Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13]N)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N(OCCC(C)C)=O.N[C@H:34]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:80]([NH:82][C@H:83]([C:86]([NH:88][C@H:89]([C:92]([OH:94])=[O:93])[CH2:90][OH:91])=[O:87])[CH2:84][OH:85])=[O:81])[CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:79])[NH:68][S:69]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)(=[O:71])=[O:70])=[O:60])[CH2:54][CH2:55][C:56](=[O:58])[NH2:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N=[N+]=[N-])=O)=O)CC(C)C>CN(C)C=O.Cl.O1CCOCC1.C(N(CC)CC)C>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:34]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:80]([NH:82][C@H:83]([C:86]([NH:88][C@H:89]([C:92]([OH:94])=[O:93])[CH2:90][OH:91])=[O:87])[CH2:84][OH:85])=[O:81])[CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:79])[NH:68][S:69]([C:72]1[CH:73]=[CH:74][C:75]([CH3:76])=[CH:77][CH:78]=1)(=[O:71])=[O:70])=[O:60])[CH2:54][CH2:55][C:56](=[O:58])[NH2:57])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NN
Agent: CC(C)CCON=O
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1

Procedure:
0.39 Gram of Z-Leu-Gly-NHNH2 was dissolved in 5 ml of dimethylformamide and 0.58 ml of 6N HCl/dioxane, then a reaction similar to that described in Reference example 1 was carried out by using 10 ml of a dimethylformamide solution containing 0.15 ml of isoamyl nitrite, 0.49 ml of triethylamine and 1.00 g of H-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH, further an equivalent amount of Z-Leu-Gly-N3 was added to the reaction mixture and reacted at 4° C. for 20 hours. The reaction mixture was extracted with butanol, the extract was washed with 2%-acetic acid, then butanol and acetic acid were removed by sistillation, the residue was crystallized from ether. The crystals were collected by filtration and washed with a hot methanol to obtain 0.65 g of Z-Leu-Gly-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH2:9][OH:10])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:12]2)=[CH:16][CH:17]=1
Reactant: OCCN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CCO)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-ethanol (0.15 g, 0.6 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.11 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified on silica. 1H-NMR (CDCl3) δ:1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10–2.60 (8H, m), 3.20–3.40 (6H, m), 3.50 (2H, m), 5.20 (2H, br, s), 6.15 (1H, t), 6.70 (1H, t), 7.18–7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.26 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8][C:7]=2[CH:14]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCCc2ccc(O)cc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A solution of 8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (116 mg, 0.607 mmol) in CH2Cl2 (20 mL) at 0° C. is treated with BBr3 (1.2 mL, 1.0 M in CH2Cl2) added dropwise. The mixture is stirred for 16 hours at room temperature and then quenched with water dropwise. The suspension is filtered and the solid is rinsed with MeOH (1.0 mL) and dried under vacuum to obtain pure product (95 mg, 89%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][CH:25]=[C:24]([N:29]([CH3:31])[CH3:30])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[I:34]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25]([I:34])=[C:24]([N:29]([CH3:30])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=1
Reactant: II
Reactant: CN(C)c1ccc(Br)c([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)n1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CN(C)c1nc([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c(Br)cc1I
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a slurry of (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (200 mg, 0.372 mmol) in MeOH (7.25 mL) under nitrogen at room temperature was added silver sulfate (116 mg, 0.372 mmol), followed by iodine (94 mg, 0.372 mmol). The resulting mixture was stirred for 1 hour. The reaction was partitioned with ethyl acetate and aqueous sodium hydroxide (1.0 M). The organic was then washed with aqueous saturated sodium thiosulfate and the combined aqueous layers were extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (180 mg, 0.271 mmol). MS ESI calc'd. for C21H18BrF6N3O2 [M+H]+ 666.0. found 666.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[NH:16][N:15]=NN=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17](O)(=[O:19])[CH3:18]>>[CH3:18][C:17]1[O:19][C:12]([CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:16][N:15]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(SCc2nnn[nH]2)cc1
Product: Cc1nnc(CSc2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C

Procedure:
To 5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (4.0 g) was added anhydrous acetic acid, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate/THF, washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,3,4-oxadiazole (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1)c1cccc(Cl)c1
Temperature: 4 °C
Yield: 30.6 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-chlorobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-chlorophenyl)-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water (2.2 g; m.p. approximately 190° C.) is dissolved in boiling propanol (400 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (3×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Chlorophenyl)-1,8-naphthyridin-2-yl]-3-chlorobenzamide (0.85 g), m.p. 222°-224° C., is obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)#[N:2].[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1.C(OCC)C>[C:1]([CH:3]([CH3:19])[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]#[N:18])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CCCN1CCC(C#N)(c2ccccc2)CC1
Agent: [Li+]
Solvent: CI
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C#N)CN1CCC(C#N)(c2ccccc2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-cyanoethyl)-4-cyano-4-phenyl-piperidine (2.81 g, 11.7 mmol) dissolved in tetrahydrofuran(110 mL) was cooled to −20° C. under an atmosphere of nitrogen and 1 M lithium bistrimethylsilylamide in tetrahydrofuran (12.3 ml) was added by syringe. The clear solution was allowed to stir for 30 min. and then methyl iodide (0.80 mL, 12.9 mmol) was added by syringe. This reaction mixture was stirred for 5 minutes and then warmed to room temperature and stirred for 30 minutes. The reaction was diluted with diethyl ether and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the solvent removed to give an oil. This residue was purified by preparative centrifugal chromatography using a 5-50% ethyl acetate/hexane gradient to give the title compound which was used as is.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.COC(=O)C[C@H]1C2C=CC(O[C@H]3C4C(=C(CBr)C(C(F)(F)F)=CC=4)CC3)=CC=2OC1.CN1CCNCC1=O>>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:19]2[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:37])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH2:30][C:31]1=[O:36]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C)C(=O)C3)ccc21
Agent: CN1CCNCC1=O
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Product: CN1CCN(Cc2c(C(F)(F)F)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)CC1=O

Procedure:
The methyl ester of the title compound, {(S)-6-[(R)-4-(4-methyl-3-oxo-piperazin-1-ylmethyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-methyl-piperazin-2-one following a procedure analogous to that described for Intermediate 42. The crude product is directly submitted to the saponification conditions described for Example 1 to give the title compound upon chromatography on reversed phase (HPLC; acetonitrile/water). LC (method 6): tR=1.03 min; Mass spectrum (ESI+): m/z=505 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 96.8 %

Procedure:
A mixture of 1-fluoro-4-(4-nitrophenoxy)benzene (6.4 g, 27.44 mmol, 1.00 equiv) and 10% palladium on carbon (1 g) catalyst in methanol (200 mL) was stirred under 1 atmosphere of hydrogen at room temperature for 4 h. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to give 5.4 g (97%) of 4-(4-fluorophenoxy)benzenamine as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 6.99-6.82 (m, 6H), 6.68 (d, J=8.7 Hz, 2H), 3.63 (br, 2H) ppm.
Reaction SMILES: Cl.C(OC1C=CC(C(N)=N)=CC=1)CC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:33]([C:35]1[C:36](O)=[N:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH3:50])=[CH:43][CH:42]=2)=[N:39][CH:40]=1)#[N:34].P(Cl)(Cl)([Cl:54])=O>C(O)C>[Cl:54][C:36]1[C:35]([C:33]#[N:34])=[CH:40][N:39]=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH3:50])=[CH:43][CH:42]=2)[N:37]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCOc1ccc(-c2ncc(C#N)c(O)n2)cc1
Agent: CCCOc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-propoxybenzamidine hydrochloride with α-ethoxymethylene- α -cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-propoxyphenyl)-pyrimidine (melting point 255.3°-256.5° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-propoxyphenyl)-pyrimidine having a melting point of 193.3°-194.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)Nc2ccccc2)cc1

Procedure:
6-(4-Aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.5 g) was reacted with phenyl isocyanate (0.88 ml) in the same manner as Example 6 to give 6-[4-(3-phenylureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.26 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:20]1([N:6]2[CH2:5][CH2:4][N:3]([C@@H:7]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]3)[C:2]2=[O:1])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(C3CC3)C2=O)C1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (10.0 g, 31.17 mmol), cyclopropylboronic acid (6.39 g, 74.35 mmol) and pyridine (8.82 g, 111.5 mmol) in anhydrous DMF (100 mL) was added Cu(OAc)2 (6.75 g, 37.17 mmol). The resulting mixture was stirred at 40° C. under O2 atmosphere (balloon) for 48 hours. After quenched with NH3.H2O (10 mL), the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine, dried, concentrated, and subjected to silica flash column chromatography using 0 to 70% EtOAc in PE to isolate (R)-tert-butyl 3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (391) (2.6 g, 23%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]=1[NH2:8].[CH:18](O)=O>[OH-].[Na+]>[N:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[S:16])=[CH:15][CH:14]=1
Reactant: O=CO
Reactant: Nc1c(N)n(Cc2ccncc2)c(=S)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=S)n(Cc2ccncc2)c2nc[nH]c12

Procedure:
The title compound was prepared in accordance with the general method described in Example 1(d), using 5,6-diamino-1-(pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.25 g, 1.0 mmol, obtained from Example 3(b)), with the exception that 20 minutes of reaction time in formic acid was used, followed by a reaction time of 45 minutes in sodium hydroxide (10% aq.). The title compound was obtained (0.033, 13%) as a solid.
Reaction SMILES: [C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11].[C:35]([O:39]O)([CH3:38])(C)C>[O-2].[Cr+6].[O-2].[O-2].CCCCCCCC>[C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([O:39][CH2:35][CH2:38][CH2:21][CH2:15][CH2:14][CH2:13][CH2:18][CH3:17])[C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])[C:15]([CH3:21])([CH3:22])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCCCCCCC
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 115 °C
Yield: 133 %

Procedure:
A mixture of 15.0 g (31.2 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 0.2 g of chromium (VI) oxide, and 120 ml of n-octane is heated to 115° C. To the above mixture is added 28.5 g (221 mmol) of 70% aqueous tert-butyl hydroperoxide over a 90-minute interval while the reaction mixture is heated at reflux. Water is collected in a Dean-Stark trap. The red mixture is heated at reflux for 3.25 hours after the addition is complete in order to discharge the color. The reaction mixture is passed through 150 g of silica gel with 2:1 heptane:ethyl acetate as the eluent. The organic solution is evaporated to obtain a yellow liquid which is purified (Waters 500A HPLC; silica gel; 20:1 hexane:ethyl acetate) to afford 15.3 g (67% yield) of the title compound. The product has the same LC retention time as the compound prepared in Example 31.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([O:28]C)=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([OH:28])=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1NS(C)(=O)=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1O
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
Cool a solution of N-[5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methoxy-phenyl]-methanesulfonamide (100 mg, 0.247 mmol) in CH2Cl2 (5 mL) to 0° C. Add 23.3□L (62 mg, 0.247 mmol) BBr3 and warm up to room temperature. Stir for 20 min, then add 30.0□L (79.5 mg, 0.317 mmol) more BBr3. Stir at room temperature for 1 h, then dilute reaction with 90 mL saturated aqueous NaHCO3. Stir overnight. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine and dry organics (MgSO4), filter, and concentrate to afford 94 mg (97%) of a white foam, mp 122.6° C. 1H NMR (CDCl3) δ 2.70 (s, 3H), 2.79-3.59 (br m, 4H), 5.94 (s, 1H), 6.39 (s, 1H), 6.70-7.98 (m, 12H); MS (ES) 414 (M+Na), 390 (M−H). HPLC shows 99% purity.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:29])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=1)[CH:9]=2)=[O:4].[NH2:30][CH2:31][C:32]([O-:34])=[O:33].[Na+]>COC(O)C>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[O:7][C:6](=[O:29])[C:5]=1[C:3]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2ccc(-c3ccc(Oc4ccccc4)cc3)cc2oc1=O
Agent: COC(C)O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2ccc(-c3ccc(Oc4ccccc4)cc3)cc2oc1=O
Yield: 96.1 %

Procedure:
A mixture of 4-hydroxy-2-oxo-7-(4-phenoxy-phenyl)-2H-chromene-3-carboxylic acid methyl ester (75 mg, 0.193 mmol) and sodium glycinate (94 mg, 0.96 mmol) in methoxyethanol (10 mL) was refluxed for 18 h; then cooled, the solvent was removed, the residue was redissolved in water, acidified with 2 M HCl, the precipitates were collected and washed with water, air dried to give the desired title product (80 mg). ESI (m/z): 432 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CON(C)[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1)=[O:11]>CCOCC>[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:13]1)=[O:11]
Reactant: CON(C)C(=O)C1CCCC(N(C)C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)C1CCCC(C=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a cold (0° C.) suspension of LiAlH4 (380 mg, 9.9 mmol) in Et2O (40 mL) was added dropwise a solution of tert-butyl N-[3-(N-methoxy-N-methylcarbamoyl)cyclohexyl]-N-methylcarbamate (2.38 g, 7.92 mmol) in Et2O (40 mL) over 10 min. The reaction mixture was stirred at 0° C. for 0.5 hr, and quenched with 1N KHSO4 (100 mL). The organic phase was separated, dried over MgSO4 and evaporated to give tert-butyl 3-formylcyclohexyl(methyl)carbamate as a colorless oil, which was used for next step without purification (1.66 g, yield; 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24](C)([O-:26])C.[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]2[C@H:10]([N:14]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:24](=[O:26])[CH2:23][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.14 g of trans-1-tert-butoxycarbonyl -4-hydroxy-3-[(1R)-1-phenylethylamino]pyrrolidine 8a in 200 of tetrahydrofuran was added 1 g of potassium tert-butoxide. The mixture was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (1:1 by volume), the titled compound 9a weighing 2.45 g was obtained as an oil.