Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]2=[O:20])=[CH:7][C:6]=1[O:21][CH3:22].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:37])([F:38])[CH:34]([F:36])[F:35])=[CH:30][CH:31]=3)=[CH:13][C:12]2=[O:20])=[CH:7][C:6]=1[O:21][CH3:22]
Reactant: FC(F)C(F)(F)Oc1ccc(Br)cc1
Reactant: COc1cc(-n2ccc(B(O)O)cc2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(-c3ccc(OC(F)(F)C(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-2-oxo-1,2-dihydropyridin-4-ylboronic acid Part A (20 mg, 0.06 mmol), 1-bromo-4-(1,1,2,2-tetrafluoroethoxy)benzene (24.6 mg, 0.09 mmol), potassium phosphate, tribasic (32 mg, 0.15 mmol), and PalladiumTetrakis (4 mg, 3.00 μmol) in DMF (0.6 mL) was stirred under nitrogen at 80° C. overnight. The mixture was filtered, concentrated, and was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA). The product was repurified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate/methanol 100:0 to 0:90:10 gradient) to afford the desired product 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)pyridin-2(1H)-one B-6 (16.43 mg, 0.032 mmol, 54.0% yield) as a light yellow solid. LC/MS 482 (M+H)+, tR 0.92 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63-7.67 (2H, m), 7.43 (1H, d, J=7.26 Hz), 7.34 (2H, d, J=8.58 Hz), 6.97-7.03 (2H, m), 6.90-6.96 (1H, m), 6.87 (1H, d, J=1.76 Hz), 6.49 (1H, dd, J=7.26, 1.98 Hz), 5.80-6.11 (1H, m), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]3=[N:12][CH2:13][CH2:14][N:9]3[C:8]=2[CH:15]=1)([O-])=O.[H][H]>[Pd].CO>[N:12]1[CH2:13][CH2:14][N:9]2[C:8]3[CH:15]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[S:11][C:10]=12
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCN=C1S2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)N1CCN=C1S2

Procedure:
A mixture of 11 parts of 2,3-dihydro-6-nitroimidazo-[2,1-b]benzothiazole and 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from dimethylbenzene. The product is filtered off and dried, yielding 5.6 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine; mp. 204°-210° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[C:5]([CH3:14])[C:6]=1C(OC(C)(C)C)=O.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=2)=[C:5]([CH3:14])[CH:6]=1
Reactant: Cc1c(-c2ccc(OC(F)(F)F)cc2)sc(N)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(N)sc1-c1ccc(OC(F)(F)F)cc1

Procedure:
The above thiophene (0.7 g) in 6 ml of trifluoroacetic acid is heated to 60° C. for 3 hr., cooled, diluted with toluene and concentrated in vacuo. The resulting oil is diluted and concentated twice more to afford 2-amino-4-methyl-5-(4-trifluoromethyloxyphenyl)thiophene trifluoroacetic acid salt.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[O:10][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[CH2:14][C@@H:13]2[OH:26])=CC=1.[C:41](O)(=[O:47])[CH2:42][CH2:43][C:44]([CH3:46])=[O:45].Cl.C(N=C=NCCCN(C)C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CN(C1C=CN=CC=1)C.ClCCl.ClCCl.C(O)C.CO>[O:45]=[C:44]([CH3:46])[CH2:43][CH2:42][C:41]([O:26][C@H:13]1[CH2:14][C@H:15]([N:17]2[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[NH:19][C:18]2=[O:25])[O:16][C@@H:12]1[CH2:11][OH:10])=[O:47]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CC(=O)CCC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
1-[(2R,4S,5R)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxyoxolan-2-yl]-5-methylpyrimidine-2,4-dione (Compound SP761) (1.09 g, 2 mmol), levulinic acid (0.29 ml, 2.8 mmol), N,N-dimethyl-4-aminopyridine (DMAP) (73 mg, 0.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 538 mg, 2.8 mmol) were dissolved in dichloromethane (2 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 minutes. 0.6 ml of methanol was added to the reaction solution, then p-toluenesulfonic acid (532 mg, 2.8 mmol) was added and the mixture was stirred at room temperature for 1 minute. 3 ml of phosphate buffer (pH=6, 1 M) was added to the above reaction solution, and the mixture was stirred for 2 minutes. 10 ml of a dichloromethane/ethanol solution (5:1) was added to the reaction solution, and the mixture was separated by 7 ml of phosphate buffer (pH=6, 1 M). The organic layer was collected, the aqueous layer was separated by 15 ml of a dichloromethane/ethanol solution (5:1) twice, and the organic layers were collected. The collected organic layers were combined, and sodium sulfate was added for drying. Sodium sulfate was then removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=65:35→100:0) to afford the desired compound (Compound SP762) (632.5 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]O)=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[I-].[Li+].[N-:47]=[N+:48]=[N-:49].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:47]=[N+:48]=[N-:49])=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCCCO)cc2)COC(C)(C)OC1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCCCN=[N+]=[N-])cc2)COC(C)(C)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 19 (168 mg, 0.40 mmol) and N,N-diisopropylethylamine (155 mg, 1.2 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. Methanesulfonyl chloride (66 mg, 0.60 mmol) was added, and the mixture was stirred at 0° C. for 2 h and then at room temperature overnight. The mixture was washed with saturated aqueous NaHCO3 solution (2×10 mL), water (2×10 mL), and brine (2×10 mL), and then dried (Na2SO4). After the solvent was removed, the residue was dissolved in dry DMF (5 mL) and lithium iodide (7 mg, 48 μmol) and sodium azide (78 mg, 1.2 mmol) were added. The reaction mixture was stirred at 80° C. for 18 h and then was cooled to room temperature. Water (15 mL) was added, and the suspension was extracted with CH2Cl2 (3×20 mL). The combined organic layer was washed with water (3×30 mL) and brine (2×20 mL), dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography (hexanes/EtOAc 4:1) to give 20 (119 mg, 67%). 1H NMR δ 7.14-7.04 (m, 4H), 5.02 (s, 1H), 3.89 (d, 2H, J=11.6 Hz), 3.67 (d, 2H, J=11.6 Hz), 3.24 (t, 2H, J=7.2 Hz), 2.60-2.50 (m, 4H), 1.97 (t, 2H, J=8.0 Hz), 1.66-1.56 (m, 4H), 1.47 (s, 9H), 1.43 (s, 3H), 1.41 (s, 3H), 1.40-1.36 (m, 2H); 13C NMR δ 154.7, 139.7, 139.2, 128.3, 128.2, 98.2, 79.1, 66.2, 51.6, 51.2, 35.2, 33.5, 30.9, 28.6, 28.5, 28.3, 27.3, 26.2, 19.6. HRMS m/z: calcd for C24H38N4NaO4 (MNa+), 469.2785; found, 469.2786.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].I[CH3:14].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2cc(Br)ccc21
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
5-Bromo-1H-indazole (1r) (10 g, 51 mmol) in THF was added slowly to a cold solution of NaH (2.2 g, 60% wt in oil, 56 mmol) in THF under nitrogen. After 15 minutes, iodomethane (10.8 g, 76 mmol) was added to the dark solution at 0° C. After 2 hours, the mixture was poured into 1N HCl (30 mL) and extracted with EtOAc (2×50 mL), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Column chromatography (silica gel): hexane:EtOAc (10-40%) resulted in 8.2 g of final product (2r). 1H NMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.84 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 4.04 (s, 3H); MS (ESI) m/z 213 (M+H)+.
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH:22]=O)[CH3:17]>O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:17]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OCC
Reaction time: 72 h

Procedure:
After a saturated hydrogen chloride-methanol solution 20 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-diethoxybenzaldehyde 1.58 ml, the mixture was srtirred for 72 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 60 ml of 55° C., and the mixture was stirred for 15 minutes and filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.762 g.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27](N2C=CC=CC2=O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:28])[C:6]([OH:8])=[O:7]
Reactant: O=C(OCCCCCCc1ccccc1)n1ccccc1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OCCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a stirred mixture of D-threonine (0.12 g, 1.0 mmol) and NaHCO3 (0.13 g, 1.5 mmol) in H2O (3.5 mL), the crude mixture containing 6-phenylhexyl-2-pyridyl-carbonate and 6-phenylhexyl-2-oxopyridine 1-carboxylate (0.45 g, 1.5 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.25 g, 78%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 324 [M−H]+; (ESI) m/z: 322 [M−H]−. 1H NMR (DMSO-d6): δ 1.08 (d, J=6.4 Hz, 3H), 1.24-1.40 (m, 4H), 1.46-1.63 (m, 4H), 2.56 (t, J=7.6 Hz, 2H), 3.88-3.99 (m, 3H), 4.00-4.12 (m, 1H), 6.67 (d, J=9.0 Hz, 1H), 7.13-7.21 (m, 3H), 7.22-7.31 (m, 2H), 12.40 (br s, 1H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[C:9]([O:8][C:6]([NH:13][CH2:14][CH2:15][C:16]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.8 %

Procedure:
To a mixture of tert-butylamine (210 μl; 2 mmol; 1 eq) and boc-beta-alanine (416.3 mg; 2.20 mmol; 1.10 eq) in DCM (30 ml), are added triethylamine (832 μl; 6 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1 533 mg; 6 mmol; 3 eq). The mixture is stirred overnight at RT. The reaction is followed by TLC (cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated, to give 639 mg of an orange oil which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title product is isolated as a slightly yellow solid (467.7 mg; 96%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([O:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([O:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(OC(C(=O)OC)c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(OC(C(=O)O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a solution of 0.041 g (0.09 mmol) of the product of Step A in 2 mL of methanol was added 0.5 mL of a 1.0N solution of sodium hydroxide and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then adjusted to pH=6 with 0.5 mL of 1.0N hydrochloric acid, then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-NH4OH (80:15:1). The purified fractions were combined, evaporated and dried in vacuo to afford 0.030 g (75%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:13]([O-])=O)=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([OH:9])[CH:8]=1.[ClH:16]>[Pd].O>[ClH:16].[ClH:16].[NH2:10][C:6]1[CH:5]=[C:4]([NH2:13])[C:3]([OH:2])=[CH:8][C:7]=1[OH:9]
Reactant: COc1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1cc(N)c(O)cc1O
Temperature: 55 °C
Reaction time: 0.06 h
Yield: 92.5 %

Procedure:
A 500 mL, 3-necked, round-bottomed flask is charged with 150 mL of water, 21.4 g (0.1 mole) of 5-methoxy-2,4-dinitrophenol and 1.0 g of 10% palladium on carbon catalyst. The reaction is stirred under a nitrogen atmosphere for 3 to 4 minutes. The stirred reaction mixture is heated to 55° C. and hydrogen gas is sparged below the surface of the reaction mixture. After 10 minutes, 19.8 g (0.2 mole) of concentrated HCl is added through the condenser while hydrogenation is continued for 4 hours. The catalyst is removed by filtration and the filtrate is passed into a solution consisting of 0.5 g of stannous chloride dihydrate and 25 mL of concentrated HCl. This solution is then saturated with dry HCl gas and charged to a 600 mL 5 Hastalloy B autoclave. The reactor is heated to 150° C. for 18 hours and cooled to 25° C. The resulting product is isolated by filtration and dried under nitrogen to yield 19.7 g (90% yield) of crude 4,6-diaminoresorcinol dihydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[K+].C(O[C:14]([S-:16])=[S:15])C.O.Cl>CN(C=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]2[S:16][C:14](=[S:15])[NH:9][C:3]=2[N:4]=1
Reactant: Nc1ncc(Br)c(N)n1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=S)[nH]c2n1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
5-Bromo-pyrimidine-2,4-diamine (2.0 g, 10.58 mmol) [prepared in a manner similar to English et. al. J. Am. Chem. Soc. 1946, 68, 453-458] and O-ethylxanthic acid potassium salt (3.39 g, 21.16 mmol) was heated in DMF (25 mL) to 140° C. After 5 h the reaction was cooled to ambient temperature and 25 mL of water was added. The pH was then adjusted to 5.0 using 1 N HCl. A red precipitate formed and was collected by filtration, yielding 900 mg (30%) of a solid: 1H NMR (400 MHz, d6-DMSO) δ 13.85 (s, 1H), 8.33 (br s, 1H), 6.90 (s 2H).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.O.C1(C)C=CC=CC=1>[NH2:47][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(c1cccc2cc(C3=NCC(CCN)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.242 g) in tetrahydrofuran (5 mL) were added triphenylphosphine (0.301 g), a 40% toluene solution (0.500 g) of diethyl azodicarboxylate and diphenylphosphorylazide (0.247 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-60:40) to give a yellow oil. To a solution of the obtained oil in tetrahydrofuran (5 mL) were added water (0.1 mL) and triphenylphosphine (0.226 g), and the mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=100:0-80:20), and recrystallized from hexane-ethyl acetate to give the title compound (0.100 g, yield in two steps 41%) as pale-yellow crystals. melting point 172-174° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[O:11][C@H:12]([C@H:22]([OH:25])[CH2:23][OH:24])[C:13]=1[O:14]CC1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+].[N:29]1[N:30]([C:38]2[CH:43]=[C:42]([CH2:44]Br)[CH:41]=[CH:40][C:39]=2[OH:46])[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12>C1COCC1.[Pd]>[N:29]1[N:30]([C:38]2[CH:43]=[C:42]([CH:41]=[CH:40][C:39]=2[OH:46])[CH2:44][O:24][CH2:23][C@H:22]([C@H:12]2[O:11][C:10](=[O:26])[C:9]([OH:8])=[C:13]2[OH:14])[OH:25])[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12
Reactant: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Reactant: O=C1O[C@H]([C@H](O)CO)C(OCc2ccccc2)=C1OCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1O[C@H]([C@H](O)COCc2ccc(O)c(-n3nc4ccccc4n3)c2)C(O)=C1O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
35 g of (R)-3,4-bisbenzyloxy-5-((R)-1,2-dihydroxyethyl)-5H-furan-2-one (98.2 mmol; 1 eq.) are dissolved in 250 ml of THF under a protective-gas atmosphere, and 3.93 g of sodium hydroxide (98.2 mmol; 1 eq.) are added at 0° C. After 30 min, the 2-benzotriazol-2-yl-4-bromomethylphenol (35.8 g; 117.9 mmol; 1.2 eq.) dissolved in 100 ml of THF is added dropwise, the mixture is stirred at 0° C. for 60 min and at 70° C. for 7 hours. After the reaction solution has been cooled to room temperature, 2 g of Pd/C are added, and the mixture is hydrogenated for 5 hours under a hydrogen atmosphere at 3 bar and 50° C. After filtration through a Celite pad, the solution is neutralised using 2 N HCl solution. The extraction is carried out twice with 250 ml of sat. NaHCO3 solution and 100 ml of sat. NaCl solution. The product is precipitated from the org. phase using 370 ml of heptane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:33][C:34]#[N:35])=[CH:27][C:26]=2[O:25]1>>[O:32]1[C:31]2[CH:30]=[CH:29][C:28](/[C:33](=[CH:18]/[C:17]3[CH:20]=[CH:21][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:15]([O:22][CH3:23])[CH:16]=3)/[C:34]#[N:35])=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCO
Yield: 65 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde and commercial [3,4-(methylenedioxy)phenyl]acetonitrile according the same procedure following for example 1 in 65% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [OH:1][CH:2]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]1[S:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][N:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5](=[O:8])[CH2:6]Cl.[Na]>CO>[CH2:9]([N:4]1[C:5](=[O:8])[CH2:6][O:1][CH:2]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]2[S:29][CH:28]=[CH:27][CH:26]=2)[CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCl)N(Cc1ccccc1)CC(O)COc1ccccc1Cc1cccs1
Agent: [Na]
Solvent: CO
Product: O=C1COC(COc2ccccc2Cc2cccs2)CN1Cc1ccccc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of 27 g of N-[2-hydroxy-3-[2-(2-thenyl)phenoxy]propyl]-N-benzyl-chloroacetamide in 100 ml of methanol was added dropwise to a solution of 2.3 g of metallic sodium in 200 ml of methanol with stirring at room temperature. The resulting mixture was stirred under reflux for 3 hours. Then the methanol was distilled off under reduced pressure, and the residue was extracted with 200 ml of benzene. The benzene layer was washed with water and dried over anhydrous magnesium sulfate, and then the benzene was distilled off to give 26 g of crude product as an oil. The oil was purified by column chromatography using a column of silica gel and chloroform as an eluent. The fractions containing the objective product were concentrated to give 23 g of 4-benzyl-2-[2-(2-thenyl)phenoxymethyl]morpholin-5-one as colorless crystals, melting at 97°-99° C.