Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[C:30]([F:37])[N:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]3)=[CH:4][CH:3]=2)[CH:31]=[C:30]([F:37])[N:29]=1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1cc(F)nc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3cc(F)nc(F)c3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 45.2 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), 2,6-difluoropyridine-4-boronic acid (11.61 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (4 ml), acidified with 1N HCl (1 ml), and diluted with methanol (2 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[2-{[4-(2,6-difluoro-4-pyridinyl)phenyl]methyl}-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (15 mg, 0.033 mmol, 44.8% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.98 (s, 1H), 10.17 (t, J=5.56 Hz, 1H), 7.89 (d, J=8.34 Hz, 2H), 7.57 (s, 2H), 7.45 (d, J=8.34 Hz, 2H), 5.33 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.20 (sept, J=6.82 Hz, 1H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 459 [M+H]+.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH:1]([CH3:3])[CH3:2])[CH2:25][CH2:24]3)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C=Cc2nc(CC3CCNCC3)no2)cc1OC
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2nc(CC3CCN(C(C)C)CC3)no2)cc1OC
Temperature: 25 °C

Procedure:
Isopropyl bromide (0.13 mL, 1.45 mmol) was added slowly into a mixture of 4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine (compound of Example 19; 0.4 g, 1.21 mmol) and anhydrous potassium carbonate (0.25 g, 1.82 mmol) in dry DMF (10 mL). The reaction mixture was heated at 55° C. to 60° C. for 4 h. The reaction mixture was cooled to room temperature and ice water (5 mL) was added into it. The solid obtained was filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH:27]1[CH2:28][CH2:29][N:30]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:31][CH2:32]1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Clc1cccc(OC2CCNCC2)c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2cccc(Cl)c2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(3-chlorophenoxy)-piperidine (Table No.1, SM 7) in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=497.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][N:30]([CH2:41][CH2:42][OH:43])[S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:36][C:35]=1[CH3:40])(=[O:32])=[O:33]
Reactant: Cc1nc(N)sc1S(=O)(=O)N(CCO)CCO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N(CCO)CCO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.8) according to general procedure II.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C.O>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of 4-chloropyridine HCl (450 mg) and 1-(4-methoxyphenyl)-piperazine (226 mg) in ethanol (20 ml) and water (2 ml) containing triethylamine (0.5 ml) was heated under reflux for 18 hours. The solution was evaporated, water (50 ml) added and the solution taken to pH 8 by addition of solid potassium carbonate to give a precipitate which was filtered, washed with water and dried. The solid (33 mg) was stirred in concentrated aqueous hydrogen bromide (2 ml) at 140° C. for 8 hours, poured into cold water (2 ml) and taken to pH 7 with aqueous ammonia (1.3 ml) to give a solid which was filtered, washed with water and dried to give 1-(4-hydroxyphenyl)-4-(4-pyridyl)piperazine (28 mg), m.p. 288-290° C.
Reaction SMILES: C[C:2]1[C:3]([S:12][C:13]2[CH:18]=[C:17](C)[CH:16]=[C:15](C)[CH:14]=2)=[C:4]([N+]([O-])=O)[C:5](=[O:8])[NH:6][CH:7]=1.C(C1C(SC2C=C(C)C=C(C)C=2)=C(C(OCC)=O)C(=O)NC=1C)C.CC1C=C(S)C=C(C)C=1>C(O)C.C(N(CC)CC)C>[C:13]1([S:12][C:3]2[CH:2]=[CH:7][NH:6][C:5](=[O:8])[CH:4]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2[N+](=O)[O-])c1
Agent: CCOC(=O)c1c(Sc2cc(C)cc(C)c2)c(CC)c(C)[nH]c1=O
Agent: Cc1cc(C)cc(S)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1cc(Sc2ccccc2)cc[nH]1

Procedure:
As for the method described for obtaining compound 7a in example 10, a mixture of compound 15 (1.00 g, 4.1 mmoles) in 10 ml of ethanol and 1 ml of triethylamine was agitated until homogeneous. 3,5-dimethylthiophenol (0.61 ml, 4.5 mmoles) was added. After 12 hours under reflux, the white precipitate was isolated by filtration and crystallised in ethyl acetate. Product 15 was obtained (1.05 g, 82%) in the form of white crystals: melting point 202° C.; NMR-1H (DMSO-d6) δ 12.17 (1H, s, NH-1), 7.22 (1H, s, H-4'), 6.92 (1H, s, H-2' and 6'), 4.09 (2H, q, J=7 Hz, COOCH2CH3), 2.45 (2H, q, J=7 Hz, CH2CH3), 2.27 (3H, s, CH3 -6), 2.25 (6H, s, CH3 -3' and 5'), 1.15 (3H, t, j=7 Hz, COOCH2CH3), 0.85 (3H, t, J=7 Hz, CH2CH3). Anal. C19H23NO3S (C, H, N, S).
Reaction SMILES: C(C1[NH:12]C(=O)CC1)C1C=CC=CC=1.CI.C(=O)([O-])[O-].[K+].[K+].[N+]([O-])([O-])=O.[CH2:26]([CH:33]1[N:37]([CH3:38])[C:36](=[O:39])[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N+]([O-])(O)=O.S(=O)(=O)(O)O>CC(CC)=O>[NH2:12][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:33]2[N:37]([CH3:38])[C:36](=[O:39])[CH2:35][CH2:34]2)=[CH:28][CH:29]=1
Reactant: O=C1CCC(Cc2ccccc2)N1
Reactant: CN1C(=O)CCC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: CCC(C)=O
Solvent: CI
Product: CN1C(=O)CCC1Cc1ccc(N)cc1

Procedure:
Methylate 5-benzylpyrrolidin-2-one with methyl iodide in the presence of potassium carbonate in ethyl methyl ketone; nitrate the thus-obtained 5-benzyl-1-methylpyrrolidin-2-one with nitric acid/sulfuric acid, pour the resulting reaction product onto ice water, extract it with methylene chloride, evaporate solvent from the extract and hydrogenate the thus-obtained 1-methyl-5-(4-nitrobenzyl)pyrrolidin-2-one with platinum/hydrogen without further purification to obtain 5-(4-aminobenzyl)-1-methylpyrrolidin-2-one.
Reaction SMILES: CCCCCCCCCCCCOS([O-])(=O)=O.[Na+:18].[CH2:19]([N:30]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][C:32]([OH:34])=[O:33])[CH2:20][N:21]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][C:23]([OH:25])=[O:24]>>[Na+:18].[Na+:18].[CH2:20]([N:21]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][C:23]([OH:25])=[O:24])[CH2:19][N:30]([CH2:35][C:36]([O-:38])=[O:37])[CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Temperature: -20 °C

Procedure:
Samples were prepared for reducing SDS-PAGE by adding 110 μl of sample to 10 μl sample Buffer (2×), 2.5 μl reducing agent (10×) and 2 μl of 0.1M EDTA (to achieve final concentration of 10 mM). The high molecular weight (HMW) marker was prepared by adding 10 μl of concentrated stock to 80 μl reducing agent (10×), 310 μl WFI and 400 μl sample buffer (2×). The diluted HMW standard was then heated at 95° C. for 5 minutes before aliquoting and storage at −20° C. for use in subsequent gels. Samples (15 μl) containing collagenases were run directly (i.e. with no prior heat treatment) on 8% Tris-Glycine gels using Tris-Glycine running buffer at 130 V for ˜1 hour 50 mins. After electrophoresis, the gels were stained with colloidal blue stain reagent as per the manufacturer's instructions.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13](I)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][C:26]=2[F:28])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)c1cc(-c2ccc(F)cc2F)sc1NC(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A suspension of benzyl[3-(aminocarbonyl)-5-iodo-2-thienyl]carbamate (250 mg, 0.622 mmol), 2,4-difluorophenylboronic acid (349 mg, 2.21 mmol), dichlorobis(triphenylphosphine)palladium (21.8 mg, 0.031 mmol), and sodium carbonate (6.22 mL, 12.43 mmol) in 1,2-dimethoxyethane (10 mL) sealed in a 5 mL microwave reaction vessel was purged of oxygen by doing 5 vacuum/argon flush cycles. The reaction solution was heated in a Biotage microwave for five minutes at 100° C. The resulting mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate (20 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate (20 mL) and brine (2×20 mL), dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography using a 0-4% methanol/dichloromethane elution to afford the title compound.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.O.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2cnc(F)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2cnc(F)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 468.7 %

Procedure:
A mixture of methyl 3-fluoroisoquinoline-6-carboxylate (0.257 g, 1.25 mmol) and lithium hydroxide, monohydrate (105 mg, 2.51 mmol) in THF:MeOH:H2O (3:2:1, 4 mL) was stirred at room temperature for 3 hours. The MeOH and THF were evaporated. 5% citric acid was added, and the mixture was further acidified to pH=4 with NaHSO4. The precipitate was recovered by filtration. The filtrate was extracted with chloroform-isopropanol. The organic extracts were washed with water, brine, dried over sodium sulfate and evaporated. The solids were combined to provide the product as a white solid (1.12 g, 100%). LCMS (API-ES) m/z: 192 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][PH:6]([C:8](OCC)(OCC)[CH3:9])=[O:7])[CH3:4].BrC[CH:18]1[CH2:23][CH2:22]C=[CH:20][CH2:19]1.O>O1CCCC1>[CH2:3]([O:5][PH:6]([CH2:8][CH:9]1[CH2:22][CH2:23][CH:18]=[CH:19][CH2:20]1)=[O:7])[CH3:4]
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Reactant: BrCC1CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 8.7 g of sodium hydride (99%) dissolved in 600 ml of tetrahydrofuran are cooled to 15° and 75 g of 1,1-diethoxyethylphosphinic acid ethyl ester in 100 ml of tetrahydrofuran are added thereto in the course of 1 hour, the reaction temperature being maintained at less than 25°. The resulting suspension is stirred at room temperature for 2 hours and then a solution of 57.2 g of bromomethylcyclohex-3-ene in 100 ml of anhydrous tetrahydrofuran is added thereto in the course of 30 minutes. The mixture is heated at reflux for 24 hours, then cooled to 0°; 10 ml of water are added and the solvent is removed. The residue is dissolved in dichloromethane, washed twice with water, dried over sodium sulfate, concentrated to dryness by evaporation and distilled. The resulting 1,1-diethoxyethyl-(cyclohex-3-ene)-phosphinic acid ethyl ester is dissolved in 300 ml of dichloromethane that contains 10% by volume ethanol and left to stand at room temperature for 24 hours. Removal of the solvent and distillation yield cyclohex-3-enylmethylphosphinic acid ethyl ester; 31P-NMR (CDCl3):δ=37.1 (s).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:34]3[CH2:33][CH2:32][N:31]([S:28]([CH2:25][CH2:26][CH3:27])(=[O:29])=[O:30])[CH2:36][CH2:35]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 27.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 1-propanesulfonyl-piperazine hydrochloride (52 mg, 0.23 mmol) and sodium triacetoxyborohydride (48 mg. 0.23 mmol) to afford 21 mg (27%) of the desired product after purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
A slurry of 22.5 g. (0.15 mole) of 4-methoxybenzoic acid in benzene at reflux is treated with 12.5 ml. (0.15 mole) of thionyl chloride and 1 ml. of N,N-dimethyl formamide. After stirring for 15 minutes the solution is evaporated and cooled to provide 4-methoxybenzoyl chloride as a yellow solid. The solid is dissolved in carbon disulfide and added to 20 g. (0.15 mole) of aluminum chloride slurried in 200 ml. of carbon disulfide. To this mixture is added 30 g. (0.15 mole) of 2,6-di(t-butyl)phenol. After stirring for 2 hours at room temperature, the resulting mixture is poured into a dilute hydrochloric acid-ice mixture, then extracted with three portions of dichloromethane. The organic layer is dried, then evaporated to provide a residue which is recrystallized twice from a benzene-hexane mixture to provide 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, m.p. 141°-142.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:39]1([CH2:45][C:46]([NH2:48])=[O:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][C:46]([NH2:48])=[O:47])[CH2:40][CH2:41]3)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound. LC-MS: 650.3 [(M+H)+]
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[O:13]1[CH2:16][CH:15]([NH2:17])[CH2:14]1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:17][CH:15]1[CH2:16][O:13][CH2:14]1)=[O:9])([O-:3])=[O:2]
Reactant: NC1COC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1COC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.3 %

Procedure:
3-Nitrobenzoic acid (0.50 g, 2.99 mmol), oxetan-3-amine (0.219 g, 2.99 mmol) were taken in pyridine (0.5 ml) and under nitrogen atmosphere and EDC.HCl (0.574 g, 2.99 mmol) was added. The reaction mixture was stirred at room temperature for 10 hrs. After completion of reaction, the reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×5 ml). Combined organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title compound (600 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)O)s1
Reaction time: 7 h

Procedure:
2.37 g (11.18 mmol) of 5-(2-methoxycarbonyl-vinyl)-thiophene-2-carboxylic acid were dissolved in 170 ml of methanol. After addition of 500 mg of 10% palladium on charcoal (Degussa E 101 R/D 10%) the mixture was hydrogenated for 7 hours at atmospheric pressure (approx. 1 bar) and room temperature. After filtration and evaporation the yield of the title compound was 2.4 g (purity>99% (HPLC)).
Reaction SMILES: [C:1]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:19][CH2:20][CH2:21][C:22](O)=[O:23]>C1C=CC=CC=1>[C:1]1([N:7]([CH:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:15][CH2:16][CH2:17]2)[C:22](=[O:23])[CH2:21][CH2:20][Cl:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCl
Reactant: c1ccc(NC2CCc3ccccc3C2)cc1
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(CCCl)N(c1ccccc1)C1CCCc2ccccc21

Procedure:
0.1 mol of 2-phenylamino-1,2,3,4-tetrahydronaphthalene, 0.15 mol of the chloride of β-chloropropionic acid and 25 ml of benzene are refluxed during 4.5 hours. The solvent and the reagent excess are then removed. The residue is recrystallized from petroleum ether. M.P. 78°-81°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]3[CH2:16][CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN(C=O)C.C(N(CC)CC)C.[CH3:30][N:31]([CH3:35])[CH2:32][C:33]#[CH:34]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:15]12[N:11]([C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:34]#[C:33][CH2:32][N:31]([CH3:35])[CH3:30])[CH:3]=3)[CH:12]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.5 %

Procedure:
To 7-(3-bromo-4-nitro-phenyl)-7-azabicyclo[2.2.1]heptane (500 mg, 1.68 mmol), Pd(PPh3)2Cl2 (59 mg, 0.08 mmol), and CuI (10 mg, 0.05 mmol) were added DMF (5 mL), triethylamine (5 mL), and N,N-dimethylprop-2-yn-1-amine (420 mg, 538 μL, 5.05 mmol) under N2 atmosphere. The reaction was heated under microwave irradiation for 10 min at 100° C. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL), water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to a red solid. Purification by silica gel chromatography (0-50% dichloromethane/ethyl acetate) provided 3-[5-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-nitro-phenyl]-N,N-dimethyl-prop-2-yn-1-amine (400 mg, 79% yield). LC/MS m/z 300.5 [M+H]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH3:30])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:9]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:26][CH:25]([O:27][CH3:28])[CH:24]([O:29][CH3:30])[CH2:23]2)[CH:19]=[CH:20][C:21]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@H]1OC
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(c2ccc(I)c(Cc3ccccc3)c2)CC1OC
Reaction time: 2 h

Procedure:
Under ice-cooling, 227 mg of N-iodosuccinimide was added to a mixture of 250 mg of (3R,4S)-1-(3-benzylphenyl)-3,4-dimethoxypyrrolidine (Production Example 11) and 3 ml of N,N-dimethylformamide, followed by stirring at the same temperature for 2 hours. 0.5 ml of a 1 M aqueous solution of sodium thiosulfate was added to the reaction mixture, and then the mixture was extracted with ethyl acetate/water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to silica gel column chromatography with 10% ethyl acetate/hexane, to give 340 mg of (3R,4S)-1-(3-benzyl-4-iodophenyl-3,4-dimethoxypyrrolidine.