Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.C(#N)C.[CH3:31][N:32]([CH3:52])[CH2:33][CH2:34][O:35][C:36](=[O:51])[C@@H:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38][CH2:39][C:40](O)=[O:41].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O>[CH3:52][N:32]([CH3:31])[CH2:33][CH2:34][O:35][C:36](=[O:51])[C@@H:37]([NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:38][CH2:39][C:40](=[O:41])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CN(C)CCOC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Product: CN(C)CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-(2-dimethylamino-ethyl)ester (370 mg, 0.70 mmol; 77% purity) described in Manufacturing Example 3-1 and ethanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-(2-dimethylamino-ethyl)ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-(2-dimethylamino-ethyl)ester (crude, 190 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (160 mg, 0.42 mmol) in this order at 0° C., which was stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=30:1), so as to obtain the titled compound (56 mg, purity of 75%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:25](OC)=[O:26])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:25][OH:26])(=[O:15])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@@H]1CCCCC[C@@H]1CO)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
A 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (7.5 mL, 7.5 mmol) was added dropwise to a solution of cis-methyl 2-(4-chlorophenylsulfonamido)cycloheptanecarboxylate (1.73 g, 5.0 mmol) in 60 mL anhydrous tetrahydrofuran under nitrogen cooled to −60° C. The reaction was stirred for 1.5 h at room temperature and quenched by the slow addition of 150 mL ethyl acetate followed by 150 mL saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted an additional two times with 150 mL ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield 4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (1.55 g, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82-7.84 (1H, m), 7.80-7.82 (1H, m), 7.48-7.50 (1H, m), 7.45-7.47 (1H, m), 5.13 (1H, d, J=9.57 Hz), 3.70-3.80 (1H, m), 3.61 (1H, dd, J=11.21, 10.20 Hz), 3.41 (1H, dd, J=11.46, 4.66 Hz), 2.69 (1H, br. s.), 1.67-1.83 (1H, m), 1.53-1.62 (2H, m), 1.26-1.51 (7H, m), 1.05-1.20 (1H, m).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]2[N:24]=[C:25]([NH2:28])[S:26][CH:27]=2)[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.ClCCl>[NH2:28][C:25]1[S:26][CH:27]=[C:23]([C@@H:7]2[CH2:6][C@H:5]([SH:4])[CH2:9][N:8]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[N:24]=1
Reactant: CC(=O)S[C@H]1C[C@@H](c2csc(N)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Nc1nc([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (2S, 4S) -4-acetylthio-2-(2-aminothiazol-4-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.26 g) in a mixture of methanol (20 ml) and dichloromethane (10 ml) was added sodium methoxide (28% solution in methanol, 1.2 ml) at -30° to -20° C. under an atmosphere of nitrogen. After stirring at 0° C. for 1 hour, acetic acid (0.36 ml) was added to the mixture. The solution was evaporated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S ,4S)-2- (2-aminothiazol-4-yl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.13 g)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=O)=O.[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40](Cl)=[O:41])[CH:36]=1>N1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:30]([C:29]([CH3:33])([CH3:32])[C:21]1[CH:22]=[C:23]2[C:28](=[C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2][CH3:1])=[CH:6][CH:7]=3)[C:40]([C:37]3[CH:36]=[C:35]([CH3:34])[O:39][N:38]=3)=[O:41])[CH:20]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)#[N:31]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(C)(C#N)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1ccc(N(Cc2cccc(-c3cc(C(C)(C)C#N)cc4cccnc34)c2)C(=O)c2cc(C)on2)cc1
Reaction time: 12 h

Procedure:
A mixture of the amine from Step 1 (1.0 eq) and 5-methyl-isoxazole-3-carbonyl chloride (1.8 eq) in pyridine (0.35M) was stirred for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 3:2) afforded the desired compound as a foam.
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:19]([C:21]1[S:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].N#N.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>>[CH:19]([C:21]1[S:25][C:24]([C:2]2[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])=[CH:23][CH:22]=1)=[O:20]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Reactant: O=Cc1ccc(B(O)O)s1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Product: O=Cc1ccc(-c2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c2=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A 2-necked round bottom flask with 5-iodouridine (100 mg, 270 μmol), 5-formyl-2-thiopheneboronic acid (1.5 eq) and Cs2CO3 (2 eq.) was purged with N2. Upon addition of TPPTS (0.0625 eq.), Na2Cl4Pd (0.025 eq.) and degassed H2O (5 mL) the mixture turned orange in colour. The reaction was stirred under N2 for 1 h at 60° C., turning brown/black. Once the starting material was fully consumed, the reaction mixture was cooled to room temperature. The pH was adjusted to 7 with HCl 1% and the reaction mixture was filtered through Celite. The solvents were removed to give a colourless powder. After purification, the title compound was obtained in 23% yield (16 mg). δH (400 MHz, DMSO-d6) 3.65-3.85 (2H, m, H-5′), 3.90-3.95 (1H, m, H-4′), 4.02-4.17 (2H, m, H-2′ and H-3′), 5.11 (1H, d, J=5.9 Hz, OH-3′), 5.54 (1H, d, J=5.0 Hz, OH-2′), 5.60 (1H, t, J=4.3 Hz, OH-5′), 5.80 (1H, d, J=3.0 Hz, H-1′), 7.56 (1H, d, J=4.1 Hz, Th), 7.93 (1H, d, J=4.0 Hz, Th), 9.02 (1H, s, H-6), 9.87 (1H, s, CHO), 11.9 (1H, s, NH); δC (75.5 MHz, DMSO-d6) 59.6 (C-5′), 68.7 (C-3′), 74.5 (C-2′), 84.4 (C-4′), 89.5 (C-1′), 106.9 (C-5), 122.9, 137.3, 138.7, 141.6, 144.4, 149.4 (C-2+C-6+C—Th), 161.4 (C-4), 184.3 (CHO). m/z (ESI) 353.0448 [M−H]−, C14H13O7N2S requires 353.0449.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.[CH3:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]N.C1(C)C=CC=CC=1.O>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:20]3[C:19](=[C:18]([CH2:17][O:16][CH3:15])[CH:23]=[CH:22][CH:21]=3)[NH:24][C:12]=2[CH3:13])[N:4]=1
Reactant: COCc1ccccc1NN
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCc1cccc2c(-c3nc(OC)cc(OC)n3)c(C)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Into a reactor were fed 6.2 g (31.6 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 4.8 g (31.5 m moles) of 2-methoxymethylphenylhydrazine, 4.76 g (34.9 m moles) of zinc chloride and 60 ml of toluene. Refluxing was made for 2 hours with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature. Water and ethyl acetate were added and phase separation was made. The ethyl acetate layer was concentrated. The resulting crystals were washed with diisopropyl ether to obtain 4.57 g (14.6 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-metoxymethylindole. Yield: 46%
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:2]1.CO[CH2:13][N:14]([CH2:20][C:21]1C=CC=C[CH:22]=1)[CH2:15][Si](C)(C)C>>[CH2:20]([N:14]1[CH2:15][C@H:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C@@H:7]([CH2:8][OH:10])[CH2:13]1)[CH:21]=[CH2:22]
Reactant: O=C(O)/C=C/c1ccsc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: C=CCN1C[C@H](CO)[C@@H](c2ccsc2)C1

Procedure:
The title compound was prepared from trans-3-(3-thienyl)acrylic acid using procedures analogous to those described in EXAMPLE 1, Steps A-C, substituting N-methoxymethyl-N-trimethylsilylmethyl(prop-2-enyl)amine for N-methoxymethyl-N-trimethylsilylmethylbenzyl amine in Step B. For the title compound: 1H NMR (500 MHz) δ 2.30-2.34 (m, 1H), 2.44 (t, J=8.5, 1H), 2.67 (t, J=9.0, 1H), 2.77 (dd, J=5.0, 9.0, 1H), 3.02-3.15 (4H), 3.53 (dd, J=7.5, 10.0, 1H), 3.64 (dd, J=5.0, 10.0, 1H), 5.07 (d, J=10.0, 1H), 5.17 (d, J=17.5, 1H), 5.83-5.91 (m, 1H), 6.97-6.99 (2H), 7.20-7.22 (m, 1H); ESI-MS 224 (M+H).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[N:16]([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:15]2[C:24]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:25][CH:26]=[CH:27][C:14]=2[N:13]=1>O1CCCC1.[Cl-].[NH4+].C(=O)([O-])O.[Na+]>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[N:16]([CH2:17][CH2:18][CH2:19][OH:20])[C:15]2[C:24]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:25][CH:26]=[CH:27][C:14]=2[N:13]=1
Reactant: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N(CC)CC)c21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
To a suspension of lithium borohydride (22.5 mg, 1.03 mmol) in tetrahydrofuran (3.5 mL) was added ethyl 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propanoate (Reference Example 28; 155 mg, 0.345 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 20 hr, the mixture was diluted with aqueous ammonium chloride at 0° C. and stirred at 0° C. for 30 min. The resultant mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25% ethyl acetate/n-hexane mixture to give the title compound as a solid (35.7 mg, 0.0876 mmol, 25%).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:4]1=[O:19])[CH3:2].S1C=CC=C1.COCCO.[H][H]>CO.[Pt]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:5]2[CH:6]=[CH:7][C:8](=[O:9])[N:3]([CH2:1][CH3:2])[C:4]2=[O:19])=[CH:15][CH:14]=1
Reactant: CCn1c(=O)ccn(-c2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: COCCO
Solvent: CO
Product: CCn1c(=O)ccn(-c2ccc(N)cc2)c1=O

Procedure:
A mixture of 28.4 parts of 3-ethyl-1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 5 parts of a solution of thiophene in methanol 4% and 500 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50° C. with 3 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was concentrated to a volume of about 150 parts. After cooling, the product was filtered off (the filtrate was set aside) and dried in vacuo at 60° C., yielding a first fraction of 16.5 parts of 1-(4-aminophenyl)-3-ethyl-2,4(1H,3H)-pyrimidinedione (int. 25). The filtrate, which was set aside (see above), was evaporated. The residue was stirred in methanol. The product was filtered off and dried in vacuo at 60° C., yielding a second fraction of 5.7 parts of int. 20. Total yield: 22.2 parts (88.3%) of int. 25; mp. 190.8° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CC#N>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1

Procedure:
To a solution of N-(4-hydroxyphenyl)acetamide (500 mg, 3.31 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (663 mg, 3.97 mmol) and K2CO3 (3 g, 21.7 mmol) at 25° C. The mixture was heated at reflux for 16 h. The mixture had water (100 mL) added and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: [H][H].C([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]2[C:17]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=3)[O:19][C:11]1=2)C1C=CC=CC=1.ClCCl.C(O)(=O)C>[Pd].C(OCC)(=O)C>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[O:19][C:11]3[NH:10][CH:15]=[CH:14][C:13](=[O:16])[C:12]=3[C:17]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:25][CH:24]=1
Reactant: O=c1ccn(Cc2ccccc2)c2oc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccccc3)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1cc[nH]c2oc(-c3ccc(O)cc3)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500-mL round bottom flask equipped with a rubber septum and hydrogen (g) balloon was charged with 7-benzyl-2-(4-benzyloxy-phenyl)-3-phenyl-7H-furo[2,3-b]pyridin-4-one (4a) (1.20 g, 2.50 mmol), dichloromethane (100 mL), acetic acid (100 mL), and ethyl acetate (20 mL). Palladium on carbon (10 wt %, 0.200 g) was added, and the system was evacuated and purged with hydrogen three times. The mixture stirred at room temperature for 24 h and was filtered through Celite. The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-(4-hydroxy-phenyl)-3-phenyl-7H-furo[2,3-b]pyridin-4-one 5 as an off-white solid. MS (MH+) 304.1; Calculated 303 for C19H13NO3.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]=[S:29]1(=[O:44])[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:42]=[CH:43][C:35]([N:32]6[CH2:31][CH2:30][S:29](=[O:44])(=[O:28])[CH2:34][CH2:33]6)=[CH:36][CH:37]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, white solid (126 mg, 89%), MS (ISP) m/z=568.5 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(1,1-dioxo-1λ6-thiomor-pholin-4-yl)-benzoic acid.
Reaction SMILES: [CH2:1]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[CH2:1]([C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A solution of 2.0 g (7.5 mmol) of 4-nonylbenzoyl chloride in 75 mL of THF at −78° C. was treated with 7.5 mL (7.5 mmol) of 1M lithium tri-(tert-butoxy) aluminum hydride in THF. After 30 min at −78° C., the reaction was quenched with 2N HCl and was allowed to warm to rt. The mixture was poured into Et2O and washed with 2N HCl, sat'd NaHCO3 and sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified on a 40M Biotage column using 100:1 v/v hexane/Et2O as the eluant to afford 708 mg (41%) of the title compound: 1H-NMR (500 MHz) δ 0.87 (t, J=7.0, 3H), 1.26-1.31 (m, 12H), 1.60-1.66 (m, 2H), 2.68 (t, J=7.8, 2H), 7.32 (d, J=8.0, 2H), 7.79 (d, J=8.0, 2H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[C:28]([CH3:41])[CH:27]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:25])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:42][O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](Br)[CH:51]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50]([C:29]2[CH:30]=[CH:31][C:26]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]4([O:20][Si:21]([CH3:23])([CH3:24])[CH3:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:8]([CH3:25])[CH:7]=3)[CH2:1][CH3:2])=[CH:27][C:28]=2[CH3:41])[CH:51]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 62.6 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 35-(4); 57.6 mg, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 30.1 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (14.1 mg, 0.0122 mmol) and potassium phosphate (27.8 mg, 0.13 mmol) in N,N-dimethylformamide (0.27 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (37.3 mg, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Reaction of 4-nitrophenacyl bromide with morpholine affords the novel intermediate 1-(4-nitrophenyl)-2-morpholinylethanone which when reduced yields the novel sunscreen 1-(4-aminophenyl)-2-morpholinylethanone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH:19][C:29]([NH:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1N
Solvent: C1COCCO1
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1NC(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A mixture of 5-methyl-4-amino-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide from Step 2 (0.6 g, 2.1 mmol) and benzyl isocyanate (0.28 g, 2.1 mmol) in 1,4-dioxane (100 mL) was stirred under an inert atmosphere and heated to reflux. After 30 minutes, the mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue was triturated in a small amount of acetonitrile, cooled, and filtered to afford 0.33 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide. A sample was recrystallized from methanol to give product with a mp 194-195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9](Br)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:13]1([Sn](C)(C)C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Li+]>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)nc1
Reactant: C[Sn](C)(C)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of 2-bromopyridine-5-carboxylic acid ethyl ester (see part (i)) (1.855 g, 8.065 mmol), phenyltrimethyl tin (3.89 g, 16.13 mmol), bis(triphenylphosphine)palladium(II) chloride (371 mg) and lithium chloride (1.03 g. 24. 195 mmol) in dry dimethylformamide (40 ml) was heated at 100° C. for 1.5 hours under nitrogen. After cooling the mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (10:1, by volume) to give the title compound (0.843 g, 46%) as a white solid.