Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:22]([CH3:30])([CH2:23][CH2:24][C:25]=32)[C:19](=[CH:20][CH3:21])[CH2:18][CH:17]=4)[C:11]1([CH3:32])[CH3:31])(=O)C1C=CC=CC=1.C([O:41][C@H:42]1[CH2:60][CH2:59][C@@:58]2(C)[C@@H:44](CCC3C4[C@](C)(CCC=32)[C@@H](C=C)CC=4)[C:43]1(C)C)(=O)C1C=CC=CC=1>>[CH3:31][C:11]1([CH3:32])[C@@H:10]([OH:9])[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:12]1[CH2:13][CH2:14][C:15]1[C:16]3[C@:22]([CH3:30])([CH2:23][CH2:24][C:25]=12)[C@@H:19]([C@H:20]([O:41][C:42]1[CH:60]=[CH:59][CH:58]=[CH:44][CH:43]=1)[CH3:21])[CH2:18][CH:17]=3
Reactant: CC=C1CC=C2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Reactant: C=C[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Product: C[C@@H](Oc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
—1,1′-(Azodicarbonyl)dipiperidine (5.54 g) was added to an ice-cooled solution of compound 13a (2.0 g), triphenylphosphine (5.76 g), and phenol (2.06 g) in dry THF (10 ml). After 5 min. stirring dry THF (60 ml) was added and the reaction mixture was stirred for 2 h at room temperature. Then it was poured into heptane (100 ml); the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography afforded (3β,5α,20R)4,4-dimethyl-20-phenoxypregna-8,14-dien-3-ol benzoate (compound 14b), together with the elimination products (3β,5α)-4,4-dimethylpregna-8,14,17(20)-trien-3-ol benzoate and (3β,5α)-4,4-dimethylpregna-8,14,20-trien-3-ol benzoate (2.80 g totally). The product was used in the following step without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:20](=[O:26])[CH:21]([CH3:25])[CH2:22][CH2:23][OH:24].CCN(CC)CC>C(Cl)Cl>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([C:20](=[O:26])[CH:21]([CH3:25])[CH2:22][CH:23]=[O:24])=[C:12]([CH3:11])[CH:17]=1
Reactant: COc1ccc(C(=O)C(C)CCO)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)CC=O)c(C)c1
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
To a 200 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added a solution of 4-bromo-3-methylanisole (2.77 g, 16.3 mmol) in 40 mL of THF under nitrogen. The solution was cooled to −68° C. with a dry ice/acetone bath. To this solution was slowly added t-BuLi (21.0 mL, 1.70 M in pentane, 35.8 mmol) followed by the addition of a solution of α-methyl-γ-butyrolactone (2.30 m L, 24.4 mmol) in THF (10.0 mL). The internal temperature was controlled <−55° C. After 1 h stirring at <−55° C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness to give 3.85 g of 1-(4-methoxy-2-methylphenyl)-4-hydroxy-2-methylbutan-1-one as light yellow oil, which was combined with another batch of material and subjected to column chromatography to give 1.26 g (18%) of clear oil. This material was used for Swern oxidation. To a 100 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added DMSO (1.75 mL, 24.6 mmol) and CH2Cl2 (20 mL). The solution was cooled to −80° C. with a MeOH/liquid nitrogen bath. To this solution was added oxalyl chloride (1.10 mL, 12.3 mmol) slowly via syringe pump. The mixture was stirred at −80° C. for 15 min followed by the addition of a solution of the above 1-(2-methyl-4-methoxyphenyl)-4-hydroxy-2-methylbutan-1-one (1.23 g) in CH2Cl2 (3.0 mL) slowly via syringe pump. After stirring at <−70° C. for 1 h, to the mixture was added Et3N (7.70 mL, 55.0 mmol). The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with hexanes (120 mL) and washed with water. The aqueous layer was extracted with hexanes. The combined organic solutions was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 0.326 g (27%) of light yellow oil as the title compound: compound: 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J=8 Hz, 1H), 6.83 (d, J=3 Hz, 1H), 6.81 (s, 1H), 3.94–3.86 (m, 4H), 3.20–3.13 (m, 1H), 2.62–2.56 (m, 1H), 2.51 (s, 3H), 1.21 (d, J=7 Hz, 3H); MS m/z 221.1 (M++H).
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])[C:9](=[CH:15][C:16]#[N:17])[NH:8][CH2:7][CH2:6]2.[OH-:18].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16](=[O:18])[NH2:17])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=CC#N)NCC2
Reactant: [OH-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(=CC(N)=O)NCC2

Procedure:
Polyphosphoric acid (10.0 g) is heated to 100° C. and 1.0 g of 6,7-dimethoxy-1-cyanomethylene-1,2,3,4-tetrahydroisoquinoline is added under mechanical stirring. The reaction mixture is heated for 1 hour, poured into crushed ice and made basic with 30% sodium hydroxide. The mixture is extracted with chloroform and the extract dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to give a white solid, yield 0.7 g, mp 156°-158° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)[N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)[N:19]2[CH2:20][C:21](=[O:23])[CH2:22]2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](c2ccc(Cl)cc2)N2CC(=O)C2)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
1-{(R*)-(4-Chlorophenyl)[4-methoxycarbonyl)-phenyl]methyl}azetidin-3-one, A isomer form, may be prepared by carrying out the procedure in the following manner: 0.90 cm3 of dimethyl sulfoxide is poured over 10 minutes into a solution, cooled to −60° C., of 0.55 cm3 of oxalyl chloride in 5 cm3 of dichloromethane. After stirring for 30 minutes at −60° C., a solution of 1.75 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, in 20 cm3 of dichloromethane is added to the mixture over 15 minutes. After stirring for 3 hours at −60° C., 2.7 cm3 of triethylamine are poured in and then the reaction medium is allowed to return to 0° C. 20 cm3 of water are then added, the mixture is stirred and then separated after settling. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness at 50° C. under reduced pressure (2.7 kPa). The orange-colored oil obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 2 cm, height 30 cm), under an argon pressure of 0.5 bar, eluting with a cyclohexane and ethyl acetate (75/25 by volume) mixture and collecting 30-cm3 fractions. Fractions 2 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.45 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, A isomer form, are obtained in the form of a yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)(O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C.O.O.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>[N:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:22][CH:23]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: OB(O)c1ccncc1
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
Solvent: O
Product: c1ccc2ncc(-c3ccncc3)cc2c1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
3-Bromo quinoline (0.2 g, 0.00096 mol) was dissolved in DMF:water (3:1, 4 mL). To this was added potassium phosphate (0.611 g, 0.00288 mol) and pyridyl-4-boronic acid (0.141 g, 0.00115 mol) at RT. The reaction mixture was degassed for 5 min, and to this was added Pd(PPh3)4 (0.055 g, 0.000048 mol). The reaction mixture was heated by microwave at 80° C. for 1.5 h. After completion of reaction (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, and the residue purified by column chromatography (45% ethylacetate:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound (0.13 g, 63% yield).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][C:24]([F:23])([F:34])[F:35])=[CH:27][CH:28]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (60 mg, 0.185 mmol, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. 4-(Trifluoromethoxy)benzaldehyde (45.7 mg, 0.240 mmol, 1.3 equivalents) was added followed by triethylamine (0.051 mL, 0.369 mmol, 2.0 equiv). After stirring for 10 minutes, sodium triacetoxyborohydride (94 mg, 0.443 mmol, 2.4 equivalents) was added, and the reaction was stirred at room temperature for an additional four hours. The suspension was loaded directly onto a 4 g silica gel column and eluted with ethyl acetate (flow rate=18 mL/minute) over 20 minutes to give the title compound as a light yellow oil (42 mg, 50%). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=1.2 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.44-5.24 (m, 1H), 4.10 (td, J=9.3, 4.5 Hz, 1H), 3.88 (dd, J=13.2, 5.2 Hz, 1H), 3.74 (dd, J=13.2, 2.0 Hz, 1H), 3.59 (s, 2H), 2.91 (dd, J=12.6, 6.8 Hz, 1H), 2.86-2.71 (m, 2H), 2.71-2.50 (m, 2H), 2.50-2.31 (m, 2H), 2.08-1.82 (m, 2H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 463.1 (M+H)+; [α]D23.6=0.08 (c=0.17, CH3OH).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)[C:18]#[N:19])=O)(C)(C)C.[OH-:30].[Na+].O>S(=O)(=O)(O)O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:20]1[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=1)[C:18]([NH2:19])=[O:30]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=C(C#N)c2nccc(C(F)(F)F)n2)Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(=C1Nc2ccccc2N1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
2-[1-(tert-Butoxycarbonyl)benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)-acetonitrile (8.1 g, 20 mmol) was dissolved in concentrated sulfuric acid (30 mL), and the solution added gradually to ice/water (100 mL), allowed to warm to room temperature, and stirred overnight. The mixture was cooled to 0° C., poured over ice, and neutralized with 50% aqueous sodium hydroxide. Water was added, and the crude product was extracted with 4:1 chloroform/isopropanol. The organic phase was dried over magnesium sulfate, the solvent was removed under vacuum, and the solid was purified by reverse phase preparative HPLC to give 2-[1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (1.18 g, 18% overall yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7]2.C([Li])(CC)C.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>C1COCC1>[F:1][C:2]1[C:3]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:8]=[CH:7]2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cccc(F)c21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c21
Temperature: -75 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
7-Fluoro-1-(triisopropylsilyl)-1H-indole (4.0 g, 14 mmol) (Prepared according to M. Schlosser, et al, Eur. J. Org. Chem. 2006, 2956-2969) was dissolved in 30 mL dry THF, cooled to −75° C., treated in portions with sec-butyl lithium (10 mL, 1.4 M, 14 mmol) and stirred for 2 h at −75° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 mL, 2.7 g, 14 mmol) was added in portions and the mixture was stirred for 1 h at −75° C. The cooling was removed and the temperature was allowed to rise to 5° C. over 30 min. The reaction was quenched by addition of 5 mL sat. NH4Cl and partitioned between ethyl acetate and water. The organic phase was washed with sat. NaCl, dried (Na2SO4), evaporated onto silica gel, and purified by flash chromatography (SiO2; eluting with hexanes) to give 4.2 g of the title compound as a thick oil (4.2 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J=7.9, 4.6 Hz, 1H), 7.38 (m, 2H), 1.75 (m, 3H), 1.38 (s, 12H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −113.07. EIMS m/z 417.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24](OC)=[O:25])=[C:22]([CH:28]([CH3:30])[CH3:29])[N:21]=[C:20]3[NH:31][CH:32]=[CH:33][C:19]=23)=[CH:14][CH:13]=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([CH2:24][OH:25])=[C:22]([CH:28]([CH3:30])[CH3:29])[N:21]=[C:20]3[NH:31][CH:32]=[CH:33][C:19]=23)=[CH:14][CH:13]=1
Reactant: COC(=O)c1c(C(C)C)nc2[nH]ccc2c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1CO
Reaction time: 1 h

Procedure:
100 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene are added slowly at -78° C. under argon to a suspension of 15.6 g (50 mmol) of the compound from Example VI in 700 ml of toluene, which leads to a clear solution. After 1 h, 40 ml of 1.5 M diisobutylaluminum hydride solution are added at the same temperature and the mixture is stirred for a further hour. It is warmed to 0°-5° C. using a water bath and stirred at this temperature for 1 h. 150 ml of water and 100 ml of ethyl acetate are cautiously added, and the mixture is stirred at room temperature for 1 h and filtered off with suction using kieselguhr. The phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The solution is dried over sodium sulphate, concentrated to dryness in vacuo and the residue which remains is thoroughly stirred in dichloromethane.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])C.[OH-].[Na+]>CCO>[O:32]1[C:28]2[CH:27]=[C:26]([C@@H:6]([N:7]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]4[CH:24]=[CH:23][C:22]5[CH2:21][CH2:20][CH2:19][NH:18][C:17]=5[N:16]=4)[C:8]3=[O:25])[CH2:5][C:4]([OH:35])=[O:3])[CH:34]=[CH:33][C:29]=2[CH2:30][CH2:31]1
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@@H](c1ccc2c(c1)OCC2)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 2 h

Procedure:
To a solution of 2-12 (2.9 g, 6.06 mmol) in EtOH (15 mL) was added 1N NaOH (7.2 ml,7.2 mmol). After stirring for 2 h, the solvents were evaporated and the residue chromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 2-13 as a white solid. TLC Rf=0.24 (15:10:1:1 ethyl acetate/EtOH/water/NH4OH). 1H NMR (300 MHz, CD3OD) δ 7.55 (d, J=7.3 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 6.81 (d, J=6.1 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J=7.3 Hz, 1H), 5.38 (t, J=7.9 Hz, 1H), 4.53 (t, J=8.9 Hz,2H), 3.14-3.53 (9H), 2.97 (m, 3H),2.80 (t, J=6.1 Hz, 2H), 2.67 (t, J=7.3 Hz, 2H), 1.93 (m,4H). ##STR14## Ethyl 3-fluorocinnamate (3-2)
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][CH:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CC(N)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To 0.19 g (0.74 mM) of methyl 4-[2-amino-2-(3-pyridyl)ethyl]benzoate in 10ml of dichloromethane in solution were added triethylamine (0.13 ml, 0.9 mM) and p-chlorobenzenesulfonyl chloride (0.19 g, 0.9 mM), and stirred overnight at room temperature. After completion of the reaction, water was poured into the reaction mixture, followed by extraction of dichloromethane. The organic phase was then washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate, to distill off the solvent. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform to yield 0.11 g of methyl 4-[2-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]benzoate. The spectrometric data thereof supports the structure of [26] as follows.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 39.6 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (5 mL) at room temperature under argon was added N-aminomorpholine (36 mg, 0.35 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.114 g, 0.35 mmol) and N,N-diisopropylethylamine (208 mg, 1.6 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (50 mg, 40%) as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.C([Li])(C)(C)C.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCOCC>[CH2:18]([C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCI
Reactant: Nc1cnc2ccccc2c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCCCc1nc2ccccc2cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of quinolin-3-ylamine in ether was added tert-butyl lithium at −78° C. and was stirred for 2 hours. To the reaction mixture was added the solution of 1-Iodo-hexane in ether and was allowed to warm up to RT. The reaction was continued for 1 day. The reaction was quenched with saturated ammonium chloride solution and extracted with chloroform. The product was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].Br[C:61]1[N:66]=[C:65]([CH:67]([N:70]2[CH2:75][CH2:74][S:73](=[O:77])(=[O:76])[CH2:72][CH2:71]2)[CH2:68][OH:69])[CH:64]=[CH:63][CH:62]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:77]=[S:73]1(=[O:76])[CH2:72][CH2:71][N:70]([CH:67]([C:65]2[N:66]=[C:61]([NH:1][C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=4)=[N:4][C:3]=3[C:17]([NH2:19])=[O:18])[CH:62]=[CH:63][CH:64]=2)[CH2:68][OH:69])[CH2:75][CH2:74]1
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Reactant: O=S1(=O)CCN(C(CO)c2cccc(Br)n2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3cccc(C(CO)N4CCS(=O)(=O)CC4)n3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (75 mg, 0.27 mmol), Pd2(dba)3 (7.4 mg, 8.1 μmol), X-PHOS (19.3 mg, 0.04 mmol), and potassium carbonate (41 mg, 0.30 mmol). The tube was evacuated and backfilled with argon 3×. 2-(6-Bromopyridin-2-yl)-2-(1,1-dioxidothiomorpholin-4-yl)ethanol (92 mg, 0.28 mmol) was placed in a separate vial which was also evacuated and backfilled with argon 3×. Fully degassed tert-amyl alcohol (700 μl) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-(1,1-dioxidothiomorpholin-4-yl)ethanol and the resulting solution was transferred to the sealed tube containing the rest of the reactants. This tube was then sealed, placed in an oil bath at 100° C., and stirred overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate (2×) and brine (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed using reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier, monitoring at 230 nM). Desired fractions were poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was extracted, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was taken up in a 1:1 mixture of methanol:ethyl acetate, 0.6 g of silica gel was added, and the solvent was removed in vacuo. The compound on silica was purified via flash chromatography (silica, 0-8% methanol/ethyl acetate) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.28 (s, 1H), 7.85 (d, 2H), 7.72 (s, 1H), 7.70 (t, 1H), 7.60 (s, 1H), 7.55 (d, 2H), 7.08 (d, 1H), 7.99 (d, 1H), 5.09 (s, 1H), 4.64 (t, 1H), 3.99 (m, 3H), 3.07 (m, 4H), 3.04 (m, 2H), 2.95 (m, 2H), 1.42 (s, 6H). LRMS (APCI) calcd for C24H30N5O5S2 [M+H]+: 532.2, found 532.0