Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.503 g, 1.7 mmoles), triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.), and 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Hexanoyl chloride (980 μl, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in 25 mL ethyl acetate and undissolved salts were removed by filtration. After evaporation of the ethyl acetate, the residue was dissolved in methanol and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and chromatographed on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (8:2). The product was further purified on the Chromatotron (2 mm silica gel plate) with a mixture of chloroform:acetone (99:1). Lyophilization afforded 0.268 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(hexanoyloxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (40% yield).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:31]([CH3:42])[CH:30]=2)[C:25]([Cl:43])=[CH:24][N:23]=1>>[Cl:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[C:31]([CH3:42])[CH:30]=2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1N1CCN(C)CC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)c(C)c3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.020 g, 24%). MP: 172-178° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.04-8.01 (m, 2H), 7.54-7.49 (m, 1H), 7.47 (s, 1H), 7.24-7.21 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 3.84 (s, 3H), 3.26 (s, 2H), 3.14 (s, 3H), 3.01-2.92 (m, 8H), 2.88-2.83 (m, 2H), 2.75-2.59 (m, 9H), 2.44-2.36 (m, 3H), 2.30 (s, 3H). MS: 593.29 (MH)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:19][C:17]([O:16][CH2:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: OCCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
2-(9-Fluorenyl)ethyl chloroformate was prepared from a solution of 2-(9-fluorenyl)ethanol (1.26 g, 6.0 mmol) in 10 ml of toluene and 4 ml of tetrahydrofuran, which was added to 12 ml of phosgene solution (12.4 mol, [1.93M in toluene). The solution was stirred for 1 hour and put under vacuum to remove the phosgene. Concentration yielded 2-(9-fluorenyl)ethyl chloroformate (1.64 g, 6.0 mmol).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[C:2]#[CH:3].[CH2:11]=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1>[N:13]1([CH2:11][C:3]#[C:2][CH2:1][N:4]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]2=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=O
Reactant: C1CCNC1
Reactant: C#CCN1C(=O)CCC1=O
Solvent: C1COCCO1
Product: O=C1CCC(=O)N1CC#CCN1CCCC1
Reaction time: 8 h

Procedure:
Following the example given in Example 1B, 19.1 g. (0.15 mole) of N-propargylsuccinimide was caused to react with 6.3 g. of paraformaldehyde and 14.2 g. (0.2 mole) of pyrrolidine in 100 ml. of dioxane in the presence of a trace of cuprous chloride. The reaction was refluxed for 5 hrs. and allowed to stand overnight. After filtration of the reaction mixture and removal of the solvent from the filtrate, the residual oil was distilled to give N-[4-(1-pyrrolidinyl)-2-butynyl]-succinimide boiling at 155° C. at 0.04 mm. This product solidified, and after recrystallization from ether, melted at 93.0 to 94.0° C. (corr.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25](=[O:46])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([CH:43]([CH3:45])[CH3:44])=[N:41][N:42]=4)[CH:39]=3)=[CH:29][CH:28]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25](=[O:46])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([CH:43]([CH3:44])[CH3:45])=[N:41][N:42]=4)[CH:39]=3)=[CH:29][CH:28]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(Sc3ccc(CC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O[Si](C)(C)C(C)(C)C)cc4)cc3)cn12
Agent: F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(Sc3ccc(CC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)cc4)cc3)cn12
Yield: 68 %

Procedure:
A solution of Example 20 step a (80 mg, 0.12 mmol) and triethylamine trihydrofluoride (40 mg, 0.24 mmol) in THF (2 mL) was stirred at RT for 24 H, then diluted with EtOAc, washed with sat. aq. sodium bicarbonate, dried (Na2SO4), and evaporated. The residue was purified by FCC (DCM/MeOH 100/0 to 95/5), dissolved in EtOAc, washed with aq. citric acid and brine, dried (Na2SO4), evaporated and dried in vacuo at 40° C. to afford the title compound (45 mg, 68%) as a pink solid. LCMS (Method 7): Rt 11.15 min, m/z 541 [MH+]. 1H NMR (400 MHz, CDCl3): δ 8.23 (1 H, s), 7.91 (1 H, s), 7.74 (1 H, d, J 9.5), 7.25-7.14 (5 H, m), 7.05 (2 H, d, J 8.4), 6.85 (2 H, t, J 8.6), 6.51 (1 H, s), 3.64 (2 H, s), 3.47-3.38 (1 H, m), 1.55 (3 H, s), 1.53 (3 H, s), 1.31 (9 H, s).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[OH:12][CH2:13][C:14]([C@H:16]([C@H:18]([C@@H:20]([CH2:22]O)[OH:21])[OH:19])[OH:17])=[O:15].C[C@@H]([C@@H]([C@@H]([C@@H](CO)O)O)O)O>[Ni]>[OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])=[O:4].[CH3:22][C@H:20]([C@H:18]([C@H:16]([C@@H:14]([CH2:13][OH:12])[OH:15])[OH:17])[OH:19])[OH:21]
Reactant: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: [Ni]
Agent: C[C@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Product: C[C@@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: C[C@H](O)[C@H](O)[C@H](O)C(=O)CO

Procedure:
As shown in FIG. 23, first, 6-deoxy L-psicose was prepared from L-rhamnose, using L-rhamnose isomerase and D-tagatose 3-epimerase (The Annual Meeting of the Japan Society of Bioscience, Biotechnology and Agrochemistry 2007). As a consequence of the hydrogenation with a nickel catalyst under high-pressure conditions, a mixture of 1-deoxy D-allitol (6-deoxy-L-allitol) and 1-deoxy D-talitol (6-deoxy-L-tallitol) was obtained (FIGS. 24 and 26). The mixture as a substrate was subjected to a bacterial cell reaction with the bacterial strain IK7 (NITE BP-271) of the genus Enterobacter (FIGS. 25 and 27). Consequently, only 1-deoxy D-allitol was selectively oxidized to 1-deoxy D-psicose. Almost no reduction of the total weight of both the substrates with the bacterial strain IK7 of the genus Enterobacter was observed. The productivity of 1-deoxy D-psicose from 1-deoxy D-allitol was about 90%. The reaction products were separated from each other. Consequently, 1-deoxy D-psicose and 1-deoxy D-talitol were obtained individually as pure products. A photograph of the crystal of the resulting 6-deoxy L-psicose is shown in FIG. 28. The product was identified by comparison with the chemically synthesized 1-deoxy D-psicose and confirmed on the basis of the coincidence of the 13C NMR spectra (FIG. 29) of the two and the optical rotation degrees of the two.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=3)[S:12][C:11]=2[C:22]2[N:26]=[CH:25][N:24](C3CCCCO3)[N:23]=2)[OH:9])=[CH:4][CH:3]=1.C(O)(C)(C)C.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=3)[S:12][C:11]=2[C:22]2[NH:26][CH:25]=[N:24][N:23]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1ncn(C2CCCCO2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)(C)O
Product: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1nnc[nH]1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of (4-Chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol (0.261 g, 0.554 mmol), tert-butyl alcohol (3.9 mL, 41 mmol), 1,4-dioxane (2.6 mL, 33 mmol) and 4.00 M HCl in dioxane (3.66 mL, 16.6 mmol) was heated at 70° C. for 2 h. The mixture was cooled down. A small amount of water was added, followed by the addition of sodium bicarbonate (0.745 g, 8.87 mmol). The mixture was stirred for 10 min and then evaporated in vacuum. The residue was purified by (HPLC to afford 4-chlorophenyl)[5-(2-fluoropyridin-4-yl)-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol as a white solid. LCMS: (AA) ES+ 387.2, 389.1; 1H NMR (300 MHz, d4-methanol) δ: 8.51 (s, 1H), 8.18 (d, J=5.41 Hz, 1H), 7.73 (s, 1H), 7.60-7.44 (m, 3H), 7.37-7.23 (m, 3H), 6.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]2[CH2:18][CH2:19][C:20](O)=[O:21].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]3[C:20](=[O:21])[CH2:19][CH2:18][CH:6]([C:5]=23)[CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(CCC(=O)O)C(c1ccccc1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c3c1C(=O)CCC3C(c1ccccc1)N2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5-methoxy-2-phenyl-2,3-dihydroindole-3-propionic acid (10.2 g) synthesized as in Example 1, steps 1 and 2, was dissolved in anhydrous methylene chloride (80 ml). Pyridine (2.77 ml), then acetic anhydride (3.24 ml) were added to the solution under cooling with ice, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice water. The organic layer of the mixture was separated, washed with 1N hydrochloric acid, water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 11.5 g (99%) of the titled compound as a crude rubber-like product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[N:28]1.CC(C)=O>ClCCl>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[S:32]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 107 %

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine hydrochloride salt (1.0 g, 2.57 mmol) in dichloromethane (20 ml) and cool in an ice-bath. Add triethylamine (1.79 ml, 12.87 mmol) and then 1-methylpyrazole-4-sulfonyl chloride (465 mg, 2.57 mmol). Remove the ice-bath and allow to warm to ambient temperature and allow to stir for 20 hr. Wash the combined organic layers with aqueous sodium bicarbonate, brine and water. Dry over sodium sulfate and concentrate. Purify by chromatography, eluting with 1:2 hexanes:acetone to afford the title compound (1.1 g, 97% yield) as a white foam. MS ES: m/z=400 [M+H]+.
Reaction SMILES: C1COCC1.[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9].[N:13]1([C:19]2[N:20]=[CH:21][C:22]3[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:23]=3[N:24]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(N(CC)CC)C>[CH2:6]([NH:10][C:11]([CH:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:19]1[N:20]=[CH:21][C:22]2[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:23]=2[N:24]=1)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CN1C(=O)Cc2cnc(N3CCNCC3)nc21
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)C1CNCCN1c1ncc2c(n1)N(C)C(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
THF (30 ml), 1 ml of triethylamine and 0.43 g (4.34 mmoles) of n-butyl isocyanate were added to 0.5 g (2.14 mmoles) of 2-piperazino-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo[2,3-d]pyrimidine, and the mixture was stirred at room temperature for 3 hours. It was concentrated under reduced pressure, and after addition of water, extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue purified by silica gel column chromatography to give 0.15 g (yield 21%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 93.3 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), benzoyl chloride (0.09 g, 0.92 mmol) and a catalytic amount of DMAP in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. Absolute MeOH (15 mL) was added and the solvent was removed under reduced pressure. CH2Cl2 (25 mL) was added to the residue and the solution was washed with 10% HCl (3×20 mL) and saturated NaCl (3×20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 13 (0.06 g, 98%) as a white solid, mp 165-170° C.; 1H NMR (CDCl3): δ 1.18 (3H, s, H-19); 1.47 (3H, s, H-20); 1.50-1.75 (4H, m, H-6β, H-7α,β and H-11β); 1.84 (1H, ddd, J=3.0, 3.0, 9.9 Hz, H-6α); 2.11 (1H, dd, J=2.4, 10.8 Hz, H-8); 2.26 (1H, s, H-10); 2.47 (2H, m, H-3α,β); 2.55 (1H, dd, J=5.1, 13.5 Hz, H-11α); 2.84 (1H, dd, J=6.9, 9.9 Hz, H-4); 3.75 (3H, s, CO2CH3); 5.40 (1H, dd, J=9.6, 10.5 Hz, H-2); 5.52 (1H, dd, J=2.1, 11.7 Hz, H-12); 6.39 (1H, dd, J=0.9, 1.8 Hz, H-14); 7.40 (1H, dd, J=1.5, 1.8 Hz, H-15); 7.42 (1H, dd, J=0.9, 1.5 Hz, H-16); 7.48 (2H, dt, J=7.2, 7.5 Hz, Ar-meta-H); 7.60 (1H, tt, J=1.2, 7.5 Hz, Ar-para-H); 8.09 (2H, dt, J=1.2, 7.2 Hz, Ar-ortho-H).
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]([OH:25])[CH:23]=[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.Br[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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:25][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[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: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: BrCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1

Procedure:
To a mixture of 0.037 (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.039 g (0.2 mmole) of 4-(2-bromo-ethyl)-morpholine and 1 mL of dimethylformamide was added 0.16 g (0.5 mmole) of cesium carbonate. The mixture was heated at 100 degrees for 3 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.014 g of 4-(3-chloro-phenyl)-2-[6-(2-morpholin-4-yl-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.26) as a white powder. MH+/Z=484
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[OH-].[Na+].CO.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1.[OH-].[Na+]>CO.CN(C)C=O>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[CH:41][C:42]([NH:43][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:44][CH:45]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 18 h

Procedure:
Two grams of α-bromoisovaleric acid (0.011 mole) dissolved in 10 ml of methanol is titrated to the phenolphthalein end point at 0° with 2 N sodium hydroxide/methanol. The alcohol is then removed and 10 ml of dimethylformamide and p-trifluoromethylaniline (3.54 g, 0.022 mole) added. The reaction mixture is heated at 100° for 2 hours and left at room temperature about 18 hours. The reaction mixture is poured into 50 ml of 0.1 N sodium hydroxide, washed with ether and the aqueous phase adjusted to pH 4 with conc. HCl and then extracted with chloroform (3×). The extracts are combined and washed with brine, dried, concentrated in a rotoevaporator and solvent removed under vacuum at about 50° to yield N-(p-trifluoromethylphenyl)valine.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH3:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:28][C:29]([CH3:31])=[O:30]>>[C:29]([OH:2])(=[O:30])[CH3:31].[CH3:28][C:29]1([CH3:31])[N:14]=[C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:27][CH:26]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:17]1
Reactant: CO
Reactant: CCCCCCCNC(=N)NC(=N)NCc1ccc(C)cc1
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C)cc2)N1

Procedure:
140 ml of methanol, 60 ml of acetone and 0.7 ml of concentrated hydrochloric acid were added to 10.0 g (26.6 mmol) of N1-4-methylbenzyl-N5-heptyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol, and to the solution were added 60 ml of water and 10.8 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with 10% aqueous sodium acetate solution, and washed with water. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methyl ethyl ketone to obtain 7.2 g of colorless crystals having a melting point of 102 to 104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(Br)cc(C2OCCO2)c1
Yield: 99.8 %

Procedure:
A suspension of 3,5-dibromo-benzaldehyde (20.0 g, 75.8 mmol, 1.0 equiv; [CAS RN 56990-02-4]), ethane-1,2-diol (12.7 mL, 14.1 g, 227.3 mmol, 3.0 equiv) and p-toluene sulfonic acid monohydrate (0.29 g, 1.52 mmol, 0.02 equiv) in toluene (50 mL) was heated to reflux under Dean-Stark conditions for 1 h. The reaction mixture was extracted with ethyl acetate (3×200 mL), the combined organic phases washed with a sat. solution of sodium carbonate (4×50 mL) and dried over MgSO4. Removal of the solvent by evaporation under reduced pressure yielded 23.3 g (100%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.00-4.12 (m, 4H), 5.76 (s, 1H), 7.55-7.56 (m, 2H), 7.65-7.66 (m, 1H). MS (EI): 306.8 [M]+.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH2:20][NH2:21].CO.[ClH:31]>ClCCl.C(OCC)C>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:21][CH2:20][CH:19]([OH:18])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH3:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31].[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:21][CH2:20][CH:19]([OH:18])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH3:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cc1ccc(OC2CCCCC2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(Cc1ccc(OC2CCCCC2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
N-[2-(4-cyclohexyloxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine was prepared from 1-(4-cyclohexyloxyphenyl)propan-2-one (2.5 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.1 g) by an analogous procedure to that described in Example 1. After chromatography on silica gel eluting with 1% methanol in dichloromethane the purified amine was dissolved in diethyl ether, cooled and hydrogen chloride passed through the solution. Evaporation of the solvent and recrystallisation of the crude hydrochloride gave N-[2-(4-cyclohexyloxyphenyl)-1methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride m.p. 164°-166° C. (ethyl acetate-hexane) as a 48:52 mixture of diastereoisomers.