CH3:44])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)C(C)C

Procedure:
Compound 12b was synthesized from compound 11 (0.33 mmol) and compound 3b (0.495 mmol), following the procedure as described for compound 12a, to give compound 12b as a yellow oil in 44% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.93 (dd, 6H), 1.70-2.00 (m, 4H), 2.01-2.10 (m, 1H), 3.51 (s, 3H), 3.59 (m, 1H), 3.82 (m, 1H), 4.00 (t, 1H), 4.51 (dd, 1H), 7.34 (d, 1H), 7.80 (s, 1H), 8.15 (s, 1H), 10.64 (s, 1H); MS (ESI, EI+) m/z=472-474 (MH+).
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Br.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C.C1CCCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][C@H:3]([C@H:2]([OH:1])[CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: COC(=O)C[C@@H](C)O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)[C@@H](C)O
Temperature: -70 °C
Yield: 47.8 %

Procedure:
9.45 g of methyl (R)-(-)-3-hydroxybutyrate was dissolved in 200 ml of tetrahydrofuran, and 112 ml of a 1.5M cyclohexane solution of lithium diisopropylamide was added thereto with stirring under cooling to -70° C. Then, the temperature was raised to -25° C. Then, 35 ml of a hexamethylphosphoric triamide solution of 21.1 g of 3,4-dichlorobenzyl bromide was dropwise added to this solution under stirring while maintaining the temperature at -25° C. After the dropwise addition, the temperature was raised to room temperature. Then, a saturated ammonium chloride aqueous solution was added to the reaction solution with stirring under cooling with ice. Then, the temperature was raised to room temperature, and ethyl ether and water were added thereto for liquid separation. The organic layer was collected by separation and post-treated by a conventional method. The product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 10.6 g (yield: 48%) of methyl (2R, 3R)-2-(3,4-dichlorobenzyl)-3-hydroxybutyrate.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=3)[CH:8]=[CH:9][C:2]=12.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][F:26]>CN(C=O)C>[F:26][CH2:25][CH2:24][O:16][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:2]3[C:3]([CH:6]=2)=[N:4][O:5][N:1]=3)[CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc(-c2ccc3nonc3c2)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FCCOc1cccc(-c2ccc3nonc3c2)c1

Procedure:
600 mg (2.83 mmol) 3-benzo[1,2,5]oxadiazol-5-yl-phenol are dissolved in 15 mL DMF and stirred for 20 hours at room temperature in the presence of 1.15 g (1.25 eq.) cesium carbonate and 0.264 mL 1-bromo-2-fluoroethane. The reaction mixture is extracted with water and ethyl acetate, the combined organic phases are washed with water and brine, dried with magnesium sulfate and evaporated to dryness. The residue is column chromatographed (gradient from hexane to hexane/ethyl acetate 3:2) to yield the desired product as a pale yellow powder. MS(ES+): 259 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH3:16])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.CCCCCC>CCOCC>[CH2:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:5]([CH2:3][OH:2])[CH2:6]1)[CH3:16]
Reactant: CCN1CC(C(=O)OC)Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCN1CC(CO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-Ethyl-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid methyl ester (123 mg, 0.56 mmol) in 1.5 mL of Et2O at 0° C. under nitrogen. LAH (1M in Et2O) was added dropwise with vigorous gas evolution and a white precipitate formation. After 30 min., TLC in 3/7 EtOAc/hexane showed complete loss of s.m. and appearance of a clean lower rf spot. The reaction was carefully quenched with 15% NaOH (3 mL) and 3 mL of Et2O was added and the mixture stirred rapidly at RT for 15 min. The layers were separated and the aqueous layer extracted 1×10 mL with Et2O. The organics were combined, dried (MgSO4), filtered and concentrated to a clear oil corresponding to the desired alcohol (105 mg, 95%).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:19])[CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:6].[C:20](OCC)(=[O:26])[C:21](OCC)=[O:22]>C(O)C>[CH2:12]([N:11]1[C:21](=[O:22])[C:20](=[O:26])[CH:9]([C:8]([O:7][CH2:5][CH3:6])=[O:19])[CH2:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCNCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
21% Sodium ethoxide in ethanol (21:79, sodium ethoxide:ethanol, 56.0 mL) was added dropwise to a mixture of ethyl-beta-benzylaminopropionate (22.178 g, 0.10700 mol) and diethyl oxalate (15.0 mL, 0.110 mol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and then water (about 200 mL) was added. The mixture was stirred for 5 min and then 1M HCl was added until pH 1. The mixture was vacuum filtered. The solids were collected and dried in vacuo overnight, and then crystallized from ethanol to give the desired product (20.946 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH:28]12[O:33][CH:29]1[CH2:30][CH2:31][CH2:32]2.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[OH:33])=[CH:25][CH:26]=1
Reactant: C1CC2OC2C1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O[C@@H]4CCC[C@H]4O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.50 g), cyclopentene oxide (1.50 g) and potassium carbonate (0.45 g) in ethanol (1.5 mL) is stirred for 75 min at 100° C. in a microwave oven. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 9:1→1:1).