Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.CC(C)(OC([N:38]1[C@H:46]([C:47]([O:49][CH2:50][O:51][C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])=[O:48])[CH2:45][C:40]2([S:44][CH2:43][CH2:42][S:41]2)[CH2:39]1)=O)C.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([CH:43]1[CH2:42][S:41][C:40]2([CH2:45][CH:46]([C:47]([O:49][CH2:50][O:51][C:52](=[O:57])[C:53]([CH3:55])([CH3:54])[CH3:56])=[O:48])[NH:38][CH2:39]2)[S:44]1)=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)OCOC(=O)C(C)(C)C)SCCS2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)C1CSC2(CNC(C(=O)OCOC(=O)C(C)(C)C)C2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture of 1.7 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid, acetonitrile and 0.96 g of carbonyldiimidazole is stirred under argon at 0° C. for 1 hour. (S)-7-[(1,1-Dimethylethoxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester (2.5 g) is treated with trifluoroacetic acid (about 2 ml) and stirred at room temperature for 30 minutes. The trifluoroacetic acid is removed in vacuo, the residue taken up in acetonitrile and added dropwise to the above mixture over a 20 minute period at room temperature. After an additional 2.5 hours, the acetonitrile is stripped and the resulting oil is partitioned between ethyl acetate and water. The layers are separated and the organic portion is washed with 5% potassium sulfate, saturated sodium bicarbonate, brine, dried (MgSO4) and evaporated. The residue (3.4 g) is chromatographed on silica (120 g) eluting with ethyl acetate/dichloromethane (1:1) and yielding 2.7 g of the title compound as a glass.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:37]O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:37][I:25])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1
Reactant: OCC1(c2ccc(Cl)cc2)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(C2(CI)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triphenylphosphine (3.45 g, 13 mmol) and imidazole (0.90 g, 13 mmol) in dichloromethane (25 ml) under an argon atmosphere was added slowly iodine (3.33 g, 13 mmol) and [1-(4-chlorophenyl)-cyclopropyl]-methanol (2.00 g, 11 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (75 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (100 ml) and hydrochloric acid (1N, 50 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow oil, (2.30 g, 72%); MS (EI): 292.0 (M+.).
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[N:11]3[CH:18]=[N:17][CH:16]=[C:12]3[S:13][C:14]=2[CH3:15])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][C:10]1[N:11]2[CH:18]=[N:17][CH:16]=[C:12]2[S:13][C:14]=1[CH3:15]
Reactant: Cc1sc2cncn2c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1sc2cncn2c1CN
Yield: 85.8 %

Procedure:
A 0.42 ml portion of hydrazine hydrate was added to 30 ml of a dry ethanol solution containing 1.7 g of 3-phthalimidomethyl-2-methylimidazo[5,1-b]thiazole, and the mixture was then heated under reflux for 2 hours. The reaction solution was cooled on ice, and the resulting crystal was filtered and then washed with a small amount of cold methanol. The filtrate was concentrated under reduced pressure, and to the resulting residue, dichloromethane was added. The solution was extracted with 1N hydrochloric acid, and the extract was then alkalified with a 1N aqueous potassium hydroxide solution. The organic layer extracted from the aqueous layer with dichloromethane was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was evaporated under reduced pressure to obtain 820 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole as a green powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[OH-].[Na+].[CH2:15](I)[CH3:16]>C(O)C.Cl>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[CH3:16]
Reactant: CCI
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cccc2c1CCCC2=O

Procedure:
A mixture of 5-hydroxy-1-tetralone (2.00 g) and sodium hydroxide (493 mg) was warmed in ethanol (40 mL) to 50° C. Ethyl iodide (3.94 mL) was then added and the reaction mixture was heated at reflux for 16 hours. The reaction mixture was diluted with 2N hydrochloric acid, extracted into ethyl acetate, dried and the solvent removed in vacuo to yield 5-ethoxy-1-tetralone as a white solid (2.06 g)
Reaction SMILES: P(Cl)(Cl)Cl.[CH:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:13]Br>>[Br:13][C:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrBr
Reactant: O=C(O)C1CCCC1
Solvent: ClP(Cl)Cl
Product: O=C(O)C1(Br)CCCC1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
Phosphorus trichloride (0.54 mL, 6.20 mmol) was added drop-wise to the mixture of cyclopentanecarboxylic acid (14.2 g, 124 mmol) and bromine (7.35 mL, 143 mmol). The mixture was then gradually heated to 85° C. and stirred at this temperature in a sealed vessel for 12 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water. The organic portion was separated, washed with water and brine, and conc. in vacuo to give the title compound as a white solid.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]1([C:33]2[N:34]3[CH:40]=[N:39][CH:38]=[C:35]3[S:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N+:34]4=[CH:40]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: c1ccc(-c2csc3cncn23)cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(-c5ccccc5)[n+]4c3)[C@H](C)[C@H]12
Yield: 13.4 %

Procedure:
The same procedure as in Example 1 was repeated except that 104 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 86 mg of 3-phenylimidazo[5,1-b]thiazole were used, thereby obtaining 16.2 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20](I)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1>O1CCOCC1.O.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>[CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([C:36]3[CH2:41][CH2:40][O:39][CH2:38][CH:37]=3)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(OCc1ccccc1)c1nn2c(I)ncc2c(=O)[nH]1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(OCc1ccccc1)c1nn2c(C3=CCOCC3)ncc2c(=O)[nH]1
Temperature: 125 °C
Yield: 75.7 %

Procedure:
To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) was added a solution of Cs2CO3 (492 mg, 1.51 mmol) in H2O (0.5 mL) dropwise, followed by addition of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (318 mg, 1.5 mmol) and Pd(PPh3)4 (86 mg, 0.075 mmol). The reaction mixture was degassed by purging with N2 for 15 min. Then the reaction was heated to 125° C. under microwave heating for 40 min. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 1:5) to afford compound 13 (200 mg, 75% yield) as white solid. LC-MS: m/z 353 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.82 (br. s, 1H), 7.91 (s, 1H), 7.37˜7.32 (m, 5H), 7.19 (br. s, 1H), 4.61 (m, 2H), 4.49 (q, J=6.8 Hz, 1H), 4.40 (m, 2H), 3.95 (t, J=5.2 Hz, 2H), 2.78 (m, 2H), 1.58 (d, J=6.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11]C#N)[CH:7]=[CH:8][C:9]=1[F:10].CO[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1)=[O:17].Cl>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[O:17])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: N#CCc1ccc(F)c(Cl)c1
Reactant: COC(=O)c1cccc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C(=O)Cc2ccc(F)c(Cl)c2)n1

Procedure:
A dispersion of sodium hydride, (60% in mineral oil, 0.7 g, 17.7 mmol) is added to ethanol (25 mL). When gas evolution ceases, 3-chloro-4-fluorophenylacetonitrile (Fluorochemicals, 2.0 g, 11.8 mmol) and 6-methyl-pyridine-2-carboxylic acid methyl ester (1.8 g, 11.8 mmol), are added. The mixture is refluxed for 2.5 h and adjusted to pH 7 with 1 N hydrochloric acid. The mixture is concentrated in vacuo. Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h. The mixture is poured over ice and adjusted to pH 8 with 5 N sodium hydroxide. The mixture is extracted with methylene chloride and the organic portions dried over anhydrous sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 2.1 g (68%), as a yellowish solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9]([O:12][Si](C)(C)C)=[CH:8][CH2:7]1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)([O-])O.[Na+].O>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]([F:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@H]1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCC(=O)[C@@H](F)C1
Reaction time: 1.25 h
Yield: 37.5 %

Procedure:
Silyl enol ether (a) (3.5 g) in acetonitrile (40 mL) at 0° C. was treated portionwise with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), (Selectfluor™), (6.16 g). After 75 min, saturated sodium hydrogen carbonate (50 mL) and water (50 mL) were added and the mixture extracted with ethyl acetate. The organic soluble material was purified by careful chromatography on silica gel eluting with 5-60% diethyl ether in hexane to give an oil (1.02 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][OH:18])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][O:18][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: OC[C@@H]1C[C@@H]1C1CCN(c2ncc(Br)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of step B (1.5 g, 4.8 mmol) was dissolved in DMF (15 mL), and sodium hydride (60 wt % dispersion in oil, 290 mg, 7.3 mmol) was added. After stirring at RT for 1 hour, (4-(bromomethyl)phenyl)(methyl)sulfane (1.35 g, 6.2 mmol) was added, and the resulting solution was stirred at RT for 18 h. The solution was partitioned between sat. NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (5/1 hexanes/EtOAc) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C1(C)C=CC=CC=1>[C:10]([C:3]1[C:4]([S:7][CH2:8][CH3:9])=[N:5][S:6][C:2]=1[NH:1][C:13](=[O:14])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:11]
Reactant: CCSc1nsc(N)c1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCSc1nsc(NC(=O)Oc2ccccc2)c1C#N

Procedure:
Under a nitrogen atmosphere, a mixture of 45.0 g of 5-amino-4-cyano-3-(ethylthio)isothiazole and 47.0 g of phenyl chloroformate in 175 ml of dried toluene was heated under reflux for 16 hours; thin-layer chromatography indicated the reaction to be complete. The reaction mixture was cooled to 10°, and the solid collected by filtration to obtain 66.2 of phenyl (4-cyano-3-(ethylthio)-5-isothiazolyl)carbamate, m.p. 223°-225° after recrystallization from acetic acid. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[O:5]=[C:6]([CH2:13][CH2:14][CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>O.C(O)(=O)C>[OH:3][N:1]=[C:7]([C:6](=[O:5])[CH2:13][CH2:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=N[O-]
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)C(=NO)C(=O)OCC
Temperature: 20 °C
Reaction time: 15.5 h

Procedure:
A solution of sodium nitrite (2.94) in water (7 ml) was added over 1.5 h at 25°-30° C. to a stirred solution of ethyl 3-oxohexanoate (5.0 g) in glacial acetic acid (6 ml). The orange mixture was stirred at 25° C. for 0.5 h before dilution with water (2 ml) and stirring at 20° C. for 15.5 h. The mixture was extracted with ether (2×20 ml) and the combined extracts washed with water (20 ml), 8% sodium bicarbonate (2×20 ml) and saturated sodium chloride solution (20 ml). The yellow solution was then dried and evaporated in vacuo, to afford a mobile yellow oil (4.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:22])[CH:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].C1C(=O)N([Br:36])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:21][C:19]1[CH:20]=[C:11]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]=[C:13]([CH3:22])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1c(C)cc(-c2cnc(OC)c(OC)c2)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cc(-c2cnc(OC)c(OC)c2)cc1CBr
Temperature: 25 °C
Yield: 76.3 %

Procedure:
As shown in step 6-ii of Scheme 6, Compound 2022 (710 mg, 2.36 mmol) was dissolved in CCl4 (20 mL) and K2CO3 (651 mg, 4.71 mmol), NBS (461 mg, 2.59 mmol), and benzoyl peroxide (57 mg, 0.24 mmol) were added. The reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was filtered and the solid washed with CCl4. The filtrate was concentrated to an oil under reduced pressure and purified by silica gel chromatography to provide methyl 2-(bromomethyl)-4-(5,6-dimethoxy-3-pyridyl)-6-methyl-benzoate (Compound 2023, 685 mg, about 70% pure). This compound was used in subsequent reactions as is.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][C:13]#[N:14].C1CCCCC1.Br.C(N)C1C=CC=CC=1>C(OCC)C>[CH2:1]([NH:8][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCBr
Reactant: NCc1ccccc1
Agent: Br
Solvent: C1CCCCC1
Solvent: CCOCC
Product: N#CCCCNCc1ccccc1
Yield: 66 %

Procedure:
32.2 g of benzylamine, 14.8 g of 4-bromobutyronitrile and 30 ml of cyclohexane are stirred at room temperature for 12 hours. After the addition of diethyl ether the separated benzylamine hydrobromide is filtered off; the ether phase is washed with water, dried and concentrated by evaporation. The residue is distilled in vacuo to yield 11.5 g (66% of theory) of 4-benzylaminobutyronitrile (B.P. 114° to 120°/0.05 mm Hg).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[CH2:11]([NH2:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:11]([NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)[CH:12]=[CH2:13]
Reactant: C=CCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCNc1nc(Cl)nc(Cl)n1

Procedure:
18.5 parts of cyanuric chloride were dissolved in 100 parts of acetone and added, while stirring, to a mixture of 300 parts of water and 400 parts of crushed ice. The suspension thus obtained was added to 5.7 parts of allylamine over a period of 30 minutes and subsequently to an aqueous solution of 5.3 parts of sodium carbonate. The white crystalline reaction product was suction-filtered, washed several times with iced water, and dried over phosphorus pentoxide.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:27](Cl)(Cl)Cl.CO.C(O)=O>CO>[Br:1][C:2]1[CH:22]=[C:21]([C:23]([O:25][CH3:27])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CCCCc1nc2cc(Br)cc(C(=O)O)c2n1Cc1ccccc1Cl
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: CCCCc1nc2cc(Br)cc(C(=O)OC)c2n1Cc1ccccc1Cl

Procedure:
A mixture of 5-bromo-2-n-butyl-1-(2-chlorophenyl)-methyl-1H-benzimidazole-7-carboxylic acid (prepared in Example 1)(1.0 g, 2.4 mmol) in methanol (15 mL) was cooled in ice and then saturated with dry hydrochloric acid. The reaction mixture was refluxed for 14 hours, and TLC on silica with 9:1 chloroform/methanol containing a trace of formic acid gave an Rf 0.87 for the product; the starting material had an Rf 0.65. The methanol was evaporated, the residue was diluted with ice water and the solid was separated, washed with water and dried at 92° C. at high vacuum to provide 0.88 g of methyl 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:21]([N:24]=[C:25]=[O:26])[CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:25]([NH:24][CH2:21][CH2:22][CH3:23])=[O:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCN=C=O
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCNC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 34.9 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) in N,N-dimethylacetamide (15 mL) was added propyl isocyanate (0.23 g, 2.67 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.23 g, yield 33%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][CH2:7][N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)[CH2:4][OH:5].C1([O:26][C:27](=O)[NH:28][C:29]2[S:30][C:31]([CH2:34][CH3:35])=[N:32][N:33]=2)C=CC=CC=1.C(N(CC)CC)C>CS(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]2[CH2:11][N:8]([CH2:7][CH2:6][C@H:3]([NH:2][C:27]([NH:28][C:29]3[S:30][C:31]([CH2:34][CH3:35])=[N:32][N:33]=3)=[O:26])[CH2:4][OH:5])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride (1.04 g, 2.82 mmol), (5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.70 g, 2.82 mmol) and triethylamine (1.6 ml, 11.28 mmol) in DMSO (70 ml) is stirred at ambient temperature for 18 hour, then partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by recrystallisation from hot ethylacetate to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea. [M+H] 426.18.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClCCN1CCCCC1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCN2CCCCC2)CC1

Procedure:
1-(2-(1-Piperidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and 1-(2-chloroethyl)piperidine essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[CH3:31]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[C:23]([CH3:31])[CH:24]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: Cc1cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)ccc1F

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-fluoro-3-methylbenzoic acid.
Reaction SMILES: [OH:1][C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](Cl)=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[N:24]([CH2:27][C@@H:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:24]([CH2:27][C@@H:28]([NH:36][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C@:2]([OH:1])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH2:16]1)=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Reaction time: 12 h
Yield: 109.8 %

Procedure:
A solution of (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (135 mg, 0.4 mmol) in CH2Cl2 (10 mL) was added to a solution of (S)-1-azido-3-phenylpropan-2-amine (156.3 mg, 0.73 mmol), triethylamine (0.6 mL, 4.3 mmol), and DMAP (16.6 mg, 0.13 mmol) in CH2Cl2. After stirring for 12 h, the reaction was taken up in CH2Cl2 (50 mL), washed with satd aq NaHCO3 (3×10 mL), and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to afford (3R)-N-((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg) as a brown residue (theoretical yield: 192.0 mg). MS ESI +ve m/z 502 (M+Na).