Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:38]1[CH:39]=[N:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C@H:10]([NH:25]C(OCC1C=CC(OC)=CC=1)=O)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl>[NH2:25][C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:38]1[CH:39]=[N:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C#CCC[C@@H](NC(=O)OCc2ccc(OC)cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a stirred solution of the title compound from Step A (83.0 g, 0.13 mol) in dichloromethane (400 mL) was added triethylamine (20 mL) and the resulting mixture was stirred for 3 h. The reaction mixture turned to dark red color. All volatiles were evaporated and the residue was diluted with water and based by NaHCO3. It was then extracted with dichloromethane (3×250 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography with dichloromethane/methanol=20:1 to afford 47.0 g (77%) of the title compound as yellow gum. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H), 4.55 (d, J=4.7 Hz, 1H), 3.93 (s, 3H), 2.96-2.93 (m, 1H), 2.64-2.53 (m, 2H), 1.71-1.68 (m, 1H), 1.52-1.41 (m, 3H), 0.90 (s, 9H), 0.20 (s, 3H), 0.00 (s, 3H). MS: m/z. (EST) 473 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH:21]=O.C(OC(=O)C)(=O)C.[F:30][C:31](Cl)(Cl)[C:32]([O:34][CH3:35])=[O:33]>O1CCCC1.C(OCC)C.[Zn]>[F:30]/[C:31](=[CH:21]\[CH:20]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)/[C:32]([O:34][CH3:35])=[O:33]
Reactant: O=C/C=C/CCCCCCCOc1ccc2ccccc2n1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)/C(F)=C/C=C/CCCCCCCOc1ccc2ccccc2n1
Reaction time: 0.5 h

Procedure:
Activated zinc powder (496 mg), powdered molecular sieve 4A (1.25 g) (ex. BDH) and cuprous chloride (84 mg) were suspended in anhydrous tetrahydrofuran (10 ml). (2E)-10-(2-Quinolinyloxy)dec-2-enal (1 g) was added followed by acetic anhydride (320 μl). The mixture was warmed to 50° under nitrogen and methyl fluorodichloroacetate (328 μl) was added. The mixture was warmed at 50-5° for 4 hours, additional zinc (0.2 g) was added and warming continued for 30 minutes. Upon cooling the reaction mixture was diluted with diethyl ether, filtered through celite and filtrate worked-up in standard fashion. Purification by column chromatography (silica; 4;1, hexane: ether) gave (2Z,4E) methyl 2-fluoro-12-(2-quinolinyloxy)dodeca-2,4-dienoate (0.26 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]CC)[N:27]=1.NC1N=NC=CC=1.C(N(CC)CC)C>C(#N)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[N:27]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: CCOC(=O)Nc1cccnn1
Agent: Cl
Agent: Nc1cccnn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 180 °C

Procedure:
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (500 mg, 1.35 mmol, from Example 1, Step 5), ethyl pyridazin-3-ylcarbamate (248 mg, 1.48 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridazine) and triethylamine (0.376 mL, 2.7 mmol) were combined in acetonitrile (4.5 mL) and heated in a microwave at 180° C. for 40 minutes. The reaction mixture was cooled to rt and concentrated to form a residue. The residue was purified by silica gel chromatography (50-100% EtOAc in CH2Cl2) to provide the title compound (340 mg). MS (APCI 10 V) AP+ 456.2, 376.2, 335.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.54 (dt, J=50.71, 5.84 Hz, 4H) 3.64 (dt, J=36.50, 5.84 Hz, 4H) 6.47 (s, 1H) 6.96-7.07 (m, 2H) 7.08-7.20 (m, 2H) 7.40 (td, J=7.72, 0.52 Hz, 1H) 7.59 (dd, J=9.13, 4.62 Hz, 1H) 8.08 (dd, J=8.67, 2.68 Hz, 1H) 8.13 (d, J=8.92 Hz, 1H) 8.43 (dt, J=1.79, 0.81 Hz, 1H) 8.79 (d, J=4.19 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.[I-].[K+]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(C2OCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: c1cc(OCc2ccc3ccccc3n2)cc(C2OCCO2)c1
Yield: 74 %

Procedure:
A solution of the ketal of Step A, above, (10 g, 0.06 mol), 2-chloromethylquinoline (10.6 g, 0.06 mol), cesium carbonate (20.0 g, 0.06 mol) and potassium iodide (0.16 g, 0.001 mol) in 250 ml acetone is refluxed 20 hours. The solution is filtered through Celite and silica gel and the solvent is removed in vacuo. The resulting crude solid is recrystallized using 2-propanol to give 13.7 g of crystalline solid (74% yield) m.p. 67°-69° C.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][C:18]1([CH3:35])[O:23][C:22]2[C:24]3[C:29]([C:30]([C:32](=[O:33])[C:21]=2[CH2:20][CH:19]1O)=[O:31])=[CH:28][CH:27]=[CH:26][CH:25]=3.C1CCN2C(=NCCC2)CC1.CO>CN(C=O)C.C(Cl)Cl>[NH:1]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][C:18]1([CH3:35])[O:23][C:22]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([C:32](=[O:33])[C:21]=2[CH2:20][CH2:19]1)=[O:31]
Reactant: CC1(C)OC2=C(CC1O)C(=O)C(=O)c1ccccc12
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.820 g (12.20 mmol) of Boc-Leu and 1.976 g (12.19 mmol) of 1,1-carbonyldiimidazole in 33 mL of DMF was stirred at room temperature for 20 min. To the solution was added 2.100 g (8.130 mmol) of 3-hydroxy-β-lapachone followed by 1.6 mL (10.70 mmol) of DBU. After stirring at room temperature for 5 hr, the reaction mixture was partitioned between 200 mL of water and 200 mL of CHCl3. The aqueous phase was washed with CHCl3 (4×50 mL). The CHCl3 extracts were combined, dried with MgSO4, and evaporated to dryness. Column chromatography on silica gel with 2% MeOH in CH2Cl2 afforded 2.038 g (53%) of quinone as an orange glassy solid (and mixture of two diastereomers): Rf=0.45 (5% MeOH in CH2Cl2); 1H NMR (250 MHz, acetone-d6, TMS) δ 8.1-8.0 (m, 1H), 8.0-7.9 (m, 1H), 7.9-7.8 (m, 1H), 7.7-7.6 (m, 1H), 6.34 (br d, NH), 5.2-5.1 (m, 1H), 4.2-4.1 (m, 1H), 2.9-2.8 (m, 1H), 2.7-2.5 (m, 1H), 1.8-1.6 (m, 3H), 1.56 (s, 1.5H), 1.53 (s, 3H), 1.52 (s, 1.5H), 1.34 (s, 4.5H), 1.33 (s, 4.5H), 0.91 (d, J=7.0 Hz, 1.5H), 0.88 (d, J=6.7 Hz, 1.5H), 0.84 (d, J=6.3 Hz, 1.5H), 0.82 (d, J=6.1 Hz, 1.5H).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].N[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2>>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[NH:2][S:1]([C:5]2[CH:6]=[CH:7][C:8]([SH:11]=[O:13])=[CH:9][CH:10]=2)(=[O:3])=[O:4])[CH:21]=[CH:22]1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2cc[nH]c12
Product: O=[SH]c1ccc(S(=O)(=O)Nc2cccc3cc[nH]c23)cc1
Yield: 69.4 %

Procedure:
767 mg (3.0 mmol) of 4-sulfamoylbenzenesulfonyl chloride was reacted with 264 mg (2.0 mmol) of 7-amino-1H-indole and treated, to give 445 mg of N-(1H-indole-7-yl)-4-sulfanoylbenzenesulfonamide. The resulting compound was chlorinated using N-chlorosuccinimide in dichloromethane, to give 349 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16](=[O:22])[NH:17]3)[CH:8]=1.[Cl-].[Cl-].[Ca+2]>O.CO.C1COCC1>[OH:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16](=[O:22])[NH:17]3)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Cc2c(cccc2-c2cccc(CCO)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a suspension of NaBH4 (600 mg, 16 mmol) in 15% H2O/MeOH (6 mL) under nitrogen at rt was added dropwise a solution of [3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid methyl ester (450 mg, 1.6 mmol) in THF (3 mL). After stirring at rt for overnight, to the reaction was added CaCl2 (300 mg) and stirring was continued for another 5 hours. The reaction was quenched with acetic acid (2 mL), concentrated, diluted with ethyl acetate, washed with 0.5 N HCl (3×15 mL), 10% NaHCO3 (3×15 mL), brine (1×), dried and concentrated. The oily residue was purified to give 384 mg (95%) of 4-[3-(2-hydroxy-ethyl)-phenyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9]/[C:10](=[CH:13]\[CH3:14])/[CH:11]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].Cl>C(Cl)Cl>[CH2:1]([NH:8][CH2:9]/[C:10](/[CH3:11])=[CH:13]/[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C/C=C(\C)C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Product: C/C=C(\C)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
Benzylamine (18.66 mmol, 2.041 ml, 2 g) was dissolved in DCM (12.00 ml). (E)-2-methylbut-2-enal (18.66 mmol, 1.803 ml, 1.570 g) and magnesium sulfate (37.3 mmol, 4.49 g) were added and the reaction mixture was stirred at room temperature for 18 hours. The resulting suspension was filtered, washing with MeOH (30 ml). The filtrate was cooled to 0° C. and sodium tetrahydroborate (93 mmol, 3.53 g) was added portionwise and the reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then acidified with 5 N HCl and organic solvents removed in vacuo. The pH was adjusted to 1 using 5 N HCl and the aqueous solution was washed with ether before addition of 4N NaOH to pH 14. The aqueous solution was then extracted with DCM (3×). The combined DCM extracts were dried over MgSO4, filtered and concentrated in vacuo to give (E)-N-benzyl-2-methylbut-2-en-1-amine (990 mg). 1H NMR (400 MHz, CDCl3) ppm 7.36-7.15 (5H, m, 5×ArH), 5.45 (1H, q, J=8 alkenyl CH), 3.73 (2H, s, CH2), 3.16 (2H, s, CH2), 1.66 (3H, s, CH3), 1.62 (3H, d, J=8, CH3).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(OCC)C.C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C=C[C@H](O[Si](C)(C)C(C)(C)C)C1
Yield: 98 %

Procedure:
Dissolve (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (1 g, 4.67 mmol, prepared in example 10) in pyridine (20 mL) and treat with acetic anhydride (2 mL). Stir the reaction overnight. Dilute the reaction with diethyl ether (100 mL), wash with 3M hydrochloric acid (3×100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide the title compound (1 g, 98% yield) Rf =0.5 (5% ethyl acetate/hexane) [α]20D =+1.3°, (c=1.00, chloroform), 1H NMR (CDCl3)δ5.9 (m, 1H), 5.5 (m, 1H), 4.7 (m, 1H), 2.8 (m, 1H), 2.05 (s, 3H), 1.6 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (CDCl3) δ170.8, 138.8, 131.1, 76.9, 74.8, 41.1, 25.8, 21.1, 18.1, -4.7, -4.6; IR (neat) νmax 2955, 2932, 2859, 1739, 1369, 1240, 1105, 1062, 1049 cm-1 ; CIMS m/e (% relative intensity) 256 (M+H+, 7), 197 (M+H+ --AcOH, 100).
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.O1CCCC1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>O.CN(C)C=O>[OH:3][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:23]1[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1OC(Cl)(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(CCN2C(=O)c3ccccc3C2(O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
12.35 parts of 3-chloro-3-phenyl-1-(3H)-isobenzofuranone in solution in 40 parts of anhydrous tetrahydrofuran are added, while stirring, over a period of approximately 15 minutes, to a solution of 10 parts of para-(β-aminoethyl)benzenesulphonamide and 5.06 parts of triethylamine in 80 parts of anhydrous dimethylformamide. The temperature rises from 25° to 50° C. and after being stirred for 2 hours the reaction mixture is diluted in 400 parts of water. The precipitate formed is suction-filtered and dried in air and then recrystallized in 360 parts of isopropanol. 12 parts of para-[β-(2,3-dihydro-3-hydroxy-3-phenyl-(1H)-isoindol-1-on-2-yl)ethyl]benzenesulphonamide are obtained melting at 225° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH2:17][S:16][C:15](=[O:18])[NH:14][N:13]=3)=[CH:11][C:6]=2[N:5]=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:2].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH2:17][S:16][C:15](=[O:18])[N:14]([CH2:28][CH2:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[N:13]=3)=[CH:11][C:6]=2[N:5]=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:2]
Reactant: CCn1c(-c2cccc(OC)c2)nc2cc(C3=NNC(=O)SC3)ccc21
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2cccc(OC)c2)nc2cc(C3=NN(CCOC4CCCCO4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To 200 mg (0.55 mM) of 5-[1-ethyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 4 ml of dimethylformamide are added 91 μl (0.6 mM) of 2-(2-bromoethoxy)tetrahydro-2H-pyran and 533.5 mg (1.64 mM) of caesium carbonate. The reaction medium is then stirred at room temperature for 16 hours. Demineralised water is added and the organic phase is isolated, washed with demineralised water and then dried over anhydrous sodium sulfate. The solvent is then evaporated off under vacuum and the residue is purified by chromatography on silica, using a dichloromethane/acetone mixture (90/10) as eluent, to give 200 mg of 5-[1-ethyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of an oil.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].[CH2:22]([O:24][CH:25]([O:47][CH2:48][CH3:49])[CH2:26][C:27](=[O:46])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH3:23].Cl>O1CCCC1>[CH2:48]([O:47][CH:25]([O:24][CH2:22][CH3:23])[CH2:26][C:27]([OH:46])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:17][C:16]([O:19][CH2:20][CH3:21])=[O:18])[CH3:49]
Reactant: CCCCCC=CCC=CCCCCCCCCC(=O)CC(OCC)OCC
Reactant: CCOC(C)=O
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC=CCC=CCCCCCCCCC(O)(CC(=O)OCC)CC(OCC)OCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Isopropyl cyclohexylamine (565 mg, 4 mmole) in 10 ml of anhydrous tetrahydrofuran was cooled to -78° C. in a 3 neck round bottom flask and n-butyl lithium (2 ml, 4 mmole) was added dropwise. After 10 minutes, ethyl acetate (300 mg, 4 mmole) in 5 ml of tetrahydrofuran was added dropwise over a 15 minute period and the reaction mixture was stirred for 30 minutes at -78° C. following the addition. 1,1-Diethoxy-12,15-heneicosadiene-3-one (1.5 g) in 5 ml of tetrahydrofuran was added within 1 minute and the mixture was maintained at -78° C. for another 30 minutes. 5% Aqueous hydrochloric acid (5 ml) was added and the mixture was warmed to room temperature. Solvent was removed in vacuo and 40 ml of pentane was added. The organic layer was washed until neutral and was dried, worked up to provide 1.0 g of crude reaction mixture. After purification from column chromatography, the desired product was obtained as heavy oil (1.4 g) of formula XI of Chart B.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21][OH:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21][OH:22]
Reactant: OCc1ccncc1Br
Reactant: Cn1c(B(O)O)cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cnccc2CO)cc2ccccc21
Temperature: 120 °C

Procedure:
A microwave reactor is charged with 1-methyl-indole-2-boronic acid (1.18 g, 6.78 mmol), (3-bromo-pyridin-4-yl)-methanol (0.850 g, 4.52 mmol), potassium phosphate (1.91 g, 9.04 mmol) and DMF (10 mL). The reactor is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.261 g, 0.226 mmol) is added. The reactor is evacuated and filled with nitrogen thrice again. The mixture is heated to 120° C. for 1 h under microwave irradiation, then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford [3-(1-methyl-1H-indol-2-yl)-pyridin-4-yl]-methanol as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 3.58 (s, 3H), 4.57 (s, 2H), 6.54 (s, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.27 (ddd, J=7.6, 1.1 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.67 (d, J=5.1 Hz, 1H). HRMS (ESI) m/z 239.1177 [(M+H)+Calcd for C15H15N2O: 239.1184].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:25])([F:24])[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].CC(C)([O-])C.Br[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46].[I-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:37]1(=[O:46])[N:36]([CH2:35][CH2:34][CH2:33][N:13]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][C:11]([F:25])([F:24])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1ccc(S(=O)(=O)NCC(F)(F)CCOCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-benzyloxy-2,2-difluorobutyl)-p-toluenesulfonamide (7.0 g, 19 mM) in dry DMF (20 mL), is added potassium-tert.-butoxide (2.34 g, 21 mmoles), and the mixture is stirred for 30 minutes. To this mixture are added N-3-bromopropyl-phthalimide (5.1 g, 19 mmoles) and sodium iodide (0.33 g), and the entire mixture is then stirred overnight under nitrogen at room temperature. Following the addition of brine, the mixture is extracted with ether, washed with 1N HCl (twice), then with brine (twice), and dried over Na2SO4. Evaporation of the solvent yields 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-benzyloxy-4-aza-octane as an oil, which crystallizes on scratching with ether/petroleum ether to form white crystals: 9.5 g (90%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CN(P(N(C)C)(N(C)C)=O)C.CI.Cl>C1COCC1.[Cl-].[NH4+]>[CH:13]1([CH2:19][CH:20]([CH3:1])[C:21]([OH:23])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)CCC1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(CC1CCCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
To a solution of diisopropylamine (19.74 ml, 140.8 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.44N, 97.8 ml, 140.8 mmol) at 0° C. under argon atmosphere. The mixture was stirred at 0° C. for 1 hour and a half, and then 3-cyclohexylpropionic acid (10.00 g, 64.0 mmol) was added dropwise. After the mixture was stirred at 0° C. for 10 minutes, HMPA (24.5 ml, 140.8 mmol) was added dropwise and the mixture was stirred for 20 minutes. Methyl iodide (8.4 ml, 134.4 mmol) was further added dropwise at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with an aqueous saturated solution of ammonium chloride, and acidified to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (50 ml×4), and then, the combined ethyl acetate layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give a crude product of 3-cyclohexyl-2-methylpropionic acid (b.p. 90.5°-101° C./0.2 mmHg, 11.8556 g). To a solution of this crude product in 100 ml of ether was added dropwise 110 ml of a solution of diazomethane in ether at 0° C. After concentration, the residue was separated and purified through column chromatography (silica gel, ether), to give a pure product of methyl 3-cyclohexyl-2-methylpropionate (10.8672 g, 59.0 mmol, 92.2%). This compound was assigned the structure by the following data:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: 1H NMR (300 MHz, CD3OD) δ 7.73 (d, J=9.0 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.25 (dd, J=9.0 Hz, 2.5 Hz, 1H), 6.80 (app. s, 4H), 4.42 (q, J=8.9 Hz, 2H), 4.17 (t, J=5.1 Hz, 2H), 4.00 (t, J=5.1 Hz, 2H), 3.51 (s, 3H); MS (APCI) m/z 419 (M+1).