Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:13][CH:22]=[C:20]([CH2:19][Cl:18])[N:14]=2)[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cccc(OCc2ccccc2)c1
Product: ClCc1coc(-c2cccc(OCc3ccccc3)c2)n1
Yield: 26 %

Procedure:
In substantially the same manner as in Reference Example 31, 3-benzyloxybenzamide was allowed to react with 1,3-dichloroacetone to give 2-(3-benzyloxyphenyl)-4-chloromethyloxazole. The yield was 26%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 49-50° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:21]([OH:27])[CH:22]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cc1O
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1O
Yield: 20.3 %

Procedure:
The product is prepared according to the procedure described in Stage 1 of Example 2, using 550 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 815 mg of 2-amino-5-fluorophenol in place of 2-aminophenol. After purification by silica gel column chromatography, elution being carried out with pure CH2Cl2 then CH2Cl2/MeOH: 95/05, 149 mg of N-(4-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:13][C:14]([NH2:25])([CH3:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[ClH:12].[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[CH2:3][NH:25][C:14]([CH3:24])([CH3:13])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: Clc1cccc(OCC2CO2)c1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(Cl)c2)cc1
Product: Cl
Yield: 83.9 %

Procedure:
Using the method of Example 25, supra, 3-chlorophenyl glycidyl ether (1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.25 mmol) yielded 168 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 348 (M−15, 0.9), 245 (7), 244 (35), 243 (25), 242 (100), 163 (7), 121 (22), 71 (11), 70 (16).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=O.[C:23]1([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[B-]C#N.[Na+].O>CO>[C:23]1([C@@H:29]2[CH2:31][C@H:30]2[NH:32][CH2:1][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][C:10]3[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=3)[CH2:5][CH2:4]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (6.7 g, 22.08 mmol) in methanol (50 mL) was added (1R,2S)-2-phenylcyclopropanamine (3.53 g, 26.5 mmol). The reaction mixture was refluxed for 5 minutes then cooled down to the room temperature. Sodium cyanotrihydroborate (2.082 g, 33.1 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organics were washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added slowly as a solid crashed out. The solid was filtered and suspended in isopropanol. The suspension was sonicated and filtered. tert-Butyl 4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (5.8 g, 13.65 mmol, 61.8% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.07 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.08 Hz, 2H), 7.28-7.37 (m, 2H), 7.10-7.28 (m, 3H), 4.43 (br. s., 2H), 3.54 (d, J=10.86 Hz, 2H), 3.08-3.26 (m, 4H), 3.03 (dt, J=3.76, 7.39 Hz, 1H), 2.54-2.71 (m, 1H), 2.03-2.29 (m, 3H), 1.67-1.84 (m, 2H), 1.58-1.67 (m, 10H), 1.40 (q, J=6.82 Hz, 1H); LC-MS Rt=0.76 min; MS (ESI): 421.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH:18]O)[C:5](=[O:20])[C:4]=2[CH:3]=1.CO.Cl>[Zn].O>[CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH2:18])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)C(=O)c1c(NO)cccc1C2=O
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)c1c(N)cccc1C2=O
Temperature: 70 °C

Procedure:
50 Parts of 2,3-dimethyl-5-hydroxylaminoanthraquinone was added to a mixture of 600 parts of methyl alcohol, 200 parts of water and 60 parts of a 35 % aqueous hydrochloric acid and the mixture was heated with stirring to 70°C, then added thereto 15 parts of zinc dust little by little over 1 hour. The reaction mixture was maintained at 70°C for additional 3 hours and then cooled to 25°C and filtered. The residue was washed with water and dried to obtain 42.8 parts of 2,3-dimethyl-5-aminoanthraquinone of a purity of 95 %.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([OH:16])=O)=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:17].C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:42]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:43][CH2:44][CH2:45][CH3:46].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:21]=[C:20]([N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:16])[NH:50][S:47](/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:17]
Reactant: CCOC(=O)N(C)c1ccc(Cn2c(C)nc3ccc(C(=O)O)nc32)c(Cl)c1
Reactant: CCCC=CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCC/C=C/S(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OCC)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
3-(2-Chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4, 5-b]pyridine-5-carboxylic acid (150 mg) was dissolved in dry N,N-dimethylformamide (1.5 ml), and carbonyldiimidazole (91 mg) was added, which was followed by stirring at room temperature for 1.5 hr. To the reaction mixture was added 1-penten-1-ylsulfonamide sodium salt (96 mg) and the mixture was stirred at room temperature for 7 hr. 1N Hydrochloric acid was added dropwise under ice-cooling to adjust to pH 4. Water (1.5 ml) was added and the mixture was applied to ultrasonic washer for 15 min and then stirred for 15 min. The precipitate was collected by filtration, washed with water, suspended in ethanol (0.5 ml), heated in a boiling bath and stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with ethanol, and recrystallized from N,N-dimethylformamide and water to give 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (165 mg) as colorless crystals. m.p.: 165-166° C.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.[NH2:7][CH2:8][CH2:9][OH:10]>C(O)C>[OH:10][CH2:9][CH2:8][NH:7][C@@H:1]1[CH2:2][CH2:3][CH2:4][C@H:5]1[OH:6]
Reactant: NCCO
Reactant: C1CC2OC2C1
Solvent: CCO
Product: OCCN[C@@H]1CCC[C@H]1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-oxabicyclo[3.1.0]hexane (3.00 g, 35.7 mmol) and 2-aminoethanol (2.18 g, 35.7 mmol) in ethanol (15 mL) was stirred at 80° C. in a sealed tube for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification using silica gel chromatography (Eluant: methanol in dichloromethane) afforded the title compound. Yield: 1.6 g, 11 mmol, 31%. 1H NMR (400 MHz, DMSO-d6) δ 4.43-4.64 (br m, 2H), 3.68-3.75 (m, 1H), 3.44 (t, J=5.6 Hz, 2H), 2.71-2.77 (m, 1H), 2.58-2.63 (m, 2H), 1.73-1.89 (m, 2H), 1.47-1.64 (m, 2H), 1.34-1.44 (m, 1H), 1.17-1.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28]CO)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33]([CH:37]([CH3:39])C)[CH:34](C)C)[CH3:32].CS(Cl)(=O)=[O:42].[Cl-].[NH4+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:34][N:33]5[CH2:37][CH2:39][O:42][CH2:32][CH2:31]5)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCN1CCOCC1
Reaction time: 1 h
Yield: 22 %

Procedure:
To a mixture of 0.070 g (0.15 mmole) of 4-(3-chloro-phenyl)-2-[6-(2-hydroxy-ethoxy)-5-methoxy-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.44a), 0.041 g (0.242 mmole) of ethyldiisopropylamine and 3 mL of dimethylformamide 0 degrees was added 0.027 g (0.24 mmole) of methanesulfonyl chloride. Stirring was continued for 1 hour and then 1 mL of saturated ammonium chloride solution was added dropwise. The mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was heated at 80 degrees for 1 hour with 2 mL of dimethylformamide and 0.080 mL of morpholine. The mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (6:94) to give 0.017 g of 4-(3-chloro-phenyl)-2-[5-methoxy-6-(2-morpholin-4-yl-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.45) as a pink solid. MH+/Z=514
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23].ClCCl.CO.N>>[ClH:1].[CH3:14][O:15][C:16]1[CH:29]=[C:28]([NH:30][C:11](=[O:12])[C:10]#[C:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]
Reactant: O=C(Cl)C#Cc1ccc(Cl)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(Cl)cc2Cl)cc1OC
Product: Cl

Procedure:
Prepared analogously to Example 2.3.f. from (2,4-dichlorophenyl)propynoic acid chloride and [2-(2-methoxy-4-aminophenoxy)ethyl]diethylamine. Yield: 0.25 g (31.2% of theory); melting point: 205° C.-207° C.; C22H24Cl2N2O3*HCl (M=471.81); calc.: molecular ion peak (M+H)+: 435/437/439; found: molecular ion peak (M+H)+: 435/437/439; Rf value: 0.6 (silica gel, dichloromethane/methanol/ammonia (50:10:0.1)).
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=2)[CH:11]=1.[OH-].[NH4+]>C1COCC1>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:18][N:17]=2)[CH:11]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: Brc1ccc(-c2cccc(-c3ccccc3)c2)nc1
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cccc(-c3ccccc3)c2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a suspension of copper(I) cyanide (17.3 g, 11 mmol) in 1730 mL of anhydrous THF in an oven-dried, five liter, three-necked flask equipped with a mechanical stirrer and a nitrogen inlet was added tert-butylmagnesium chloride (200 mL, 2.0 M, 400 mmol) via an addition funnel, and the mixture was stirred at −78° C. for 30 min. A solution of 2-(biphenyl-3-yl)-5-bromopyridine (15.0 g, 48 mmol) in 100 mL of dry THF was then added dropwise, and the mixture was stirred for 3 hours at −78° C. and then overnight at room temperature. Saturated aqueous ammonium hydroxide was then added to quench the reaction mixture, the pH was adjusted to 10 with aqueous sodium hydroxide, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and evaporated to dryness to give 9.0 g of light yellow liquid that was purified by flash silica gel chromatography with a 2.5/97.5 to 7.5/92.5 ethyl acetate/hexane gradient as the eluent, affording 2.6 g (19%) of 2-(biphenyl-3-yl)-5-tert-butylpyridine as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C=O.Cl.O.[Cl:20][CH:21](Cl)C(Cl)Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[C:5]([CH2:21][Cl:20])=[CH:6][C:7]=1[CH3:8]
Reactant: ClC(Cl)C(Cl)Cl
Reactant: CC(=O)NC(C)Cc1ccc(C)c(C)c1
Agent: C=O
Agent: Cl
Solvent: O
Product: CC(=O)NC(C)Cc1cc(C)c(C)cc1CCl
Reaction time: 8 h

Procedure:
4.1 g of rac. 1-(3,4-dimethylphenyl)-2-acetamidopropane was dissolved in 40 ml of 1,1,2,2-tetrachlorethane in a 100-ml RB flask provided with a stirrer, thermometer, condenser, and gas inlet tube. Twelve ml of 37% formaldehyde was added, and a stream of hydrogen chloride passed into the stirred mixture as the temperature rose to 50°, where it was maintained for 5 hrs. At this point, the mixture remained overnight at room temperature. The reaction mixture was poured into water, the organic phase was washed twice with water, dried, and the solvent distilled in the rotary evaporator, leaving 4.2 g of a colorless oil. The oil was refluxed with four 100-ml-portions of petroleum ether (b.p. 60-0-°), and from the combined extracts, a mass of cottony needles separated. The solid was collected by filtration and freed of solvent in vacuo to yield the above-named product, m.p. 72°-73°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CCOC(C)=O>[Br-:28].[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:29][C:30](=[O:31])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@H]1CN2CCC1CC2
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
To a solution of (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (600 mg, 1.60 mmol) in EtOAc (10 ml), was added portionwise 2-bromo-1-phenylethanone (303 mg, 1.52 mmol). The reaction was stirred at RT for three days. The precipitate was collected by filtration and dried under vacuum to obtain (R)-3-((S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (740 mg, 81% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].BrC[CH2:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1>C(O)C>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1
Reactant: NCCS
Reactant: BrCCc1ccsn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1ccsn1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g.) to sodium (0.83 g.) dissolved in ethanol (50 ml.) with stirring at 0° under a nitrogen atmosphere. After starting for 2 hours at 0°, 3-bromoethylisothiazole (3.2 g.) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, filtered and concentrated to yield the amine base as an oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methyl isothiocyanate (0.66 g.) added, and the solution heated under reflux for 30 minutes. Concentration, followed by purification of the crude product by chromatography on a column of silica gel with ethyl acetate as eluant followed by chromatography on a column of alumina with benzene/ethyl acetate as eluant gave N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9; H, 5.4; N, 16.5; S, 38.3. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]1([C:13]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:7]1([C:13]2([CH2:19][C:20]([NH2:1])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC1(c2ccccc2)CCCCC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)CC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a suspension of NH4Cl (2.34 g, 43.65 mmol) in toluene (20.0 mL) was added drop-wise a solution of trimethyl aluminium (3.15 g, 43.65 mmol, 2M in toluene) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h prior to the addition of a solution of (1-phenyl-cyclohexyl)-acetonitrile (253) (2.9 g, 14.55 mmol) in toluene (10.0 mL). The resulting solution was heated to 80° C. for 16 h. The cooled reaction mixture was poured into a slurry of silica-gel (10.0 g) in CHCl3 (20.0 mL) followed by vigorous stirring for 30 min. The silica gel was filtered off and the cake was rinsed in turn with methanol. The solvent was evaporated and the crude product was taken up in 10% methanol in dichloromethane (200.0 mL) and stirred for 30 min. The solid suspension was removed by filtration and the filtrate was evaporated. The crude product was triturated in diethyl ether and the solid was collected by filtration and dried under vacuum to afford HCl-salt of 2-(1-phenyl-cyclohexyl)-acetamidine (254) (2.5 g, 68.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[S:7][CH2:8][C:9]1[CH2:16][S:15][C@H:14]2[N:11]([C:12](=[O:26])[C@H:13]2[NH:17][C:18](=[O:25])[CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:10]=1[C:27]([O:29]C(C)(C)C)=[O:28].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.ClCCl>[CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[S:7][CH2:8][C:9]1[CH2:16][S:15][C@H:14]2[N:11]([C:12](=[O:26])[C@H:13]2[NH:17][C:18](=[O:25])[CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:10]=1[C:27]([OH:29])=[O:28]
Reactant: Cc1snnc1SCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1snnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 40.6 %

Procedure:
A cold (0° C.) solution of 2.62 g of the product of Example 7 in 20 ml of dry anisole and 25 ml of dichloromethane was treated with 20 ml of trifluoroacetic acid. After evaporation the residue was chromatographed as described in Example 7, giving 950 mg of the desired product. 'H NMR (300 MHz, CDCl3): δ 2.57 (s, 3H); 3.70 (AB quartet, 2H, 4-CH2); 3.87 (s, 2H); 4.17 (AB quartet, 2H, CH2S--); 4.97 (d, 1H, J=4.8 Hz, 6-H); 5.76 (dd, 1H, J=9.24 Hz, 4.8 Hz, 7-H); [6.98 (m, 2H) and 7.24 (m, 1H)(thienyl)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(Cl)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
2-{[4-(2-{(4-Chlorophenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 286-1 and thiophenol (0.26 mL) were dissolved in N,N-dimethylformamide (12 mL), potassium carbonate (0.88 g) was added, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 3:1) to give the title compound (0.52 g) as a colorless oil.