Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]=[CH:19][C:18]3=O)=[O:13])=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]([OH:21])=[C:17]([C:18]3[N:2]([CH3:1])[N:3]=[CH:20][CH:19]=3)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1ccc2occc(=O)c2c1
Reactant: CNN
Solvent: c1ccncc1
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a cooled and stirred solution of methyl hydrazine (1.46 g, 31.6 mmol) in pyridine was added slurry of 1-(4-Chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea (2.5 g, 7.9 mmol) in pyridine over a period of 10 mins. The reaction mixture was left at this temperature for another 2 hrs and then warmed to room temperature slowly. After 6 hrs the reaction mixture turned clear. The reaction was stirred at this temperature for 18 hrs and pyridine was evaporated. The dark colored residue was dissolved in DMSO and purified using Varian Prep. HPLC system. (The two regioisomers were separated. The fractions containing Compound 119 were dried in vacuo to produce a colorless powder (1.78 g, 47%) 1-(4-Chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea. LCMS m/z (%)=343 (M+H, 35Cl 100), 345 (M+H, 37Cl, 32.5). 1H NMR (400 MHz, DMSO-d6) δ: 9.59 (bs, 1H), 8.72 (bs, 1H), 8.48 (bs, 1H), 7.43-7.46 (dd, J=6.8, 2.07 Hz, 2H), 7.41 (d, J=1.83 Hz, 1H), 7.28-7.30 (dd, J=7.13, 2.09 Hz, 2H), 7.26 (d, J=2.72 Hz, 1H), 6.88-6.90 (d, J=9.36 Hz, 1H), 6.21 (d, J=1.84 Hz, 1H), 3.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][C:10]([C:20]2[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:12]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:48]OS(O)(=O)=O>O1CCCC1.C(OCC)(=O)C.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[S:9][C:10]=2[C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:48])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(F)cc2)cc1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of the methyl sulfone (Example 16) (0.21 g, 0.47 mmol) in tetrahydrofuran (THF) (5 mL) at 0° C. under nitrogen was added 2M n-butyl magnesium chloride in THF (1.0 mL, 2.0 mmol) slowly, via syringe, and the mixture stirred at 0° C. for 30 minutes and then at room temperature (25° C.) for 2 hours. After cooling to 0° C., a 1.0M solution of triethyl borane in THF (2.5 mL, 2.5 mmol) was added and the mixture warmed to room temperature and stirred for 2 hours, and then heated to reflux overnight (18 hours). After cooling to room temperature and stirring for 3 hours, water (3 mL) was added followed by sodium acetate (1.2 g) and hydroxylamine-O-sulfonic acid (0.82 g). After stirring at room temperature overnight, the mixture was poured into 3 volumes of ethyl acetate, and the organic layer washed with water and brine and dried over MgSO4. After solvent removal, the white solids (a mixture of product and starting material) was recrystalized from ethyl acetate/hexane to provide 0.11 g of a white solid. Anal. Calc'd for C21H14N2O2S2FCl: C, 56.69; H, 3.17; N, 6.30. Found: C, 55.99; H, 2.97; N, 6.15.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[F:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1ccccc1-c1cc(F)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(F)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.075 g, 37%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.27 g, 0.6 mmol) and methylamine (0.198 g, 6.0 mmol). mp 175-176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 42.1 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249a) (0.212 g, 1.18 mmol), Cs2CO3 (0.578 g, 1.77 mmol) and 3-chloro-1-iodopropane (0.265 g, 1.3 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-2) gave the title compound (81MF2249b) (0.127 g, 42%). 1H NMR (CDCl3) d 6.88 (d, J=8.8 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.50 (s, 2H), 4.05-4.01 (m, 2H), 3.76 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 2.16-2.09 (m, 2H); 13C NMR (CDCl3) d 164.8, 155.5, 139.3, 129.2, 117.4, 107.8, 101.9, 67.8, 55.8, 42.4, 38.9, 30.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20](CC2C=CC(Cl)=CC=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl}glycyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.3 g, 11.4 mmol), Pd(OH)2 (1.68 g), HCO2H (3.7 mL), and methanol (80 mL) was stirred at 50° C. overnight. After the mixture was cooled to room temperature, the Pd catalyst was filtered off through Celite and the filtrate was concentrated. Column chromatography (SiO2, AcOEt, AcOEt/MeOH=5/1-4/1) gave (R)-3-[{N-2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl}glycyl]aminolpyrrolidine (4.42 g, 90%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ1.48 (s, 9 H), 2.0-2.4 (m, 2 H), 3.42-3.71 (m, 5 H), 4.00-4.22 (m, 2 H), 4.56 (br, 1 H), 7.48 (d, J=9.0 Hz, 1 H), 7.93 (s, 1 H), 8.17 (br, 1 H), 8.33 (d, J=9.0 Hz, 1 H), 8.45 (br, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=O)(C)(C)C.[Cl:17][CH:18]([CH:22](OCC)OCC)[C:19](=O)[CH3:20]>CC(O)=O>[Cl:17][C:18]1[C:19]([CH3:20])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[CH2:9][NH:8][CH2:15][C:14]3=2)[CH:22]=1
Reactant: CCOC(OCC)C(Cl)C(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2cc1Cl)CNC3
Yield: 31.5 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (5.8 g; 25.9 mmol; 1 eq.) and 3-chloro-4,4-diethoxy-butan-2-one (5.6 g; 25.9 mmol; 1 eq.) in AcOH (26 mL) was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was poured onto sat. aq. NaHCO3 and the formed precipitate was filtered off and dried. Purification by column chromatography (30% EA in heptane) afforded the title compound (1.7 g, 22%) as a white solid. 1H NMR (DMSO-d6) δ 9.48 (s, 1H), 4.62-4.54 (m, 4H), 2.60-2.57 (m, 3H), 1.48 (s, 9H). HPLC (max plot) 97.0%, Rt 3.93 min. UPLC/MS: (MS+) 309.3 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(O[C:23]1(O[Si](C)(C)C)[CH2:25][CH2:24]1)C.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH:23]1([N:17]2[CH2:16][CH:15]=[C:14]([C:6]3[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:19][CH2:18]2)[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C2=CCN(C3CC3)CC2)cc(C(F)(F)F)c1
Yield: 78.6 %

Procedure:
Stir the mixture of 4-(3-nitro-5-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.55 mmol), (1-ethoxycyclopropoxy)trimethylsilane (700 mg, 2.4 mmol), sodium cyanoborohydride (200 mg, 3.3 mmol) and acetic acid (240 mg, 4.0 mmol) in ethanol (10 mL) at 60° C. overnight. Concentrate the mixture to get a residue, partition between EtOAc and water, collect the organic layer, wash with water and brine sequentially, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the product as a yellow solid (135 mg, 79%). MS: (M+1): 313.1.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[O:27]1[CH2:32][CH2:31][O:30][C:29]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:28]1=2>>[C:7]([N:6]1[C:2]([C:34]2[CH:35]=[CH:36][C:28]3[O:27][CH2:32][CH2:31][O:30][C:29]=3[CH:33]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Reactant: OB(O)c1ccc2c(c1)OCCO2
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc2c(c1)OCCO2

Procedure:
Using 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid and by reaction and purification in the same manner as in the method described in Example 43, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CN(C=O)C.C(N(CC)CC)C.[CH2:21]([O:23][SiH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH3:22]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[O:23][CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
[Rh(cod)(MeCN)2]BF4 (22.0 mg, 0.0600 mmol, 0.0300 equiv) and 1-bromo-4-iodobenzene (563 mg, 2.00 mmol, 1.00 equiv) were charged in 20 mL vial capped with a rubber septum. The vial was evacuated and backfilled with nitrogen. To this vial, DMF (8 mL), triethylamine (0.830 mL, 6.00 mmol, 3.00 equiv) and triethoxysilane (0.730 mL, 4.00 mmol, 2.00 equiv) were added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to 23° C. The mixture was diluted with ether (100 mL) and washed three times with water (3×40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Kugelrohr distillation to give 508 mg of the title compound as a colorless oil (80% yield). Rf=0.63 (hexanes). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 7.53−7.52 (m, 4H), 3.85 (q, J=7.0 Hz, 6H), 1.24 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 136.34, 131.04, 129.86, 125.33, 58.77, 18.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][OH:19])=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboximidamide (10.0 mg, 0.0218 mmol) was stirred in MeOH (500 μL) and hydrogen chloride in 1,4-dioxane (500 μL, 4.0 M) was added. The mixture was stirred for 30 min at rt. Purification by preparative LCMS gave the desired product (2.8 mg, 42%). 1H NMR (400 MHz, d6-DMSO): δ 11.00 (s, 1H), 8.99 (s, 1H), 7.09 (m, 1H), 6.82 (m, 1H), 6.53 (m, 1H), 5.92 (s, 1H), 4.95 (s, 1H). MF═C10H8ClFN4O2S; LCMS calculated for C10H9ClFN4O2S(M+H)+: m/z=303.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[C:37]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:13]1([C@H:11]([O:10][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:46][S:43]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:45])=[O:44])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)c5ccccc5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 1 using 1-{4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and benzenesulfonamide.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:7][CH3:8])[CH2:5][OH:6].Cl[CH2:10][C:11](OCC)=[O:12].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:7]([C@H:4]1[NH:3][C:11](=[O:12])[CH2:10][O:6][CH2:5]1)[CH3:8]
Reactant: CC[C@@H](N)CO
Reactant: CCOC(=O)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC[C@@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To an ice cold, stirred suspension of sodium hydride (60% in oil, 2.1 g, 52.0 mmol) in toluene (65 mL) was added dropwise a solution of (R)-2-aminobutan-1-ol (2.0 g, 22.0 mmol) in toluene (48 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (3.0 g, 25.0 mmol) in toluene (12 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.7 g, 52.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol) to give (R)-5-ethylmorpholine-3-one (2.0 g, 70%) as a light yellow solid. To ice-cold tetrahydrofuran (10 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 31.0 mL, 31.0 mmol). Once the addition was complete, a solution of (R)-5-ethylmorpholine-3-one (2.0 g, 16 mmol) in tetrahydrofuran (10 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and tot his was slowly added water (1.3 mL), then a 15% solution of sodium hydroxide (1.3 mL), and then water (1.3 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with ethyl acetate (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (R)-3-ethylmorpholine (1.6 g, 90%) as a light yellow oil. 1H NMR and MS consistent.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=5)=[CH:18][C:16]=4[S:17][C:13]=3[C:12]([C:32]#[N:33])=[CH:11][N:10]=2)=CC=1.[OH:36]S(O)(=O)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[NH2:8][C:9]1[C:14]2[C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([C:32]([NH2:33])=[O:36])=[CH:11][N:10]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(C(F)(F)F)cc5)ccc4c23)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cnc(N)c2c1sc1cc(-c3ccc(C(F)(F)F)cc3)ccc12

Procedure:
1-[(4-Methoxybenzyl)amino]-7-[4-(trifluoromethyl)phenyl][1]benzothieno[3,2-c]pyridine-4-carbonitrile was placed in a flask cooled to 0° C. before conc. H2SO4 (excess) was added dropwise under vigorous stirring. The final mixture was warmed to room temperature and, after 1 h, poured into THF/EtOAc and aqueous NaHCO3 previously saturated with NaCl solid. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were dried over MgSO4 and filtered. After evaporation of the organic solvents, the crude material was purified by a wash with Et2O to provide the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][C:10]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])[CH3:11].CC(C)([O-])C.[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C([O-])(O)=O.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:14](=[O:15])[O:13][C:10]([CH3:11])([CH3:9])[CH3:12])[CH2:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cc2)CC1
Temperature: 120 °C
Yield: 67 %

Procedure:
To a p-xylene (25 mL) solution containing 4-fluorobromobenzene (275 μL, 2.5 mmol, 1.0 eq), 4-N—BOC-aminopiperidine (1.0 g, 4.99 mmol, 2.0 eq), and potassium t-butoxide (393 mg, 3.5 mmol, 1.4 eq) was added palladium (II) acetate (6 mg, 1 mol %) and tri-t-butylphosphine (20 mg, 4 mol %). The resulting mixture was then heated to 120° C. for 4 h at which time it was poured into a sat. NaHCO3 solution and extracted (2×) with EtOAc. The combined extracts were dried over MgSO4 and concentrated in vacuo. The resulting oil was purified via column chromatography using 1:1 hexanes/EtOAc as the mobile phase. Isolated 485 mg (1.65 mmol, 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([O:25][C:26]([N:28]=[C:29]=[O:30])=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]([NH:28][C:29]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:30])=[O:27])[CH3:24]
Reactant: CCOC(=O)N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 28 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, ethoxycarbonyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 20 mg of the title compound (yield: 28%).
Reaction SMILES: C(OC(C)C)(=O)[C@H]([C@@H](C(OC(C)C)=O)O)[OH:3].[CH2:17]([OH:24])/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH3:23].C(OO)(C)(C)C.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Fe+3].C1(C)C=CC=CC=1.ClCCl>[CH2:20]([C@H:19]1[O:3][C@@H:18]1[CH2:17][OH:24])[CH2:21][CH2:22][CH3:23]
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C
Reactant: CCCC/C=C/CO
Agent: [Fe+3]
Agent: [Ti+4]
Agent: CC(C)(C)OO
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCCC[C@H]1O[C@@H]1CO
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 632.8 %

Procedure:
Under argon atmosphere, to anhydrous dichloromethane suspension (150 ml) containing 3.4 g of Molecular Sieves 4A were added 3.3 g (14.08 mmol) of diisopropyl D-(−)-tartarate, 3.3 g (11.73 mmol) of titanium tetraisopropoxide and 13.4 g (117.30 mmol) of (trans)-2-heptene-1-ol at −30 to −40° C. and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −60° C., and under stirring, 105 ml of a toluene solution containing 2.23M of t-butylhydroperoxide was added dropwise to the mixture over 20 minutes, and the temperature of the resulting mixture was returned to room temperature over 2 hours. After completion of the reaction, the reaction mixture was added to an aqueous solution (400 ml) containing iron (III) sulfate heptahydrate (80 g) and L-tartaric acid (40 g), and the resulting mixture was extracted with dichloromethane (400 ml). The organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue were added ether (400 ml) and 1N-sodium hydroxide (200 ml), and the mixture was stirred at room temperature for one hour. After completion of the reaction, the organic layer was separated, and the aqueous layer was extracted with ether (50 ml). The organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was evaporated under reduced pressure to obtain 11.6 g (Yield: 76.2%) of the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC1CCC(=O)CC1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 2,000 mL (inside volume) three-necked flask equipped with a reflux condenser, 700 mL of anhydrous tetrahydrofuran (THF) and 27 g of magnesium shavings were charged, to which 160 g of bromobenzene were added dropwise at a speed to ensure continuous mild reflux. After the dropping was completed, the mixture was further stirred for 1 h. To this mixture, a solution of 170 g of 4-n-pentylcyclohexanone (available from Tokyo Chemical Industry Co., Ltd.) in 100 mL of THF was added at 50° C. The mixture was then refluxed for 2 h. The obtained reaction product liquid was cooled to room temperature, poured into an aqueous ammonium chloride solution and then extracted with benzene. The benzene solution was added with 1 g of p-toluenesulfonic acid and refluxed while removing water generated. When water was no longer distilled, the reaction mixture was cooled to room temperature, washed with an aqueous sodium hydrogen carbonate solution and then with brine, dried and then concentrated. The residue was purified by silica gel column chromatography to obtain (4-n-pentylcyclohexenyl)benzene. The thus obtained product was dissolved in 1,000 mL of ethyl acetate and subjected to hydrogenation at 0.5 MPa using 2 g of 5% by mass-Pd/C as a catalyst. When a theoretical amount of hydrogen was consumed, the catalyst was separated by filtration. The resulting filtrate was concentrated to obtain 220 g of (4-n-pentylcyclohexyl)benzene. As a result of gas chromatographic analysis, it was confirmed that the (4-n-pentylcyclohexyl)benzene purity was 97.8% and the cis/trans molar ratio was 0.67. In 100 g of hexane were dissolved 220 g of (4-n-pentylcyclohexyl)benzene. The resulting solution was cooled to −30° C. Precipitated crystals were collected by filtration in an amount of 100 g. As a result of analyzing the obtained crystals by gas chromatography, it was confirmed that the (4-n-pentylcyclohexyl)benzene purity was 98.0% and the cis/trans molar ratio was 0.02.