Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.[H-].[Na+].I[CH3:39].O>CN(C=O)C>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH3:39])[CH:21]3[CH2:22][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CN(S(C)(=O)=O)C2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)C2CN(S(C)(=O)=O)C2)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine (Example 28) (170 mg, 0.33 mmol) in DMF (4 mL) at 0° C. was added NaH (24 mg, 1.0 mmol). The mixture was stirred for 30 min at this temperature and iodomethane (0.3 mL, excess) was added. The resulting mixture was allowed to warm to 20° C. and stirred for 2 hrs. Water was added and the resulting precipitate was filtered, washed with water, and dried. Recrystallization from CH2Cl2/MeOH gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine (156 mg, 89% yield): mp (CH2Cl2/MeOH) 242-244° C.; 1H NMR (DMSO-d6) δ7.97-7.60 (m, 2H), 7.42 (t, J=8.1 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 5.50 and 5.26 (2m, 1H), 4.17-4.12 (m, 4H), 3.98 (s, 3H), 3.81 (m, 4H), 3.71-3.69 (m, 4H), 3.24 (s, 3H), 3.09 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.3. Found: C, 48.0; H, 5.0; N, 21.3%.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:11][B-:12]([F:15])([F:14])[F:13].[H+].[N:17]([O-])=O.[Na+]>O>[F:11][B-:12]([F:15])([F:14])[F:13].[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:17]
Reactant: Cc1c(F)ccc(N)c1F
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc([N+]#N)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4-difluoro-3-methylaniline (20 g) are added 42% tetrafluoroboric acid (56 ml) and water (28 ml) under ice cooling and thereto a solution of sodium nitrite (10 g) in water (20 ml) is added dropwise at below 10° C. After dropwise addition, the mixture is stirred at 0° C. for 15 minutes and the formed crystals are filtered, which is washed with a mixture of ethanol--diethyl ether (1:2), then with diethyl ether, followed by drying under reduced pressure to give 2,4-difluoro-3-methylbenzene diazonium tetrafluoroborate (28.95 g), m.p. 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1.[CH3:22][NH2:23].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH3:22])[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1
Reactant: CN
Reactant: CCCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CCCc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-propylphenoxy)-benzonitrile (0.35 g, 1.1 mmol) in ethanol (20 mL) was added methylamine (33% in ethanol, 9.0 mL, 72 mmol), and the reaction mixture stirred 18 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (127 mg, 1.1 mmol) in methanol (5 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(3-methylaminomethyl-2-propyl-phenoxy)-benzonitrile fumarate (354 mg, 75%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=[CH:23][C:24]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ccc(OC)c(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c1
Yield: 84 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,5-dimethoxyphenylboronic acid (118 mg, 0.65 mmol) were reacted. After purification the title compound (101 mg, 85% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (bm, 1H), 7.85 (a dd, J=2.2, 7.6 Hz, 1H), 7.73 (m, 2H), 6.95 (m, 2H), 6.91 (m, 1H), 3.77 (s, 3H), 3.63 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=365, HPLC 2.42 min.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:24]([O:23][C:21]([NH:20][C:18]12[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:19]2)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC12CCCCC1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCC1CCNC2

Procedure:
A 10% palladium-carbon catalyst (83.0 mg, 20 wt %) was added to a solution of 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer B) (415 mg, 1.11 mmol) in methanol (11.1 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for one hour. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give the title compound quantitatively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:18][C:19]1[N:20]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])=[CH:31][CH:30]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1.4 g, 6.8 mmol), 4-(2-methylimidazol-1-yl)benzyl chloride hydrochloride (1.65 g, 6.8mmol) and potassium carbonate (7.2 g, 68 mmol) in dry DMF (10 ml) was stirred at 120° C. for 2 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate - benzene (300 ml, 2:1 v/v). The organic phase was washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated. Purification of the residual yellow solids by column chromatograghy on silica gel (100 g) eluting with CH2Cl2 /methanol=10:1 and recrystallization from ethyl acetate-hexane gave 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1.0 g, 39%) as off-white solids.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].Cl.Cl.Cl.[N:14]1([CH2:18][CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=3)[N:22]=[C:21]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:14]1([CH2:18][CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=3)[N:22]=[C:21]2[CH:33]2[CH2:34][CH2:35][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH2:9][CH3:10])[CH2:37][CH2:38]2)[CH2:15][CH2:16][CH2:17]1
Reactant: CCc1c(N)ncnc1Cl
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
The reaction mixture of 6-chloro-5-ethyl-pyrimidin-4-ylamine (30.0 mg; 0.19 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine trihydrochloride (86.0 mg; 0.19 mmol; 1.0 eq.), and Cs2CO3 (310.1 mg; 0.95 mmol; 5.0 eq.) in DMSO (1.5 ml) was stirred at 120° C. for 48 hr. The crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=464, obsd=464). 1H NMR (400 MHz, DMSO-d6) δ 8.49-8.39 (m, 1H), 8.10-8.01 (m, 1H), 7.96 (s, 1H), 7.93-7.85 (m, 1H), 7.50 (t, J=8.9 Hz, 1H), 6.69-6.61 (m, 2H), 4.30 (q, J=5.4, 4.7 Hz, 2H), 2.71-2.62 (m, 2H), 3.93 (d, J=12.5 Hz, 2H), 3.54 (q, J=6.3, 5.8 Hz, 4H), 3.33 (t, J=12.5 Hz, 3H), 3.11 (q, J=5.3, 4.0 Hz, 2H), 2.33 (dd, J=28.0, 11.5 Hz, 6H), 1.54 (q, J=6.7, 6.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=1)([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C(OC)=O>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:35])[CH:4]([NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a solution of the title E compound, 2-(3-benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic acid dimethyl ester (6.98 g, 14.3 mmol) in DMSO (68 mL) and water (1.46 mL) sodium chloride (0.85 g, 14.6 mmol) is added and the mixture is gradually heated to 150° C. for 1 h. The mixture is cooled to RT, diluted with water (300 mL) and extracted 3 times with EtOAc. The organic extracts are washed with water and brine, dried over anhydrous MgSO4, decolorized with charcoal, filtered and evaporated. The residue is purified by chromatography (silica gel column, 6×30 cm, on EtOAc-hexane 1:1) to give 3-(3-Benzyloxy-4-nitro-phenyl)-2-tert-butyloxycarbonylamino-propionic acid methyl ester as a crystalline solid: mp=104-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O:14][C:15]([CH:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][N:22]2[C:10](=[O:11])[N:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[C:15](=[O:14])[CH:17]2[CH2:18]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 136.1 %

Procedure:
3,5-Dichlorophenyl isocyanate (2.85 g, 15.2 mmol) was added portionwise to a mixture of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.61 g, 10.1 mmol, prepared as described in Bioorg. Med. Chem. Lett. 1999, 9, 1121-6) and potassium carbonate (1.68 g, 12.1 mmol) in DCM (30 mL) at 5° C. After 30 min at 5° C., the reaction mixture was stirred at 20° C. for 48 h. The white precipitate was discarded and the filtrate concentrated in vacuo to give an oil (5.5 g) which was chromatographed over silica gel (CH2Cl2), to yield the above compound (2.77 g) as a white solid. Mp=144° C.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=[N:55][C:50]2C=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCNCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:32][CH2:33]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20]([N:54]3[CH2:49][CH2:50][NH:55][CH2:52][CH2:53]3)=[O:22])[CH2:16][CH2:15]2)=[O:7])=[CH:38][CH:39]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNCCN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5CCNCC5)CC4)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (100 mg, 0.186 mmol) in DMF (3 mL) was added HATU (74.4 mg, 0.196 mmol) and DIPEA (0.036 mL, 0.205 mmol). The suspension was stirred for 15 minutes at RT. A solution of piperazine (161 mg, 1.863 mmol) in DMF (1 mL) was added, and the reaction was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated and the residue purified by HPLC (15-90% ACN/0.1% TFA). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (67 mg, 59.5% yield). MS, m/z (C34H45FN6O3): calcd, 604.3. found, 605.1 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=1[O:30][CH3:31]>C(OCC)C>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)[OH:27])=[CH:24][C:23]=1[O:30][CH3:31]
Reactant: COc1cc(C=O)ccc1F
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene, prepared as described in Procedure 3, (1.00 g, 3.44 mmol) in diethyl ether in (10 mL) at −72° C. was added 2.5 M n-BuLi (1.37 mL, 3.44 mmol) dropwise. Upon completion of addition, the reaction mixture was stirred for 15 minutes at −72° C., then 4-fluoro-3-methoxybenzaldehyde (0.53 g, 3.44 mmol) was added while the reaction mixture temperature was maintained below −52° C. The reaction mixture was stirred for 3 h at −72° C. The reaction mixture was quenched by the addition of 1N HCl and the aqueous portion was extracted with EtOAc (2×). The combined organic layers were washed with sat. NaCl, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by ISCO using a gradient of 0-50% EtOAc/hexane as eluent to yield (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (0.83 g, 66% yield). HPLC: RT=3.85 min (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); 1H NMR (CDCl3): 7.05-6.8 (m, 6H), 5.87 (tt, J=2.8, 52.9 Hz), 5.75 (s, 1H), 3.85 (s, 3H).
Reaction SMILES: [H-].[K+].O1CCOCC1.[CH:9]([S:12][CH2:13][S:14](=[O:18])[CH:15]([CH3:17])[CH3:16])([CH3:11])[CH3:10].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>C(Cl)Cl>[CH:9]([S:12][C:13]1([S:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:11])[CH3:10]
Reactant: BrCCCCCBr
Reactant: CC(C)SCS(=O)C(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)SC1(S(=O)C(C)C)CCCCC1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Potassium hydride (995 mg) was suspended in 15 ml. of dioxane, and with ice cooling, 1.804 g of formaldehyde diisopropyl mercaptal S-oxide was added gradually. The mixture was stirred for 1 hour with ice cooling, and then 2.411 g of 1,5-dibromopentane was added. Then, the mixture was stirred for 18 hours at room temperature. Methylene chloride (100ml) was added, and the isoluble matter was separated by filtration. After the evaporation of the filtrate at reduced pressure, the residue was separated by column chromatography (basic alumina, eluted with benzene, methylene chloride, and ethyl acetate) to afford 1.463 g of cyclohexanone diisopropyl mercaptal S-oxide as a colorless oil. The yield was 59%. The physical properties and the results of elemental analysis were as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)=[O:18]>>[CH2:24]([C@H:16]([NH:15][C:12]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])=[O:14])[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSC1)c1cc2cc(F)cc(F)c2[nH]1

Procedure:
From 5,7-difluoro-1H-indole-2-carboxylic acid and (S)-2-amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one.
Reaction SMILES: [CH3:1]I.C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[CH2:13][CH2:14][SH:15])C.[Na]>C(O)C>[CH3:1][S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:5])=[O:17])=[O:16]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)CCS
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: CSCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (71 g) is added to a solution of 1-(3-mercaptopropanoyl)-L-proline ethyl ester (115 g) and sodium (11.5 g) in ethanol (400 ml). The reaction is allowed to proceed overnight, the ethanol is removed in vacuo and the residue is dissolved in a mixture of ethyl acetate and water. The organic layer is dried and concentrated to dryness in vacuo. The resulting 1-(3-methylthiopropanoyl)-L-proline ethyl ester (98 g) is suspended in a mixture of methanol (200 ml) and 5 N sodium hydroxide (200 ml) and stirred at room temperature for five hours. The methanol is removed in vacuo, and the aqueous phase is extracted with ethyl acetate, acidified and reextracted with ethyl acetate. This last organic phase is washed with water, dried and concentrated to dryness to yield 1-(3-methylthiopropanoyl)-L-proline.
Reaction SMILES: [CH2:1]([C:3]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:2].O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([C:3]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCC1=C(c2ccc(O)cc2)Oc2ccccc2S1
Reactant: OCCCN1CCCC1
Product: CCC1=C(c2ccc(OCCCN3CCCC3)cc2)Oc2ccccc2S1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-ethyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-3 and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][O:8][C:5]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:4][CH2:3]2.[Li]CCCC.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:1][C:2]12[CH2:3][O:4][C:5]([C:10]3[O:11][C:12]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:8][CH2:9]2
Reactant: CC12COC(c3ccco3)(OC1)OC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C23OCC(C)(CO2)CO3)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
2-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)furan (2.0 g, 10.2 mmol) was dissolved in THF (20 ml) and the solution was cooled to −78° C. n-BuLi (1.6M solution in hexanes, 7.7 ml, 12.32mmol) was added and the mixture stirred at −78° C. for 30 min, allowed to warm to 0° C. for 20 min. and then recooled to −78° C. The tributyltin chloride (3.5 ml, 4.68 g, 14.4 mmol) was added and stirring was continued at −78° C. for 15min. The mixture was allowed to warm gradually to room temperature and stirring continued for three days. The reaction was quenched by the addition of water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (4.7 g, 9.7 mmol, 95%); δH [2H6]DMSO 6.52 (1H,d), 6.38 (1H, d), 3.96 (6H,s), 0.77-1.63 (30H,m).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])[C:5]=12.N1CCCC1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:27]1([CH2:33][CH2:34][CH:35]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[C:19]2=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1COC(=O)N1CCCCOc1cccn2ccnc12
Reactant: O=CCCc1ccccc1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1OC(=CCCc2ccccc2)C(=O)N1CCCCOc1cccn2ccnc12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.45 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]oxazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of pyrrolidine was added. Next, an ethanol solution of 0.66 ml (5 mmol) of 3-phenylpropionaldehyde was added, followed by refluxing for 19 hours. 3.5 hours later, 0.66 ml (5 mmol) of 3-phenylpropionaldehyde and 0.05 ml (0.5 mmol) of pyrrolidine were added. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 15 mg (0.74%, yellow oily substance) of the desired product.