Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([O:15][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Cc1ccncc1)c1ccccc1
Product: O=C(OC(=Cc1ccncc1)c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
Following a similar procedure to that described in reference example 4, but using 1-phenyl-2-(4-pyridyl)ethanone (obtained in reference example 3) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and benzoyl chloride instead of 4-fluorobenzoyl chloride, the title compound was obtained (yield: 62%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][C@@H:40]1[C@@H:44]([OH:45])[C@@H:43]([OH:46])[CH2:42][N:41]1[CH2:47][CH2:48][OH:49]>>[OH:45][C@H:44]1[C@@H:43]([OH:46])[CH2:42][N:41]([CH2:47][CH2:48][OH:49])[C@@H:40]1[CH2:39][NH:38][C:32]([N:12]1[C@@:13]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)([CH3:24])[C@@:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC[C@@H]1[C@@H](O)[C@@H](O)CN1CCO
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC[C@@H]1[C@@H](O)[C@@H](O)CN1CCO

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (2R,3R,4S)-2-aminomethyl-1-(2-hydroxy-ethyl)-pyrrolidine-3,4-diol (AFID Therapeutics) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O5 [(M+H)+] 698.2871, observed 698.2873.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[O:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C@H:17]([OH:28])[C@@H:18]4[O:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 79.9 %

Procedure:
In 200 ml of tetrahydrofuran was dissolved 11.7 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one, followed by addition of 36 ml of a 1.0M solution of diisobutylaluminum hydride in toluene under ice-cooling. The mixture was stirred under ice-cooling for minutes. Then, the reaction mixture was worked up in the same manner as Example 68 to recover 9.4 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3α-ol (yield: 80%) showing the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19].ClCCNC(NC1C2C(=CC=CC=2)N=C(C)C=1)=O>>[Cl:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)=[O:19]
Reactant: O=C=NCCCCl
Reactant: Cc1cc(N)c2ccccc2n1
Agent: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Product: Cc1cc(NC(=O)NCCCCl)c2ccccc2n1

Procedure:
The title compound is prepared from 4-amino-2-methylquinoline and 3-chloropropylisocyanate by the method used in the preparation of Example 1A, 1-(2-chloroethyl)-3-(2-methyl-quinol-4-yl)-urea.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15](=[O:41])[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:18][C:17]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:9]2)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:34]([O:33][C:17]1[CH:18]=[C:19]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]([CH:22]([CH3:24])[CH3:23])=[CH:21][C:16]=1[C:15]([N:10]1[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH:4]=[O:5])[CH:7]=2)[CH2:11]1)=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CON(C)C(=O)c1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OCc3ccccc3)cc1OCc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)N2Cc3ccc(C=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methoxy-methyl-amide (0.226 g, 0.4 mmol) in THF (5 ml) cooled to 0° C., treated with 1M LiAlH4/THF (0.3 ml, 0.3 mmol), stirred 1 hour, further LiAlH4 (0.05 ml) added then stirred for 30 minutes. The reaction was quenched with saturated KHSO4 solution, extracted with EtOAc, dried (MgSO4), filtered and evaporated to give 0.2 g of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde. MS: [M+H]+ 504.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14])(=[O:17])[CH3:16]
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(=O)O)ccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
3 g. of 2-amino-α,α,α-trifluoro-p-toluic acid is dissolved in 20 ml. of acetic anhydride and the resultant solution is heated to 80° C. After 30 minutes at a temperature of 80° C., the excess acetic anhydride is removed from the reaction mixture on a rotary evaporator and water is added to the residue. The resultant precipitate is filtered, washed with water and dried to yield 2-acetamido-α,α,α-trifluoro-p-toluic acid (N-acetyl-4-trifluoromethylanthranilic acid), m.p. 195°-197° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]12[CH2:15][C@@:12]([NH:16][C:17]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2)(C)(C)C.[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[NH2:7][C@@:8]12[CH2:15][C@@:12]([NH:16][C:17]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2
Reactant: CC(C)(C)OC(=O)N[C@]12CCC[C@](NC(=O)c3cnccn3)(CC1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@]12CCC[C@](NC(=O)c3cnccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic acid tert-butyl ester (intermediate 15, 0.9 g, 2.6 mmol) in methylene chloride (5.0 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (6.5 mL). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to afford 0.7 g of pyrazine-2-carboxylic acid ((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt, which was used in the next step without further purification. ESI-MS m/z: 247 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:25][OH:26])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@@H:15]([OH:19])[C@H:14]([NH:20][CH:21]1[CH2:24][CH2:23][CH2:22]1)[CH2:13][CH2:12]2)C1C=CC=CC=1.C[OH:28]>[Pd]>[C:25]([OH:26])(=[O:28])[CH3:10].[CH:21]1([NH:20][C@@H:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[C:10]=3[CH2:25][OH:26])[C@H:15]2[OH:19])[CH2:22][CH2:23][CH2:24]1
Reactant: CO
Reactant: OCc1c(OCc2ccccc2)ccc2c1CC[C@@H](NC1CCC1)[C@@H]2O
Agent: [Pd]
Product: CC(=O)O
Product: OCc1c(O)ccc2c1CC[C@@H](NC1CCC1)[C@@H]2O

Procedure:
In 20 ml. of methanol is dissolved 300 mg. of trans-6-benzyloxy-2-cyclobutylamino-1-hydroxy-5-hydroxymethyl-1,2,3,4-tetrahydronaphthalene and catalytic reduction is carried out in the presence of 5% palladium-on-carbon as the catalyst. When no more hydrogen is absorbed, the catalyst is filtered off and 60 mg. of acetic acid is added to the filtrate. The mixture is concentrated under reduced pressure and the residue is recrystallized from methanolethyl acetate. The procedure yields trans-2-cyclobutylamino-1,6-dihydroxy-5-hydroxymethyl-1,2,3,4-tetrahydronaphthalene acetate as colorless platelets melting at 143°-145° C (decomp.)
Reaction SMILES: [C:1](=[O:10])([O:7][CH2:8]Cl)[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:1](=[O:10])([O:7][CH2:8][O:16][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[O:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCOC(=O)OCCl
Reactant: C=C(C)C(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCOC(=O)OCCCC
Yield: 60.4 %

Procedure:
The intermediate n-butyl chloromethyl carbonate (2.5 g 15.0 mmol) was dissolved in dimethyl formamide (80 ml), and potassium methacrylate (1.77 g, 15.0 mmol) was added together with a catalytic amount of 18-crown-6 (0.2 g, 7.5 mmol). After 3 days at 25° C. the solvent was removed under reduced pressure, cholorform (30 ml) and water (20 ml) were added and the product was extracted into chloroform. The solvent was removed under reduced pressure after drying (MgSO4). Flash chromatography gave 1.96 g (61%) of butyl methacryloyloxymethyl carbonate.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([OH:16])=[S:15])=[CH:3]1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([O:16][CH3:23])=[S:15])=[CH:3]1
Reactant: O=C1CC(O)C=C1CCCCCC(C(O)=S)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=S)C(CCCCCC1=CC(O)CC1=O)c1ccccc1

Procedure:
A stirred mixture of 4.38 g. of 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-2-phenylthioheptanoic acid, 1.99 g. of potassium carbonate, 1.63 ml. of iodomethane and 26 ml. of acetone is refluxed for 3.5 hours. The acetone is evaporated and the residue is partitioned between water and ether. The ether layer is washed with brine, dried and concentrated, giving the product as an oily liquid, identified by PMRδ 3.67 (3, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[CH2:10]([O:12][C:13]#[CH:14])[CH3:11]>ClCCl.[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1.[Cl-]>[CH2:13]([O:12]/[CH:10]=[CH:11]/[B:4]1[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]1)[CH3:14]
Reactant: C#COCC
Reactant: CC1(C)OBOC1(C)C
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Solvent: ClCCl
Product: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Di(cyclopenta-2,4-dien-1-yl)zirconium(IV) chloride (0.685 g, 2.344 mmol) was added to a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.0 g, 39.1 mmol) in dichloromethane (15 mL) followed by ethoxyethyne (3.01 g, 43.0 mmol) at 0° C., and the mixture was stirred for 16 h at 25° C. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford title compound (6.04 g, 78.13%) as oil. 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J=14.0 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H), 3.84 (q, J=7.2 Hz, 2H), 1.32-1.2 (m, 15H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Product: Cl

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 593.4 [(M+H)+]
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10]C(C#N)=[C:6]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:5]=1.Cl.[CH2:25]([OH:28])[CH2:26]O>>[Cl:3][C:4]1[CH:11]=[CH:10][C:26]([C:25]([OH:28])=[O:1])=[C:6]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:5]=1
Reactant: OCCO
Reactant: N#Cc1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Temperature: 190 °C
Reaction time: 5 h

Procedure:
Ethylene glycol and sodium hydroxide were added to 4-chloro-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzonitrile, followed by stirring at 190° C. for 5 hours. After neutralizing the reaction liquid by adding hydrochloric acid, the organic layer was extracted with chloroform and the solvent was evaporated to obtain 4-chloro-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCCOC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydro-2H-pyran. LCMS (Method B): tRET=1.13 min; MH+=364
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[C:5](=[O:16])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:34]([C:36]1[CH:50]=[CH:49][C:39]([CH2:40][NH:41][CH2:42][CH2:43][C:44]2[N:48]=CNC=2)=[CH:38][CH:37]=1)#[N:35].[CH3:51][N:52]1CCOC[CH2:53]1>CN(C=O)C>[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][N:41]2[C:42]([CH2:43][CH2:44][NH:48][C:17]([C:4]3[C:5](=[O:16])[N:6]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=4)[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[O:19])=[CH:53][N:52]=[CH:51]2)=[CH:49][CH:50]=1)#[N:35]
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cc(Cl)cn(Cc2cccc(Cl)c2)c1=O
Reactant: N#Cc1ccc(CNCCc2c[nH]cn2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)c2cc(Cl)cn(Cc3cccc(Cl)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Chloro-1-(3-chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.10 g, 0.335 mmol) was dissolved in DMF (10 mL) and treated with EDC (0.077 g, 0.402 mmol), HOBT (0.054 g, 0.402 mmol), 4-cyanobenzyl histamine (0.079 g, 0.352 mmol) and NMM (0.11 mL, 1.00 mmol) and stirred at ambient temperature for 18 hr. The reaction mixture was concentrated to remove the DMF, then partitioned between EtOAc and aq saturated NaHCO3 solution, the organic layer separated, washed with brine and dried (MgSO4). The title compound was obtained upon purification by RP HPLC on a PrepPak column eluting with an acetonitrile/H2O/TFA gradient followed by neutralization with NaHCO3 and extraction.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: O=C(O)/C(=N\OCc1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-hydroxyimino)acetate with benzyl bromide followed by hydrolysis of the ester to give 2-(2-tritylaminothiazol-4-yl)-2-((Z)-benzyloxyimino)-acetic acid; n.m.r. in solvent C: 5.44(s, 2H); 6.69(s, 1H); 7.2-7.7(m, 20H).
Reaction SMILES: I.CS[C:4]([C:6]1[S:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)=[NH:5].[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](OCC)(OCC)[CH:32]([NH2:42])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.CCOCC>O1CCCC1>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]2[N:5]=[C:4]([C:6]3[S:7][C:8]4[C:14]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=4[N:10]=3)[NH:42][C:32]=2[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1N
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=N)SC)nc12
Agent: FB(F)F
Agent: I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CN(Cc3ccccc3)CC4)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
To a suspension of 0.04 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboximidothioic acid methyl ester hydroiodide in 1.8 ml tetrahydrofurane were added 0.1 g 1-benzyl-4,4-diethoxy-piperidin-3-ylamine in 1.8 ml tetrahydrofurane and the mixture was stirred at room temperature for 16 hours. Then 0.015 ml boron trifluoride etherate was added and the solvent was distilled off under vacuum. Again 0.015 ml boron trifluoride etherate was added and the mixture was dissolved in 1.5 ml dimethylformamide and heated for 15 minutes at 125° C. The solvent was distilled off and the residue was dissolved in dichloromethane and extracted with water. The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. Chromatography on silicagel with ethylacatate/heptane 1:1 to 2:1 yielded 0.4 mg (1%) 5-benzyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine as an amorphous solid; m/e=462 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1>C(O)C.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: CNC(=O)/C=C/c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)CCc1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]-N-methylacrylic amide (100 mg, 0.30 mmol, 1 eq) and Pd(OH)2 (2.82 mg) in ethanol (1 ml) and THF (0.4 ml) is stirred for 19 h at RT under a hydrogen atmosphere. Filtration and concentration of the reaction mixture on a rotary evaporator yields the desired product in quantitative yield.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N+:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])=[CH:6][CH:5]=1>C(O)(=O)C.[Pd].[C]>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[CH2:18][CH2:17]3)[O:12][C:11]2=[O:31])=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CC(C[n+]3ccc(-c4ccc5c(c4)OCO5)cc3)OC2=O)cc1
Agent: [Pd]
Agent: [Br-]
Solvent: CC(=O)O
Product: COc1ccc(N2CC(CN3CCC(c4ccc5c(c4)OCO5)CC3)OC2=O)cc1

Procedure:
A solution of 4.87 g of 1-(3-p-methoxyphenyloxazolidin-2-one-5-yl-methyl)-4-(3,4-methylenedioxyphenyl)pyridinium bromide [obtainable from 3-p-methoxyphenyl-5-bromomethyloxazolidin-2-one and 4-(3,4-methylenedioxyphenyl)pyridine] in 60 ml of acetic acid is hydrogenated over 1 g of 10% strength Pd/carbon at 20° and atmospheric pressure until the absorption of hydrogen has ceased. After filtration, evaporation and usual workup, 3-p-methoxyphenyl-5-[4-(3,4-methylenedioxyphenyl)piperidinomethyl]oxazolidin-2-one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21].[H][H]>C(O)C.C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21]
Reactant: COC(=O)c1cc(Br)ccc1C=Cc1cccc(OC)c1C
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1CCc1cccc(OC)c1C
Temperature: 38 °C

Procedure:
To 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-vinyl]-benzoic acid methyl ester (5) (4.99 g; 13.8 mmol), stirring in ethyl alcohol (70 mL) and acetic acid (23 mL), was added PtO2 (0.075 g; 2.4%). The solution was stirred in a hydrogen atmosphere (balloon pressure) and the temperature of the solution was raised to 38° C. The reaction was monitored closely by TLC and the mixture was cooled after three hours. The reaction mixture was filtered and evaporated to give compound 6 as a residue. The residue was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C(OCC)(OCC)OCC.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(O)C.N1C=CC=CC=1>[CH:32]([O:14][C:13]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:2]2([CH3:1])[C@H:7]3[CH2:6][CH2:5][C:3]2=[O:4])[CH:12]=1)([CH3:37])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCOC(OCC)OCC
Product: CC(C)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Yield: 1677.5 %

Procedure:
Androstenedione (10 g.) was dissolved in propan-2-ol (500 ml). Triethyl orthoformate (7.15 ml) was added, followed by p-toluenesulphonic acid (250 mg) and the solution refluxed for fifteen minutes. A few drops of pyridine were added and the solution evaporated under reduced pressure to give a pale yellow solid. This was recrystallised from methanol to give 3-iso-propoxy-androsta-3,5-dien-17-one (8.0 g) as white crystals, M.p. 147°-151°. ##STR14##