Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CC(C)=O>[Br:12][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(CBr)c1ccc(F)c(Br)c1
Reactant: Nc1ccccn1
Solvent: CC(C)=O
Product: Fc1ccc(-c2cn3ccccc3n2)cc1Br
Reaction time: 8 h

Procedure:
In analogy to the method as described in J. Heterocyclic Chem. 1988, 25, 129-137, 2-Bromo-1-(3-bromo-4-fluoro-phenyl)-ethanone (89 mg, 0.3 mmol) and 2-Aminopyridine (28 mg, 0.3 mmol) were dissolved in 2 ml of acetone and shaken overnight. The solvent was evaporated and and the residue was dissolved in 1 ml of DMF. The title compound (m/e=292.6, [M+H+]) was isolated from this solution by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient 10-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14](O)=[O:15])=[C:5]2[O:17][CH3:18].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][OH:15])=[C:5]2[O:17][CH3:18]
Reactant: COc1c(C(=O)O)n(C)c(=O)c2ccc(Cl)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1c(CO)n(C)c(=O)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
6-Chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (0.67 g, 2.5 mmol) was dissolved in tetrahydrofuran (10 ml) and oxalyl chloride (0.26 ml, 3 mmol) and N,N-dimethylformamide (2 drops) were added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (0.33 g, 8.8 mmol) in 1,2-dimethoxyethane (20 ml) at 0° C. The obtained mixture was stirred at 0° C. for 1 h, and the reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-chloro-3-hydroxymethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.42 g, 66.7%) as crystals.
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([OH:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:19]([O:14][C:8]1[CH:7]=[C:6]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 91.2 %

Procedure:
In 20 ml of 1-methyl-2-pyrrolidone were dissolved 1.86 g (7.46 mmol) of 4-dibutylamino-2-hydroxybenzaldehyde and 1.66 g (9.71 mmol) of benzyl bromide. To this mixture was added 2.06 g (14.9 mmol) of anhydrous potassium carbonate and the mixture was stirred with heating at 50° C. for 2 hours. After the reaction mixture was added to water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.31 g of a pale yellow crystal (yield: 91.3%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]=1[CH3:12].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:13][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:26])[F:27])[CH:17]=2)(=[O:24])=[O:23])=[N:10][C:11]=1[CH3:12]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(N)ccc1COCCF
Product: Cc1nc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1COCCF

Procedure:
This material was prepared in analogy to example 1 from 5-(2-fluoro-ethoxymethyl)-6-methyl-pyridin-2-ylamine (0.05 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.073 g) as a light yellow gum (39 mg g). MS (ESI−): 391.2 ([M−H]−)
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH:2]([N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])[CH3:13])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: CC(Br)C(=O)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)c1ncc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To 5.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)-1-propanone in 20 ml of N,N-dimethylformamide, 3.27 g of potassium phthalimide was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), and the resulting organic layers were combined, washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.02 g of the desired crude product as brown crystals. The crystals were used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:40]1([C:43]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:11][C:10]=3[F:32])[CH:5]=[CH:4][N:3]=2)=[O:44])[CH2:42][CH2:41]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (217 mg, 0.5 mmol) in DCM (5 mL) was added Et3N (253 mg, 2.5 mmol) and cyclopropanecarbonyl chloride (125 mg, 1.2 mmol) at 0° C. The reaction mixture was stirred at rt for 4 hours, quenched with H2O (10 mL) and extracted with DCM (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in CH3OH (20 mL), and a solution of Na2CO3 (106 mg, 1.0 mmol) in H2O (1 mL). The resulted mixture was stirred at rt for 1 hour and concentrated in vacuo. The residue was purified by a silica gel column chromatography (pure DCM) to give the title compound as a beige solid (158 mg, 63.2%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=S(=O)=O)[N:10]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:6]=[CH:5]1)([CH3:3])[CH3:2].[CH:25]1([N:31]2C(C3C=CNC(=S(=O)=O)N=3)=C(C3C=CC(F)=CC=3)N=C2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:10]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)=c1nc(-c2c(-c3ccc(F)cc3)ncn2C2CCCCC2)cc[nH]1
Reactant: CC(C)n1cnc(-c2ccc(F)cc2)c1-c1cc[nH]c(=S(=O)=O)n1
Product: CC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccnc(Nc2ccccc2)n1

Procedure:
The reaction was conducted in a manner analogous to Example 2d except substituting polymer-bound 1-isopropyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole for polymer-bound 1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole: ESMS m/z=374 (MH)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10]=1[O:11][CH3:12])[CH:6]=O>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:10]([CH3:9])[C:3](=[O:2])[CH3:4])[CH:8]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(S(C)(=O)=O)c1OC
Solvent: CCC(C)=O
Product: COc1cc(C=C(C)C(C)=O)cc(S(C)(=O)=O)c1OC

Procedure:
The procedure described in Example 8 was repeated using 2.44 g of 3,4-dimethoxy-5-methylsulfonylbenzaldehyde and 1.0 g of 2-butanone. Yield 2.0 g (63%), viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[NH:28][C:27](=[O:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:30]1(I)[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH:30]1([O:29][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([CH2:18][N:15]3[CH2:14][CH2:13][N:12]([S:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)(=[O:10])=[O:11])[CH2:17][CH2:16]3)[N:28]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: IC1CCCC1
Reactant: COc1ccc(S(=O)(=O)N2CCN(Cc3nc4ccccc4c(=O)[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(Cc3nc(OC4CCCC4)c4ccccc4n3)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-ylmethyl]-3H-quinazolin-4-one (83 mg, 0.2 mmol), cyclopentyl iodide (46 μL, 0.4 mmol), and potassium carbonate (138 mg, 1 mmol) in DMF (1 mL) was heated to 90° C. for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was concentrated in vacuo and the residue was purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 5.73 (quintet, J=3.0 Hz, 1H), 3.88 (m, 5H), 3.12 (m, 4H), 2.84 (m, 4H), 1.90 (m, 8H); HPLC ret. time 2.85 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 483.5 (M+1)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([O:26][CH:27]([CH3:29])[CH3:28])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:26][CH:27]([CH3:28])[CH3:29])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CC(C)Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)O
Yield: 16.2 %

Procedure:
To the stirred solution of 6-chloro-4-(3-chloro-phenyl)-2-isopropoxy-quinoline-3-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) in DCM (4 ml) was added 0.2 ml TFA and reaction mixture was refluxed for 16 h. After cooling, the volatiles were removed under vacuum and the reaction mixture was diluted with ethyl acetate (40 ml) and washed with NaHCO3 solution (10 ml). The separated organic layer was washed with brine (7 ml), dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100% ethyl acetate) to afford 6-chloro-4-(3-chloro-phenyl)-2-isopropoxy-quinoline-3-carboxylic acid (14 mg, 16%) as an off white solid. LC-MS (ESI): 374 (M−H)−.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:17][C@@H:18]1[CH2:32][C@H:31]2[C@@H:21]([CH2:22][C:23]3[C:33]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]2=4)[NH:25][CH:24]=3)[N:20]([CH3:34])[CH2:19]1)(=O)=O>O>[CH3:34][N:20]1[C@H:21]2[C@@H:31]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:33]=3[C:23]([CH2:22]2)=[CH:24][NH:25]4)[CH2:32][C@@H:18]([CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:19]1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2cncn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
0.4 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of 1,2,4-triazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. After allowing the mixture to cool, water was added to the reaction mixture, and the precipitated crystals were separated by filtration, washed with water and purified by alumina column chromatography (eluted with dichloromethane). The product was recrystallized from methanol to obtain 0.8 g of the titled compound as colorless needles having a melting point of 245°-253° C.
Reaction SMILES: N#N.Br[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:63]([NH2:67])([CH3:66])([CH3:65])[CH3:64]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:63]([NH:67][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)N
Reactant: Cc1cccnc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cccnc1NC(C)(C)C
Temperature: 70 °C

Procedure:
To a 3 or 4-necked flask (100 L) with water cooling condenser, mechanical stirring and N2 was charged toluene (40 L), 2-bromo-3-methylpyridine (4.966 kg), sodium t-butoxide (5.60 kg). The slurry was then sparged N2 for 10 min; then tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.065 kg, 0.071 mol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 0.106 kg, 0.171 mol) and t-butylamine (4.51 L) were charged. The resulting dark mixture was stirred 10 min at 23° C. under N2 and then heated to 70° C. (internal temp) with a steam bath. No t-butyl amine reflux was noticed.
Reaction SMILES: [OH:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].CCOCC>CN(C=O)C.[Cl-].[Na+].O>[Si:26]([O:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 29.0 g (0.1 mol) of di-tert-butyl 2-hydroxypropane-1,3-diyldicarbamate and 17.0 g (0.25 mol) of imidazole in 200 ml DMF at 0° C., was added 18.09 g (0.12 mol) of t-butyldimethylsilylchloride (TBDSMCl) in portions. The reaction was warmed up to RT and stirred for 2 hours. To this mixture was added 400 ml ether and 400 ml brine. The layers were separated and the aqueous layer was extracted with 400 ml ether. The combined organic layer was dried and concentrated to give 35 g of di-tert-butyl 2-(tert-butyldimethylsilyloxy)propane-1,3-diyldicarbamate (86% yield).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1ccc(NCC2CC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(NCC2CC2)nc1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a 0° C. solution of 855 mg (3.50 mmol) of cyclopropylmethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine in 7 mL of THF, was slowly added 7.0 mL (7.0 mmol) of 1M TBAF in THF. The mixture was stirred for 2 h, then poured into water and extracted with Et2O. The Et2O was washed with brine. The washes were extracted once with Et2O, and the combined extracts were diluted with 10 mL of CH2Cl2 and left to sit for 10 min. The solution was then decanted from the water that had separated, and was dried with Na2SO4, filtered, concentrated, and chromatographed (1-20% EtOAc in hexanes) to provide 467 mg of 2-(cyclopropylmethyl)amino-5-ethynyl pyridine.
Reaction SMILES: CC([N:5]([C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=2)[N:12]([C:31](=[O:33])[CH3:32])[C@@H:11]([CH3:34])[CH2:10]1)C(=O)[O-])(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[C:31]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([C:19]#[C:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:15][CH:14]=2)[C@H:9]([NH2:5])[CH2:10][C@@H:11]1[CH3:34])(=[O:33])[CH3:32]
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](N(C(=O)[O-])C(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](N)C[C@@H]1C
Reaction time: 7 h
Yield: 75 %

Procedure:
A solution of 1,1-dimethylethyl((2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Intermediate 107) (1.96 g, 4.04 mmol) in 1,4-dioxane (10 mL) at room temperature was treated with HCl (4N in dioxane, 20 mL, 80 mmol) and the resulting mixture was stirred at this temperature for 7 h then the solvent was removed in vacuo. The residue was triturated with Et2O then filtered off and dried under house vacuum to give (2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (1.28 g, 3.04 mmol, 75% yield) as a white solid. The mother liquors were concentrated in vacuo to give (2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (396 mg, 0.940 mmol, 23.26% yield) as a very pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:13]1([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2I)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[CH:13]3[CH2:15][CH2:14]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(Cl)cc21
Reactant: Ic1cnccc1C1CC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)ccc2CCN1c1cnccc1C1CC1
Yield: 25.5 %

Procedure:
7-Chloro-3,4-dihydroisoquinolin-1(2H)-one (I-1d: 100 mg, 0.552 mmol) was reacted with 4-cyclopropyl-3-iodopyridine (I-73c: 162 mg, 0.662 mmol), 1,4-dioxane (5 mL), copper iodide (31 mg, 0.165 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (8 mg, 0.055 mmol) and potassium phosphate (351 mg, 1.657 mmol for 48 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 42 mg of the product (25.45% yield).
Reaction SMILES: O[C:2]1[NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]2=[C:4]([OH:20])[N:3]=1>FC(F)(F)C(O)=O>[OH:20][C:4]1[N:3]=[CH:2][NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]=12
Reactant: OC[C@H]1N[C@@H](c2cnc3c(O)nc(O)[nH]c2-3)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of the product from Example 1.6 (66 mg) in trifluoroacetic acid (3 ml) was allowed to stand at room temperature overnight. The solution was concentrated and a solution of the residue in water was washed (x2) with chloroform and then evaporated. The residue was dissolved in methanol and treated with Amberlyst A21 base resin until the solution was pH-7. The solids and solvent were removed and the residue was dissolved in water, treated with excess aqueous HCl and then lyophilized. Trituration of the residue with ethanol gave (1S)-1,4-dideoxy-1-C-(4-hydroxypyrrolo[3,2-d]pyrimidin-7-yl)-1,4-imino-D-ribitol (7) hydrochloride salt as a white solid (25 mg). Recrystallised from 90% ethanol, the crystalline solid darkened but did not melt below 300° C. NMR (300 MHz, D2O with DCl, d ppm): 13C (relative to internal acetone at 33.2 ppm) 58.1 (C-1'), 61.4 (C-5'), 68.8 (C-4'), 73.3 (C-3'), 76.7 (C-2'), 107.5 (q), 121.4 (q), 133.5 (C-2), 135.0 (q), 148.0 (C-6) and 155.4 (q); 1H (relative to internal acetone at 2.20 ppm), 3.90 (H-4'),3.96 (m, H-5',5"), 4.44 (dd, H-3', J2',3' 5.4 Hz, J3',4' 3.2 Hz), 4.71 (dd, J1',2' 9.0 Hz, H-2'), 5.00 (d, H-1'), 8.00 (s, H-6) and 9.04 (s, H-2). ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(O)[CH:15]([OH:27])[CH2:14]3)=[N:9][C:8]2=[O:28])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:15](=[O:27])[CH2:14]3)=[N:9][C:8]2=[O:28])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CCC1c1ccc(F)cc1
Yield: 7.8 %

Procedure:
A toluene solution (10 mL) of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-3,4-dihydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (202 mg, 0.468 mmol) synthesized in Synthesis Example 91 and p-toluenesulfonic acid monohydrate (341 mg, 1.99 mmol) was stirred under reflux by heating for 4 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and to the resultant residue, saturated sodium bicarbonate aqueous solution was added, and extraction with ethyl acetate was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by reverse-phase column chromatography (water/acetonitrile) to obtain the title compound (15.0 mg, yield: 8%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15]Cl)([CH3:11])[CH3:10]>CN(C=O)C>[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15][C:7]1[NH:6][N:5]=[N:4][N:3]=1)([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCc1nnn[nH]1
Reaction time: 0.5 h

Procedure:
To a Suspension of 1.1 mmol NaH in 5 mL DMF at 0° C. was added a solution of 1.0 mmol tetrazole in 2 mL DMF. After 30 min, trimethylsilylethoxymethylchloride was added and the mixture stirred for 16 h. Extraction and chromatography provided trimethylsilylethoxymethyltetrazole as an oil.