Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[B]1OC2C(=CC=CC=2)O1>C(Cl)Cl.C1(C)C=CC=CC=1.C(Cl)Cl>[F:21][C:2]([F:1])([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: CSc1ccc(OC(F)(F)C(=O)c2ccc(F)cc2)cc1
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1ccc(OC(F)(F)[C@H](O)c2ccc(F)cc2)cc1
Temperature: -70 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
To a solution of 2,2-difluoro-1-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanone (2.76 g, 8.84 mmol) and S-methyl-CS-oxazaborolidine in a mixture of DCM/Toluene (1/1, 40 ml) under nitrogen, at −70° C., a solution of catecholborane (1.27 g, 10.6 mmol) in DCM (2 ml) was slowly added. After stirring at −70° C. for 18 h, the reaction mixture was quenched by adding 4M solution of HCl in dioxane (3 ml). The heterogeneous mixture was stirred for 15 min at −70° C., then warmed to room temperature. Solvent was removed on a rotary evaporator and the resulting solution was diluted with hexanes (80 ml). Water (0.5 ml) was added and the mixture was stirred for 15 min. The solids were filtered and the filter cake was washed with hexanes. The filtrate was washed with 10% aqueous sodium metabisulfite (15 ml) and brine (15 ml). The organic phase was dried over sodium sulfate and the crude purified by flash chromatography, using EA/H (1/10) as eluent to give 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanol (1.55 g, 56%) as a white solid.
Reaction SMILES: O[CH2:2][N:3]([CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4](=[O:7])[O:5][CH3:6].B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[S:10][CH2:9][CH2:8][N:3]([C:4]([O:5][CH3:6])=[O:7])[CH2:2][C:16]=2[CH:15]=1
Reactant: COC(=O)N(CO)CCSc1ccc(OC)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N1CCSc2ccc(OC)cc2C1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A solution of compound 9 (20.0 mg) in 10 mL CH2Cl2 was treated with 1.1 eq. of BF3—OEt2 under Ar. The mixture was stirred overnight and washed with 1N HCl and sat. NaHCO3 Removal of the solvent gave the crude product and TLC analysis showed one major spot. The crude product was further purified on SiO2 column to provide the title compound (16 mg). The structure was confirmed by NMR and TLC comparison with authentic sample prepared by the reaction of 7-MeO-2,3,4,5-tetrahydro-1,4-benzothiazepine with methyl chloroformate.
Reaction SMILES: C([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])C1C=CC=CC=1.N[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:34]([CH:26]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[C:25]([NH:24][CH:15]1[CH:14]2[C:13](=[O:39])[CH2:12][CH:11]([C:9](=[O:10])[NH:8][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:23][N:21]3[C:22]2=[C:18]([CH:19]=[CH:20]3)[CH2:17][CH2:16]1)=[O:38])[CH:35]([CH3:36])[CH3:37]
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Reactant: Nc1ccccc1
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)Nc1ccccc1)C3
Yield: 38 %

Procedure:
The compound of Example 3h was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using aniline as the amine in the last step. Cleavage of 50 mg of functionalized resin (0.54 mmol/g) and purification by RP-HPLC provided 4.0 mg (38%) of the title compound as a white powder. MS (M+H)+=519.4.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].P(=O)(O)(O)O.[O-2:12].[Mg+2]>O>[OH:12][CH2:4][C@@H:2]([C@H:1]([C@@H:4]([C@@H:2]([CH2:1][OH:6])[OH:3])[OH:12])[OH:6])[OH:3]
Reactant: [O-2]
Reactant: CC(O)C(=O)O
Agent: O=P(O)(O)O
Agent: [Mg+2]
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 120 °C
Yield: 2941.2 %

Procedure:
The poly(lactic acid) was made by adding 102.77 grams of 85% lactic acid into a 4000 ml beaker. 3.03 grams of 85% phosphoric acid was then added. The mixture was heated to 120° C. for four hours until it was apparent that the water had been removed. After the water was removed, 11.75 grams of sorbitol was added and the polylactate continued to react for another 2 hours. The phosphoric acid was neutralized with 1.0 gram of magnesium oxide. A total of 66.47 grams of sorbitol hexapolylactate was produced. The sorbitol hexapolylactate is the hardest and thickest of the three esters.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10](=[C:17]([C:22]#[N:23])[C:18](OC)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4].C1CCCCC1>[CH:10](=[C:17]([C:22]#[N:23])[C:18]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(C#N)=Cc1ccccc1
Reactant: CCCCCCC(C)O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: C1CCCCC1
Product: CCCCCCC(C)OC(=O)C(C#N)=Cc1ccccc1
Temperature: 130 °C

Procedure:
143.60 g 2-octanol, 206.40 g methyl benzylidenecyanoacetate, 211.70 g cyclohexane and 0.56 g titanium (IV) tetrabutoxide were charged to a flask fitted with an oil bath for heating. The oil bath was heated to 130° C. and methanol was removed as an azeotrope for a period of approximately 25 hours. The methyl benzylidenecyanoacetate used in this synthesis was made by mixing 1.198 kg benzaldehyde, 1.119 kg methyl cyanoacetate, 0.920 kg absolute ethanol and 0.66 g piperidine. The mixture is refluxed for two hours and allowed to cool. The resulting product was a mobile liquid that was ±2-octyl benzylidenecyanoacetate having a representative structure shown below.
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])[CH3:4].[F:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([F:35])[CH:34]=1)[NH2:31]>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([NH:31][CH:3]([C:5]2[CH:6]=[C:7]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]3=[O:21])[CH3:4])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Solvent: CN(C)C=O
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
To a suspension of 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (3.63 g, 7.41 mmol, as described in Example 3.03) in DMF (35 mL) under nitrogen was added 3,5-difluoroaniline (3.82 g, 29.62 mmol). The resulting yellow solution was stirred at 50° C. for 5 hrs. The reaction mixture was concentrated to dryness, then purified by flash chromatography on silica gel eluting with 1 to 7% methanol in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.32 g, 68.5%) as a pale yellow solid. Mass Spectrum: M+H+ 458. NMR Spectrum: (DMSOd6) 1.52 (d, 3H), 2.74 (s, 3H), 2.95 (s, 3H), 3.50-3.64 (m, 4H), 3.70-3.79 (m, 4H), 4.97-5.05 (m, 1H), 5.60 (m, 1H), 6.15 (dd, 2H), 6.22 (tt, 1H), 6.96 (d, 1H), 7.54 (d, 1H), 7.81 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CNC(=O)[C@@H](NC(=O)c1cccc(-c2cccc(Cl)c2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (EI): m/e=360.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate, hydrochloride (71 g), and potassium hydroxide (38 g) in ethanol (450 ml) was refluxed for 6 hours. After cooling inorganic salts were filtered off and ethanol evaporated in vacuo. To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml). The organic phase was separated and worked-up as above. Yield of crude title product: 45 g (semicrystalline).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.CCOC(C)=O>[N:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of 4-bromobenzylbromide 1 (2.95 g, 11.8 mmol) in DMSO (5 mL) at room temperature, was added NaN3 (1.53 g, 23.5 mmol). The solution was heated to 80° C. and stirred for 1 h at this temperature. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using EtOAc/hexanes (10%) to give 1.88 g (76%) of 2 as a colorless oil. 1H NMR spectra was consistent with literature data. Shi, H.; Liu, J.; Geng, J.; Tang, B. Z.; Liu, B. J. Am. Chem. Soc. 2012, 134, 9569.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]3[NH:14][C:15](=[O:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.[CH3:26]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]3[N:14]([CH3:26])[C:15](=[O:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 35 mg) in dry N,N-dimethylformamide (5 ml) was added a solution of 2-(4-fluorophenyl)-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (250 mg) in dry N,N-dimethylformamide (3 ml) dropwise under ice cooling. The mixture was stirred for 30 minutes and to the mixture was added a solution of methyl iodide (125 mg) in dry N,N-dimethylformamide (2 ml). The mixture was stirred at ambient temperature for 2 hours and poured into water. The separated oil was extracted with dichloromethane and the solution was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of dichloromethane and diisopropyl ether to give 2-(4-fluorophenyl)-4-methyl-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (180 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](=[O:29])[CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.CN(C=O)C>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH2:45])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:24][N:23]([C:25]([CH3:27])([CH3:28])[CH3:26])[C:22](=[O:29])[CH:21]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(=O)n(C(C)(C)C)s2)cc1)C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(=O)n(C(C)(C)C)s2)cc1)C(N)=O
Yield: 139.3 %

Procedure:
A solution of 1-F (0.76 g, 1.8 mmol), Boc2O (0.52 g, 2.4 mmol), pyridine (99 μL, 1.3 mmol), and NH4CO3H (0.22 g, 2.8 mmol) in dioxane (4 mL) and DMF (1 mL) was stirred at 25° C. for 12 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with 0.1 N HCl (2×20 mL), saturated NaHCO3 (2×20 mL), and brine (20 mL), dried with Na2SO4, filtered, and concentrated to give a crude residue which was purified using flash column chromatography (100% CH2Cl2→10% MeOH/CH2Cl2) to yield 1-G as a brown-red solid (0.76 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 6.38 (s, 1H), 6.01 (br s, 1H), 5.45 (br s, 1H), 5.15–5.10 (m, 1H), 4.50–4.38 (m, 1H), 3.15 (dd, J=13.9, 6.8 Hz, 1H), 3.08 (dd, J=13.5, 6.5 Hz, 1H), 1.68 (s, 9H), 1.41 (s, 9H); LCMS found for C21H30N3O4S (M+H)+: m/z=420.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:24][CH:25]=1)[CH:6]=[CH:7][CH:8]=[C:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[O:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:24][CH:25]=1
Reactant: COc1cc(C=CC=C2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Agent: O=[Pt]
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Yield: 18.8 %

Procedure:
A mixture of 5-[3-methoxy-4-(2-phenyl-4-oxazolyl-methoxy)cinnamylidene]-2,4-oxazolidinedione (1.0 g), platinum oxide (PtO2) (0.2 g) and tetrahydrofuran (THF)-acetic acid (4:1, 190 ml) was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in chloroform, which was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, successively, followed by drying (MgSO4). The chloroform layer was concentrated under reduced pressure, and the concentrate was subjected column chromatography on silica gel. From the fraction eluted with chloroform-ethyl acetate (4:1), 5-[3-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione (0.19 g, 19%) was obtained. Recrystallization of the product from ethyl acetate-hexane gave colorless prisms, m.p.134-135° C.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)(=O)=O.FC(F)(F)C1C=CC(C2(C[C:40]#[N:41])CCCC2)=CC=1>>[F:20][C:18]([F:19])([F:21])[C:16]1[CH:17]=[C:12]([C:7]2([CH2:6][C:40]#[N:41])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:13]=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Product: N#CCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
2-(1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)acetonitrile (459) was synthesized as a brown solid from (1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl methanesulfonate (458) following the procedure described for [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241).
Reaction SMILES: [NH2:1][OH:2].Cl.NO.[OH-].[K+].CS[C:10](=[N:20][CH3:21])[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>CO>[CH2:13]([N:11]([CH3:12])[C:10]([NH:20][CH3:21])=[N:1][OH:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: CN=C(SC)N(C)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNC(=NO)N(C)Cc1ccccc1
Reaction time: 4 h
Yield: 1.2 %

Procedure:
A 100 ml. solution of hydroxylamine generated from hydroxylamine hydrochloride (5.86 g., 0.088 mol) and potassium hydroxide (4.59 g., 0.088 mol) was cooled to 0°. To this was added a 25 ml. methanol solution of S-methyl-N-benzyl-N,N'-dimethylisothiourea (3.53 g., 0.017 mol) over a 10 minute period. The mixture was allowed to stir for 4 hours. Methanol was then removed by evaporation and the residue redissolved in methylene chloride. After two washes with 100 ml. quantities of water, the organic layer was extracted with 20 ml. 1N hydrochloric acid. The aqueous layer was then made basic to pH 9 and extracted with methylene chloride. The organic layer was dried, evaporated, and resulted in 0.100 g. of an oil. The oil was separated into its components using high pressure liquid chromatography and 40 mg. (1.2% yield) of pure 1-benzyl-1,3-dimethyl-2-hydroxyguanidine was isolated. It had thin layer chromatographic and NMR properties identical to those of an authentic sample.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.O>CN(C=O)C>[CH2:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=2)[C:6](=[O:11])[CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 4-hydroxy-1-indanone (25.0 g, 169 mmol) and imidazole (28.7 g, 422 mmol) in DMF (500 ml) was added tert-butyldimethylchiorosilane. The reaction mixture was stirred overnight at room temperature and treated with water (500 ml) and extracted with diethyl ether (500 ml). The organic phase was collected and dried over sodium sulfate. Evaporation gave a yellow oil which was distilled under reduced pressure to give indanone (1) (35.44 g, 135 mmol, 79.9%) as a colourless oil (120–121° C./0.1 mbar).
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([OH:26])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: C#CCCCCCCCCCCCCCCCCCCCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C#CCCCCCCCCCCCCCCCCCCCC(=O)O
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Docos-21-ynol (12 g, 0.037 mol) was dissolved in warm acetone (600 ml) treated with Jones reagent (20 ml). After stirring for 30 minutes tlc showed complete reaction so the excess Jones reagent was quenched with propane-2-ol and the volatile components removed in vacuo. The organic fractions were combined, dried (MgSO4), filtered and evaporated to leave docos-21-ynoic acid (32) as a pale green solid (10.4 g, 83%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3[C:30](=[O:35])[CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[N:27]=[C:26]2[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[C:29]3[C:30]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[N:27]=[C:26]2[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl acetate (0.695 mL) was added dropwise to a stirred solution of LiHMDS, 1M in THF (7.10 ml) cooled to −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 30 minutes. Intermediate 14 was dissolved in THF (3 ml) and added dropwise. The RM was stirred at −78° C. under nitrogen for 2 hours. An excess of sat. NH4Cl aq. sol. added and the resulting suspension warmed up to room temp and extracted with EtOAc (100 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (50 ml), the phases were separated. The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a Dichloromethane:Ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (420 mg). LC/MS MH+419, Rt 1.93 min (5 minute run).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[CH:13]2)[C@@H:6]1[OH:22])[CH:2]=[CH2:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)Cl.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[NH4+].[OH-]>N1C=CC=CC=1.O>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH:17][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:15]=3[N:14]=[CH:13]2)[C@@H:6]1[OH:22])[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [NH4+]
Solvent: O
Solvent: c1ccncc1
Product: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reaction time: 1 h
Yield: 60.3 %

Procedure:
2′/3′-O-allyl adenosine (15.19 g, 51.1 mmol) was dried over P2O5 under high vacuum overnight at 40° C. It was then dissolved in anhydrous pyridine (504.6 mL) under inert atmosphere. Trimethylchlorosilane (32.02 mL, 252.3 mmol) was added at 0° C. and the reaction mixture was stirred for 1 hr under inert atmosphere. Then benzoyl chloride (29.4 mL, 252.3 mmol) was added dropwise. Once the addition of benzoyl chloride was over, the reaction mixture was brought to room temperature and stirred for 4 hrs. Then the reaction mixture was brought to 0° C. in an ice bath. Water (100.9 mL) was added and the reaction mixture was stirred for 30 minutes. Then NH4OH (100.0 mL, 30% aqueous solution w/w) was added, keeping the reaction mixture at 0° C. and stirring for an additional 1 hr. Solvent evaporated residue partitioned between water and ether. Product precipitates as an oil, which was then chromatographed (5% MeOH in CH2Cl2) to get the title compound as a white foam (12.67 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[N:20]=[C:19]([N:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18]([C:28]#[N:29])=[C:17]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=4)[C:16]=3[C:40]#[N:41])[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[NH2:29][C:28]1[C:18]2[C:19](=[N:20][C:15]([O:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][CH:10]=3)=[C:16]([C:40]#[N:41])[C:17]=2[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:34][CH:35]=2)[N:21]([CH3:27])[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CN(C)c1nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1c(N)c2c(-c3ccc(OCCO)cc3)c(C#N)c(OCc3coc(-c4ccc(Cl)cc4)n3)nc2n1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
20 mg (0.04 mmol) of the compound from Example 51A were initially charged in 1 ml of acetonitrile, and 45 mg (0.14 mmol) of cesium carbonate were added. The reaction mixture was stirred at 50° C. for 4 h. After cooling to RT, the mixture was filtered off. The precipitate was washed with acetonitrile and suspended in water. The mixture was extracted three times with in each case 10 ml of ethyl acetate, and the combined organic phases were dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the residue was purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gave the product as a solid.