Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20].Cl>O.COCCOC>[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reaction time: 2 h

Procedure:
4-Amino-2-chlorobenzoic acid was stirred in water (60 ml) and 1,2-dimethoxyethane (25 ml) with sodium bicarbonate (5.04 g) and the brown suspension cooled to 0°-5° C. 2-Methylpropionyl chloride (4.26 g) was added dropwise over 10 minutes with vigorous stirring, and the mixture was then stirred at 0°-10° C. for 2 hours. The mixture was poured into 2 M hydrochloric acid and the pale brown precipitate washed with water and filtered and dried to give 2-chloro-4-(2'-methylpropionamido)benzoic acid as a pale brown crystalline solid (6.30 g), m.p. 206°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH3:36]>>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:36])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(Oc4ccccc4)cc3Cl)cc2O1
Product: CCOC(=O)C1(C)CCc2ccc(OCCCOc3ccc(Oc4ccccc4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedure described in Example 2 employing ethyl 7-(3-(2-chloro-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 17) instead of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate, and iodomethane instead of iodopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:21][C:22]2[C:23]([NH2:31])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=CC=1>C(O)C.[OH-].[Na+].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[C:8]3=[N:31][C:23]4[CH:24]=[C:25]5[O:29][CH2:28][O:27][C:26]5=[CH:30][C:22]=4[CH:21]=[C:7]3[CH2:6][C:5]=2[CH:4]=1
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2c(c1)Cc1cc3cc4c(cc3nc1-2)OCO4
Temperature: 100 °C
Yield: 134.9 %

Procedure:
To 5-methoxyindan-1-one (350 mg, 2 mmol) is added 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (512 mg, 1 mmol) in ethanol (4 mL) and 2N sodium hydroxide (1 mL). The reaction mixture is heated at reflux (about 100° C.) for 16 hrs. Upon cooling the reaction product is dissolved in methylene chloride (200 mL) and extracted with a saturated sodium chloride solution (200 mL). The organic layer is dried with a rotatory evaporator. The resulting residue is chromatographed on silica gel with 2:3 ethyl acetate/hexanes to yield 8-Methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (393 mg, 67.4% of theory).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:2][C:3]([CH3:4])=[O:5])=[CH:10][CH:9]=1
Reactant: COc1ccc(O)cn1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC(C)=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A solution of chloroacetone (3.7 g) and potassium iodide (65 mg) in acetone (7 mL) was stirred at approximately 25° C. overnight. In a second reactor, 6-methoxypyridin-3-ol (4.0 g, mmol) and potassium carbonate (1.3 g, 10 mmol) in acetone (5 mL) was refluxed for 15 min., then ¼ of chloroacetone/KI solution was added followed by additional potassium carbonate (1.3 g). This was repeated three times more, then the reaction stirred at approximately 25° C. overnight. The mixture was concentrated in vacuo. The residue was dissolved in Et2O and washed with H2O, brine and dried with Na2SO4. The solution was filtered and concentrated in vacuo yielding 3.5 g of clear oil that was used without further purification. This material darkened on standing over time.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][NH2:22].C(OCC)C.CCCCCC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
1-(4-Benzyloxyphenyl)propan-2-one (2.28 g) was added to a solution of 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.75 g) in dry toluene (100 ml) and the solution was boiled under reflux for 90 minutes in an apparatus incorporating a water-trap. The solution was cooled and the solvent removed under reduced pressure. The residue, dissolved in methanol (100 ml), was cooled to less than 10° C. and treated portionwise with sodium borohydride (3.0 g) over 30 minutes, with stirring. The mixture was stirred for one hour at room temperature and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried (magnesium sulphate), filtered and evaporated to dryness to give a solid. Trituration of the solid with diethyl ether followed by addition of hexane and filtration gave N-[2-(4-benzyloxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine of analytical purity, mp 95°-99° C., as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzaldehyde (5.13 g, 25.4 mmol) in DMF (25 mL) were added K2CO3 (7.15 g, 51.8 mmol) and 3,4-dichloro-phenol (4.67 g, 28.8 mmol). The mixture was heated at 90° C. for 24 h and then was allowed to cool to room temperature (rt). Water was added and the mixture was extracted with Et2O. The combined organic layers were dried (MgSO4) and concentrated. The residue was diluted with DCM and hexanes and the resulting solids were collected by vacuum filtration to provide the desired product (4.74 g, 54%). 1H NMR (CDCl3): 10.36 (s, 1H), 8.06 (d, J=2.5, 1H), 7.67 (dd, J=8.8, 2.6, 1H), 7.46 (d, J=8.8, 1H), 7.17 (d, J=2.8, 1H), 6.92 (dd, J=8.8, 2.8, 1H), 6.84 (d, J=8.8, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([OH:25])([OH:24])=[O:23])[C@@H:17]([O:26][P:27]([O:30][CH2:31][C@@H:32]3[C@@H:36]([O:37][C:38](=[O:62])[C@@H:39]([NH:54]C(OC(C)(C)C)=O)[CH2:40][CH2:41][C@@H:42]4[S:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43]4)[C@@H:35]([OH:63])[C@H:34]([N:64]4[CH:72]=[N:71][C:70]5[C:65]4=[N:66][CH:67]=[N:68][C:69]=5[NH2:73])[O:33]3)([OH:29])=[O:28])[CH2:16]2)[C:11](=[O:74])[N:10]=1>ClCCl>[NH2:54][C@H:39]([CH2:40][CH2:41][C@@H:42]1[S:46][CH2:45][NH:44][CH2:43]1)[C:38]([O:37][C@H:36]1[C@@H:35]([OH:63])[C@H:34]([N:64]2[CH:72]=[N:71][C:70]3[C:65]2=[N:66][CH:67]=[N:68][C:69]=3[NH2:73])[O:33][C@H:32]1[CH2:31][O:30][P:27]([O:26][C@H:17]1[CH2:16][C@H:15]([N:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[N:10][C:11]2=[O:74])[O:19][C@@H:18]1[CH2:20][O:21][P:22]([OH:24])([OH:25])=[O:23])([OH:29])=[O:28])=[O:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CC[C@H]3CNCS3)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 155.5 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.16 mL) was added to a solution of (5S)-tert-butyl 5-((3S)-4-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy) (hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)Oxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk4) (8.5 mg, 8.43 μmol) in dichloromethane (0.2 mL), and the mixture was stirred at room temperature for 1.25 hours. Following concentration under reduced pressure, (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-4-((S)-thiazolidin-5-yl)butanoate (Ala(Tzm)-pdCpA) (Compound tk5) (10.6 mg, quant.) was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.S(=O)(=O)(O)O.[N:12]([O-])=O.[Na+].[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>O.CC(O)=O>[CH3:22][C:20]1[C:21](=[N:12][NH:1][C:2]2[N:3]=[N:4][NH:5][N:6]=2)[C:17]([NH2:16])=[N:18][N:19]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=N[O-]
Reactant: Nc1nnn[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1=NN=C(N)C1=NNc1nn[nH]n1
Reaction time: 2 h
Yield: 3.3 %

Procedure:
A solution of aminotetrazole (0.1 g, 1.1 mmol) in 4 M sulfuric acid (3.0 mL, 12.0 mmol) was cooled to −5° C. To this mixture was then added a cooled solution of sodium nitrite (0.08 g, 1.1 mmol) in 0.5 mL of water. The solution was then added to a solution of 3-amino-5-methylpyrazole (0.2 g, 2.1 mmol) and NaOAc trihydrate (1.5 g, 11 mmol) dissolved in a mixture of water (1 mL) and HOAc (3 mL). After stirring for 2 hours, water (50 mL) was added and the crude material was extracted from the aqueous layer three times with ethyl acetate (150 mL). The combined ethyl acetate solutions were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude material was purified by column chromatography (CHCl3:MeOH:NH4OH=3:1:0.005). The isolated material was then further purified by preparative TLC (CHCl3:MeOH:NH4OH=3:1:0.005) to yield 7 mg (3%) of the title compound as a red solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][Br:28]>>[Br-:28].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: Fc1ccccc1CBr
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3F)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 127 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 2-fluorobenzyl bromide (36 μL, 0.3 mmol) as reactants. White solid. (Yield 70.3 mg, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][CH:21]([CH3:25])[C:22](=O)[CH3:23].C(N(CC)CC)C>C(O)C>[ClH:20].[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][C:21]([CH3:25])=[C:22]([CH3:23])[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Reactant: CC(=O)C(C)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(Nc2ncc(Br)cc2OCc2ccccc2)sc1C
Product: Cl
Yield: 16.5 %

Procedure:
A mixture of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)thiourea (0.50 g, 1.48 mmol), 3-chlorobutan-2-one (0.236 g, 2.22 mmol), triethylamine (0.412 ml, 2.96 mmol), and ethanol (15 mL) was heated overnight. The reaction mixture was cooled, partitioned between ethyl acetate and water, washed with water and brine, dried, and concentrated. The residue was purified by MPLC eluting with 5:1 hexane:ethyl acetate to afford the free base of the title compound (104 mg) as a tacky oil. The free base was dissolved in ether (4 mL) and a 1M solution of HCl in ether was added (1.5 mL). The mixture was stirred 10 minutes and filtered. The solids were washed with ether, hexanes, and dried to afford 3-(benzyloxy)-5-bromo-N-(4,5-dimethylthiazol-2-ylpyridin-2-amine hydrochloride (0.093 g, 14.7% yield). 1H NMR (DMSO-d6) δ 2.21 (s, 3H), 2.26 (s, 3H), 5.34 (s, 2H), 7.35-7.44 (m, 3H), 7.58 (d, 2H), 7.81 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][C:5]=1[CH3:18])([O-])=O.CCO.C(OCC)(=O)C>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][C:5]=1[CH3:18]
Reactant: Cc1cc(C(=O)Nc2nccs2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2nccs2)ccc1N
Yield: 95 %

Procedure:
4-Nitro-3-methyl-N-thiazol-2-yl-benzamide (63 mmol) was suspended in abs. EtOH (200 mL) and ethyl acetate (100 mL) and glacial acetic acid (10 mL) was added followed by 10% Pd/C (1 g). The mixture was hydrogenated over night at 3 bar H2. The hydrogenation mixture was filtered and the solvent was removed under reduced pressure. The crude product was added NaHCO3 (sat.) and ethyl acetate, the remaining solid fraction was removed by filtration and dried in vacuo. The liquid phases were separated, the organics were washed with brine, dried over MgSO4, filtered and evaporated to yield the product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][S:39]([C:38]([F:44])([F:43])[F:37])(=[O:41])=[O:40])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(O)cc2C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 0 °C
Yield: 54.9 %

Procedure:
To an ice cold solution of 4-{[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.75 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added triethylamine (0.16 ml, 1.125 mmol) followed by trifluoromethanesulfonyl chloride (0.08 ml, 0.78 mmol). The reaction was stirred in the ice bath for 30 min. and then added to water (60 ml). The organic layer was separated, dried over MgSO4, filtered, and concentrated. Chromatography with 40% acetone in hexanes affords 4-{[propyl-(7-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (220 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CN1CCCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CN1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 1-methyl-1,4-diazepane (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 15-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (61 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 2.33 (d, J=1.77 Hz, 2H) 2.91 (d, J=4.55 Hz, 3H) 3.32-3.46 (m, 1H) 3.51-3.64 (m, 2H) 3.64-3.86 (m, 4H) 4.65 (dd, J=15.54, 4.42 Hz, 1H) 6.33 (d, J=2.27 Hz, 1H) 7.32 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 7.99 (d, J=8.34 Hz, 2H) 8.08 (d, J=2.27 Hz, 1H) 9.62 (br. s., 1H) 10.85 (s, 1H). ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:16])[CH2:11][O:12][C:13]([Cl:15])=[O:14])([O-:3])=[O:2].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>ClCCl>[Cl-:15].[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:16])[CH2:11][O:12][C:13]([N:20]1[CH:21]=[CH:22][N+:18]([CH3:17])=[CH:19]1)=[O:14])([O-:3])=[O:2]
Reactant: Cn1ccnc1
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(COC(=O)n1cc[n+](C)c1)c1ccccc1[N+](=O)[O-]
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
1.07 ml 2-(2-nitrophenyl)propoxycarbonyl chloride (1) (4.4 mmol) are slowly added dropwise to a solution of 1.24 ml N-methylimidazole (14.7 mmol) in 40 ml dichloromethane at 0° C. over molecular sieve 4 Å. Following stirring for 30 minutes in an ice bath this solution is used directly for acylation with 1.2 equivalents of the 5′-O-protected nucleoside building blocks.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:13](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:14][C:4]=2[CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:32]>>[ClH:32].[CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:14][C:4]=2[CH2:3]1
Reactant: CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NCCC1=O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2cc(/C=C/C(=O)O)cnc2NCCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of (E)-tert-butyl 3-(5-methyl-4-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocin-8-yl)acrylate (391 mg, 1.23 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 2 h, the solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl in dioxane (4 mL, 4.0 M) and sonicated until the oil was converted to a fine off-white solid. After stirring for 20 min, the suspension was concentrated. The solid was washed with Et2O, isolated by filtration and dried under vacuum. Yield: 388 mg (quant); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.04 (s, 1H), 7.48 (d, J=16.0 Hz, 1H), 6.48 (d, J=16.0 Hz, 1H), 4.78 (bs, 1H), 3.90 (s, 2H), 2.99 (s, 2H), 2.79 (s, 2H), 2.58 (s, 3H); ESI MS m/z 298 [C13H15N3O3+H]+
Reaction SMILES: ClCC([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S:17][CH3:18])([OH:15])[CH:11]([C:19]2([CH3:27])[O:26][CH:20]2[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH:10]1[O:28][CH3:29])=[O:7])=O.[CH3:30][S-:31].[CH3:32][CH2:33]OCC>CN(C)C=O>[O:26]1[CH:20]([CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[C:19]1([CH:11]1[CH:10]([O:28][CH3:29])[CH:9]([O:8][C:6](=[O:7])[NH:5][C:30](=[S:31])[CH2:32][CH3:33])[CH2:14][CH2:13][C:12]1([CH2:16][S:17][CH3:18])[OH:15])[CH3:27]
Reactant: CCOCC
Reactant: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reactant: C[S-]
Solvent: CN(C)C=O
Product: CCC(=S)NC(=O)OC1CCC(O)(CSC)C(C2(C)OC2CC=C(C)C)C1OC
Reaction time: 1 h
Yield: 79 %

Procedure:
In dimethylformamide (3 ml) was dissolved 4-O-chloroacetylcarbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg). To the solution was added thiomethoxide (156 mg), and the mixture was stirred for one hour. The reaction mixture was diluted with ether (50 ml), which was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate - hexane=2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-4-methylthioacetylcarbamoyloxy-1-methylthiomethylcyclohexanol (407 mg: yield 79%) as colorless powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.Cl.[CH3:26][NH:27][CH3:28].C(N(CC)CC)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: CNC
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNc1nc(-c2ccc(F)cc2)cs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt, 66.8 mg (0.81 mmol) of dimethylamine hydrochloride and 165.7 mg (1.64 mmol) of triethylamine. Yield: 52 mg.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].Cl.[NH:17]1[CH2:38][CH2:37][CH2:36][C@H:18]1[C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:20]>>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([N:17]1[CH2:38][CH2:37][CH2:36][C@H:18]1[C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:20])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Agent: Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
Starting from 13.79 g (63.45 mmol) of BOC-Val-OH and 21.5 g (63.45 mmol) of HCl.H-Pro-Pro-OBzl (VIII) and operating as described in Step 7, 22.28 g (70% yield) of compound IX were obtained as an oil after purification by column chromatography on silica gel (Merck) 0.040-0.063 mm eluting with ethyl acetate: methanol=98:2.
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cc(OC)c(C2=CCN(C)CC2OC(C)=O)c(OC)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2.79 g (10 mmol) of 3(R,S)-hydroxy-1-methyl4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) were dissolved in 15 ml of acetic anhydride and stirred at 100° C. for 4 h. The solution was then evaporated in vacuo in a rotary evaporator and the residue was dissolved in 10 ml of water, adjusted to pH >12 with sodium hydroxide solution and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.