Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH2:34][C:35](OC)=[O:36]>CN(C)C=O>[F:33][CH2:34][C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: COC(=O)CF
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CF)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
A solution of 100 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.3 ml of N,N-dimethylformamide is treated successively with 100 μl (0.6 mmol) of N-ethyl-diisopropylamine and 55 μl (0.6 mmol) of methyl fluoroacetate. The resulting beige suspension is heated to 50° C. for 18 hours. For the working-up, the reaction mixture is evaporated, thereafter, the residue is dissolved in dichloromethane and the solution washed with 1 ml of hydrochloric acid (1N). The organic layer is separated, dried over sodium sulfate, and evaporated. For purification, the crude product is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 30 mg (28% of theory) of (S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=378 (M+NH4)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][O:12][CH2:11]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: Ic1ccncc1NCC1CCCOC1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ccncc1NCC1CCCOC1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((tetrahydro-2H-pyran-3-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 5 hours at reflux. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) followed by EtOAc:MeOH (100:0 to 90:10). Yellow oil (106%). MS (ESI): m/z=317.166 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]34[O:46][CH:23]3[CH2:22][CH2:21][CH2:20][C@H:19]4[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(C[C@@H]2CCCC3OC32c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 48.4 %

Procedure:
A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (800 mg) and m-chloroperbenzoic acid (600 mg) in dichloromethane (20 ml) was stirred for 2 hours at room temperature. The mixture was diluted with EtOAc and washed with water and brine. Then, it was dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl {3-{[(1S)-2-(4,5-diphenyloxazol-2-yl) -2,3-epoxy-1-cyclohexyl]methyl}phenoxy}-acetate (400 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([Cl:11])[CH:20]=[C:19]([Cl:21])[CH:18]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 83.9 %

Procedure:
Reaction of 4-aminoacetophenone (76 mg, 0.56 mmol) in THF (6 mL) with 3,5-dichlorobenzoyl chloride (145 mg, 0.69 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-3,5-dichloro-benzamide (145 mg, 0.47 mmol, 84% yield) as a white powder after washing by dichloromethane.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[C:28]([C:32]([O:34][CH3:35])=[O:33])[NH:29]2)=[CH:25][CH:24]=1)=[O:22])[CH2:11][O:12][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[C:28]([C:32]([O:34][CH3:35])=[O:33])[NH:29]2)=[CH:25][CH:24]=1)=[O:22])[CH2:11][OH:12]
Reactant: COC(=O)c1cc2ccc(C(=O)NC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)cc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(C(=O)NC(CO)CO)cc2[nH]1
Yield: 73 %

Procedure:
A solution of N-[1,3-bis(t-butyldimethylsilyloxy)-2-propyl]-2-(methoxycarbonyl)indole-6-carboxamide (744 mg, 1.43 mmol) and tetrabutylammonium fluoride (2.9 mL of a 1M solution in THF, 2.9 mmol) in THF (20 mL) was stirred at 20° C. for 80 min and evaporated. The residue was crystallised from MeOH (10 mL) giving N-(1,3-dihydroxy-2-propyl)-2-(methoxycarbonyl)indole-6-carboxamide as a white solid (305 mg, 73%), mp 205-207° C. Dry column chromatography of the mother liquor (eluting with 20:1 EtOAc:MeOH) gave a second crop (57 mg, 14%). 1H NMR [(CD3)2SO] δ12.22 (s, 1H, indole NH), 7.97 (s, 1H, H-3 or H-7), 7.94 (d, J=8.0 Hz, 1H, amide NH), 7.70 (d, J=8.5 Hz, 1H, H-4), 7.59 (dd, J=8.5, 1.3 Hz, 1H, H-5), 7.20 (d, J=1.6 Hz, 1H, H-3 or H-7), 4.66 (t, J=5.7 Hz, 2H, OH), 4.03-3.95 (m, 1H, CONHCH), 3.90 (s, 3H, CO2Me), 3.54 (t, J=5.8 Hz, 4H, CH2OH). Anal. (C14H16N2O5) C,H,N.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-:28].[Na+]>C1COCC1.CO>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: [OH-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
A solution of the fluorobenzoate (46, 27 mg, 0.051 mmol) in THF (2 mL) and MeOH (2 mL) was treated with 1M NaOH (0.2 mL, 0.2 mmol) and allowed to stand at ambient temperature for 7 h. After the solvent was evaporated, the residue was treated with CHCl3 (40 mL) and 10% Na2CO3 solution (30 mL); we then separated the layers, dried the organic layer over MgSO4, and filtered and evaporated it under reduced pressure. Purified on 2 g of Merck grade 60 flash silica gel using MeOH/CHCl3 (5:95) afforded 13 mg (60%) of 25-fluoro-3β-ol (47), mp 196°-198° C. EIMS (m/z): 428 (M+H), 413 (M-M3). 1H NMR: δ3.70 (m, 1H), 1.49 (s, 3H), 1.27 (s, 3H), 1.09 (s, 3H), 1.02 (d, 3H, J=6.4 Hz), 0.81 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:25][N:23]([CH3:24])[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:22]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (2S)-2-amino-N,N,4-trimethyl-pentanamide hydrochloride (1:1) (CAN 207595-81-1) as starting materials, and isolated (68 mg, 85%) as yellow solid; LC-MS (UV peak area, ESI) 100%, 375.2387 (M+H).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[C:25]([C:32](Cl)=[O:33])[CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1.Cl>O1CCOCC1>[CH3:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[C:25]([C:32]([NH:19][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([N:8]4[CH2:9][CH2:10][CH2:11][CH2:12]4)[N:18]=3)=[O:33])[CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:42])[F:44])[CH:36]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Cl)cccc2c1=O
Reactant: Nc1cccc(N2CCCC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Nc3cccc(N4CCCC4)n3)cccc2c1=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
Triethylamine (100 μL) and 6-pyrollidin-1-ylpyridin-2-amine 35 (0.136 mmol) was added to a solution of 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazoline-8-carbonyl chloride 34 (50 mg, 0.136 mmol) in dioxane (1 mL). The reaction was stirred at 70° C. for 2 d, after which 1N HCl (4 mL) was added. The resulting precipitate was collected by filtration, rinsed with 5 mL H2O, 5 mL pentane, and dried under vacuum to give Compound 350 (40 mg, 56% yield). MS (ESI) calc. for C26H22F3N5O2: 493.17. found: 494 [M+H].
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1ccoc1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccoc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-furaldehyde (0.5 g, 5.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.103 g, 87%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:44]I.O>CN(C=O)C>[F:41][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:31][CH2:32]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:44])[N:12]=1
Reactant: CI
Reactant: FC(F)(F)c1cc(CN(Cc2cnc3ccccc3c2N(CC2CC2)CC2CC2)c2nn[nH]n2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cnc3ccccc3c2N(CC2CC2)CC2CC2)n1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-quinolin-4-yl)-bis-cyclopropylmethyl-amine (300 mg, 0.52 mmol) and sodium hydride (31 mg, 0.78 mmol) were taken in DMF (10 mL) at 0° C. and stirred for 20 min, then methyl iodide (0.067 mL, 1.04 mmol) was added at that temperature and stirred for 1 h. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL×3) and the organic layer was washed with water (75 mL). Drying over sodium sulfate and concentration under vacuum yielded the crude product that was purified by column chromatography using 230-400 mesh silica gel eluting with 5% ethyl acetate in petroleum ether to afford 0.107 gm (yield: 35%) of yellow colored gummy mass.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]=O.[BH4-].[Na+]>CO>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][CH2:14][C:10]1[N:9]([CH3:8])[CH:13]=[CH:12][N:11]=1
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ccnc1CNCCC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,3-dimethylbutylamine (2.81 g, 27.8 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (3.21 g, 29.1 mmol) in methanol (30 mL) at room temperature, sodium borohydride (1.05 g, 27.8 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated, and hydrochloric acid (6 N, 5 mL) was then added. The resulting solution washed with diethyl ether once. The aqueous phase was made basic by adding sodium hydroxide solution (3 N). The resulting solution was extracted with chloroform three times. The combined chloroform extracts were washed with brine and dried over magnesium sulfate. The solution was filtered and concentrated to yield (3,3-dimethyl-butyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amine as a colorless oil.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:20]=[CH:21][C:22]([NH:24][NH2:25])=[O:23])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:31][C:30]([C:27]1[CH:26]=[C:19]([CH:20]=[CH:21][C:22]2[O:23][C:1](=[O:2])[NH:25][N:24]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:28]=1[OH:29])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
Carbonyl diimidazole (0.7 g, 0.004 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-cinnamic acid hydrazide (1.0 g, 0.003 mole) and triethylamine (0.4 g, 0.004 mole) in tetrahydrofuran (12 ml). The mixture is stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stir 45 minutes. The solution is concentrated and the residue dissolved in ether (50 ml) and washed with aqueous 2M HCl. The product is extracted from the organic layer by treatment with aqueous 1M NaOH (20 ml). The aqueous extract is made acidic by treatment with cold aqueous 2M HCl and the product is extracted with ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 1.0 g (1.1 g theor., 94%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-one, mp >260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BrH:16].S(=O)(=O)(O)O.O>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][Br:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O
Product: Clc1ccc([C@H]2CC[C@H](CBr)CC2)cc1

Procedure:
To a stirred suspension of trans-(4-(4-chlorophenyl)cyclohexane)carboxylic acid (47.74 g) in dry ether (250 ml), under nitrogen, was added dropwise borane-methyl sulphide complex (8 ml; ca.10M solution--Aldrich). After 30 min the mixture was heated to reflux and further borane-methyl sulphide complex (16 ml) added. After 1 hr the mixture was cooled to room temperature and poured into methanol (500 ml). The solvent was evaporated in vacuo and the residue treated again with methanol (100 ml) followed by concentration in vacuo, to give trans-(4-(4-chlorophenyl)cyclohexyl) methanol (44 g), m.p. 60°-63°. A portion of this alcohol (41 g) was added to 48% hydrobromic acid (61 g) and conc. sulphuric acid (20 g). The mixture was stirred and heated at 140° for 5.5 hr, cooled and poured into iced water. The precipitate was filtered, dissolved in ether, washed with satd. aq. sodium bicarbonate and brine, dried over magnesium sulphate and the solvent evaporated in vacuo to leave a brown oil. Trituration with cold hexane gave trans-(4-(4-chlorophenyl)cyclohexyl)methyl bromide (44 g), m.p. 36°-38°. To magnesium turnings (33.06 g) in dry ether (70 ml) under nitrogen was added a crystal of iodine followed by a solution of the bromide (19.7 g) in ether (20 ml). The mixture was heated at reflux for a further 30 min, cooled to room temperature and then added dropwise to vigorously stirred acetic anhydride in dry ether (70 ml) at -78°, such that the temperature did not exceed -70°. The mixture was stirred at -78° for a further 1 hr, then allowed to warm to 0° and poured into satd. aq. ammonium chloride (200 ml). The mixture was stirred for 30 min then the organic phase was separated and washed with satd. aq. sodium bicarbonate and brine, dried over magnesium sulphate and concentrated in vacuo, to leave a white solid , which was recrystallised from hexane to afford the title compound (9.3 g), m.p. 58°-60°, NMR δH (CDCl3) 7.3-7.0 (4H, m), 2.55-2.3 (1H, m), 2.4-2.3 (2H, m), 2.15 (3H, s), 2-1.75 (5H, m), 1.6-1.45 (2H, m), 1.25-1.0 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[OH:20].Br[C:22]1C(O)=C(C)C=C2C=1C=CC=N2>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[C:3]([OH:20])=[C:2]([CH3:22])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(Cl)cc2n1
Reactant: Cc1cc2ncccc2c(Br)c1O
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1O

Procedure:
Compound 3E was prepared following the procedure used to prepare compound 1E of Example 1, except that 5-bromo-7-methylquinolin-6-ol (3D) was used instead of compound 1D.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)N=CC)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[OH:25][CH2:26][CH2:27][CH2:28][C:29](=O)[CH3:30]>C(O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]3[C:17]4[C:22](=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:28]([CH2:27][CH2:26][OH:25])=[C:29]3[CH3:30])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)CCCO
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(CCO)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A solution of acetaldehyde N1 -(7-chloroquinazolin-4-yl)p-methoxyphenylhydrazone hydrochloride (3.2g.) and 5-hydroxy-pentane-2-one (1.1g.) in ethanol (60ml.) was refluxed for 18 hours. The mixture was cooled and filtered and the filtrate evaporated in vacuo. The residue was chromatographed on silica gel (100g.) using, as eluant, petroleum ether (b.p. 40° -60° C.) containing an increasing proportion of ether (polarity increased by incremental addition of 10% v/v ether) to give 1-(7-chloroquinazolin-4-yl)-3-(2-hydroxyethyl)-5-methoxy-2-methylindole, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:10][C:8]1[S:9][C:5]2[S:4][CH:3]=[C:2]([Cl:1])[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2c(Cl)csc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1csc2sc(CBr)nc12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 310 mg(1.62 mmol) of 6-chloro-2-methylthieno[3,2-d]thiazole (from Step 2) and 10 mg of benzoyl peroxide in 15 ml of CC14 was added 306 mg(1.72 mmol) of NBS at r.t. The mixture was stirred at 75° C. under radiation from a sunlamp for 30 min. The solid was filtered, the solution was evaporated to dryness and the residue purified on silica gel with hexane/EtOAc=8:1 to give 300 mg (69%) of the title product. 1H NMR (CDCl3) 7.35(s, 1H), 4.80(s,2H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[CH3:32][NH:33][CH:34]1[CH2:36][CH2:35]1.Cl>CN(C=O)C>[F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:33]([CH:34]2[CH2:36][CH2:35]2)[CH3:32])[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CNC1CC1
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N(C)C1CC1
Yield: 14.6 %

Procedure:
To a mixture of 6.0 g (0.017 mol) of product from Example 105, 1.71 g (0.017 mol) of triethylamine in 30 ml of DMF was added 1.76 g (0.025 mol) of N-methylcyclopropylamine at such a rate that the temperature remained below 30° C. After 4 hours the reaction mixture was poured into 3.7% HCl and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 5.8 g of a green oil. The crude product was purified by HPLC in 5% ethyl acetate/cyclohexane, followed by kugelrohr distillation at 67 Pa, oven temperature 150° C., affording 1.02 g (15.5%) of product as a green oil, nD25 1.4758.
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>>[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH:20][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCN)=C(Cc1ccccc1)C2
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)NCCC1=C(Cc2ccccc2)Cc2ccc(OC)cc21

Procedure:
Starting with 2-(2-benzyl-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and butyryl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 97%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]([CH3:25])[C:8](=[O:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([O:22][CH3:23])=[CH:11][CH:10]=2.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[OH:1][CH2:2][CH2:3][S:4]([CH2:5][C:6]1[N:7]([CH3:25])[C:8](=[O:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:13][C:12]([O:22][CH3:23])=[CH:11][CH:10]=2)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(=O)n(C)c(CSCCO)c(-c3ccccc3)c2c1
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(CS(=O)CCO)c(-c3ccccc3)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-{[(2-hydroxyethyl)thio]methyl}-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (31 mg, 0.087 mmol) in 2 mL of dichloromethane was added at 0° C. meta-chloroperbenzoic acid (16 mg, 0.091 mmol). After 15 minutes, the reaction mixture was partitioned between EtOAc and 2M Na2S2O3 solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. 1H-NMR (500 MHz, CDCl3) δ 8.43 (d, J=9.0 Hz, 1H), 7.44-7.55 (m, 3H), 7.33 (br d, J=8 Hz, 2H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 4.28 (d, J=13.9 Hz, 1H), 3.98 (d, J=13.9 Hz, 1H), 3.96-4.04 (m, 2H), 3.84, (s, 3H), 3.68 (s, 3H), 2.85 (m, 1H), 2.70 (m, 1H), ppm. ESI+ MS: 372.19 [M+H]+.