Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]1)(C)(C)C>CO>[ClH:1].[NH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:14]1
Reactant: CC(=O)NC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)NC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl (2.0 M in MeOH, 200 mL) was added to a suspension of (4-acetylamino-cyclohexyl)-carbamic acid tert-butyl ester (14.3 g) in MeOH (100 mL) and the resulting mixture was stirred at RT for 18 h. A second aliquot of HCl (2.0 M in MeOH, 100 mL) was then added and the resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated under reduced pressure and the residue was triturated with Et2O. The very hygroscopic solid was collected by filtration after treatment with toluene, was then dried at 50° C. under reduced pressure to afford 12.46 g of N-(4-amino-cyclohexyl)-acetamide hydrochloride.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].Cl>>[O:2]=[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: Oc1ncccn1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1cccnc1=O
Temperature: 105 °C

Procedure:
To 2-hydroxypyrimidine hydrochloride (1.00 g, 7.54 mmol) and chloroacetic acid (0.713 g, 7.54 mmol) was added 5 N sodium hydroxide solution (4.5 mL). The reaction mixture was heated at 105° C. for 2 h. After cooled down to ambient temperature and neutralized with 2 M hydrochloric acid (3.8 mL), the title compound was collected by crystallization and filtration as a pale yellow solid. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.59 (dd, J=3.9, 3.0 Hz, 1H), 8.16 (dd, J=6.4, 2.8 Hz, 1H), 6.46 (dd, J=6.4, 4.1 Hz, 1H), 4.58 (s, 2H). LC/MS 155.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5]([C:8]1[NH:9][C:10](=[O:14])[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH3:3].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.O>ClCCl>[CH3:3][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[N:9]=1)(=[O:7])=[O:6])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NS(=O)(=O)c1cccc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)NS(=O)(=O)c1cccc(OS(C)(=O)=O)n1
Reaction time: 0.75 h

Procedure:
2-[(N-prop-2-yl)sulphamoyl]pyrid-6-one (0.052 g) was dissolved in dichloromethane (4 cm3). Methane sulphonylchloride (0.027 g) was added dropwise in dichloromethane (1 cm3) and the reaction mixture was stirred for 45 minutes. Triethylamine (0.024 g) in dichloromethane (1 cm3) was added dropwise and the reaction mixture was stirred for 2 hours. The mixture was left overnight and then refluxed for 2 hours. The cooled reaction mixture was poured into water and the product extracted into dichloromethane twice. The dichloromethane extracts were combined, dried, and evaporated under reduced pressure to leave the crude product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Cl:39]C1C=CC=CC=1CC(=O)C(OCC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:39])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1ccccc1Cl
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1ccccc1Cl)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 16 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(2-chlorophenyl)-2-oxopropanoate B11 (100 mg, 0.441 mmol), sodium hydride (11.65 mg, 0.485 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-glucose bromide (181 mg, 0.441 mmol). The resulting compound was isolated in the form of white solid in 16% yield.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:21]2)=[N:16]1)[CH3:14]>>[Cl:8][C:7]1[C:2]([N:25]([CH2:24][C:20]2[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][N:15]([CH2:13][CH3:14])[N:16]=3)[CH:21]=2)[S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCn1cc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc2n1
Product: CCn1cc2cc(CN(c3ncc(C(F)(F)F)cc3Cl)S(=O)(=O)c3ccc(C(=O)OC)cc3)ccc2n1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((2-ethyl-2H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-5 of Example 13).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Na+].[CH3:10][N:11]1[CH:15]=[N:14][N:13]=[C:12]1[CH2:16][Br:17].[CH3:18][N:19]1C=NN=C1CO.Cl.NCCS>Br.O>[BrH:17].[BrH:17].[NH2:19][CH2:18][CH2:16][C:12]1[N:11]([CH3:10])[CH:15]=[N:14][N:13]=1
Reactant: Cn1cnnc1CO
Reactant: Cn1cnnc1CBr
Agent: Br
Agent: Cl
Agent: NCCS
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cn1cnnc1CCN

Procedure:
The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.), water (150 ml.) and sodium nitrate (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration, the residue was extracted with ethanolether 1 l and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazle (30 g.). b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours, concentrated to dryness and the residue obtained (a mixture of 4-methyl-3-bromomethyl-1,2,4-triazole and 4-methyl-3-hydroxymethyl-1,2,4-triazole) was used directly in the reaction with cysteamine hydrochloride and hydrobromic acid as described in Example 1 (i)(a) to give 3-(2-aminoethyl)-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175°-177°.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(S(N)(=O)=O)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:6]=[C:5]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[S:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(Br)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Yield: 68.18 %

Procedure:
To a solution of ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in J. Chem. Soc. Perkin Trans-1:Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 2.0 g (6.36 mmol) in a mixture of toluene: water (35:2 ml) was added (4-chlorophenyl)boronic acid [0.99 g, 6.36 mmol] and potassium carbonate (1.76 g, 12.73 mmol) at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.31 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite and the celite cake was washed with ethyl acetate (50 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using and 6% ethyl acetate in hexanes as an eluent to obtain the title compound (1.5 g, 68.18%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(N)cccc1N
Reaction time: 2 h
Yield: 96 %

Procedure:
Methyl 2,6-dinitrobenzoate (15.0 gm.) is suspended in methanol (500 ml.) and 5% palladium on charcoal (1.5 gm.) added. Reduction is carried out on a Parr apparatus for two hours. The solution is filtered with suction and the catalyst washed with a few ml. of methanol. Removal of the methanol gives a brown crystalline product. Extraction with chloroform (50 ml.) and treatment with Darco® gives the product (10.9 gm. 96% yield, m.p. 78°-79.5°). The thin layer chromatogram (Silica gel, 3% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1=[N:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[O:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Product: ClC1=Nc2ccccc2Oc2ccccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one (1.00 g, 4.74 mmol) and phosphorus oxychloride (40 mL) was stirred for 5 h at reflux. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved into AcOEt and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give an orange oil. The residue was purified by silica gel column chromatography with EtOAc (10%) in hexanes to afford 554 (939 mg, 86%) as a yellow solid. LRMS (ESI): (calc) 229.0 (found) 230.1 (MH)+.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12])=O)(C)(C)C.[Br-:38].Cl.C(OCC)C.N>C(Cl)Cl.CO>[CH3:6][NH:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:12].[Br-:38]
Reactant: CN(CCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CNCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
N3-(tert-butoxycarbonyl)-N3-methyl-N-[4-(triphenylphosphonio)butyl]-β-alaninamide bromide (1.08 g, 1.80 mmol) was dissolved in methylene chloride (5.4 mL) and methanol (0.54 mL). The solution at room temperature was treated with 2.0 M hydrogen chloride in diethyl ether (1.98 mL, 3.96 mmol). The mixture was stirred overnight at room temperature, then cooled with an ice bath and treated with 7N ammonia in methanol (0.75 mL, 5.22 mmol). After 30 minutes, the resulting slurry was filtered, and the solids were washed with methylene chloride. The filtrate was concentrated to give the title compound (980 mg, 110%, 84% pure) as a white foam. The product of step 2 was used crude in the next step.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C1COCC1.C(N(C(C)C)C(C)C)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[N:32]=[C:33]=[S:34]>C(OCC)(=O)C>[NH2:3][C:4]1[C:8]([NH:9][C:33]([NH:32][C:26]2[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])=[S:34])=[CH:7][S:6][CH:5]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cscc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1cscc1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.87 g of 3,4-diaminothiophene dihydrochloride, 60 ml of anhydrous THF and 2.58 g of N-ethyl-N,N-diisopropylamine was stirred at room temperature for 30 minutes and then admixed with 2.04 g of 2,6-dichlorophenyl isothiocyanate. After the mixture had been heated to 40° C. for 10 minutes, it was stirred at room temperature for approx. 18 hours, and the solvent was distilled off, and the residue admixed with water and extracted repeatedly with ethyl acetate. After the combined organic phases had been treated with activated carbon, they were dried over sodium sulfate and the solvent was again distilled off. A crystalline solid was obtained and, after stirring with a little ethyl acetate, was filtered off. M.p. 165° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.O1CCOCC1>[C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Methyl 4-(phenylamino)benzoate (0.080 g; 0.352 mmol) was added to a mixture of NaOH in water (0.6 mL; 2M) and dioxane (0.6 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a solution of hydrogen chloride 6M and the precipitated product was collected by filtration and used without further purifications to yield 0.048 g (64%) of the title compound as a white solid which was used without further purifications.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccc(-c2ccncc2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3ccncc3)cc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 82.9 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)ethanol (100 mg, 0.40 mmol), 2-amino-4,6-dichloropyrimidine (60 mg, 0.38 mmol), and cesium carbonate (468 mg, 1.44 mmol) was dissolved in 2 ml of 1,4-dioxane in a 50 ml sealed tube. The mixture was heated at 110° C. overnight, then was cooled to room temperature; 10 ml of ethyl acetate was added and then filtered through Celite. The filtrate was concentrated to give 120 mg of 4-chloro-6-[2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine, yield: 80%.
Reaction SMILES: C([N:8]([CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:28][N:27]1C([O-])=O)[CH2:9][C:10](=O)[CH:11](C1C=CC=CC=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[C:42](O)(=O)[CH3:43]>CO.[Pd]>[CH:11]([CH:10]1[N:27]2[CH2:28][C@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:30][C@H:26]2[CH2:25][NH:8][CH2:9]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:43]1[CH:42]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN(CC(=O)C(c2ccccc2)c2ccccc2)Cc2ccccc2)N(C(=O)[O-])C1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNCC(C(c3ccccc3)c3ccccc3)N2C1
Yield: 227.3 %

Procedure:
A solution of (2S,4R)-2-[[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]-4-[(tert-butyldimethylsilyl)oxy]-1-pyrrolidinecarboxylate (4.82 g) and acetic acid (0.87 g) in methanol (100 ml) was hydrogenated over 10% palladium-charcoal (50% wet, 1.0 g) at room temperature under 2-3 atoms for 15 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (4.05 g) as a syrup.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@@H:14]([OH:17])[CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].ClCCl.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>O>[CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@H:14]([OH:17])[CH2:15][O:16][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1nc2c([C@@H](O)CO)cccc2cc1C
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c([C@H](O)CO[Si](C)(C)C(C)(C)C)cccc2cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
1.72 g (7.45 mmol) of (−)-2-ethyl-3-methyl-8-(1(R),2-dihydroxyethyl)quinoline, 25 ml of dichloromethane and 0.75 g of imidazole are introduced into a 100 ml round-bottomed flask. The mixture is cooled to 0° C., 1.12 g (7.45 mmol) of tert-butyldimethylchlorosilane are added and the resulting mixture is stirred for 2 hours at 0° C. 50 ml of water are added and this mixture is extracted with ethyl acetate (3×80 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a column of silica (elution solvent: 10% ethyl acetate in hexane). 1.85 g (yield: 72%) of (+)-2-ethyl-3-methyl-8-(1(S)-hydroxy-2-[tert-butyldimethylsilyloxy]-ethyl)quinoline are obtained in the form of an oil.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([O:15]C(=O)CC2C3C=CC=CC=3OC3C2=CC=CC=3)[CH2:13][CH3:14])[C:7]=1[NH:33][C:34](=[O:50])[CH2:35][CH:36]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:43][C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:5].O>C(OCC)C>[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([OH:15])[CH2:13][CH3:14])[C:7]=1[NH:33][C:34](=[O:50])[CH2:35][CH:36]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=2[O:43][C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:5]
Reactant: CCc1cccc(C(CC)OC(=O)CC2c3ccccc3Oc3ccccc32)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCc1cccc(C(O)CC)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
9.6 mg (0.18 mmol) of sodium methoxide were added to 3 ml of a methanolic solution containing 37 mg (0.060 mmol) of N-(2-ethyl-6-{1-[2-(9H-xanthen-9-yl)acetoxy]propyl}phenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 55). The mixture was then stirred for 4 hours at 60° C. At the end of this time, the reaction solution was diluted with diethyl ether. Water was then added to the reaction mixture, and the title compound was distributed between the organic solvent and the water. The organic layer was then separated and washed with water 3 times. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through 5 g of silica gel. Elution with mixtures of methylene chloride and ethyl acetate ranging from 10:1 to 5:1 by volume afforded 21 mg (yield 89%) of the title compound as crystals, melting at 167°-168° C. (after recrystallization from a mixture of diethyl ether and hexane).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([C:45]#[N:46])[N:40]=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.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>[C:45]([C:41]1[N:42]=[C:43]([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:44]=[CH:39][N:40]=1)#[N:46]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)c12
Reactant: N#Cc1nccc(Br)n1
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: COCCOC
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4ccnc(C#N)n4)c3)c12
Temperature: 95 °C

Procedure:
A mixture of ethyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (54.4 mg, 0.104 mmol), 4-bromopyrimidine-2-carbonitrile (38.2 mg, 0.208 mmol), and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) in 2 M aqueous sodium carbonate (150 uL) and DME (500 μL) was purged with argon. The reaction vessel was then sealed and heated at 95° C. overnight. The reaction mixture was filtered through Celite and rinsed with ethyl acetate. The reaction solution was concentrated under reduced pressure and the residue purified by chromatography on silica eluting with 40-60% ethyl acetatehexane to give the desired product. LRMS calc'd for C26H29N6O3Si [M+H]+: 501, found 501.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19]([CH3:41])[C:20]2[O:26][C:25]3[C:27]([Cl:37])=[CH:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:30][C:24]=3[CH2:23][S:22](=[O:39])(=[O:38])[C:21]=2[CH:40]=1)=[O:16].C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19]([CH3:41])[C:20]2[O:26][C:25]3[C:27]([Cl:37])=[CH:28][C:29]([N:31]4[CH2:32][CH2:33][N:34]([CH2:1][C:2]5[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=5)[CH2:35][CH2:36]4)=[CH:30][C:24]=3[CH2:23][S:22](=[O:38])(=[O:39])[C:21]=2[CH:40]=1)=[O:16]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: COc1ccc(C=O)cc1OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccc(OC)c(OC)c4)CC3)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Veratraldehyde (0.114 g, 0.687 mmol) and titanium isopropoxide (0.26 mL, 0.858 mmol) were added to a suspension of Example 104k (0.3 g, 0.687 mmol) in methanol (30 mL). The reaction mixture was refluxed for 1.5 h, cooled to room temperature, treated with sodium cyanoborohydride (0.042 g, 0.66 mmol) and stirred for 3 h. It was concentrated treated with water and extracted with 1-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 1% methanol/chloroform) to obtain the title compound. Yield: 0.335 g, (58.3%); 1H NMR (DMSO-d6): δ 2.65 (s, 3H, CH3), 3.2 (h, 4H, 2CH2), 3.4 (m, 4H, 2CH2), 3.5 (s, 2H, CH2), 3.75 (s, 6H, 20CH3), 3.9 (s, 3H, OCH3), 5.2 (s, 2H, CH2), 6.85-7.0 (m, 3H, Ar), 7.1 (s, 1H, Ar), 7.15 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.24 (s, 1H, Ar); MS: m/e (ES+) 588 (M+1).