Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=O>>[O:16]=[C:10]1[C:9](=[CH:17][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][N:28]([CH:31]=[O:32])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1ccc(N2CCN(C=O)CC2)cc1
Product: O=CN1CCN(c2ccc(C=C3C(=O)Nc4cccc(-c5ccncc5)c43)cc2)CC1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-(4-formylphenyl)-piperazine-1-carbaldehyde to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[CH:35].C(#N)C>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: ClCCl
Product: COc1cnc2c(Oc3ccc(Nc4nnc(C#CC(C)(C)C)c5ccccc45)cc3)ccnc2c1
Temperature: 90 °C

Procedure:
A resealable pressure bottle, purged with argon, was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.28 mmol), bis(triphenylphosphine)palladium(ii) chloride (24 mg, 0.03 mmol), copper(I) iodide (6.4 mg, 0.03 mmol), 3,3-dimethyl-1-butyne (86 μl, 0.70 mmol), and ACN (2.8 mL, 0.1 M). To the mixture was added TEA (0.785 mL, 5.6 mmol). The reaction vessel was sealed and the mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with DCM and filtered over Celite. The filtrate was concentrated under reduced pressure to give a brown residue, which was purified by Gilson HPLC {5-65% (0.1% TFA in CH3CN) in H2O over 20 min}. The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with DCM. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(3,3-dimethylbut-1-ynyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine MS [M+H]=476.1 Calc'd for C29H25N5O2: 475.5.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1C=CC=CC=1.Cl.[N:19](=[CH:27][CH2:28]Cl)[CH2:20][CH2:21][CH2:22][CH2:23]CCCl.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd].O.CN(C=O)C>[N:19]1([CH2:4][CH2:3][O:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:28][CH2:27]1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: ClCC=NCCCCCCCl
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Oc1ccc(OCCN2CCCCCC2)cc1
Temperature: 60 °C
Yield: 59879.3 %

Procedure:
Add sodium hydride (18 g, 0.45 mol) into a solution of 4-benzyloxylphenol (41 g, 0.20 mol) and 2-(hexamethyleneimino)ethyl chloride hydrochloride (44 g, 0.22 mmol) in TIE (600 mL) and DMF (100 mL) at room temperature. Heat to 60° C. for 30 minutes. Pour the solution into ice and water. Dilute with ethyl acetate (500 mL) and separate layers. Dry the organic layer with magnesium sulfate, filter and concentrate under reduced pressure to give brown oil. Dissolve the oil in ethyl acetate (500 mL) and methanol (500 mL). Add ammonium formate (100 g, 1.59 mol) and palladium on carbon (10 g, 9.4 mmol). Heat the mixture to reflux for 30 minutes. Add ammonium formate (100 g, 1.59 mol) and palladium on carbon (10 g, 9.4 mmol). Heat the reaction mixture for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 31 g (64%) of 4-(2-azepan-1-yl-ethoxy)-phenol.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]([CH3:24])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]([CH3:24])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1cccnc1)c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cccnc1)c1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
N-tert-butyl-2-(methyl(pyridin-3-yl)amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 83.6 μmol) was dissolved in dichloromethane (1.5 mL) and treated with trifluoroacetic acid (191 mg, 129 μL, 1.67 mmol). After 16 h, the mixture was concentrated and the residue re-dissolved in dichloromethane (1.5 mL), methanol (0.75 mL) and ammonium hydroxide (0.2 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated then triturated with water and filtered to obtain a solid. This was washed with ether then dried to give N-tert-butyl-2-(methyl(pyridin-3-yl)amino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 49.3 μmol, 59%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.33 (s, 1H), 8.64 (d, J=2.5, 1 H), 8.40 (dd, J=4.7, 1.2, 1 H), 8.05 (d, J=3.1, 1 H), 7.96 (s, 1H), 7.92 (s, 1H), 7.82 (m, 1H), 7.46 (m, 1H), 3.50 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 325.1 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(F)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 21.2 %

Procedure:
To a solution of 2.48 g (13.1 mmol) of the product prepared in step 10.1 in 26 mL of acetonitrile are added 2.43 g (13.1 mmol) of tert-butyl piperazinecarboxylate and 3.36 mL (19.65 mmol) of diisopropylethylamine. The reaction mixture is heated at 90°C. for 20 hours. It is diluted with ethyl acetate and washed with water and then with saturated aqueous NaCl solution. The crude solid is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (85/15 to 50/50). A 3.25 g fraction predominantly containing the regioisomer tert-butyl 4-(5-fluoro-3-methoxy-2-nitrophenyl)piperazine-1-carboxylicate is isolated. An impure secondary fraction is purified again on a column of silica, eluting with a dichloromethane/ethyl acetate gradient (96/4 to 94/6). 0.985 g of expected product is finally obtained in the form of a yellow solid. Yield=21%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[O:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[O:23]1[CH:27]=[CH:26][C:25]([CH2:28][N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)=[CH:24]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccccc2N2CCN(Cc3ccoc3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (50 mg, 0.166 mmol) produced in Example (8b), furan-3-carbaldehyde (0.02 mL, 0.231 mmol) and tetrahydrofuran (3 mL) was added sodium triacetoxyborohydride (43 mg, 0.203 mmol), followed by stirring for 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Diethyl ether was added to the obtained residue to produce a solid, and after further adding hexane, the solid was triturated by sonication. The supernatant solution was removed and the obtained solid was dried to give 33 mg of the title compound as colorless crystals.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:14]([NH2:16])=[O:15])[CH2:11][CH2:12][CH3:13].Cl.CCN(CC)CC>>[CH:1](=[N:16][C:14](=[O:15])[C@H:10]([CH2:11][CH2:12][CH3:13])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCC[C@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC[C@H](N)C(=O)N=Cc1ccccc1
Temperature: 23 °C
Reaction time: 1.17 h
Yield: 72.9 %

Procedure:
Fresh benzaldehyde (4.02 g, 37.9 mmol) was added to a slurry of 4.0 g L-norvalinamide.HCl (XII) (26.2 mmol) in 70 mL 1-PrOH, followed by 4.08 mL Et3N (29.3 mmol). The mixture, which became clear after stirring at 23° C. for 70 minutes, was then evaporated to 15 mL, and 175 mL Et2O added. After filtration, the precipitated salts were washed with additional Et2O, solvent evaporated from the combined filtrate, and residual benzaldehyde removed under high vacuum to give 5.13 g N-benzylidene-L-norvalinamide (XIII) as a light yellow solid (UV λmax =249 nm in MeOH). The purity of this material was determined by normal phase HPLC.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[CH:5]=1.S(=O)(=O)(O)O.[CH3:19]O>>[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:19])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: CO
Reactant: NCc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CN)cc1F

Procedure:
4-Aminomethyl-2-fluorobenzoic acid hydrochloride (500 mg) was dissolved in methanol (10 mL), concentrated sulfuric acid (6 μL) was added, and the mixture was stirred with heating under reflux for 9 hr. After completion of the reaction, the solvent was evaporated, saturated aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (181 mg).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>>[N+:32]([C:28]1[CH:27]=[C:26]([NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[C:9]([S:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:24])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: Nc1cccc2c1C(=O)c1cccc(Sc3ccccc3)c1C2=O
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2cccc(Sc3ccccc3)c2C(=O)c2cccc(Nc3cccc([N+](=O)[O-])c3)c21
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of 23.2 parts of 1-amino-5-phenylmercaptoanthraquinone, 14.35 parts of 1-chloro-3-nitrobenzene, 7 parts of sodium carbonate and 140 parts of nitrobenzene is dehydrated in the course of one hour, whilst stirring at the boiling point and whilst passing a stream of nitrogen through the mixture. After adding 0.42 part of copper-I chloride, the mixture is kept at 205°-210° for 18 hours, whilst a moderate stream of nitrogen is passed through. After cooling to 20°, the reaction product is filtered off, washed with nitrobenzene, ethanol and hot water and finally heated to the boil with 5% strength hydrochloric acid, filtered off, washed until acidfree and dried. This gives 25.7 parts (81% of theory) of 1-(3'-nitrophenylamino)-5-phenylmercaptoanthraquinone; melting point 246°. The colorant dyes polyester orange in bulk.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[CH2:1]([N:9]1[CH2:10][CH2:11][CH:12]([O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[CH2:13][CH2:14]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OC1CCN(CCc2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OC1CCN(CCc2ccccc2)CC1
Yield: 91.3 %

Procedure:
Similarly as in Reference Example 1, 5.40 g of 1-phenethyl-4-hydroxypiperidine and 2.65 g of diketene were reacted. The reaction mixture was concentrated, and then purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 6.95 g of acetoacetic acid-N-phenethyl-4-piperidinyl ester (yield: 91.3%).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[C:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:25]([CH:24]([NH:23][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:22])=[C:12]([C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:32])[N:3]=2)[C:13]1=[O:31])[CH2:28][CH2:29][CH3:30])[CH2:26][CH3:27]
Reactant: CCCC(CCC)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC(CCC)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
The product of Example 227A (0.032 g, 0.07 mmol) in tetrahydrofuran (2 mL) and methanol (0.010 mL, 0.14 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.055 mL, 0.11 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was suspended in tetrahydrofuran (2 mL) and adsorbed onto approximately 0.5 g of silica gel and evaporated. A slurry of the crude product and silica in dichloromethane was loaded onto a 2 g Alltech Sep-pack and eluted with dichloromethane. Product containing fractions were combined and concentrated under vacuum to give the title compound (0.013 g, 40%). MS (ESI−) m/z 453 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (m, 6 H) 1.33 (m, 8 H) 3.13 (m, 1 H) 5.66 (d, J=4.04 Hz, 1 H) 7.05 (m, 1 H) 7.28 (m, 2 H) 7.51 (m, 2 H) 7.68 (m, 2 H) 8.06 (dd, J=7.72, 1.47 Hz, 1 H) 16.32 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21].[S:29](=[O:33])(=[O:32])([OH:31])[OH:30]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[S:29](=[O:31])(=[O:30])([OH:33])[OH:32].[C:23]1([S:20]([O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([OH:30])=[O:1])(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OCCOCCOCCOCCOCCOCCO)c1ccccc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: O=C(O)COCCOCCOCCOCCOCCOS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A 1.5.M aqueous solution of sulfuric acid (10 mL) was prepared at 0° C. and stirred while chromium trioxide was added to give an orange solution. The alcohol 12 (1 g, 2.29 mmol) was dissolved in acetone (15 mL) and the solution added dropwise to the sulfuric acid at 0° C. The mixture was allowed to warm to rt and stirred for 16 h. The resulting green solution was filtered through celite and concentrated in vacuo. The resulting aqueous residue was diluted with H2O and extracted with CH2Cl2 (3×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give 13 (672 mg, 65%) as a pale yellow oil which was not purified further.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24])[C:2]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:27]=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(OC)OC)c2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(OC)OC)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of methyl 2-bromo-3-cyclohexyl-1-(2,2-dimethoxyethyl)-1H-indole-6-carboxylate (0.16 M, 1 eq, from Step 1) in dioxane and Na2CO3 (6 eq of a 2M solution) was degassed by sonication for 10 min. 2-Formylphenylboronic acid (1.5 eq) and bis(triphenylphosphine) palladium(II)dichloride (20 mol %) were added and the reaction placed in a pre-heated oil bath at 108° C. for 20 min. After cooling to RT, the reaction was partitioned between H2O and EtOAc (×3). The combined organics were washed with HCl (1N), H2O, and brine before being dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (Biotage, 10% EtOAc/PE) gave the title compound as a pale yellow solid (85%); MS (ES+) m/z 472 (M+Na)+, 450 (M+H)+.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:17]1([N:23]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CCO
Product: C1=C(c2ccccc2)NN(c2ccccc2)C1c1ccccc1

Procedure:
20.8 g benzylideneacetophenone was condensed with 10.8 g phenylhydrazine in 400 ml boiling ethanol over 5 hours, and then allowed to cool. During the cooling process the desired reaction product separates. The sediment was filtered, washed with ethanol and dried.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[N:15]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16]1.CC(C)=[O:24].[OH-].[Na+]>O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[N:15]1[CH:19]=[CH:18][C:17]([C:20]([OH:24])=[O:21])=[CH:16]1
Reactant: O=Cc1ccn(-c2c(Cl)cccc2Cl)c1
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccn(-c2c(Cl)cccc2Cl)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 0.9 g of potassium permanganate in 10 ml of water was added dropwise to a mixture of 0.58 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-3-carbaldehyde and 20 ml of acetone while the mixture was maintained at 40° C. The resulting mixture was stirred at 40° C. for 2 hours. A deposited precipitate was filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.34 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-3-carboxylic acid of the formula:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([N:36]2[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]2)=[O:35])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([C:34]([N:36]5[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]5)=[O:35])[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CNC1)N1CC[C@@H](O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CC[C@@H](O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (75 mg, 0.19 mmol), azetidin-3-yl-((R)-3-hydroxypyrrolidin-1-yl)methanone (65 mg, 0.38 mmol), and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to afford 461 as a white solid (17 mg, 16%). LCMS (Method I): RT 2.34 min, [M+H]+ 546. 1H NMR (400 MHz, CDCl3): δ 7.96-7.95 (1 H, m), 7.73-7.69 (1 H, m), 7.22 (2 H, s), 4.52-4.48 (2 H, m), 4.31 (4 H, s), 3.82-3.82 (8 H, m), 3.59-3.57 (9 H, m), 3.32-3.30 (2 H, m), 1.98-1.97 (2 H, m), 1.40 (3 H, t, J=7.48 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([OH:14])[CH2:10]2)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)N1C2CCC1CC(O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.250 g, 6.28 mmol) in dichloromethane (62 mL) was added triethylamine (1.40 mL, 10.0 mmol) and methanesulfonyl chloride (0.722 mL, 9.38 mmol) dropwise. The solution was stirred 2 hrs, washed with sodium bicarbonate, dried over MgSO4, filtered, and concentrated. The crude oil (1.74 g) was taken on with no purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H), 2.04 (m, 6H), 2.18 (m, 2H), 3.02 (s, 3H), 4.14 (q, J=7.1 Hz, 2H), 4.29 (m, 2H), 5.02 (m, 1H); MS (ESI+Q1MS) m/z 278 [M+H]+