Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[CH:6][C:5]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+]>CN(C)C=O.CCOC(C)=O>[CH2:20]([N:7]1[CH:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([N+:1]([O-:3])=[O:2])=[N:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn[nH]c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of C1 (2.86 g, 15.4 mmol) in N,N-dimethylformamide (60 mL) was added anhydrous potassium carbonate (12.8 g, 92.6 mmol), benzyl bromide (2.20 mL, 18.5 mmol) and a catalytic amount of potassium iodide. The reaction was heated at 60° C. for 18 hours, then diluted with EtOAc and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) provided C2 as an oil. Yield: 1.35 g, 4.90 mmol, 32%. An NOE experiment revealed a strong interaction between the pyrazole CH and aromatic protons on the phenyl group, supporting the indicated regiochemistry for C2. LCMS m/z 276.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.1 Hz, 3H), 4.31 (q, J=7.1 Hz, 2H), 5.33 (s, 2H), 7.30-7.35 (m, 2H), 7.40-7.45 (m, 3H), 7.78 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:4]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 105 %

Procedure:
As in Example 115, (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid (5.8 g) and 4-nitrophenol (2.5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 2 hours. The usual work up furnished 8 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CCN(CC)CC.[C:31]([O-:34])(O)=O.[Na+].C(=O)([O-])[O-].[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[CH2:50][CH2:51][NH2:52]>ClCCl.C(OCC)(=O)C>[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[CH2:50][CH2:51][NH:52][C:31](=[O:34])[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(C)c1ccccc1O
Reactant: NCCc1ccc2ccccc2c1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1OC(=O)NCCc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of 2-isopropylphenol (5.0 g, 36.713 mmol) in dichloromethane (183.0 mL) was added 4-nitrophenyl chloroformate (8.1 g, 40.385 mmol) and Et3N (10.3 mL, 73.426 mmol) at 0° C. After stirring at 0° C. 2 hours, the reaction mixture was treated with 30.0 mL of saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was used without further purification. To a solution of crude carbonate intermediate in dichloromethane (150 mL) was added 2-(naphthalen-2-yl)ethanamine (6.9 g, 40.385 mmol) and Et3N (10.3 mL, 73.426 mmol) at 0° C. After stirring at 0° C. 2 hours, the reaction mixture was treated with 30.0 mL of saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane:ethyl acetate as solvent to afford title compound (11.5 g, 94% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].O>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[C:2]2[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34]
Reactant: CNc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(F)c(NC(=O)OC(C)(C)C)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloro-5-nitropyrimidin-4-yl thiocyanate (2.73 g, 12.6 mmol) and sodium hydrogen carbonate (2.76 g, 32.9 mmol) in tetrahydrofuran (80 mL) was added a solution of tert-butyl [2-fluoro-5-(methylamino)phenyl]carbamate (2.63 g, 11.0 mmol) produced above in tetrahydrofuran (20 mL), and the mixture was stirred for 1.5 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {2-fluoro-5-[methyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=1)(=[O:3])[CH3:2].S(Cl)([Cl:19])(=O)=O.CCOCC>C(O)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([Cl:19])[C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)Oc1ccc2c(c1)COC(=O)N2
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)Oc1cc(Cl)c2c(c1)COC(=O)N2
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A quantity of 14.5 gm (0.07 mol) of 6-acetoxy-4H-3,1-benzoxazin-2-one (prepared from 6-hydroxy-4H-3,1-benzoxazin-2-one and acetic anhydride; m.p. 173°-175° C.) is dissolved in 150 ml of glacial acetic acid, mixed with 10.8 gm (6.5 ml=0.08 mol) of sulfuryl chloride, and stirred for 36 hours at ambient temperature. After addition of 30 ml of ether, the mixture is cooled to 0° C., and the precipitate is subjected to suction filtration, washed with ether, and dried.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH3:11][C:12](O)([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:21](O)(=O)C(O)=O.C(O)(=O)C>O>[CH3:11][C:12]([C:8]1[C:7]([O:10][CH3:21])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1)([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(C)(O)c1ccccc1
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(C)(C)c1ccccc1)OCO2

Procedure:
(α,α-Dimethylbenzyl)-3,4-methylenedioxy-6-methoxybenzene was prepared as follows: A mixture of sesamol (44 g), α,α-dimethylbenzyl alcohol (44 g), oxalic acid (3g), acetic acid (100 ml) and water (10 ml) was refluxed for 2.5 hours, diluted with water and extracted with chloroform. Distillation of the chloroform extract gave an oil, b.p. 160°-163° at 0.5 mm Hg (60 g) which crystallized from aqueous methanol to give colorless needles, m.p. 75°-76° (Found: C, 75.0; H, 6.26. Calc. for C16H16O3 : C, 75.0; H, 6.29%); pmr spectrum: δ1.63, 6H, S; 4.12, 1H, S; δ5.81, 2H, S; δ6.33, 1H, S; δ6.98, 1H, S; δ6.31, 5H, S.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[BrH:21].C(=O)([O-])O.[Na+]>C(O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][Br:21])[OH:16])[CH3:8]
Reactant: Br
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC1C(O)CCC(O)(CBr)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of fumagillol (230 mg) in ethanol (2 ml) was added a 5% aqueous solution of hydrobromic acid (1 ml), and the mixture was stirred for one hour at room temperatures. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=7:3) to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy1-bromomethyl-1,4-cyclohexanediol (242 mg: yield 80%) as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](O)=[O:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[N:21]1[C:26](C)=CC=C[C:22]=1C.CNC>ClCCl.CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](=[O:8])[N:21]([CH3:26])[CH3:22])[N:6]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1sc(Cl)nc1C(=O)N(C)C
Temperature: 45 °C
Yield: 76 %

Procedure:
To a stirred solution of 2-chloro-5 (ethoxy carbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 2 g, 8.01 mmol) in dry dichloromethane (20 mL) was added oxalyl chloride (1.37 mL, 16.02 mmol) and 2 drops of dry dimethylformamide. The reaction mixture was heated to 45° C. for 90 minutes. After the completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dry dichloromethane (20 mL) and was cooled to 0° C., then 2,6-lutidine (0.97 mL, 8.4 mmol) was added followed by addition of N,N-dimethylamine (2 M solution in tetra hydro furan, 4.19 mL, 8.4 mmol). After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate (2×50 mL). The organic layer was washed with 1 N hydrochloric acid, water and brine (1×50 mL), and concentrated after drying over anhydrous sodium sulfate to afford 1.6 g (72.7%) of the title compound as a thick syrup.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:62][C:63]1[C:64]([N:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[N:65][CH:66]=[CH:67][CH:68]=1>C1COCC1>[Cl:62][C:63]1[C:64]([N:69]2[CH2:70][CH2:71][N:72]([C:17]([CH:14]3[CH2:13][CH2:12][C:10]4([O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:11]4)[CH2:16][CH2:15]3)=[O:18])[CH2:73][CH2:74]2)=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Reactant: Clc1cccnc1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC2(CC1)CC(c1ccccc1)=NO2)N1CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (750 mg, 2.9 mmol) was slowly added to a solution of N-ethyldiisopropylamine (1.02 g, 7.1 mmol), 1-hydroxybenzotriazole hydrate (320 mg, 2.4 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (758 mg, 2.4 mmol) and 1-(3-chloropyridin-2-yl)piperazine (467 mg, 2.4 mmol) in abs. THF (17 ml). The reaction mixture was stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc (100 ml). The precipitate formed was removed by suction-filtration. The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. ammonium sulphate solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The precipitate and the residue were purified by column chromatography (silica gel, hexane/EtOAc 1:1). The desired product [4-(3-chloropyridin-2-yl)piperazin-1-yl]-(3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)methanone was obtained as a cis isomer (294 mg, 24% of the theoretical amount) and trans isomer (192 mg, 15% of the theoretical amount).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH2:33])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:32])=[N:20][C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])=[CH:10][CH:9]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[NH2:33][CH:4]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:32])=[N:20][C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])=[CH:12][CH:13]=1)[C:3]([OH:34])=[O:2]
Reactant: COC(=O)C(N)CCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCCC(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Amino-4-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)butyric acid methyl ester (140) (110 mg, 0.223 mmol) was dissolved in a mixture of methanol (1 mL)/THF (1 mL)/water (1 mL). Lithium hydroxide monohydrate (14 mg, 0.334 mmol) was added and the reaction mixture was stirred at room temperature for 16 h before it was concentrated in vacuo. The resulting residue was diluted with water (1 mL), acidified to pH 2 with 1N aqueous HCl, and purified through a DOWEX 50WX 8-200 ion exchange resin eluting with 10% aqueous ammonium hydroxide. The desired product was obtained as a yellow solid (75 mg, 70% yield). 1H NMR (300 MHz, CD3OD) δ 1.55-1.78 (m, 4H), 2.10-2.45 (m, 2H), 2.52-2.65 (m, 2H), 3.30-3.35 (m, 2H), 3.65-3.75 (m, 1H), 4.05-4.15 (m, 2H), 6.85 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H). m/z (ESI) 479 [C20H27ClN8O4+H]+. mp 178-180° C.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([NH:17][CH:18]=[N:19]2)=[C:15]([Cl:22])[N:14]=1.[CH:23]([O:26][C:27]([O:36][CH:37]([CH3:39])[CH3:38])([P:32]([OH:35])([OH:34])=[O:33])[O:28][CH2:29][CH2:30]Cl)([CH3:25])[CH3:24]>CN(C=O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:30][CH2:29][O:28][C:27]([O:26][CH:23]([CH3:24])[CH3:25])([O:36][CH:37]([CH3:38])[CH3:39])[P:32]([OH:35])([OH:34])=[O:33])=[C:15]([Cl:22])[N:14]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)OC(OCCCl)(OC(C)C)P(=O)(O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)OC(OCCn1cnc2c(Cl)nc(N)nc21)(OC(C)C)P(=O)(O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
In 120 ml DMF, 29.3 g of DBU, 32.45 g (0.191 mol) of 2-amino-6-chloropurine were added, stirred at 80° C. for 30 min, then 50 g (0.193 mol) of 2-(diisopropyloxy-phosphonomethoxy)-ethyl chloride was added, the reaction was performed at 100° C. for 8 h, cooled, distilled at a reduced pressure to remove DMF, added with water and ethyl acetate, layered, the water phase was extracted twice with ethyl acetate, the organic phases were combined, dried, separated by silica gel column chromatography, eluted with MeOH:CH2Cl2=1:30, yield 46 g of II1.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C@:15]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@@H:11]([C@:12]([CH3:42])([CH2:28][CH2:29][CH2:30][C:31]([CH3:41])([O:33][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:32])[C@@H:13]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14]2)[C:10](=[O:43])[CH:9]=1.Cl[Si:45]([CH3:48])([CH3:47])[CH3:46].[Li]N1C(C)(C)CCCC1(C)C>CCOC(C)=O.CCCCCC>[CH3:6][O:7][C:8]1[C@:15]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@@H:11]([C@:12]([CH3:42])([CH2:28][CH2:29][CH2:30][C:31]([CH3:41])([O:33][Si:34]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:39][CH3:40])[CH3:32])[C@@H:13]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14]2)[C:10](=[O:43])[C:9]=1[Si:45]([CH3:48])([CH3:47])[CH3:46]
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@@H]1C(=O)C=C2OC
Reactant: C[Si](C)(C)Cl
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@@H]1C(=O)C([Si](C)(C)C)=C2OC
Temperature: 0 °C
Yield: 90.2 %

Procedure:
A THF (1 mL) solution of 44 (22.9 mg, 42.0 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL test tube, and chlorotrimethylsilane (53 μL, 0.42 mmol, 10 equiv.) and a freshly prepared THF solution of lithium tetramethylpiperidide (0.50 M, 420 μL, 0.21 mmol, 5 equiv.) were sequentially added. The golden yellow solution was slowly warmed to 0° C. over 1 h and quenched at 0° C. with saturated aqueous NaHCO3. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. Flash column chromatography (20 mL SiO2, 98:2 hexane:EtOAc) afforded 23.4 mg (37.9 μmol, 90% yield) of 45 as a colorless oil. TLC Rf 0.40 (95:5 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.02-4.97 (m, 2H), 3.83 (s, 3H), 3.11 (s, 1H), 2.51 (dd, J=14.4, 6.3 Hz, 1H), 2.37 (dd, J=14.5, 7.5 Hz, 1H), 2.15-2.11 (m, 1H), 1.99 (dd, J=14.0, 3.7 Hz, 1H), 1.69 (s, 3H), 1.68-1.63 (m, 9H), 1.57 (s, 3H), 1.48 (td, J=12.7, 3.9 Hz, 1H), 1.46-1.37 (m, 2H), 1.30 (td, J=12.2, 4.1 Hz, 1H), 1.26-1.24 (m, 1H), 1.21 (s, 3H), 1.21 (s, 3H), 1.14 (td, J=12.6, 4.2 Hz, 1H), 0.94 (t, J=7.9 Hz, 9H), 0.80 (s, 3H), 0.57 (q, J=8.1 Hz, 6H), 0.23 (s, 9H). 13C NMR (126 MHz; CDCl3): δ 207.9, 198.6, 185.7, 133.70, 133.59, 127.7, 122.8, 120.0, 73.7, 72.6, 64.1, 59.7, 46.7, 45.7, 41.8, 39.29, 39.27, 30.6, 30.0, 29.7, 27.6, 26.02, 25.97, 18.21, 18.14, 17.88, 17.83, 7.4, 7.0, 0.8. HRMS-ESI (m/z): [M+H]+ calculated for C36H64O4Si2, 617.4416. found, 617.4395.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:5]1[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1cc(C(F)(F)F)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 79 using 4-(trifluoromethyl)-1H-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid in 24% yield, 1.32 g.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=O)[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>O.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:8](=[O:9])[C:7]([C:5]3[S:6][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:20]([OH:21])[C:19]=2[CH:22]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1oc2ccc(Br)cc2c(O)c1-c1ccc(Br)s1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
A solution of titanium trichloride (7.71 g) in water (50 ml) was added to a solution of ethyl (5-bromo-2-thienyl)glyoxylate (5.0 g) and 5-bromo-2-hydroxybenzaldehyde (4.36 g) in dry acetic acid (50 ml) with stirring at 4° C. and the mixture was stirred for 11/2 hours. It was extracted with ethyl acetate and the extract was washed with water, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in toluene and p-toluenesulfonic acid (2.5 g) was added and the mixture heated under reflux for 21/2 hours. It was allowed to stand at room temperature overnight and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-3-(5-bromo-2-thienyl)-4-hydroxy-2H-1-benzopyran-2-one, m.p. 234-6° C. (compound 27)
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30]>>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[C:31]1[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:17][CH:18]=1)=[O:30]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCO)c1cc2ccccc2[nH]1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2cc3ccccc3[nH]2)cc1
Yield: 91 %

Procedure:
The product of Example 2 (0.27 g, 0.83 mmol) was coupled to N-(3-hydroxypropyl)-1H-indole-2-carboxamide, prepared according to Example 18, (0.20 g, 0.91 mmol) using the procedure of Example 3 to provide 0.4 g (91% yield) of yellow solid powder. MP 199° C.; 1H NMR (DMSO-d6): δ 1.9 (s, CH3), 2.0-2.1 (m, CH2), 3.20 (s, CH3), 3.32-3.51 (m, CH2, CH2), 6.8-7.2 (m, 8 Ar H), 7.36 (d, 1 Ar H), 7.58 (d, 1 Ar H), 7.78 (d, 1 Ar H), 7.93 (s, 1 NH), 8.52 (s, NH), 12.0 (s, OH). Electrospray Mass Spec: m/z 522.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22](C(C)(C)C(C)C)O[SiH](C)C)=[C:14]([CH:33]=[O:34])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.[F-].[NH4+]>CO>[NH3:8].[CH3:21][C@@H:19]1[CH2:20][NH:8][CH2:9][C@@H:10]2[N:18]1[C:17]1[N:16]=[C:15]3[CH2:22][O:34][CH2:33][C:14]3=[CH:13][C:12]=1[CH2:11]2
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)COC4
Product: N
Temperature: 25 °C
Reaction time: 17 h
Yield: 152.5 %
Yield: 25 %

Procedure:
A mixture of 22.7g (0.046 mol) (4R,9aR)-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-7-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and 22.7 g ammonium fluoride (0.61 mol) in 500 ml methanol was heated to reflux for 1 h. The reaction mixture cooled to room temperature and partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with water and brine dried over sodium sulfate filtered and evaporated. The residue was taken up in 230 ml of dichloromethane and cooled to 0° C. To the resulting solution was added 23 ml triethylsilane and 113 ml trifluoroacetic acid and the mixture was stirred with thawing to room temperature for 17 h. The resulting orange red solution was evaporated under aspirator vacuum. The residue was partitioned between 200 ml water and 200 ml ethyl acetate. The phases were separated and the organic phase was extracted twice with 100 ml water. The combined aqueous phases were mixed with 300 ml dichloromethane and the pH of the mixture was adjusted to 12.00 by addition of a 28% solution of sodium hydroxide in water. The phases were separated and the aqueous phase was extracted two more times with 100 ml dichloromethane. The combined dichloromethane phases were dried over sodium sulfate evaporated to dryness and purified by chromatography on silica gel with dichloromethane:methanol:25% aqueous ammonia=90:10:1 to yield 8.11 g (76%) of (5R,8aR)-5-methyl-1,3,5,6,7,8,8a,9-octahydro-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene as yellow orange foam. (MS: 232 (M+H+))