Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[Na+].[CH3:7][C:8]1[CH2:9][C:10]2[C:15]([CH:16]=1)=[C:14](Cl)[CH:13]=[CH:12][CH:11]=2.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=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].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O>[CH3:7][C:8]1[CH2:9][C:10]2[C:15]([CH:16]=1)=[C:14]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])[CH:13]=[CH:12][CH:11]=2
Reactant: CC1=Cc2c(Cl)cccc2C1
Reactant: CNc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Product: CC1=Cc2c(cccc2N(C)c2ccccc2)C1
Temperature: 70 °C
Yield: 69.4 %

Procedure:
Pd(dba)2 (0.25 g, 0.4 mmol, 1.4 mol %), PtBu3 (0.11 g, 0.5 mmol, 1.8 mol %), NaOtBu (4.5 g, 45.4 mmol, 1.5 eq), 2-methyl-4-chloroindene (5 g, 30 mmol, 1 eq) and N-methyl phenylamine (3.25 g, 30 mmol, 1 eq.) were mixed together and stirred at 70° C. After 2 h of stirring, the reaction was cooled down and H2O was added. The formed layers were separated and the organic phase was washed with NH4C1 and H2O. The organic layer was then dried over MgSO4, filtered and concentrated. Chromatography over SiO2 (Hexan/CH2Cl2:2/1) gave a green oil (4.9 g) in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=O)[CH2:12][C:11]([CH2:15][CH2:16][CH3:17])=[N:10]2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:19]>CC#N>[Br:19][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:11]([CH2:15][CH2:16][CH3:17])[CH:12]=1
Reactant: CCCC1=NN(c2ccc(OC)cc2)C(=O)C1
Reactant: BrP(Br)Br
Solvent: CC#N
Product: CCCc1cc(Br)n(-c2ccc(OC)cc2)n1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 45.6 %

Procedure:
1-(4-Methoxyphenyl)-3-propyl-1H-pyrazol-5(4H)-one (495 mg, 2.13 mmol) was put in a microwave tube and closed, MeCN (2.1 mL) and PBr3 (6.4 mL, 68.2 mmol) were added via syringe and the reaction was stirred at 150° C. for 40 min in the microwave. The product poured onto ice and was extracted with EtOAc. The organic phase was separated from the water phase and evaporated. The crude product was purified on silica column (CH2Cl2/Et2O, 1:1) to give 5-bromo-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole (287 mg, 46%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH2:24][CH2:25][NH2:26].O>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:26][CH2:25][CH2:24][CH2:23][C@@H:22]([C:27]([OH:29])=[O:28])[NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: NCCC[C@H](N)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCNCCC[C@H](N)C(=O)O
Yield: 90.1 %

Procedure:
ornithine oleate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 29.1 g of Nδ-oleyl ornithine (yield 86.9%). This is designated Derivative B.
Reaction SMILES: C([O:9][CH2:10][CH2:11][S:12]([O-:15])(=[O:14])=[O:13])(=O)C1C=CC=CC=1.[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+].Cl.C(C(C)=O)C(C)C>CO>[OH:9][CH2:10][CH2:11][S:12]([O-:15])(=[O:14])=[O:13].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCCS(=O)(=O)[O-])c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: O=S(=O)([O-])CCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.9 g (6 mmol) of triphenylsulfonium 2-benzoyloxyethanesulfonate prepared in Synthesis Example 1-11, 56 mg (0.3 mmol) of 28 wt % sodium methoxide in methanol, and 15 g of methanol was stirred at room temperature for 12 hours. To the reaction solution, 30 mg of 35% aqueous hydrochloric acid was added to quench the reaction. The reaction solution was combined with methyl isobutyl ketone and concentrated in vacuum while distilling off the residual water. Diisopropyl ether was added to the residue for recrystallization. The crystals were collected and dried, obtaining the target compound, triphenylsulfonium 2-hydroxyethanesulfonate. White crystals, 2.1 g, yield 96%. The compound, designated PAG intermediate 1, has the following structure.
Reaction SMILES: C1(=O)CCCCC1.O=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O.[NH2:23]O>>[CH2:21]1[C:16]2[CH:17]([NH:23][CH:9]3[C:10]([CH:15]=2)=[CH:11][CH:12]=[CH:13][CH2:14]3)[CH2:18][CH2:19][CH2:20]1
Reactant: NO
Reactant: O=C1CCCCC1CC1CCCCC1=O
Solvent: O=C1CCCCC1
Product: C1=CCC2NC3CCCCC3=CC2=C1

Procedure:
Sym. octahydroacridine was prepared by converting cyclohexanone to di-(2-oxo-cyclohex-1-yl)-methane and further reacting with hydroxylamine according to the method of Gill et al. (JACS 1952, 74, 4923) and was isolated as a colourless oil b.p. 110-15°/0.5 mm. in 40% overall yield.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:32]3[CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nc(Cl)ccc3n2Cc2cccc(Cl)c2)C1
Temperature: 106 °C
Reaction time: 2 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol, Strem) was added to a degassed mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (0.50 g, 1.1 mmol, prepared as in Example 103, Step 2), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.414 g, 1.40 mmol, Combi-Blocks) and Na2CO3 (0.60 g, 5.6 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL), and the sealed reaction mixture was heated at 106° C. for two hours. Additional tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.33 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) were added, and heating was continued for additional two hours. Upon cooling to room temperature, the reaction mixture was diluted with water, and the aqueous layer was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes. Yield: (0.12 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>CCCCC>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5]([CH2:2][CH2:3][CH:4]([CH3:5])[CH3:12])([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Reactant: CC(C)CCBr
Solvent: CCCCC
Product: CC(C)CCC1(CCC(C)C)c2cc(Cl)ccc2-c2ccc(Cl)cc21
Yield: 90 %

Procedure:
Following the procedure of Example 1,2,7-dichloro-9,9-di(3-methyl-1-butyl)fluorene is prepared from 2,7-dichlorofluorene and 1-bromo-3-methylbutane as colorless crystals (recrystallized from pentane) in 90 percent yield, melting point 116° C. to 117.5° C. The spectral data is consistent with the title structure and HPLC analysis shows the purity as 99 percent and greater.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[CH:17]=[C:12]2[CH:11]=[C:10]1[C:28]([N:30]1[CH2:35][CH2:34][C:33]([F:37])([F:36])[CH2:32][CH2:31]1)=[O:29])(C)(C)C.FC(F)(F)C(O)=O>>[F:37][C:33]1([F:36])[CH2:34][CH2:35][N:30]([C:28]([C:10]2[N:9]([CH2:8][CH2:7][OH:6])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CCO[Si](C)(C)C(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CCO)CC1
Yield: 66.4 %

Procedure:
The solution of 55 mg (97 μmol) [1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone was cooled down to 0° C. and 1 ml (1.49 g, 13 mmol) trifluoroacetic acid was added. The cooling bath was removed and stirring was continued for another hour at room temperature. The reaction was neutralized with 1M aqueous sodium hydroxide solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 29 mg (66%) of the product as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5]2.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.CCOC(C)=O>[CH2:20]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of 21A (310 mg, 1.096 mmol) in 1,2-dichloroethane (7 mL) was added benzaldehyde (235 mg, 2.193 mmol), followed by sodium triacetoxyborohydride (650 mg, 3.069 mmol) and AcOH (200 mg, 3.29 mmol). The reaction mixture was stirred at RT for 4 h, then diluted with EtOAc, washed with saturated aqueous NaHCO3, water, brine, dried Na2SO4) and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc/hexane 1:5 to give the title compound as light yellow foam (325 mg, 80%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:20])([F:19])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:9]>ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:7]([F:6])([F:20])[F:19]
Reactant: COc1ccccc1NC(=O)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1NC(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
Placed chlorosulfonic acid (33 mL, 274 mmol) in a 500 mL four necked round bottomed flask. Then added, 2,2,2-Trifluoro-N-(2-methoxyphenyl)acetamide (20 grams, 91.3 mmol) in dichloro methane (100 mL) drop wise, under stirring in 45 minutes at 0° C. The reaction mass was allowed to reach room temperature and stirred for another 2 hours. Quenched the reaction mass into ice cold water and extracted with ethyl acetate (4×200 mL), the combined organic layer was washed with brine solution (1×50 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to obtain syrupy product. Yield: 17.5 grams.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>C1COCC1>[O:19]=[C:17]1[O:10][C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:8][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCC(=O)NNc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1nn(-c2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.4 mmol) of 3-(N′-phenyl-hydrazinocarbonyl)-propionic acid were dissolved in 10 ml of THF and 213 mg (0.7 mmol) of triphosgene were added. The reaction mixture was stirred at room temperature overnight. Then a saturated sodium hydrogencarbonate solution was added, and the mixture was evaporated to dryness under reduced pressure. The residue was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 315 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:20])([CH3:19])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[CH3:19][C:7]1([CH3:20])[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])=[CH:3][CH:4]=2)[CH:8]1[C:11]1[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1ncncc1C1c2cc(N)ccc2CC1(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ncncc1C1c2cc(NS(=O)(=O)c3ccccc3)ccc2CC1(C)C

Procedure:
To a solution of 1.0 g (3.5 mmol) of 5-(6-amino-2,2-dimethylindan-1-yl)-4-methylthiopyrimidine in 20 mL of dry pyridine was added with stirring 0.45 g (3.7 mmol) of benzenesulfonyl chloride. The mixture was allowed to react for 16 hr and was then poured into dilute aqueous hydrochloric acid with stirring. The resulting mixture was extracted with ether and the ethereal extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The remaining oil was diluted with a small amount of dichloromethane and then hexane was added. The precipitate that formed was collected by filtration and dried under reduced pressure to obtain 700 mg (88 percent of theory) of the title compound as a tan solid melting at 174°-176° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([O:31][CH3:32])=[O:30])=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:43]1[CH:48]=[CH:47][CH2:46][CH2:45][CH2:44]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[C:1]([O:5][C:6]([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[O:35][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([O:31][CH3:32])=[O:30])=[CH:22][N:23]3[CH:26]([CH3:27])[CH3:28])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1=COCCC1
Reactant: COC(=O)c1cn(C(C)C)c2cc(-c3ccc(CCN(C[C@H](O)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cn(C(C)C)c2cc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc12

Procedure:
To a solution of methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylate (340 mg) in dichloromethane (5 ml) were added 3,4-dihydro-2H-pyran (0.105 ml) and a catalytic amount of pyridinium p-toluenesulfonate at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylate (310 mg).
Reaction SMILES: CO[C:3]([C:5]1[C:10]2[S:11][C:12]([CH3:15])=[C:13]([Br:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH:27][O:28][CH3:29].CCN(CC)CC>CN(C=O)C.C(Cl)Cl.O>[CH3:29][O:28][N:27]([CH3:26])[C:3]([C:5]1[C:10]2[S:11][C:12]([CH3:15])=[C:13]([Br:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c(Br)c(C)sc12
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
3-Bromo-2-methyl-benzo[b]thiophene-7-carboxylic acid methyl ester 7.82 g, 27.43 mmol) was treated with NaOH (5 M, 28 mL, 140 mmol) and H2O (100 mL). It is refluxed for 4 h; cooled to 0° C., and acidified to pH (3-4) using 5 M HCl. The resulting precipitate is collected by filtration, washed with H2O (50 mL), and dried in a vac-oven. The material obtained is then treated with oxalyl chloride (2M, 27 mL) with a few drops of DMF. The reaction is stirred at 0° C. for 10 min, and at rt for 4 h. The excess reagent and solvent are removed in vacuo. The residue is finally treated with N,O-dimethyl hydroxylamine hydrochloride (4.00 g, 41.14 mmol) and Et3N (9.6 mL, 68.58 mmol) and CH2Cl2 (200 mL), and the resulting reaction mixture is stirred at rt for 2 h. It is diluted with CH2Cl2 (200 mL), washed with 0.1 M HCl (3×300 mL); dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (6.87 g, 21.89 mmol, 53%). 1H NMR (CDCl3): δ. 2.56 (s, 3H), 3.42 (s, 3H), 3.59 (s, 3H), 7.45 (t, J=7.9 Hz, 2H), 7.81-7.87 (m, 1H) ppm. ES-MS (m/z): calcd for C12H12BrNO2S (M)+: 314.1. found: 314.2.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[C:21]1([CH2:27][C:28]2[O:32][N:31]=[C:30]([CH2:33][CH2:34][CH2:35]O)[N:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:35][CH2:34][CH2:33][C:30]3[N:29]=[C:28]([CH2:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:32][N:31]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: OCCCc1noc(Cc2ccccc2)n1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 16.7 %

Procedure:
To a stirred solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20, 0.67 mmol) in THF (5 ml) was added 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (0.162 g, 0.74 mmol), DBAD (0.186 g, 0.81 mmol) and triphenylphosphine (0.212 g, 0.81 mmol) and the solution stirred for 18 h. To the solution was added Pd(PPh3)4 (75 mg, 0.067 mmol) and morpholine (604 μl, 6.7 mmol) were added and stirred for at rt under nitrogen for a further 3 h. 75 mg of Pd(PPh3)4 was added and the mixture left to stir for another 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH to elute the compound. The product fractions were combined and concentrated then further purified by MDAP. The product fractions were combined and concentrated give the title compound as a white solid (51 mg, 20%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][NH2:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([NH:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])=[N:15][CH:16]=1
Reactant: CCCCc1noc(C)c1CN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)OC)cn1
Temperature: 160 °C
Yield: 48.6 %

Procedure:
C-(3-Butyl-5-methyl-isoxazol-4-yl)-methylamine (320 mg, 1.90 mmol) was dissolved in DMSO (3 mL), methyl 6-chloronicotinate (326 mg, 1.90 mmol) and N,N-diisopropylethylamine (492 mg, 3.80 mmol) added, and the reaction mixture heated under microwave irradiation at 160° C. for 1 h. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (280 mg, 49%) as a white solid. MS: m/e=348.5 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BrH:13]>>[BrH:13].[Br:13][CH2:2][CH2:3][NH:4][C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NCCO)c1ccccc1
Agent: Br
Product: C[C@@H](NCCBr)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
11.0 g (66.58 mmole) of (R)-(+)-N-(2-hydroxyethyl)-α-methylbenzylamine produced in Example 8(1) above was suspended in 52 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 55 ml of acetone, and 50 mg of ethyl acetate and 70 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 30 ml of ethyl acetate and then dried to obtain 10 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 60 ml of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of acetone, diluted with 70 ml of ether and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected and washed with 30 ml of ethyl acetate to obtain 3.1 g of the second crop of the title compound.