Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][O:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]2[N:61]=[C:62]([CH:64]=O)[N:63]=[C:56]2[N:55]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][O:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:64][C:62]3[N:63]=[C:56]4[N:55]=[C:54]([CH3:53])[CH:59]=[C:58]([CH3:60])[N:57]4[N:61]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: COCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione (Example A(194)) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in that example. 1H NMR (400 MHz, DMSO-d6): δ 1.5–2.0 (m, 11H) 2.46–2.75 (m, 11H), 3.25 (s, 3H), 3.73 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H), 4.32 (s, 2H), 6.70 (d, J=8 Hz, 1H), 6.94–7.04 (m, 3H), 9.20 (s, 1H). Anal. Calcd. For C28H34N4O5.1.5H2O: C, 63.02; H, 6.99; N, 10.50. Found: C, 63.92; H, 6.74; N, 10.42. MS (ESI): 507.2 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[H][H].C(OCC)C>CN(C)C=O.[Pd]>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
3-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (Example 11b, 0.100 g, 0.180 mmol) was dissolved in N,N-dimethylformamide (15 mL) at 25° C. Palladium on carbon (5%, 0.250 g) was added and the atmosphere in the reaction flask replaced with hydrogen from a balloon. After stirring for 1 h under a hydrogen balloon, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→3% methanol in dichloromethane) to afford a yellow solid. Trituration of this material with diethyl ether afforded the desired product, 3-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.050 mmol, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ: 2.08-2.18 (1H, m), 2.23-2.29 (1H, m), 2.32-2.43 (1H, m), 3.20-3.28 (1H, m), 3.31-3.37 (1H, m), 4.56-4.61 (1H, m), 5.65 (2H, s), 6.60 (2H, d, J=7.0 Hz), 6.59-6.61 (1H, m), 7.02-7.03 (1H, m), 7.14-7.18 (2H, m), 7.42-7.46 (1H, m), 7.67-7.75 (2H, m), 7.87 (1H, bs), 13.73 (1H, s). LC-MS (ESI) calcd for C25H21FN4O6S2 556.09. found 557.15 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:14])([F:13])[C@@H:10]([OH:12])[CH3:11].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]([F:14])([F:13])[C@@H:10]([O:12][C:16](=[O:17])[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[CH3:11]
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Triethylamine (2.3 mL) is added to a solution of 4-dimethylaminopyridine (13 mg), (S)-1,1,1-trifluoro-propan-2-ol (75% in tert-butyl methyl ether; 2.00 g), and 4-nitrophenyl chloroformate (2.90 g) in dichloromethane (80 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 30 min and then at room temperature overnight. The solution is washed with 10% aqueous K2CO3 solution and water and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane) to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10](F)=[O:11])[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3].[OH:17][CH:18]([C:31]1[CH:36]=[CH:35][C:34](/[C:37](=[N:39]/O)/[NH2:38])=[CH:33][CH:32]=1)[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1.CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[OH:17][CH:18]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:39]=[C:10]([C:7]3[C:6]([C:13]([F:16])([F:15])[F:14])=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[O:9][N:8]=3)[O:11][N:38]=2)=[CH:33][CH:32]=1)[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1
Reactant: CC(C)Cc1onc(C(=O)F)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4noc(CC(C)C)c4C(F)(F)F)n3)cc2)C1
Yield: 54.5 %

Procedure:
A mixture of 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride; Int-V-D (0.045 g, 0.188 mmol), (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (0.063 g, 0.188 mmol), and DIEA (0.043 mL, 0.245 mmol) in acetonitrile (1 mL) was stirred at room temperature for 4 days. The reaction was complete by HPLC. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated. The crude reaction mixture was purified by flash silica gel chromatography using a 20% mixture of ethyl acetate in hexane to give (3S)-ethyl 1-(2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (0.055 g, 0.103 mmol, 54.5% yield) as a clear, colorless oil. The product was >99% pure by HPLC with a ret. time=2.87 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=537.2.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO>[Br:1][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CO
Product: O=C(CBr)c1ccc(Cl)c(Cl)c1
Yield: 95.1 %

Procedure:
43.9 g (0.275 mol) of bromine was added dropwise to a solution of 50.5 g (0.267 mol) of 3′,4′-dichloro acetophenone in 120 g of methanol at a reaction temperature of 50 to 55° C. After the addition was complete, the methanol was evaporated off the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (150 ml×3 times). Thereafter, the toluene was evaporated off under reduced pressure, giving 68.0 g (0.254 mol) of crude brown oily 2-bromo-3′,4′-dichloroacetophenone.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[CH2:6][C:5]([CH3:13])([CH3:12])[CH2:4]1.Cl.[NH2:15]O>C(O)C.O>[CH3:12][C:5]1([CH3:13])[CH2:4][C:3]2[CH:2]=[N:15][O:9][C:8]=2[C:7]([CH3:11])([CH3:10])[CH2:6]1
Reactant: NO
Reactant: CC1(C)CC(=CO)C(=O)C(C)(C)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)Cc2cnoc2C(C)(C)C1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere and with stirring, a solution of 16 (140 mg, 0.77 mmol) in ethanol (19.1 mL) was added to a solution of hydroxylamine hydrochloride (7.98 mmol, 555 mg, 10.4 eq) in water (980 μL) at room temperature. The mixture was heated to 110° C. and stirred at reflux for 1 hour. After heating, the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with methylene chloride/ethyl ether (1:2, 3×10 mL). The organic layers were then combined and washed with saturated aqueous sodium bicarbonate solution (1×12 mL) and brine (2×12 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 17 as a yellow oil (122 mg, 0.68 mmol, 89%). The material was used in the next reaction without further purification: 1H NMR (CDCl3) δ 8.00 (1H, s), 2.24 (2H, s), 1.60 (2H, s), 1.34 (6H, s), 1.03 (6H, s); 13C NMR (CDCl3) δ 173.2, 150.0, 110.4, 52.4, 34.4, 32.6, 32.4, 29.7, 29.3. MS: No molecular ion peak is observed by ESI+ and EI methods.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[BH4-].[Na+]>CO.C(Cl)Cl.[Cl-].[NH4+]>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH:10][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH2:5][CH2:6][NH:7][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCCN(CCN)CCN
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(CNCCN(CCNCc2ccc(F)cc2)CCNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Tris(2-aminoethyl)amine (0.01 mol) and 4-fluoro-benzaldehyde (0.03 mol) were dissolved in MeOH (50 mL). After stirring at 25° C. for 15 h, NaBH4 (1.90 g, 0.05 mol) was added to the above solution at 0° C. The reaction mixture was stirred for 2 h at 25° C. It was then diluted with CH2Cl2 (100 mL) and ammonium chloride aqueous solution (10%, 70 mL).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.[Cl-].[Li+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:20]([C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)=[CH2:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)OCCC2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
To a solution of 4-oxochroman-7-yl trifluoromethanesulfonate (Preparation 2C, 2.00 g, 6.75 mmol) in dioxane (10 mL) in a sealed tube was added sequentially tributyl(vinyl) stannane (2.18 mL, 7.43 mmol) and lithium chloride (0.859 g, 20.3 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (2×). To the mixture was added tetrakis(triphenylphosphine) palladium(0) (0.780 g, 0.675 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred overnight. The reaction mixture was cooled to room temperature and filtered under reduced pressure. The solid was washed with ethyl acetate (4×50 mL), and the filtrate was concentrated. The crude product mixture was diluted with ether (˜100 mL), sonicated for several minutes, and filtered (the cake was rinsed with ether). The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12%-15%) to give 7-vinylchroman-4-one (0.938 g, 5.38 mmol, 80% yield) as a yellow oil. The product had a HPLC ret. time=1.93 min. (condition A); LC/MS M+1=174.9; 1H NMR (400 MHz, CDCl3) δ ppm 2.78-2.85 (m, 2H), 4.52-4.58 (m, 2H), 5.42 (d, J=10.78 Hz, 1H), 5.88 (d, J=17.61 Hz, 1H), 6.69 (dd, J=17.61, 11.00 Hz, 1H), 6.98 (d, J=1.54 Hz, 1H), 7.09 (dd, J=8.25, 1.43 Hz, 1H), and 7.87 (d, J=8.14 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:9][CH2:10][C@H:11]([OH:13])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@H]1CN[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4) (890 mg, 3.14 mmol) in DCM (5 mL) at room temperature was added TFA (5 mL). The mixture was stirred at room temperature for 2 hours then concentrated to dryness. The crude was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to yield (3R,5R)-5-(3-fluorophenyl)pyrrolidin-3-ol (I-32), which was used without purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[C:18]([OH:23])=[C:19]([CH:21]=O)[CH:20]=2)(=[O:14])=[O:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:36]([NH2:38])=[NH:37].C1(=O)C=CC(=O)C=C1>C(O)C>[OH:23][C:18]1[C:19]([C:21]2[NH:42][C:41]3[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][C:33]=3[N:32]=2)=[CH:20][C:15]([S:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]
Reactant: O=Cc1cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc(-c2ccccc2O)c1O
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4ccccc4)cc(-c4ccccc4O)c3O)nc2c1
Yield: 39.6 %

Procedure:
N-(3-Phenylpropionyl)-5-formyl-6,2′-dihydroxy-biphenyl-3-sulfonamide (0.065 g, 0.15 mmol), prepared as in Reference 22, 3,4-diaminobenzamidine hydrochloride (0.043 g 0.23 mmol) and benzoquinone (0.018 g, 0.16 mmol) were combined in ethanol (15 mL) and the mixture was heated under reflux for 1 hour. The solvent was evaporated in vacuum and the product was purified from the residue by reverse phase HPLC (acetonitrile/0.02N HCl gradient) to give 2-[2,2′-dihydroxy-5-(3-phenylpropionylaminosulfonyl)biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.033 g). 1H NMR (DMSO-d6): δ 2.50 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 6.82-7.22 (m, 9H), 7.72 (dd, J1=9.2 Hz, J2=1.7 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 8.18 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.99 (s, 2H), 9.34 (s, 2H), 12.06 (s, 1H). MS. found (M+H+) 556.4, (M−H+) 554.4, calc 555.16.
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:7]1([CH2:17][C@@H:18]2[O:20][C@@:19]2([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:12]([O:13][CH3:14])=[CH:11][CH2:10][CH:9]=[C:8]1[O:15][CH3:16])[CH:5]=[CH2:6].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCOC(C)=O.CCCCCC>[CH2:4]([C@:7]12[CH2:17][CH:18]3[O:20][C@@:8]1([O:15][CH3:16])[C@@H:9]([C@:19]3([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:10][CH:11]=[C:12]2[O:13][CH3:14])[CH:5]=[CH2:6]
Reactant: C=CCC1(C[C@@H]2O[C@@]2(C)CCC=C(C)C)C(OC)=CCC=C1OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CC[C@]12CC3O[C@@]1(OC)[C@H](CC=C2OC)[C@]3(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A DCM (6 mL) solution of 8 (100 mg, 0.30 mmol, 1 equiv.) and 2,6-di-tert-butyl-4-methylpyridine (124 mg, 0.60 mmol, 2 equiv.) was cooled to −78° C. in a 20-mL scintillation vial, and trimethylsilyl trifluoromethanesulfonate (65 μL, 0.36 mmol, 1.2 equiv.) was added dropwise. Immediately upon this addition, the solution turned bright yellow. After stirring at −78° C. for 30 min, the reaction was quenched with saturated aqueous NaHCO3 and allowed to warm to room temperature. The mixture was then extracted four times with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a slight yellow oil. Flash column chromatography (50 mL SiO2, 99:1 hexane:EtOAc) afforded 85 mg (0.26 mmol, 85% yield) of 9 as a clear, colorless oil. TLC Rf 0.53 (9:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 6.02 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.04 (t, J=7.1 Hz, 1H), 5.01-4.95 (m, 2H), 4.54 (dd, J=5.7, 2.1 Hz, 1H), 3.75 (d, J=5.3 Hz, 1H), 3.48 (s, 3H), 3.47 (s, 3H), 2.42 (dd, J=14.1, 7.3 Hz, 1H), 2.29 (dd, J=14.1, 7.0 Hz, 1H), 2.19 (ddd, J=18.1, 6.7, 2.2 Hz, 1H), 2.07-2.02 (m, 2H), 2.01-1.93 (m, 1H), 1.86 (dd, J=12.4, 5.3 Hz, 1H), 1.81 (d, J=12.4 Hz, 1H), 1.72-1.65 (m, 4H), 1.58 (s, 2H), 1.47-1.42 (m, 1H), 1.25-1.20 (m, 1H), 1.14 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 158.1, 138.3, 131.7, 124.9, 115.8, 112.5, 90.7, 79.1, 54.6, 51.3, 46.3, 44.4, 42.0, 38.87, 38.72, 33.6, 28.1, 25.9, 22.9, 20.1, 17.8. IR (NaCl, thin film, cm−1) 2966, 2930, 1671, 1578, 1460, 1439, 1376, 1304, 1215, 1168, 1136, 1062, 1001, 906. HRMS-ESI (m/z): [M+Na]+ calculated for C21H32O3, 355.2244. found, 355.2245.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([C:16]3[S:17][C:18]4[C:24]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=5)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35]CC)=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=4[N:20]=3)[CH:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>C1COCC1.CO>[N:1]1([C:10]2[CH:15]=[C:14]([C:16]3[S:17][C:18]4[C:24]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=5)=[C:23]([C@H:32]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[C:33]([OH:35])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=4[N:20]=3)[CH:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-(2-(2-(1H-indazol-1-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (6.8 mg, 0.011 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H28ClN4O3S: 583.2; found: 583.3. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J=8.8 Hz, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.81-7.77 (m, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.58-7.50 (m, 4H), 7.30 (t, J=7.2 Hz, 1H), 5.35 (s, 1H), 2.61 (s, 3H), 1.02 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])O.[Na+].C>C(O)(CC)C.O>[OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Yield: 64.5 %

Procedure:
A mixture of 20 g (80 mmol) of 2,4-dihydroxy-4'-chlorobenzophenone, 21.9 g (88 mmol) of 1-bromododecane and 8.4 g (100 mmol) of sodium hydrogen carbonate in 77.6 g of sec-butyl alcohol and 25.6 g of H2O is heated with stirring and maintained at reflux for 20 h. The reaction mixture is stirred for an additional 15 min in the presence of 0.8 g of activated charcoal and is then filtered while hot. After the filtrate has cooled, the product crystallizes. It is recrystallized from sec-butyl alcohol to give 21.5 g of pale yellow crystals having a melting point of 61°-63° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 40 °C
Reaction time: 6 h

Procedure:
140 mg of (RS)-methyl 4-[2-(4,4-dimethyl-thiochroman-6-yl)-heptyloxy]-benzoate, dissolved in 20 ml THF/5 ml H2O/5 ml methanol, was treated with 200 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 5 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 20 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 10 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (10% methanol/methylene chloride), yielding a colorless oil. Trituration in hexanes provided a white solid, m.p. 168-169° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[C:9]2=[O:18])=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:15][C:10]1[C:9](=[O:18])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Cn2ccc(C)c(N)c2=O)cc1
Reaction time: 5.5 h
Yield: 96.4 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.5 g, 5.5 mmol) and 10% Pd/C (0.15 g) in ethanol (150 mL) was hydrogenated at 40 psi in a Parr apparatus for 5.5 hours. The catalyst was removed by filtration, and the solvent was evaporated to give 3-amino-1-(4-methoxybenzyl)-4-methyl-2-pyridone (1.3 g, 5.3 mmol, 96%).
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[C:8]([CH3:20])[C:9]3[NH:15][C:14]4[CH:16]=[CH:17][N:18]=[CH:19][C:13]=4[C:10]=3[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:21]P(=O)(Cl)C1C=CC=CC=1.[OH-].[Na+]>>[Cl:21][C:3]1[C:12]2[C:7](=[C:8]([CH3:20])[C:9]3[NH:15][C:14]4[CH:16]=[CH:17][N:18]=[CH:19][C:13]=4[C:10]=3[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: COc1nccc2c(C)c3[nH]c4ccncc4c3cc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccncc12
Temperature: 160 °C
Yield: 54.2 %

Procedure:
1.053 g (0.004 mole) of 10-methoxy 6-methyl 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline are suspended in 5.6 ml (0.040 mole) of dichlorophenylphosphine oxide and the suspension is heated at 160° C. for 2 hours. The reaction mixture is poured onto ice and the pH is brought to 7 by the addition of 10N sodium hydroxide. After filtration and drying of the precipitate formed, 0.580 g of 10-chloro 6-methyl 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline are obtained.