Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH3:3][N:4]([CH3:18])[CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:19]1([S:25]([N:9]2[C:8]3[CH2:7][CH2:6][CH:5]([N:4]([CH3:18])[CH3:3])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C1CCc2c(c3ccccc3n2S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Taken potassium hydride 153.80 mg, 1.15 mM (30% suspension in mineral oil) in tetrahydrofuran (15 ml) and stirred at 25° C. for 10 mt. The reaction mixture was cooled to 10-15° C. Dimethyl-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)amine (190 mg, 0.88 mM), dissolved in 5 ml of THF, was added slowly under stirring maintaining mass temperature below 25° C. The reaction mass was further stirred for 1 hour at 25° C. Then added a solution of Benzene sulphonyl chloride (235 mg, 1.33 mM, dissolved in 5 ml of THF) drop wise over a period of 15 mts. The reaction mass was stirred, while monitoring the progress of the reaction by TLC, for 2 hours at 25° C. After the completion of reaction, the mixture was diluted with 75 mL of ice water and extracted with ethyl acetate; Organic layer was washed with brine solution. The ethyl acetate extract was dried over anhydrous sodium sulfate; filtered and solvent was removed under reduced pressure to obtain the exude product. The residual mass was purified by flash chromatography (silica gel, EtoAc/n-Hexane, 9/1) to get the title compound, which was characterized by IR, NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([N:47]3[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]3)=[O:22])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(O)CC3)(CC1)CC2
Yield: 82.9 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-hydroxypiperidine (11.7 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-hydroxypiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (39.0 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][C:4]=2[O:3]1.Br[C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=1[CH2:41][CH3:42]>O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[C:8]([C:16]3[C:21](=[O:22])[N:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:28][CH:29]=4)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=3[CH2:41][CH3:42])[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A mixture of (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.33 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g) and 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) was stirred overnight at 100° C. under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH2:27])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].[CH2:29]=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([CH2:7][O:8][CH3:9])[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[NH:12][C:11]=2[CH2:29][NH:27]1)=[O:28])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(Cc3ccccc3Cl)c12
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCc2[nH]c3cccc(Cc4ccccc4Cl)c3c2C1COC
Yield: 18.6 %

Procedure:
5.2 g (0.013 mol) of 2-amino-3-[4-(2-chlorobenzyl)-indol-3-yl]-4-methoxybutyric acid ethyl ester is refluxed for one hour with 0.44 g of paraformaldehyde in 500 ml of toluene under argon on a water separator. Then it is filtered off from a turbidity. The evaporation residue is chromatographed on silica gel with equal parts of acetone and dichloromethane and yields 1 g (19% of theory) of 1,2,3,4-tetrahydro-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27](O)=[O:28])=[CH:15][C:14]=1[O:30][CH3:31].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])=[O:28])=[CH:15][C:14]=1[O:30][CH3:31]
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)O)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(C)c3c2)ccc1Cl
Temperature: 30 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
3-Methyl-1H-indazol-5-amine (87 mg, 0.592 mmol, 1.0 equiv) was combined with the product of Example 93, Step 4 (175 mg, 0.592 mmol, 1.0 equiv), EDC (134 mg, 0.710 mmol, 1.2 equiv) and Et3N (99 μL, 0.710 mmol, 1.2 equiv) in DMF (1.75 mL) and stirred at 30° C. for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. Solid precipitated out of the organic phase and was filtered and triturated with ether to provide 155 mg (62%) of the title compound as a white solid. MS (ES+) m/e 425 [M+H]+
Reaction SMILES: Cl.[NH2:2]O.[C:4]1([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO.[Ni]>[C:4]1([CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[NH2:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CCc1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: NC(CCc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
Hydroxylamine hydrochloride (2.1 g, 0.03 mol) was added to a solution of 3-phenyl-1-[4-(trifluoromethyl)phenyl]propan-1-one (Journal of the American Chemical Society 1994, 116(6), 2312-17, 2.8 g, 0.01 mol) in EtOH (30 ml). The solution was heated to reflux temperature for 18 hours. After cooling to RT, the solvent was evaporated under reduced pressure and the residue diluted with EtOAc (30 ml). The organic phase washed with water (3×20 ml), dried over Na2SO4 and concentrated. The crude reaction was then dissolved in EtOH (20 ml) and Raney Nickel (5 spoons) added. The reaction mixture was stirred for 2 days under a balloon of nitrogen and then filtered through a pad of celite. The filtrate was concentrated and purified by chromatography on silica gel eluting with 50% AcOEt/Hexane to afford the title compound (0.8 g, 28%); 1H NMR δ (ppm)(CDCl3, 360 MHz): 7.64 (2 H, d, J=7.7 Hz), 7.47 (2 H, d, J=7.7 Hz), 7.32 (2 H, m), 7.22-7.19 (3 H, m), 4.00 (1 H, t, J=6.7 Hz), 2.73-2.57 (2 H, m), 2.07-2.00 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[I:15]I>CO.FC(F)(F)C([O-])=O.[Ag+]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[I:15]
Reactant: COC(=O)C(C)(C)c1ccc(N)nc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)C(C)(C)c1cnc(N)c(I)c1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (10.0 g, 51.5 mmol) in MeOH (50 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred suspension of iodine (17.0 g, 67.0 mmol) and silver trifluoroacetate (14.8 g, 67.0 mmol) in MeOH (200 mL) at room temperature. After 3 h, the reaction was quenched sequentially with 1M Na2S2O3 followed by saturated aqueous NaHCO3. The resulting mixture was filtered through celite® washing copiously with ethyl acetate, the filtrate concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution; 35-40% ethyl acetate/hexanes as eluent) to give the title compound as an off-white solid (10.3 g, 62%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C.CCOC(C)=O.O>[F:28][CH:27]([F:29])[O:26][C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])[CH2:17][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([O:14][CH3:15])=[O:13])=[CH:25][CH:24]=1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(OC(F)F)cc1
Reaction time: 18 h
Yield: 38 %

Procedure:
Potassium tert-butoxide (430 mg, 3.82 mmol) was added to a solution of methyl 1H-pyrrole-2-carboxylate (435 mg, 3.48 mmol), and 2-bromo-1-[4-(difluoromethoxy)phenyl]ethanone (1.01 g, 3.82 mmol) in DMF (7.5 mL) at 0° C., the resulting red suspension was stirred from 0° C. to room temperature for 18 h. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layers were then separated and washed with further water (10 mL), dried (MgSO4) filtered and concentrated in vacuo to give an orange residue. The residue was purified by flash column chromatography (Biotage SP4, 40 g cartridge, 10%-20% EtOAc gradient in n-hexanes) to give methyl 1-{2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}-1H-pyrrole-2-carboxylate as a yellow gum, (417 mg, yield 38%). 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 5.69 (s, 2H), 6.23 (dd, 1H, J 4.0, 2.6 Hz), 6.60 (t, 1H, J 73.0 Hz), 6.82 (dd, 1H, J 2.5, 1.9 Hz), 7.03 (dd, 1H, J 4.0, 1.8 Hz), 7.19 (d, 2H, J 8.8 Hz), 7.97-8.03 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[CH2:16]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)[CH3:17]
Reactant: CCI
Reactant: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(C)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 3-methyl-5-nitro-1H-indazole (1.50 g, 8.44 mmol, commercially available) in dry DMF (30 mL) under Argon was added NaH (0.43 g, 17.79 mmol) portionwise at 0° C. After 30 min, ethyl iodide (1.98 g, 1.03 mL, 12.7 mmol) was added and the mixture stirred at ambient temperature for 1 h then quenched by the addition of H2O (2 mL), concentrated and redissolved in EtOAc (30 mL) then washed with H2O (3×15 mL). The combined aqueous layers were extracted with EtOAc (3×15 mL) and the combined organic layers dried over Na2SO4, filtered and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) afforded the title compound (1.17 g, 67%) as a yellow solid. MS m/e: 206.0 [M+H]−.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[C:28]([CH:38]=1)[CH2:29][NH:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.[C:44]([O:48][C:49]([N:51]1[CH2:54][CH2:53][C:52]1([CH3:58])[C:55](O)=[O:56])=[O:50])([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[C:28]([CH:38]=1)[CH2:29][NH:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:55]([C:52]1([CH3:58])[CH2:53][CH2:54][N:51]1[C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])=[O:56]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC1(C)C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC1(C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
EDC (0.104 g, 0.54 mmol), HOAt (24.6 mg, 0.18 mmol), NMM (0.079 mL, 0.72 mmol), and N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide hydrochloride (Example 26, Step B, 0.143 g, 0.42 mmol) were added to a stirred solution of racemic 1-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid (0.143 g, 0.36 mmol in DMF (1.1 mL). After 3 h at room temperature the reaction was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The two diastereomers were separated and purified by reverse phase HPLC. The more polar diastereomer was concentrated in vacuo. N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-1-[(1-tert-butoxycarbonyl-2-methylazetidin-2-yl)carbonyl]-L-prolinamide (diastereomer A) was obtained as a glass. MS m/z=404.6).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH3:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)[CH3:15]>C(N(CC)CC)C.[Cu]I.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>[CH3:13][O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:21]3[CH:22]=[CH:23][C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])=[CH:19][CH:20]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]1[O:17][C@H:16]1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CS(C)=[O:26]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][C@@H:9]([OH:26])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[CH:15]\[C@@H:16]([OH:17])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CS(C)=O
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(=O)O
Product: CCCCC/C=C\C[C@@H](O)/C=C/C=C/C=C\[C@@H](O)CCCC(=O)O
Reaction time: 0.03 h

Procedure:
Immediately before the assay, LTA4 was diluted to a concentration of 10 μM in assay buffer (without DMSO) and added to the reaction mixture to a final concentration of 2 μM to initiate the enzyme reaction. After incubation for 120 sec at room temperature, the reaction was stopped by adding 2 volumes of chilled quenching buffer, containing acetonitril with 1% acetic acid and 225 nM LTB4-d4 (Biomol). The samples were then kept at 4° C. overnight to complete protein precipitation and centrifuged for 15 min at 1800 g. LTB4 formed was measured by LC-MS/MS using LTB4-d4 as an internal standard and an external LTB4 standard (Biomol) as reference. Based on the amounts of LTB4 found at each inhibitor concentration, a dose-response curve was fitted to the data and an IC50 value was calculated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C[O-].[Na+]>>[C:16]1([C:14]2([OH:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]3[CH2:2][CH2:3][CH2:4][N:5]=[C:6]23)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1(c2ccccc2)C(NCCCCl)=Nc2ccccc21
Agent: C[O-]
Agent: [Na+]
Product: OC1(c2ccccc2)C2=NCCCN2c2ccccc21

Procedure:
Cyclisation of 2-(3-chloropropylamino)-3-phenyl-3H-indol-3-ol with sodium methoxide by a process analogous to that described in Example 3 gives 2,3,4,10-tetrahydro-10-phenylpyrimido[1,2-a]indol-10-ol.
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8]>CCCCCCC>[CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8]
Reactant: CC/C=C\CCCC=O
Solvent: CCCCCCC
Product: CC/C=C\CCCCO
Temperature: 80 °C

Procedure:
(Z)-oct-5-enal (63 g, 0.5 mol.), heptane (63 g, 100 wt. %, technical grade), and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium[bis((adamantane-1-carboxylate)] (45.9 mg, 0.05 mmol, 0.01 mol.%) were loaded altogether in a 300 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 20 bars hydrogen. It was then heated to 80° C. and hydrogen pressure was maintained to 20 bars during all the reaction to afford desired product with 95% selectivity. After complete reaction conversion (checked by both hydrogen consumption and GC), autoclave was cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After initial flash distillation and further fractional distillation, (Z)-oct-5-en-1-ol was obtained in 90% yield.
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH2:19]Cl)[CH3:14].Cl>CN(C)C=O>[C:8]([C:2]([Cl:1])([CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH3:26])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:9])[CH3:10]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCOc1ccc(CCl)cc1OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)(Cc1ccc(OCC)c(OCC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
In 100 ml of dry dimethylformamide is dissolved 9.6 g of ethyl 2-chloroacetoacetate, and under ice cooling, 2.32 g of 60% sodium hydride in oil is added. The mixture is stirred at room temperature for 30 minutes. To this mixture are added 12.5 g of 3,4-diethoxybenzyl chloride and 30 ml of dry dimethylformamide, and the mixture is stirred at 70° C. for 2 hours. The mixture is then poured into a mixture of 200 g ice and 50 ml 6N-HCl and extracted with ether. The ethereal layer is washed with water, dried over MgSO4 and distilled to remove the ether. Column chromatography is carried out on the oily residue with 200 g of silica gel, elution being carried out with a 1:4 mixture of ether and n-hexane. The above procedure provides 14.2 g (71.4%) of ethyl 2-acetyl-2-chloro-3-(3,4-diethoxyphenyl)propionate as oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>[Cl-].[Zn+2].[Cl-].C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:16])([F:17])[CH2:3][N:4]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:7][C:5]1=[O:6]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(N(CC(F)(F)F)C(N)=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=O)N2CC(F)(F)F
Yield: 62 %

Procedure:
A mixture of 3.23 g (0.013 mole) of N-(2,2,2-trifluoroethyl)-N-(p-methoxyphenyl)urea, 1.6 g (0.015 mole) of benzaldehyde, 5.3 g (0.039 mole) of anhydrous zinc chloride, and 65 ml of xylene was stirred for a while and then heated under reflux for 15 hours, removing the water formed azeotropically. Thereafter, 20 ml of 1N-hydrochloric acid was added to the reaction mixture and the mixture was stirred for a while. The organic layer was separated from the reaction mixture, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was treated with isopropyl alcohol to give 2.71 g (62%) of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 168°-169° C.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:25](OCC)[O:26]CC)=[C:11]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C(OCC)(=O)C.CC(O)C>O1CCCC1>[N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:25]=[O:26])=[C:11]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12
Yield: 7.1 %

Procedure:
To a solution of diethyl 4-(4-benzofurazanyl)-2-(diethoxymethyl)-1,4-dihydro-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (7.6 g, 14.5 mmoles) in tetrahydrofuran (100 ml) was added 25% aqueous hydrochloric acid solution (100 ml) and the resulting solution heated at reflux. After 1.5 hours the cooled solution was poured into ethyl acetate (200 ml). The organic phase was separated and washed with water, saturated aqueous sodium bicarbonate solution, brine and dried (MgSO4). Evaporation of the solvent left an oil (7.5 g) which was purified by chromatography on silica (300 g) using ether-petroleum ether (60°-80°) as eluent. The major component was obtained as an oil which gave a solid on trituration with 2-propanol. Recrystallisation from 2-propanol gave the title compound (0.45 g) as yellow crystals mp 94°-5°.