Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2CC1)=O.[C:24]([C:27]1[C@:28]2([CH2:46][CH2:45][C@H:44]3[C@@H:33]([CH2:34][CH2:35][C@@H:36]4[C@:42]3([CH3:43])[CH2:41][CH2:40][C@@H:38]([OH:39])[CH2:37]4)[C@@H:30]2[CH2:31][CH:32]=1)[CH3:29])([OH:26])=[O:25].C[O-].[Na+].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C1(C)C=CC=CC=1.CO>[CH3:1][O:25][C:24]([CH:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:44]([CH2:45][CH2:46][C@:28]12[CH3:29])[C@:42]1([CH3:43])[C:36](=[CH:37][C:38](=[O:39])[CH2:40][CH2:41]1)[CH2:35][CH2:34]3)=[O:26]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)O)=CC[C@@H]12
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: C[O-]
Agent: [Al+3]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: COC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A preferred process for preparing 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, an especially preferred compound of the present invention, comprises the following steps: (a) pregnenolone (V), an available starting material, is treated by the haloform King reaction with iodine and pyridine to form the 20-pyridinum iodide derivative of the pregnenolone (VI); (b) the pyridinium iodide derivative (VI) is methanolyzed to the methyl ester of 17-carboxy androstenol (VII) with sodium methoxide and methanol, the ester form being preferred for carrying out the following Oppenhauer reaction; (c) the methyl ester of 17-carboxy androstenol (VII) is treated with aluminum isopropoxide and cyclohexanone in an appropriate solvent such as toluene to yield methyl-4-androstene-3-one-17-carboxylate (VIII) (d) the methyl-4-androstene-3-one-17-carboxylate (VIII) thus formed is hydrolyzed to the 17-acid (IX) under acid conditions in a methanol: water solvent of approximately 4:1 proportions; (e) the 17 acid (IX) is then treated with an oxalyl chloride: pyridine complex of approximately 1:1 proportions in toluene or other suitable solvent, e.g. xylene, to form the 17 -acid chloride (X); (f) the 17-acid chloride (X) is then treated in situ with an excess of diethylamine to form the 17β-N,N-diethylcarbamoyl-4-androstene-3-one (XI); (g) the 4-androstene-3-one (XI) thus formed is oxidized by treatment with sodium periodate and potassium permanganate, using tert-butanol and water as a solvent system, to the corresponding 5-oxo-3,5-secoandrostan-3-oic acid (XII); (h) the secoandrostanoic acid (XII) is then converted to the corresponding 4-aza compound (XIII) by treating it with methylamine in ethylene glycol for a period of about 1 hour over which time the reaction mixture temperature is raised to from 140°-180° C. where it is maintained from 0.5 to 5 minutes; (i) the resulting 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one (XIII) is then hydrogenated by treating it with hydrogen at room temperature to 60° C. or higher, using platinum oxide as the catalyst, to form the 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (XIV) final product, which is then separated and purified.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17].C(=O)(O)[O-].[Na+].COC(C)(C)C>C1(C)C=CC=CC=1>[Cl:17][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(CO)cc1OC1CCCC1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: COc1ccc(CCl)cc1OC1CCCC1
Temperature: 22.5 °C

Procedure:
A 12 liter round bottom flask equipped with an overhead stirrer, internal thermometer, and a reflux condensor equipped with a nitrogen inlet was flushed with nitrogen. The flask was charged with 3-cyclopentyloxy-4-methoxybenzyl alcohol (495 g, 2.2 mol, 1 equivalent) in a solution of toluene. To the vigorously stirred reaction at 22° C. was added concentrated hydrochloric acid (600 g, 2.75 equivalents). The reaction was maintained at 20 to 25° C. for 30 minutes. The top organic layer was isolated and the bottom acidic layer was discarded. To the top organic layer was charged a solution of 10% sodium bicarbonate (550 g, 0.65 mol, 0.36 equivalents) and t-butyl methyl ether (814 g). The contents of the flask were vigorously stirred, and allowed to settle. The product, 4-chloromethyl-2-cyclopentyloxy-1-methoxybenzene, was isolated as a solution in toluene and t-butyl methyl ether (96.8% solution yield). This was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O>C(O)(=O)C>[CH3:12][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:8](=[O:13])[CH:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccn1
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccccc2n1

Procedure:
All the 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones were prepared from commercially available 2-aminopyridine derivatives. Thus, 2-aminopyridine derivative was reacted with ethyl acetoacetate in refluxing acetic acid to give 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in good yield. This intermediate was brominated using bromine in acetic acid to give 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-ones in good yield. All the intermediates prepared in this manner were characterized by spectral and analytical methods before using them for the preparation of compounds of invention.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]([N:15]1[CH:20]=[CH:19][CH2:18][CH:17]=[CH:16]1)=[O:14].FC(F)(F)S(O)(=O)=O.C(OCC)(=O)C.CCCCCC>ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C@H:12]1[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:16]2[CH2:17][CH2:18][CH:19]=[CH:20][N:15]2[C:13]1=[O:14]
Reactant: O=C([C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)N1C=CCC=C1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reaction time: 2.5 h

Procedure:
Add a solution of (S)-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine (1.1 g, 3.1 mmol) in dichloromethane (2 mL) to trifluoromethanesulfonic acid (1.2 mL). After 2.5 hours, add trifluoromethanesulfonic acid (1.2 mL). After 4 hours, partition the reaction mixture between ethyl acetate and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 25% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[C:22]3Cl)=[CH:4][N:3]=1.Br[C:31]1[CH:32]=[C:33](NS(C2C=CC(F)=CC=2)(=O)=O)[C:34](Cl)=[N:35][CH:36]=1.ClC1C2C(=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)N=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[C:22]3[N:35]2[CH2:36][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Reactant: O=S(=O)(Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl)c1ccc(F)cc1
Agent: [Pd]
Agent: CC1(C)OB(c2ccc3nccc(Cl)c3c2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3nccc(N4CCCCC4)c3c2)cnc1Cl)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide. To a 5 mL CEM microwave tube was added N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.4 g, 1 mmol), 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.4 g, 1 mmol), sodium carbonate (2 mL, 3 mmol), Pd fibrecat PPh (Sigma-Aldrich, St. Lois, Mo.) (20% wt, 80 mg) and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 120° C., with 100 Watts of power via Powermax. LC/MS showed a desired product mass as the major peak. The reaction mixture was partitioned between DCM/water. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (120 g) chromatography with hexanes:acetone=80%:20% as the solvent system to afford the product as light yellow solid (270 mg). MS (ESI pos. ion) m/z: calc'd for C20H12Cl2FN3O2S: 447.5; found: 448.3 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.99 (br. s., 1 H) 7.13-7.24 (m, 2 H) 7.60 (d, J=4.68 Hz, 1 H) 7.88 (dd, J=8.99, 4.90 Hz, 2 H) 7.97 (dd, J=8.77, 2.05 Hz, 1 H) 8.28 (d, J=8.77 Hz, 1 H) 8.33 (d, J=2.19 Hz, 1 H) 8.38 (d, J=1.90 Hz, 1 H) 8.52 (d, J=2.34 Hz, 1 H) 8.87 (d, J=4.68 Hz, 1 H).
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[N:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][C:13]=2[O:23]C)=[CH:10][CH:11]=1.CO>C(Cl)Cl>[Cl:5][C:6]1[N:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][C:13]=2[OH:23])=[CH:10][CH:11]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
BCl3 (1 M in DCM, 91 mL, 91 mmol) was added to a solution of 3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine (Intermediate 2-1, 8.6 g, 30 mmol) in DCM (150 mL) at 0° C. and the reaction was stirred for 5 h at RT. MeOH (50 mL) was added to the reaction at 0° C., then the reaction was warmed to RT and the solvent was evaporated under reduced pressure. The crude material was treated with hot CH3CN then cooled to 5° C. The mixture was filtered and 2-(6-chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (7.6 g, 86%) was afforded as yellow solid. MS [M+H]: 273.2; 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (dd, J=8.5, 2.0 Hz, 1H), 6.59 (t, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4].[C:35](=O)([O-])[O-:36].[Cs+].[Cs+]>CO.O>[CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([O:36][CH3:35])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4]
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(OC)nc1)C2
Yield: 94.2 %

Procedure:
A solution of (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester (0.3 g) in methanol (10 mL) was treated with cesium carbonate (0.98 g) and water (0.5 mL) for 20 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, the combined organic extracts dried over sodium sulfate and the residue concentrated under reduced pressure to provide a white foam (0.28 g). LCMS (Method G): 499.1 (M+H)+, Retention time 3.77 minutes.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29](C)C)[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O.COC(=O)[C@H](C)NC(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH3:29])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=1)=[O:19]
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Reactant: CNCc1coc(C(C)C)n1
Agent: COC(=O)[C@H](C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: COC(=O)[C@H](C)NC(=O)N(C)Cc1coc(C(C)C)n1
Yield: 66 %

Procedure:
Using the procedure of Example 1S, but replacing 2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with 2-isopropyl-4-(((N-methyl)amino)methyl)-oxazole and relacing N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester with N-(((4-nitrophenyl)oxy)carbonyl)-L-alanine methyl ester provided the desired compound in 66% yield. 1H NMR (CDCl3) δ 1.32 (d, 6 H), 1.42 (d, 3 H), 2.96 (s, 3 H), 3.05 (m, 1 H), 3.75 (s, 3 H), 4.30 (s, 2 H), 4.47 (m, 1 H), 5.80 (br d, 1 H), 7.46 (s, 1 H). Mass spectrum: (M+H)+ =284.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[NH:5][C:6](=[O:24])[CH:7]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[NH:18])[NH:16]O)=[CH:11][CH:10]=1>C(O)(=O)C.[Pd]>[C:3]([OH:31])(=[O:2])[CH3:4].[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:5][C:6](=[O:24])[CH:7]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[NH:16])[NH2:18])=[CH:11][CH:10]=1)[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)NO)cc1)C(=O)N(C)C)C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N(C)C)C1CCCCC1
Reaction time: 9 h

Procedure:
(S)-Cyclohexyl-{2-(R,S)-dimethylcarbamoyl-3-[4-(N-hydroxycarbamimidoyl)-phenyl]-propionylamino}-acetic acid methyl ester (13 g, 30 mmol) was dissolved in acetic acid (150 ml). After addition of palladium on charcoal (10%, 100 mg) the mixture was hydrogenated at 50° C. for 9 hours. The catalyst was filtered off, the solvent evaporated and the residue dissolved in water and lyophilized. Yield: 14.3 g (100%); MS m/z: 417.4 (M+H)+.
Reaction SMILES: ClC(Cl)C(O)=O.COC1C=CC(C([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][N:41]2[C:45](=[O:46])[C:44]3=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]3[C:42]2=[O:51])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>CO>[C:42]1(=[O:51])[N:41]([O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][OH:28])[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]12
Reactant: COc1ccc(C(OCCOCCOCCOCCON2C(=O)c3ccccc3C2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C(O)C(Cl)Cl
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1OCCOCCOCCOCCO
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of dichloroacetic acid in CH2C32 (100 mL, 3:97, v/v) and methanol (20 mL) was added to N-[11-(4,4′-dimethoxytrityloxy)-3,6,9-trioxaundecanyloxy]phthalimide (2.3 g, 3.6 mmol), and the reaction mixture was stirred for 18 hours. All volatile material was evaporated in vacuo and the residue was dissolved in CH2Cl2 (10 mL). Silica gel column purification using an eluent system with a stepwise gradient of acetic acid in CH2Cl2 (0-4%) gave 0.88 g (72%) of 11-(phthalimidooxy)-3,6,9-trioxaundecan-1-ol after coevaporation of the pooled fractions with water and pyridine.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([O:26][CH3:25])=[O:36])=[CH:11][CH:10]=1
Reactant: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Yield: 43.9 %

Procedure:
N-(2,4-Difluorobenzyl)-3-(4-hydroxyphenyl)-N-propylpropanamide (290 mg, 0.87 mmol) was dissolved in acetonitrile (10 ml). 2-Bromomethyl-benzoic acid methyl ester (209 mg, 0.913 mmol) was added followed by potassium carbonate, anhydrous (180 mg, 1.305 mmol). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE®SI, 20 g/70 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 184 mg the desired product, yield 44%.
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[CH3:17][O:15][C:14](=[O:16])[CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH2:5])=[CH:11][CH:10]=1
Reactant: CO
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(N)cc1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
SOCl2(1.5 mL) was added slowly to MeOH (6 mL) at 0˜5° C., and the mixture was stirred for 10 minutes. 3-(4-Amino-phenyl)-propionic acid (1 g, 6.05 mmol) was added thereto at the same temperature. After the temperature was elevated to room temperature, the mixture was stirred for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with saturated sodium bicarbonate aqueous solution, and extracted with EtOAc. The organic layer was added with NaCl aqueous solution, extracted again, and then filtered by using celite. The filtrate was concentrated under reduced pressure. The residue was added with n-Hex, and then concentrated under reduced pressure again. n-Hex (20 mL) was added to the obtained solid, and the mixture was stirred under reflux for 1 hour, and then stirred at room temperature for 2 hours. The mixture was filtered to obtain the title compound (0.85 g, 78%).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.[CH:9]1([C:12](=[O:31])[C:13](=[CH:27]OCC)[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[F:26])=[O:15])[CH2:11][CH2:10]1>C(O)C>[CH:9]1([C:12]([C:13]2[CH:27]=[N:7][O:15][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[F:26])=[O:31])[CH2:11][CH2:10]1
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2oncc2C(=O)C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (7.4g) was added to a mixture of hydroxylamine hydrochloride (6.3 g) and 3-cyclopropyl-2-ethoxymethylene-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (29.0g) in ethanol. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (anhydrous magnesium sulphate) filtered and evaporated to dryness. The residue was triturated with ether and filtered. The resultant solid was recrystallized from methanol. The mother liquors from the recrystallization were combined and evaporated to dryness. The residue was purified by column chromatography on silica gel to give 4-cyclopropylcarbonyl-5-(2-fluoro-4-methylsulphonylphenyl)-isoxazole (compound 1) as a white solid, m.p. 129.5°-130.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: N#CCc1ccc(Br)cn1
Reactant: BrCCCCCBr
Product: N#CC1(c2ccc(Br)cn2)CCCCC1
Yield: 60 %

Procedure:
The title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,5-dibromopentane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 60% of theory; Mass spectrum (ESI+): m/z=265/267 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncccn2)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncccn2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
0.64 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyrimidinyl)-2H-pyridazin-3-one and 10.4 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice-cooled sodium bicarbonate water was added. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.56 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.49 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2-pyrimidinyl)pyridazine (hereinafter, described as compound (6) of the present invention(6).).
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.[Zn:13].Cl>CO>[Zn:13].[SH:4][CH:5]([CH2:1][CH2:2][SH:3])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCCCC1CCSS1
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: O=C(O)CCCCC(S)CCS
Temperature: 50 °C
Reaction time: 1 h

Procedure:
6.2 g of DL-α-lipoic acid was dissolved in 70 ml of methanol, and to this were added 3.5 g of zinc powder and 15 ml of 2 N hydrochloric acid and stirred for one hour at 50° C. When the solution turned colorless, unreacted zinc was removed by filtration, and the filtrate was concentrated under reduced pressure. Addition of 150 ml of water to the oily residue, collection of thus precipitated white crystals by filtration and washing with water gave the free acid form of 6,8-dimercaptooctanoic acid zinc chelate compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][NH2:37]>>[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][NH:37][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:14][C:9]3[CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:29])([F:1])[F:28])[CH2:11][C:10]=3[CH2:12]2)=[N:16][CH:17]=1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCc1nccs1
Agent: Cl
Product: O=C(NCc1nccs1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 28 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (54 mg, 0.134 mmol) was reacted with C-thiazol-2-ylmethylamine, hydrochloride analogously to example 3d. Yield: 28%, M+H+: 500.22.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][CH2:15][C:16]#[N:17])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC#N)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCO[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans (4-cyanomethoxy-cyclohexyl)-carbamic acid tert-butyl ester (280 mg, 1.10 mmol) in DCM (22 mL) was treated with trifluoroacetic acid (22 mL) and stirred at ambient temperature for 30 minutes. The mixture was diluted with toluene and concentrated under vacuum. The residue was azeotroped with toluene to afford 450 mg (quantitative yield) of trans (4-amino-cyclohexyloxy)-acetonitrile trifluoroacetic acid salt as a colourless oil. LCMS (Method Q, ESI): RT=0.59 min, m+H=154.0; 1H NMR (400 MHz, DMSO) δ: 7.75 (br s, 2H), 4.43 (s, 2H), 3.35 (m, 1H), 2.95 (d, 1H), 1.99 (d, 2H), 1.90 (s, 2H), 1.25 (m, 4H).