Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([CH2:17][C:18]([OH:20])=[O:19])[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)([OH:3])=[O:2].S(=O)(=O)(O)O>[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH2:6][CH2:5][C:4]([C:1]([OH:3])=[O:2])([CH2:17][C:18]([OH:20])=[O:19])[C:9]=2[CH:10]=1
Reactant: O=C(O)CC1(C(=O)O)CCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1ccc2c(c1)C(CC(=O)O)(C(=O)O)CCO2
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A mixture of 4-carboxy-3,4-dihydro-6-nitro-2H-1-benzopyran-4-acetic acid (4.1 g, 14 mmol), 10% palladium on carbon (1.6 g) and sulfuric acid (1 mL) in ethanol is hydrogenated at 45 psi for 2 hours and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain the title product as a tan solid (2.6 g) which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([OH:12])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:21](=[O:22])([O:23][CH2:24][CH3:25])[O:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:10])([Cl:11])[Cl:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 6.17 grams (g) (0.025 mole (m)) of 2-chloro-6-hydroxy-4-(trichloromethyl)pyridine in 100 milliliters of toluene. To this solution was added 2.53 g (0.025 m) of triethylamine. To this mixture was then added 2.71 g (0.025 m) of ethyl chloroformate dissolved in 20 ml of toluene. The mixture was stirred at 50° C. for 4 hours. The salt which formed was removed by filtration and the toluene was removed by evaporation under reduced pressure. Using a short path distillation (Kugelrohr) at 130° C. and 80 millimeters of mercury, 6-chloro-4-(trichloromethyl)-2-pyridinyl ethyl carbonate was obtained in a yield of 6.65 g (83 percent of theory). The product had a refractive index of n(25/d)=1.5354. The structure of the product was confirmed by its NMR spectrum (Compound No. 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Cl:12][CH2:13][CH2:14]Cl.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:12][CH2:13][CH2:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(c1)c(I)nn2CCCl
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 5-fluoro-3-iodo-indazole (3.0 g, 11.5 mmol) and 1,2-dichloroethane (5.7 g, 57.3 mmol) in ACN (50 mL) was added K2CO3 (3.2 g, 22.9 mmol) at rt. The reaction was stirred overnight at reflux. The reaction mixture was filtered and concentrated in vacuo. Purification by silica gel chromatography (30:1:5 hexanes/EtOAc/DCM) gave 2.5 g (67%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 3.97 (2H, t, J=6.0 Hz), 4.69 (2H, t, J=6.0 Hz), 7.13 (1H, dd, J=1.8, 7.8 Hz), 7.22-7.29 (1H, m), 7.42 (1H, dd, J=3.9, 9.3 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[CH2:8][CH:7]2[CH3:16]>O.C1(C)C=CC=CC=1.[Zn]>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[CH:7]([CH3:16])[CH2:8][CH2:9]2
Reactant: COc1cc2c(cc1OC)C(C)CC2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(C)CC2
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a suspension of 53.3 g (815 mmol) of zinc dust in 74 ml of water were added 4 ml of concentrated hydrochloric acid. The supernatant was decanted off after stirring for 30 min, and to the residue were added, with ice cooling, 42 ml of water and then, dropwise, 55 ml of concentrated hydrochloric acid. 28.0 g (136 mmol) of 5,6-dimethoxy-3-methylindan-1-one dissolved in 53 ml of toluene were added and the mixture was refluxed for 3 days (d), in the course of which, after 48 h, a further 55 ml of concentrated hydrochloric acid were added. After cooling, the reaction mixture was poured into 200 ml of water and the product was extracted twice in 300 ml of ether. The combined extracts were washed with 100 ml of water and 25 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. After flash chromatography (pentane/ether, 9:1, Rf=0.23) on silica gel, 19.6 g (75%) of 5,6-dimethoxy-1-methylindane were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH3:37]>>[CH:30]([C:27]1[CH:26]=[CH:25][C:24]([N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:3][CH:4]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:29][CH:28]=1)([CH3:32])[CH3:31]
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Reactant: CCCCCBr
Product: CCCCCNc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 162 using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) and pentyl bromide (0.14 mL) as starting materials, N-(4-isopropylphenyl)-7-methoxy-N-[(4-pentylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]([S:28]([CH3:27])(=[O:30])=[O:29])[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Compound 52 (0.16 g, 0.605 mmol) was dissolved in anhydrous THF (5 mL). To the clear solution were sequentially added triethylamine (0.18 mL, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.121 mmol). The mixture was cooled to about −10° C. for 15 min by a methanol-ice bath. To the cold solution was slowly added methanesulfonyl chloride (51 μL). The solution was further stirred at the temperature (about −10° C.) for an additional 30 min, then allowed to slowly warm up to room temperature by removing the cooling bath. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0–35%) and hexanes (100–65%), to afford 0.212 g (83%) of the product 53 as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52–1.70 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 3.13–3.18 (m, 2H), 3.40 (s, 6H), 4.53 (br s, 1H), 7.27 (s, 4H). m/z (APCI)=321 [C17H28N2O6S2-Boc+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:20][N:19](C(=O)C)[CH2:18][CH2:17][C:10]=3[N:11]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:20][NH:19][CH2:18][CH2:17][C:10]=3[N:11]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCc2nc(C(C)C)nc(-c3ccc(F)cc3)c2C1
Agent: Cl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Temperature: 25 °C

Procedure:
A mixture of crude 1-[4-(4-fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanone in 10% aq. HCl (800 mL) was heated at reflux for 2 h and then cooled to rt. The aqueous solution was washed with EtOAc (400 mL) and then was basified with NaOH pellets (˜120 g) to pH>12. The basic solution was extracted with CH2Cl2 (2×500 mL). The combined organic layers were washed with 1 N NaOH (400 mL), dried (MgSO4), and concentrated to give the crude product (100 g), which was used in the next reaction without further purification. HPLC: RT=6.89 min. MS (ESI): exact mass calcd. for C16H18FN3, 271.15; m/z found, 271.9 [M+H]+.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[CH:10]([N:23]=[C:24]=[S:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:10]([N:23]1[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:24]1=[S:25])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CNC
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(C(c2ccccc2)c2ccccc2)C1=S
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), benzhydryl-isothiocyanate (11.25 g), triethyl amine (12 g) and chloroform (200 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl (2×200 mL), then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethanol to give the title compound (7.40 g) as an off-white solid, m.p. 139°-141° C. Anal. Calcd. for C17H16N2O S: C, 68.89; H, 5.44; N, 9.45. Found: C, 68.92; H, 5.43; N, 9.58. Mass spectrum (EI, M.+) m/z 296.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Br[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (4.0 g, 11.2 mmol, 1.0 equiv) and 2,5-dibromopyridine (3.2 g, 13.4 mmol, 1.2 equiv) in 50 Ml toluene/ethanol (1:1) was added 2 M Na2CO3 (16.8 Ml, 3 equiv) followed by Pd(PPh3)4 (0.38 g, 0.34 mmol, 0.03 equiv). The biphasic mixture was sparged with nitrogen for 10 min, then heated to 60° C. for 3 days. The reaction was cooled to room temperature and then partitioned between ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Purification by silica gel chromatography (7-40% EtOAc in hexanes) afforded the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.11 (dd, J=13.01, 2.15 Hz, 2H) 1.41-1.54 (m, 2H) 1.76-1.90 (m, 5H) 2.20 (d, J=6.57 Hz, 2H) 2.46 (tt, J=12.09, 3.19 Hz, 1H) 3.62 (s, 3H) 7.23 (d, J=8.08 Hz, 2H) 7.53 (dd, J=8.59, 0.76 Hz, 1H) 7.77 (dd, J=8.46, 2.40 Hz, 1H) 7.81 (q, J=3.87 Hz, 1H) 7.81 (d, J=8.34 Hz, 1H) 8.64 (d, J=1.77 Hz, 1H); (M+H)+390.0.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:18]=2)[CH2:16][CH2:15][CH2:14]1.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>O1CCCC1>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH2:20][CH2:19][N:18]=[C:17]2[C:13]2([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Reactant: CC(C)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(C1(CC(C)C)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.83 ml, 1.8M in hexanes) was added dropwise to a solution of diisopropylamine (0.71 ml) in dry tetrahydrofuran (5 ml) at ambient temperature. After 15 minutes the solution was cooled to -23° C. and treated slowly with a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (1 g) in tetrahydrofuran (11 ml). The dark green solution was stirred for 30 minutes, further cooled to -78° C. and treated with 1-bromo-2-methylpropane (5.1 ml). After 1 hour at -78° C. the mixture was allowed to warm to ambient temperature, then heated under reflux for 1 hour. The mixture was poured onto water, acidified, and washed with ether. The aqueous phase was then basified by addition of aqueous sodium hydroxide solution and extracted with ethyl acetate. The solvent was removed in vacuo to yield an orange gum which was purified by flash chromatography over silica gel using a 1:4 mixture of ethyl acetate and light petroleum ether as eluant to give 7-methoxy-1-[1-(2-methylpropyl)cyclobutyl]-3,4-dihydroisoquinoline as an oil (0.85 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([SH:10])=[C:5]([NH:11][CH3:12])[N:4]=1)[CH3:2].Cl[CH2:14][C:15]([OH:17])=O.O.[OH-].[Na+].Cl>>[CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH2:14][C:15](=[O:17])[N:11]([CH3:12])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc(NC)c(S)c(=O)[nH]1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2c(c(=O)[nH]1)SCC(=O)N2C
Yield: 77.2 %

Procedure:
2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin- 4-one (6.6 g, 0.036 mole) from Example 112 and 3.37 g (0.036 mole) of chloroacetic acid were added to approximately 120 ml of water containing 4.27 g (0.107 mole) of sodium hydroxide. The resultant solution was refluxed for approximately 4 hours, allowed to cool and acidified to about pH 2 with concentrated hydrochloric acid. The white solid was separated by filtration and dried (7.4 g), then refluxed in approximately 100 ml of acetic anhydride for about 2 hours and allowed to cool. The precipitate was removed by suction filtration, washed with diethyl ether and dried, providing 6.26 g (78%) of 6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido [5,4-b][1,4]thiazine-4,7-dione. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Cl
Yield: 41.8 %

Procedure:
8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55 mg, 0.22 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (69 mg, 0.23 mmol), and a 4 M solution of hydrogen chloride in dioxane (0.06 mL, 1.1 eq), were added to isopropyl alcohol (2 mL). The reaction mixture was microwaved on 300 watts, at 130° C. for 40 minutes. The reaction mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and then concentrated on SiO2. Flash chromatography on SiO2 (MeOH/dichloromethane 0-15%) gave 2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a white solid (47 mg, 42%). MP: 109-112° C.; 1H-NMR (CDCl3) δ 10.98 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.10 (s, 1H), 8.09 (d, J=7.4 Hz, 1H), 7.40-7.54 (m, 3H), 7.07 (d, J=7.6 Hz, 1H), 6.64 (s, 1H), 6.20 (m, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.57 (m, 2H), 3.37 (s, 3H), 3.03 (d, J=4.8 Hz, 3H), 2.60-2.98 (m, 10H); LC/MS (ESI+): 510.99 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:10]=1)[OH:6].[CH2:17]([NH:24][CH:25]([CH3:38])[CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:33]([C:32]1[CH:36]=[C:28]([CH:29]=[CH:30][C:31]=1[OH:37])[O:27][CH2:26][CH:25]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([OH:6])[CH:7]=1)[CH3:38])(=[O:34])[NH2:35]
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Reactant: COC(=O)c1ccc(OCC2CO2)cc1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc(O)c(C(N)=O)c2)cc1O
Reaction time: 40 h

Procedure:
After 40 hours' boiling and working up analogously to Example 4a), 22.4 g of 4-(2,3-epoxypropoxy)salicylic acid methyl ester and 30 g of 5-(2-benzylaminopropoxy)salicylamide in 200 ml of isopropanol yield crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-(3-hydroxy-4-methoxycarbonylphenoxy)propan-2-ol as a light-coloured foam which is further processed as a crude product.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]([OH:19])=O)[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:32]>CCOCC>[C:1]1([C:7]2([CH2:16][C:17]([NH2:32])=[O:19])[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1(c2ccccc2)Oc2ccccc2O1
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: NC(=O)CC1(c2ccccc2)Oc2ccccc2O1
Reaction time: 12 h

Procedure:
To 22 g. of (2-phenyl-1,3-benzodioxol-2-yl)-acetic acid in 300 cc. of anhydrous benzene, in the cold, 18.1 g. of PCl5 are added. After leaving the mixture for 2 hours to allow the reaction to be completed a cold solution of NH3 in anhydrous ether is added to the mixture, in drops and with shaking. After 12 hours, the mixture is poured onto ice. The organic phase is separated, washed with H2O until neutral, and finally dried with Na2SO4. The solvent is removed under vacuum and the residue is recrystallised from benzene, m.p. 114°-15°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH3:26][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]1=[O:18]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cccnc2[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2Cl)c2cccnc2n(C)c1=O
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of ethyl 4-(2-chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylate (4.50 g, 13.7 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% oily, 547 mg, 13.7 mg) at room temperature, and the mixture was stirred for 0.5 hour. To the mixture was added methyl iodide (1.9 g, 13.7 mmol) at 0° C. to 5° C., and the mixture was stirred at the same temperature for 0.5 hour, and then stirred at room temperature for five hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (4.60 g, 13.4 mmol), which was used without further isolation in the subsequent reaction.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@@:16]1([C@@H:19]([OH:21])[CH3:20])[CH2:18][O:17]1.C(O)(=O)C(O)=O>CS(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([OH:21])[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C[C@H](O)[C@]1(c2cc(F)ccc2F)CO1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
1,2,4-Triazole (274 mg; 3.89 mmol) is dissolved in DMSO (3 ml). Sodium hydride (124 mg; 60% suspension in paraffin; 3.24 mmol) is added and the reaction mixture is heated to 70° C. for one hour. The reaction mixture is cooled to room temperature and 1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (275 mg; 1.3 mmol) dissolved in DMSO (2 ml) is added slowly over a period of 10 minutes. The reaction mixture is then heated to 70° C. for three hours. The solvent is evaporated. The residue is taken-up in ethyl acetate (10 ml) and water (5 ml). The phases are separated. The aqueous layer is extracted 3 times with ethyl acetate (3 times 5 ml). The combined organic phases are washed twice with water (2 times 5 ml). The organic phase is dried over sodium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude product is dissolved in ethyl acetate (16 ml). Oxalic acid (164 mg; 1.3 mmol) is added and the solution is stirred for 30 minutes. The mixture is stored at 0° C. overnight. The crystalline (2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol oxalate salt is filtered off. The crystals are washed with hexanes and dried under vacuum. The desired compound is obtained as a white powder (337 mg); yield 66.7% with an optical purity higher than 95% (no other isomer is visible in NMR).
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:22]1[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]1[OH:33])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][C:42]#[CH:43])([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(NCC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][C:42]#[C:43][C:19]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@@H:22]2[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]2[OH:33])=[C:12]([NH:11][C@H:8]([CH2:9][OH:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:20]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)NCC#Cc1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C

Procedure:
N-{(1S,2R,3S,4R)-4-[6-((S)-1-Benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate GC) (1 eq.), prop-2-ynyl-carbamic acid tert-butyl ester (10 eq.), CuI (0.25 eq.), bis(triphenylphosphine)-palladium(II) chloride (0.25 eq.) and triphenylphosphine (0.5 eq.) are dissolved in diethylamine and DMF. The reaction mixture is heated in a microwave for 1 hour at 120° C. The title compound is obtained by column chromatography.