Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:32]([NH2:36])[CH2:33][CH2:34][NH2:35]>C1COCC1>[NH2:35][CH2:34][CH2:33][CH2:32][NH:36][C:13]([C:6]1[C:5]([NH:4][C:3]2[CH:27]=[CH:28][C:29]([I:31])=[CH:30][C:2]=2[F:1])=[CH:10][C:9](=[O:11])[N:8]([CH3:12])[CH:7]=1)=[O:15]
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NCCCN
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCN)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (0.20 g, 0.4 mmol) in THF (5 ml) was added to 1,3-propanediamine (0.35 ml, >10 eq) in THF (5 ml) and stirred at RT for 15 h. The solution was then concentrated under reduced pressure and the residue dissolved in 5% MeOH/EtOAc. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated to give crude N-(3-aminopropyl)-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide which was then recrystallised (MeOH/Hexane/EtOAc) (0.04 g, 22%); m.p. 201-206° C. 1H NMR [400 MHz, (CD3)2SO] δ 8.42 (br s, 1H), 8.25 (s, 1H), 7.74 (dd, J=10.2, 1.9 Hz, 1H), 7.57 (dt, J=8.5, 0.9 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 5.60 (d, J=0.9 Hz, 1H), 3.38 (s, 3 H, obscured), 3.3-3.25 (m, 2 H, obscured), 2.81 (t, J=7.4 Hz, 2H), 1.75 (p, J=7.4 Hz, 2H). HPLC 94.4% (254 nm). HRMS (FAB+) calcd for C16H19FIN4O2 445.0537 (M+), found 445.0543.
Reaction SMILES: [I-:1].[Na+].Br[CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]
Reactant: [I-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCI
Yield: 75 %

Procedure:
To a solution of 15 g (100 mmol) of sodium iodide in 120 ml of acetone was added 3 g (11 mmol) of N-(3-bromopropyl)phthalimide and the mixture was heated at reflux for 30 minutes. The cooled mixture was filtered and evaporated. The residue was partitioned between 50 ml of diethyl ether and 50 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 2.6 g (75%) of N-(3-iodopropyl)phthalimide as a white solid. [Mass spectrum (ESI) MH+ =316].
Reaction SMILES: [OH-].[Na+].[I:3]I.[C:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][C:8]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([OH:14])[C:12]#[CH:13])=[CH:7][CH:6]=1>CO>[C:5]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]=[CH:9][C:8]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([OH:14])[C:12]#[C:13][I:3])=[CH:7][CH:6]=1
Reactant: C#CC(O)(c1ccc(-c2ccccc2)cc1)c1cccc(Cl)c1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(C#CI)(c1ccc(-c2ccccc2)cc1)c1cccc(Cl)c1
Yield: 56.9 %

Procedure:
40 ml of concentrated sodium hydroxide solution and 25.4 g (0.1 mol) of iodine were simultaneously introduced into a solution of 31.9 g (0.1 mol) of 3-(4-biphenylyl)-3-(3-chlorophenyl)-1-propyn-3-ol in 350 ml of methanol at 20° C., with slight external cooling and while stirring. The mixture was stirred for three hours and filtered to remove a slight turbidity and the filtrate was stirred into 1,000 ml of water. The reaction product thereby separated out as a semi-solid mass. The supernatant liquid was decanted, the residue was taken up in ethyl acetate and the solution was washed several times with 100 ml of water each time and dried over sodium sulphate. Thereafter, it was concentrated by distilling off the solvent in vacuo, and the oily residue was dissolved in a little ether. After adding petroleum ether, crystallization occurred. 25.3 g (56.9% of theory) of 3-(4-biphenylyl)-3-(3-chlorophenyl)-1-iodo-1-propyn-3-ol were obtained as colorless crystals of melting point 99°-100° C.
Reaction SMILES: O.[SH-:2].[Na+].F[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>CN(C=O)C>[SH:2][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: [SH-]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(S)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 60 °C
Yield: 89.6 %

Procedure:
Sodium hydrosulfide monohydrate (237 mg, 4.3 mmol) was added to a solution of 4-fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 350 mg, 1.2 mmol) in DMF (15 mL) and the reaction mixture was heated at 60° C. for 20 hours under N2. After cooling to room temperature and quenching with 2M HCl, the reaction mixture was partitioned between ethyl acetate and water. Further extraction of the aqueous layer with ethyl acetate, combination of all organic layers, drying and concentration provided a white powder (326 mg, 89% yield): 1HNMR DMSO-d6) δ2.99 (t, J=4 Hz, 4H), 3.58 (t, J=4. Hz, H), 7.48 (d, J=8 Hz,1H), 7.87 (dd, J=8, 2 Hz, 1H), 8.29 (d, J=2 Hz, 1H), 13.20 (s, 1H): MS (ESI) [M−H]− m/z 304.
Reaction SMILES: I[C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]([CH3:7])[N:6]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:7][N:5]1[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=2[C:2]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[N:6]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2c1CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC2
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-Iodo-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (177 mg, 714 μmol) was dissolved in THF (3 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath). isopropylmagnesium chloride 2 M in THF (400 μL, 799 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (267 mg, 223 μL, 821 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution and then extracted with EtOAc (3×30 mL), the combined organics were washed with water (20 mL), brine (2×20 mL), dried over MgSO4 and concentrated. The residue was dried under high vacuum yielding 1-methyl-3-(tributylstannyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole which was taken into the next step without further treatment.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.Br[C:40]1[CH:41]=[C:42]2[C:64](=[CH:65][CH:66]=1)[C:46]1[NH:47][C:48]([C@@H:50]3[C@@H:55]4[CH2:56][C@@H:52]([CH2:53][CH2:54]4)[N:51]3[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][C:45]=1[CH:44]=[CH:43]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:36][O:35][C:34]([NH:33][C@@H:3]([CH:2]([CH3:38])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18]([C:40]1[CH:41]=[C:42]2[C:64](=[CH:65][CH:66]=1)[C:46]1[NH:47][C:48]([C@@H:50]4[C@@H:55]5[CH2:56][C@@H:52]([CH2:53][CH2:54]5)[N:51]4[C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])=[N:49][C:45]=1[CH:44]=[CH:43]2)=[CH:17][CH:16]=3)=[O:32])=[O:37]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (372 mg, 0.715 mmol), (1R,3S,4S)-tert-butyl 3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (317 mg, 0.715 mmol), Pd(PPh3)4 (83 mg, 0.0715 mmol) and K2CO3 (2M in H2O, 0.7 mL, 1.4 mmol) were suspended in DME (3.6 mL). The mixture was degassed for 13 min with bubbling N2, then heated to reflux. After 18 h, the reaction mixture was cooled to RT and 5 mL MeOH was added. EtOAc was added and the organics were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford the title compound (196 mg, 36%).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CO>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: CCCCCCCOc1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCCCOc1ccc(NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (16 mg, 0.10 mmol) and diisopropylethylamine (52 uL, 0.30 mmol) in MeOH (2 mL) was added 1-(heptyloxy)-4-isocyanatobenzene (46 uL, 0.20 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (9 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 7.24 (d, 2H, J=9.2 Hz), 6.84 (d, 2H, J=8.8 Hz), 4.71-4.69 (m, 1H), 3.93 (t, 2H, J=6.4 Hz), 3.77-3.53 (m, 2H), 3.25 (s, 9H), 2.74-2.70 (m, 2H), 1.77-1.72 (m, 2H), 1.49-1.34 (m, 8H), 0.92 (t, 3H, J=6.8 Hz); MS ESI 394.3 [M+H]+, calcd for [C21H35N3O4+H]+ 394.52.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH2:28][OH:29]>ClCCl>[CH2:21]([O:20][CH2:19][C@@H:16]1[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[C@H:14]([CH2:28][OH:29])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (17.8 mL, 132 mmol) was added to a solution of C6 (48.7 g, 133 mmol) in dichloromethane (1.34 L), and the reaction mixture was allowed to stir at room temperature for 18 hours. Removal of solvent in vacuo afforded the product as a white solid, which was used without additional purification. Yield: 72.2 g, assumed quantitative. LCMS m/z 527.2 [M+H]+. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 7.89-7.93 (m, 2H), 7.62-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.42-7.54 (br m, 1H), 7.31-7.36 (m, 2H), 7.17-7.28 (m, 3H), 6.86-6.98 (m, 2H), 4.57 (AB quartet, JAB=11.9 Hz, ΔνAB=11.8 Hz, 2H), 3.84-3.91 (m, 1H), 3.64 (br dd, half of ABX pattern, J=10.6, 6.0 Hz, 1H), 3.58 (dd, half of ABX pattern, J=10.6, 3.8 Hz, 1H), 3.44-3.54 (br m, 1H), 2.32-2.59 (br m, 1H), 1.82-2.06 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:9][CH2:8][CH2:7][C:6]2=1.[CH:25]1(O)[CH2:29]CC[CH2:26]1>O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH:23]4[CH2:29][CH2:25][CH2:26][CH2:24]4)=[O:21])[CH2:17][CH2:18][CH2:19]3)[NH:9][CH2:8][CH2:7][C:6]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: OC1CCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: O
Product: O=C(OC1CCCC1)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
4.0 g of the compound of Example 1 are heated at the reflux of 80 ml of cyclopentanol in the presence of 1 ml of titanium tetraisopropoxide. After reaction for 24 hours, the reaction mixture is diluted with water and then filtered. After extraction with dichloromethane, drying and evaporation under reduced pressure, crystallisation of the residue from an ethanol-diethyl ether-hydrogen chloride mixture enables the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C@H:7]([CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:6][CH2:5]2.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CN(C)C=O>[CH2:23]([O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C@H:7]2[CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:3][C:2]=1[Br:1])[CH:22]=[CH2:21]
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)cc21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1Br)CC[C@H]2CCNC(=O)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
A solution of (S)-N-[2-(5-bromo-6-hydroxyindan-1-yl)ethyl]propionamide (48.8 g, 156 mmol.) in N,N-dimethylformamide (110 mL) was cooled with ice, to which was gradually added sodium hydride (6.35 g, 172 mmol., content 65%). The mixture was stirred for about 15 minutes. When the bubbling of hydrogen gas ceased, allyl bromide (22.7 g, 188 mmol.) was added, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was poured into ice-water, which was neutralized with dilute hydrochloric acid. The organic matter was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel gel column chromatography (ethyl acetate) to afford the title compound (yield 52.97g, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17](O)([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClC(Cl)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:11]2)=[CH:15][CH:16]=1)#[N:2]
Reactant: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Yield: 86 %

Procedure:
To a mixture of 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol), DMAP (1.84 g, 15.0 mmol), and tert-butanol (14.1 mL, 150 mmol) in dichloroethane (150 mL) was added EDC (4.32 g, 22.5 mmol), and the reaction mixture was allowed to stir over the weekend. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with water (250 mL), washed with brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a light yellow oil which was chromatographed on a 5×15 cm silica gel column, eluting with a 0-40% ethyl acetate/hexane gradient to give tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (3.5 g, 12.9 mmol, 86% yield) as a colorless liquid. HPLC retention time=1.38 minutes—Column: YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.26 (m, 3H), 3.52 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.3 Hz, 2H), and 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])OC4C=CC=CC=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:31][CH:32]([NH:34][CH2:35][C:36](OCC)=[O:37])[CH3:33].O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:36](=[O:37])[CH2:35][N:34]([CH:32]([CH3:33])[CH3:31])[C:22]4=[O:30])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CCOC(=O)CNC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)CN(C(C)C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 5 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 3 parts of ethyl [(1-methylethyl)amino]acetate, 1 part of N,N-dimethyl-4-pyridinamine and 100 parts of 1,4-dioxane was stirred and refluxed overnight. The warm solution was saturated with water and allowed to cool. The solution was poured onto water and extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from methylbenzene, yielding 3.7 parts (73%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1-(1-methylethyl)-2,4-imidazolidinedione; mp. 193.7° C. (38).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][C:35]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cc(C(F)(F)F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.00 mg, 40.4% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.67 (m, 2H), 7.55 (m, 2H), 7.50–7.40 (m, 3H), 7.30–7.10 (m, 3H), 7.17 (d, 1H, J=8.9 Hz), 7.07 (apparent d, 1H, J=6.7 Hz), 6.97 (apparent d, 1H, J=7.8 Hz), 5.37 (apparent dd, 1H, J=4.2, 8.1 Hz), 3.37 (m, 2H), 2.93 (m, 2H), 2.63 (s, 1H), 2.50 (apparent sept, partially hidden, 1H, J=7.9 Hz), 2.30–2.10 (m, 6H), 1.85 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 542.7 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](I)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C)C=O.O>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([C:20]#[N:21])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(=O)n2nc(SCc3ccccc3)sc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 120 ml of dimethylformamide, 9 g of 90% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved, and 3.05 g of cuprous cyanide and 1.57 g of sodium cyanide were added thereto. The reaction mixture was heated to 100° C. and stirred at that temperature for 1 hour. After the reaction was finished, the reaction mixture was cooled, diluted with water and extracted with chloroform. The organic layer was washed with water, and the chloroform was distilled off. Water was added to the residue and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the dried organic layer, and the organic layer was shaken well. After the Florisil® was separated, the solvent was distilled off, and thus 3.0 g of 2-benzylthio-7-cyano-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 50%. (Florisil® (a registered trademark of Floridin Company) is a highly selective magnesium silicate absorbent.)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:12]([O:19][NH:20][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NOCc1ccccc1)c1ccc(O)cc1
Yield: 45.3 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (E18) (0.424 g, 3.07 mmol), O-benzylhydroxylamine hydrochloride (E19) (0.490 g, 3.07 mmol), and 4-dimethylaminopyridine (0.414 g, 3.39 mmol) in dichloromethane (30 ml) under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.643 g, 3.35 mmol) was added and the resultant mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into a mixture of saturated NaH2PO4 (30 ml) and water (70 ml), and extracted with ethyl acetate (2×75 ml). The extract was washed with a mixture of saturated NaH2PO4 (15 ml) and water (35 ml), brine (50 ml), and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate-acetic acid (75:25:1, 100 ml) and benzene-ethyl acetate-acetic acid (50:50:1, 300 ml) as eluents to give the title compound (0.338 g, 45%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 4.88 (2H, s); 6.79 (2H, d, J=8.8 Hz); 7.23-7.55 (5H, m); 7.59 (2H, d, J=8.8 Hz); 10.02 (1H, br s); 11.48 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](F)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH2:32]([SH:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([S:34][CH2:32][CH3:33])[CH:21]=3)(=[O:18])=[O:19])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCS
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Yield: 86 %

Procedure:
Starting with {(R)-4-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester and ethanethiol using a method analogous to the one described for the 1st step of example 7-1, {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (136 mg, 86%) was obtained as a white solid. MS cald. for C21H26F3N3O4S2 505, obsd. (ESI+) [(M+H)+] 506.