Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[C:41]([NH2:48])=[C:40]([Cl:49])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([O:34]CC)=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([C:44]([F:46])([F:45])[F:47])[C:41]([NH2:48])=[C:40]([Cl:49])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([OH:34])=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: CCOC(=O)[C@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 6.1 from 60 mg (0.08 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-ethoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2.9 mg (0.12 mmol) LiOH.
Reaction SMILES: [C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:19])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2F)/[N:6]([CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[C:5]=1[CH3:26])(=[O:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30].CC(C)([O-])C.[K+]>O1CCCC1.O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:19])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:30][CH2:29][C:28]([F:32])([F:31])[F:27])/[N:6]([CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[C:5]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)c1s/c(=N\C(=O)c2cc(Cl)ccc2F)n(C[C@H]2CCCO2)c1C
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1s/c(=N\C(=O)c2cc(Cl)ccc2OCC(F)(F)F)n(C[C@H]2CCCO2)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of the product from Example 280A (360 mg, 0.91 mmol) in tetrahydrofuran (4 mL) was added 2,2,2-trifluoroethanol (227 mg, 2.27 mmol) and a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (2.27 mL, 2.27 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with water, and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by reverse phase HPLC afforded the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.64-1.75 (m, 1H) 1.90-2.00 (m, 2H) 2.10-2.20 (m, 1H) 2.51 (s, 3H) 2.80 (s, 3H) 3.73 (dd, J=15.9, 7.3 Hz, 1H) 3.88 (dd, J=15.3, 6.7 Hz, 1H) 4.07 (dd, J=13.7, 8.2 Hz, 1H) 4.33-4.41 (m, 1H) 4.47 (dd, J=16.8, 8.2 Hz, 2H) 4.62 (dd, J=13.7, 2.8 Hz, 1H) 7.03 (d, J=8.5 Hz, 1H) 7.39 (dd, J=8.5, 2.8 Hz, 1H) 8.02 (d, J=2.8 Hz, 1H); MS (ESI) m/z 477 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:25])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(5,7-difluoro-quinolin-6-yl)-methanone (Stage 182.3, 3.05 g, 8.41 mmol) was suspended in THF (65 mL) and the mixture was cooled down to 0° C. with an ice bath. Then the methylmagnesium bromide (1.4 M, 15.01 mL) was added slowly. The RM was stirred for 30 min and was then allowed to warm up to rt. After 2 h, it was quenched with a few mL of water. The solution was filtered. The solid residue was washed with water and the filtrate extracted with EtOAc twice. Then the organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The crude was purified with DCM and MeOH by MPLC to give the title compound as a yellow solid (tR 0.9 min (conditions 2), MH+=361).
Reaction SMILES: C(Br)Br.[CH3:4]N(C)C=O.[Cl:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][NH:16][C:17](=[S:19])[S-:18])=[CH:12][CH:11]=1.[K+].S1CCS1>O>[Cl:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][N:16]=[C:17]2[S:18][CH2:4][S:19]2)=[CH:12][CH:11]=1
Reactant: S=C([S-])NCOc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: C1CSS1
Agent: [K+]
Solvent: BrCBr
Solvent: O
Product: Clc1ccc(OCN=C2SCS2)cc1
Reaction time: 1.5 h

Procedure:
To a mixture of 19.3 g. of methylene bromide and 3.7 g. of treithylamine in 100 ml. of dimethylformamide was added 10.0 g. of potassium p-chlorophenoxymethyldithiocarbamate in portions. After another 1 to 2 hours, the mixture was poured into water and partitioned into ethylene chloride. The dried ethylene chloride mixture was saturated with dry hydrogen chloride and the resulting salt collected by filtration. Hydrolysis of the salt in a chloroform-water mixture followed by separation, drying and concentration of the chloroform layer gave 3.5 g. of the dithietane as pale yellow crystals, m.p. 64.5°-66.0°C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([CH3:33])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=1[CH3:33]
Reactant: Cc1c(F)cccc1B(O)O
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: Cc1c(F)cccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 7 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-fluoro-2-methylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2,3′-difluoro-2′-methylbiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 7%): m/z (ES+) 397 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Cc2ccc(C(=O)O)cc2OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and ethanol (5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to ambient temperature, acidified with 2 mol/L hydrochloric acid, and the mixture was stirred under ice-cooling for 30 minutes. The resulting precipitated crystals were collected by filtration, washed with water and dried to give 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid (1.4 g).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH3:6][Si:7]([O:10][P:11]([O-:17])[O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8].C(N([Si](C)(C)C)CC)C>>[P:11]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([O:10][Si:7]([CH3:6])([CH3:9])[CH3:8])[O:17][Si:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)OP([O-])O[Si](C)(C)C
Agent: CCN(CC)[Si](C)(C)C
Product: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (40.4 g, 40.4 mmol) was added dropwise to a mechanically stirred solution of phosphorous acid (16.5 g, 201 mmol) and chlorotrimethylsilane (44 g, 405 mmol) in diethyl ether (1200 cm3). Immediately, a white precipitate of triethlyamine hydrochloride formed. After the addition was complete (2 h) the mixture was stirred for a further 2 hours. The insoluble salt was removed by filtration and the filtrate concentrated to about 200 cm3. The small quantity of additional precipitate formed during this process was subsequently filtered off and the filtrate evaporated to give a cloudy liquid. The product was purified by distillation under reduced pressure, the fraction boiling in the range 45-50° C. at 0.1 mbar being collected. The bis(trimethylsilyl) phosphite was isolated as a colourless oil (35 g, 77%). 31P NMR: δ−12.8. Chlorotrimethylsilane (20 g, 185 mmol) was added dropwise to a stirred solution of bis(trimethylsilyl)phosphite (30 g, 132 mmol) and N,N-diethyltrimethylsilylamine (20 g, 137 mmol) and the mixture stirred at room temperature for 1 h. The solid formed was removed by filtration and the filtrate distilled in vacuo. A colourless fraction boiling at 77-80° C. at 0.1 mbar was collected (30 g, 75%). 31P NMR: δ+116.3.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3([NH:18][C:19]([C:21]4([NH:24][C:25]([C:27]5[N:31]6[C@:32]([CH3:56])([CH2:44][C:45]7[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=7)[C:33](=[O:43])[N:34]([C:35]7[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=7)[C:30]6=[N:29][CH:28]=5)=[O:26])[CH2:23][CH2:22]4)=[O:20])[CH2:17][CH2:16]3)[CH:12]=[CH:11][CH:10]=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2([NH:18][C:19]([C:21]3([NH:24][C:25]([C:27]4[N:31]5[C@:32]([CH3:56])([CH2:44][C:45]6[CH:46]=[CH:47][C:48]([O:51][C:52]([F:53])([F:55])[F:54])=[CH:49][CH:50]=6)[C:33](=[O:43])[N:34]([C:35]6[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=6)[C:30]5=[N:29][CH:28]=4)=[O:26])[CH2:22][CH2:23]3)=[O:20])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(C3(NC(=O)C4(NC(=O)c5cnc6n5[C@](C)(Cc5ccc(OC(F)(F)F)cc5)C(=O)N6c5cc(Cl)cc(Cl)c5)CC4)CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cccc(N)n5)CC4)CC3)n21
Yield: 51.6 %

Procedure:
A solution of (R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-{6-[bis-(4-methoxy-benzyl)-amino]-pyridin-2-yl}-cyclopropylcarbamoyl)-cyclopropyl]-amide (80 mg, 0.084 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 4 h. The solvent was removed under a stream of N2 and the residue was partitioned between EtOAc (4 mL) and saturated aqueous NaHCO3 (4 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×4 mL). The combined organics were evaporated in vacuo, and the residue was purified via reverse phase HPLC. The purified material was then passed through a basic amino group functionalized solid phase extraction cartridge to give 31 mg (51%) of the title compound as a white solid, m/z 715.0 [M+2]+.
Reaction SMILES: [NH2:1][OH:2].O.[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].S(Cl)(Cl)(=O)=O>C1COCC1.C(Cl)Cl>[OH:2][NH:1][S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([S:5]([CH3:4])(=[O:7])=[O:6])[CH:9]=1)(=[O:16])=[O:15]
Reactant: NO
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(S(=O)(=O)NO)c1

Procedure:
To a solution of aqueous hydroxylamine (16 mL of a 50% aqueous solution, 245 mmol) in THF (150 mL) and water (25 mL) cooled to −5° C. was slowly added 3-methanesulfonylbenzene-1-sulfonyl chloride (25 g, 98 mmol) while maintaining a reaction temperature of less than 10° C. The reaction was maintained at this temperature until substantially complete consumption of the sulfonyl chloride was observed (about 5 min), after which time the reaction was diluted with DCM (250 mL), the organic portion was separated and washed twice with 50 mL of water. The aqueous extracts were combined and rewashed twice with DCM (250 mL for each wash). All of the organic portions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a beige solid. Trituration was carried out using heptanes:EtOAc (1:1; v:v) to provide the title compound as a beige solid (14 g, yield 56%). LC-MS tR=0.90 min; High Resolution Mass Spectroscopy (HRMS): theoretical (C7H9NO5S2)=249.9844, measured=249.9833; 1H NMR (500 MHz, DMSO-d6) δ ppm 9.85 (2H, q, J=3.3 Hz), 8.31 (1H, t, J=1.6 Hz), 8.28 (1H, dt, J=7.8, 1.3 Hz), 8.14-8.19 (1H, m), 7.93 (1H, t, J=7.9 Hz), 3.32 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](O)([C:15]3[C:23]([OH:24])=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1.OC1(C2C(O)=CC3OCOC=3C=2)C2C(=CC=CC=2)N(CCCCC)C1=O>>[OH:24][C:23]1[C:15]([CH:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH2:4][CH2:1][CH2:2][CH3:3])[C:7]2=[O:26])=[CH:16][C:17]2[O:21][CH2:20][O:19][C:18]=2[CH:22]=1
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.67 (br, 1H), 7.39-7.29 (m, 2H), 7.18-7.13 (m, 1H), 6.94 (d, 1H), 6.62 (s, 1H), 6.32 (s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H), 3.71-3.63 (m, 2H), 1.71-1.61 (m, 2H), 1.35-1.27 (m, 4H), 0.86 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.8, 151.3, 147.6, 143.9, 141.53, 128.7, 126.4, 126.2, 123.1, 115.3, 109.4, 106.5, 101.5, 101.2, 47.4, 40.5, 28.9, 26.9, 22.3, 13.9; MS (ES+) m/z 340 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][C:22]([CH3:25])([CH3:26])[CH2:21][CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 0.1 %

Procedure:
To a solution of N-isopropyl-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 227 mmol) in dichloromethane (3 mL) was added TFA (1.48 g, 1 mL, 13.0 mmol). The reaction mixture was stirred at 25° C. for 15 h then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide; 60:10:1 and stirred at 25° C. for 3 h, then evaporated to a yellow solid. The solid was dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (40 g, 50 μm particle size, Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane, 15 min). The pure product was re-dissolved in MeOH and allowed to stand for solid formation. The solid was separated by decanting the mother liquors and then dried to give N-isopropyl-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 164 μmol, 72%) as a white needles. MS (M+H)+=367; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.47-12.74 (m, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 7.92 (d, J=8.31 Hz, 1H), 4.07-4.48 (m, 1H), 3.78 (s, 3H), 2.72 (s, 2H), 2.64 (t, J=6.42 Hz, 2H), 1.60 (t, J=6.42 Hz, 2H), 1.26 (d, J=6.42 Hz, 6H), 1.01 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: COc1ccc(Cc2oc3c(Cl)ccc(O)c3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c12
Temperature: 25 °C
Yield: 113.2 %

Procedure:
To a solution of 4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran (164) (Example 44) (1.5 g, 5 mmol) in 30 mL acetone was added potassium carbonate (690 mg, 5 mmol) and allyl bromide (605 mg, 5 mmol). The mixture was refluxed for 20 h, then filtered through celite after cooling to room temperature. Concentration of the filtrate gave 1.94 g of the 4-allyloxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran as a light brown oil. The crude material was refluxed in 8 mL o-dichlorobenzene for 6 h. Evaporation of the solvent followed by chromatography gave the title compound as a white solid, mp 90°-93° C
Reaction SMILES: C(O[C:4](=[O:38])[C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7][CH:6]=1)C.[CH:39]([NH2:42])([CH3:41])[CH3:40]>>[CH:39]([NH:42][C:4](=[O:38])[C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7][CH:6]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cncc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)NC(C)C)c3)cc12
Reaction time: 48 h
Yield: 35 %

Procedure:
Into a 5 mL screw-cap vial were added 5-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester (50.2 mg, 0.095 mmol) and isopropylamine (500 μL). The vial was sealed and placed in heated block at 100° C. for 48 h. The reaction solution was concentrated and the residue was dissolved in 1:1 MeOH/acetone (2 mL total) and treated with 100 μL of 50% w/w KOH(aq) for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was partitioned between EtOAc and water, then the layers were separated, and the organic phase was washed 2× with water. The organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexanes afforded the title compound as a white powder (13 mg, 35%). 1H-NMR (500 MHz, d6-DMSO) δ=11.96 (br. s, 1H), 9.05 (d, J=2.5 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.76 (s, 1H), 7.61 (d, J=5.5 Hz, 1H), 7.29 (dd, J=2, 7.5 Hz, 1H), 7.12 (d, J=7.5 1H), 7.04 (d, J=7.5 Hz, 1H), 4.11 (m, 1H), 3.84 (s, 3H), 1.17 (s, 6H); MS: m/z 387.1 [MH+].
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:23].[CH3:24][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C[O-].[Na+]>CO>[I-:23].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N+:25]=3[CH3:24])=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: Cc1cccc[n+]1C
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=Cc2cccc[n+]2C)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.12 g, 0.38 mmol), 1,2-dimethylpyridinium iodide (0.12 g, 0.51 mmol) and methanolic sodium methoxide (1M, 0.38 ml, 0.38 mmol) in methanol (10 ml) was carefully heated until the reagents had completely dissolved, after which the reaction mixture was allowed to cool to room temperature. A yellow precipitate started to separate after about 2 h. The reaction mixture was left over-night (18 h), after which the precipitate was filtered off and washed well with methanol to give (17c)(0.11 g, 54%) as a fine yellow solid, m.p. 210°-230° C. (decomp.), [α]D -14° (c 1, DMSO).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([CH3:16])=[C:14](Br)[CH:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])[S:5][CH:6]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([CH3:16])=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)[CH:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1csc(NC(=O)c2nc(C)cc(Br)c2C)n1
Product: Cc1csc(NC(=O)c2nc(C)cc(-c3ccc(F)c(Cl)c3)c2C)n1

Procedure:
The title compound, was prepared from 4-Bromo-3,6-dimethyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide and 3-Chloro-4-fluorophenylboronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a light yellow solid, MS (ISP): m/e=376.2, 378.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH2:15][OH:16])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.C1COCC1>O=[Mn]=O.C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2-n2nc(CO)cc21
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)NC2=O

Procedure:
A solution of 5.85 g. (17 mmol) of the end product of Example 14 in 600 ml. dry THF was mixed with 24 g. of activated MnO2 and heated to reflux for 17 hours. The mixture was cooled, filtered and the collected solids washed thoroughly with THF. The combined filtrate and washings were concentrated in vacuo. Recrystallization of this crude product from THF/hexane yielded the desired end product. An analytical sample was prepared by an additional recrystallization from THF/hexane and was obtained as colorless plate: mp 276°-278°.
Reaction SMILES: [CH3:1][C@H:2]1[C@:10]2([OH:24])[C@H:11]3[C@:16]([OH:22])([CH2:17][C:18]([CH2:20][OH:21])=[CH:19][C@H:9]2[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@:4]2([OH:25])[C@@H:3]1O)[C:14](=[O:15])[C:13]([CH3:23])=[CH:12]3.S(=O)(=O)(O)O>>[CH3:1][C@H:2]1[C@:10]2([OH:24])[CH:11]3[C@:16]([OH:22])([CH2:17][C:18]([CH2:20][OH:21])=[CH:19][C@H:9]2[C@H:5]([C:6]([CH3:8])=[CH2:7])[C:4](=[O:25])[CH2:3]1)[C:14](=[O:15])[C:13]([CH3:23])=[CH:12]3
Reactant: CC1=C[C@H]2[C@@]3(O)[C@H](C)[C@@H](O)[C@]4(O)[C@H]([C@@H]3C=C(CO)C[C@]2(O)C1=O)C4(C)C
Agent: O=S(=O)(O)O
Product: C=C(C)[C@@H]1C(=O)C[C@@H](C)[C@]2(O)C3C=C(C)C(=O)[C@@]3(O)CC(CO)=C[C@@H]12
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a 50 mL round-bottom flask containing a stirbar and phorbol (1.76 g, 4.82 mmol, 1.0 eq) at ambient temperature (23° C.) was added sulfuric acid (0.01 M aqueous H2SO4 solution: 16 mL, 0.3 M with respect to phorbol). The flask was equipped with a reflux condenser, the system flushed with a stream of dry nitrogen, and the cloudy, slightly yellow mixture heated to 90° C. After 1 h, the reaction vessel was cooled to room temperature (23° C.), the aqueous solution extracted with EtOAc, and the organic phase washed with brine. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography on a 4.5×18 cm silica gel column eluting with a solvent gradient from 75% to 90% EtOAc/petrol ether followed by elution with 100% EtOAc. The eluant was collected in 75 mL portions, and the crotophorbolone containing fractions were combined and concentrated to give crotophorbolone (654 mg).