Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:5]=[CH:6][C:7]=1C1C(C)=NC(O[C@@H]2COC3=NC([N+]([O-])=O)=CN3C2)=CC=1.Br[C:40]1[C:41]([C:59]([F:62])([F:61])[F:60])=[N:42][C:43]([O:46][C@@H:47]2[CH2:52][O:51][C:50]3=[N:53][C:54]([N+:56]([O-:58])=[O:57])=[CH:55][N:49]3[CH2:48]2)=[N:44][CH:45]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:5]=[CH:6][C:7]=1[C:40]1[C:41]([C:59]([F:62])([F:61])[F:60])=[N:42][C:43]([O:46][C@@H:47]2[CH2:52][O:51][C:50]3=[N:53][C:54]([N+:56]([O-:58])=[O:57])=[CH:55][N:49]3[CH2:48]2)=[N:44][CH:45]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)nc3C)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](Oc1ncc(Br)c(C(F)(F)F)n1)C2
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)nc3C(F)(F)F)c(F)c2)C(=O)O1

Procedure:
(S,S)—N-(3-{3-Fluoro-4-[2-methyl-6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except 6(S)-(5-bromo-4-trifluoromethyl-pyrimidin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine was used in place of 6(S)-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 582.5 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.63 (d, J=11.6 Hz, 1H), 7.48 (s, 1H), 7.32-7.25 (m, 2H), 6.02 (t, J=6.2 Hz, 1H), 5.75 (s, 1H), 4.94 (d, J=12.0 Hz, 1H), 4.83-4.82 (m, 1H), 4.60 (d, J=12.4 Hz, 1H), 4.49 (brs, 2H), 4.10 (t, J=9.8 Hz, 1H), 3.84 (t, J=7.8 Hz, 1H), 3.72-3.62 (m, 2H), 2.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][N:11]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[S:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=S(=O)(NC1CCCC1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)nc1)N(CCCOCc1ccccc1)C1CCCC1
Temperature: 40 °C
Yield: 105.1 %

Procedure:
A mixture of 1 g (3.84 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 1.32 g (9.59 mmol) of K2CO3 and 0.88 mL (4.99 mmol) of [(3-bromopropoxy)methyl]benzene in 8 mL of anhydrous DMF is heated for 12 hours at 40° C. After cooling to room temperature, the medium is taken up in 300 mL of EtOAc, washed successively with water (2×100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 1.65 g of N-[3-(benzyloxy)propyl]-6-chloro-N-cyclopentylpyridine-3-sulfonamide are thus obtained in the form of an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)O1.Br[C:44]1[NH:48][C:47]([C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH3:62][O:61][C:60]([NH:59][C@H:55]([C:54]([N:50]1[CH2:51][CH2:52][CH2:53][C@@H:49]1[C:47]1[NH:48][C:44]([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)=[CH:45][N:46]=1)=[O:64])[CH:56]([CH3:58])[CH3:57])=[O:63]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CO4)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3c2ccc2[nH]c([C@@H]4CCCN4C(=O)OC(C)(C)C)nc23)[nH]1)C(C)C
Temperature: 85 °C
Yield: 46.6 %

Procedure:
A mixture of tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (450 mg, 0.79 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (325 mg, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.02 mmol), PdCl2(dppf) (35 mg, 0.05 mmol), 2M aqueous potassium carbonate (1.2 mL, 2.4 mmol), dimethoxyethane (6.8 mL) and dimethylformamide (1.2 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85° C. for 2.5 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography (EtOAc/MeOH) to yield tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (270 mg, 46% yield).
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH:35]=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][OH:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C=O)ccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(CO)ccc23)cc1
Yield: 70.8 %

Procedure:
Sodium borohydride (51 mg, 1.33 mmol) was added to a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 94, 305 mg, 0.66 mmol) in ethanol (10 ml) at room temperature under a nitrogen atmosphere. After 1 h the ethanol was removed in vacuo and the product was extracted from 0.5N hydrochloric acid (50 ml) with dichloromethane (2×50 ml). The organic layers were dried (MgSO4) and concentrated. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (230 mg) as a white foam.
Reaction SMILES: [CH2:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3]1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C1CCc2c(O)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCc2c(O)cccc21
Yield: 93579.3 %

Procedure:
A mixture of 1-methylene-indan-4-ol (200 mg, 1.37 mmol) and 10% Pd/C (60 mg, 10% weight) in methanol (6 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 1-methyl-indan-4-ol (190 g, 94%)
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([S:3][CH2:1][CH3:2])=[CH:12][CH:11]=2)=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CCSc1ccc(C(=O)O)cc1
Product: CCSc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
General procedure G was performed using 4-(ethylthio)benzoic acid and 4-chloro-3-(pyridin-2-yl)aniline to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylthio)benzamide.
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][O:15][C:16](=[O:35])[C@H:17]([CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([OH:33])=[C:28]([Cl:34])[CH:27]=1)[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].[C:36]1(B(O)O)[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.C([O-])(=O)C>ClCCCl.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:35])[C@H:17]([CH2:25][C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([O:33][C:44]2[C:45]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:41]=[CH:42][CH:43]=2)=[C:30]([Cl:32])[CH:31]=1)[NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22]
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cc(Cl)c(Oc2cccc3ccccc23)c(Cl)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.3 %

Procedure:
Pyridine (0.584 ml, 7.22 mmol) and triethylamine (0.968 ml, 6.94 mmol)were added in turn to a suspension of 3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (500 mg, 1.39 mmol), 1-naphthlene boronic acid (765 mg, 4.44 mmol), molecular sieves 4A powder (720 mg) and cppoer(II) acetate (390 mg, 2.08 mmol) in 1,2-dichloroethane(20 ml), and the mixture was stirred under air atmosphere (without argon) at room temperature for 24 hrs. The reaction mixture was diluted with ethyl acetate, and the insoluble materials were filtered off (celite (Trade mark)) and washed with ethyl acetate. The filtrate and washings were combined, washed with 10% hydrochloric acid and brine in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/diethyl ether=2) to give 3,5-dichloro-N-trifluoroacetyl-O-(1-naphthyl)-L-tyrosine methyl ester (151 mg, 22%) as colorless crystals.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccco1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1ccco1

Procedure:
2-(furan-2-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and furan-2-ylboronic acid (38 mg, 93.2 mg theoretical, 40.8%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:22][C:23]([OH:40])([CH3:39])[CH2:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:28]4[CH:27]=[N:26][N:25]([CH2:24][C:23]([OH:40])([CH3:39])[CH3:22])[CH:29]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)cn1

Procedure:
10-bromo-9-fluoro-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similarly to as described in Example 4 to produce crude 10-bromo-9-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. This intermediate was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 11 mg (10%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C.C(OCC)(=O)C>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH3:3])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
Sodium hydride (2.45 g; 61.0 mmol, 60% dispersion in oil) was added to a solution of 2-methylimidazole (5.0 g, 60.9 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 0.25 h before adding 4-nitrobenzyl bromide (13.2 g, 61.0 mmol) and heating at 110° C. for 2 h followed by stirring at room temperature for 16 h. Water (200 ml) and ethyl acetate (500 ml) were added, the aqueous separated and extracted with ethyl acetate (2×500 ml). The combined extracts were washed with water (3×250 ml), dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH (4%) to give the title-product (1.58 g, 10.5%); δ (360 MHz, CDCl3) 2.34 (3H, s, Me); 5.16 (2H, s, CH2); 6.67 (1H, d, J= 1.3 Hz, Ar--H); 7.03 (1H, d, J=1.3 Hz, Ar--H); 7.19 (2H, d, J=9.5 Hz, Ar--H); 8.22 (2H, d, J=9.5 Hz, Ar--H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNC(=O)C(C)(C)C)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 μL, 0.170 mmol), pivaloyl chloride (19 mg, 19 μL, 0.155 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-29 (65 mg, 89%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 7.65 (t, J=6.2 Hz, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 6.39 (br s, 2H), 5.90 (s, 2H), 4.26 (t, J=6.0 Hz, 2H), 3.04 (q, J=6.0 Hz, 2H), 2.68 (s, 6H), 1.83-1.87 (m, 2H), 1.27 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 178.8, 154.9, 152.9, 151.9, 148.3, 147.5, 146.6, 144.7, 119.8, 119.7, 109.5, 102.5, 101.7, 45.3, 40.3, 38.8, 34.8, 28.9, 27.7; (ESI) m/z [M+H]+ calcd. for C22H30N7O3S, 472.2131. found 472.2128.
Reaction SMILES: CON(C)[C:4](=[O:16])[CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[CH2:6][CH2:5][CH:4]=[O:16]
Reactant: CON(C)C(=O)CCc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=CCCc1c(Cl)cc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a stirred solution N-methoxy-N-methyl-3-(2,4,6-trichloro-phenyl)-propionamide (0.9 g, 3.04 mmol) in toluene (18 mL), DIBAL-H (15.2 mL, 15.2 mmol) was added at −60° C. slowly in drops over a period of 20 minutes and the reaction mass was stirred at −60° C. for 3 hours. Reaction mass was then quenched with dil. HCl (20 ml) in drops, followed by dilution with water (10 ml) and stirred for 15 minutes. Toluene layer was separated and resulting aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with water and brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 2% ethyl acetate in hexane) to afford white crystalline solid of 3-(2,4,6-trichloro-phenyl)-propionaldehyde (0.45 g, 62.5%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:38])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:38][CH2:39][C:15]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:16]3=[O:37])[C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(OCc3ccccc3)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 5-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (88%): 1H NMR (300 MHz, CDCl3) δ7.43-7.26 (m, 15H), 7.17-7.10 (m, 1H), 7.06 (s, 1H), 7.05-6.91 (m, 2H), 6.90-6.76 (m, 2H), 6.55-6.46 (m, 1H), 6.30-6.23 (m, 1H), 4.85 (ABq, 2H), 4.79 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-].[Na+].S(=O)(O)[O-:23].[Na+]>O1CCOCC1>[CH3:14][C:13]1[C:4]([C:1]([OH:23])=[O:3])=[CH:5][C:6]2[C:7]([CH3:17])([CH3:18])[CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]=2[CH:12]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 8.2 g (0.0336 mol) of 2-acetyl-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene, 90 ml of 1.19M (0.107 mol) aqueous sodium hypochlorite and 10 ml of dioxane was stirred at room temperature for 0.5 hours and at 60° C. for 2 hours. A further 70 ml of 1.19M (0.0833 mol) of aqueous sodium hypochlorite was then added to the reaction mixture and the mixture stirred at 70° C. for 1 hours. The reaction mixture was then cooled and treated with aqueous sodium bisulfite solution until the mixture was negative to starch/iodide paper. The mixture was washed with ether and then acidified with H2SO4. The mixture was extracted with three portions of ether and the ether extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The ether solution was then concentrated and the title compound obtained as colorless crystals by recrystallization from cold ether. PMR (CDCl3): δ 1.29 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.60 (3H, s), 7.17 (1H, s), 7.26 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][C:12]=1[O:17]C)[N:7]=2.[Cl-].[Cl-].[Cl-].[Al+3].C1C=CC=CC=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:19][C:5]1[CH:4]=[C:3]([OH:2])[CH:16]=[C:15]2[C:6]=1[N:7]=[C:8]1[C:13](=[N:14]2)[C:12]([OH:17])=[CH:11][CH:10]=[CH:9]1
Reactant: COc1cc(C)c2nc3cccc(OC)c3nc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(O)cc2nc3c(O)cccc3nc12
Temperature: 25 °C
Yield: 84 %

Procedure:
A magnetically stirred mixture of 0.509 g (2 mmol) of 3.6-dimethoxy-1-methylphenazine, 1.0 g of aluminum trichloride (7.5 mmol), and 20 ml of benzene was heated at reflux for 18 hours. The mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue was treated with crushed ice and the resulting mixture was taken up in 1N sodium hydroxide and washed with dichloromethane. The combined dichloromethane layers were back-extracted with 1N sodium hydroxide and the combined aqueous layers were acidified to pH 4-5. The solution was extracted with dichloromethane containing a trace of methanol. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was was stripped to yield 1.06 g of a brown and yellow solid mixture. Flash chromatography in 6:1 toluene-acetone yielded 0.38 g of a yellow solid. This was recrystallized from toluene to yield 298 mg of orange crystals; decomposition at >256° C.
Reaction SMILES: [CH2:1]1[C@@H:9]2[N:4]([C:5](=[O:11])[CH2:6][C:7](=O)[CH2:8]2)[CH2:3][CH2:2]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[NH:4]1[CH2:9][CH2:1][CH2:2][CH2:3]1.[N:12]1([C:7]2[CH2:8][C@H:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[C:5](=[O:11])[CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CC(=O)N2CCC[C@H]2C1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1C=C(N2CCCC2)C[C@@H]2CCCN12
Reaction time: 0.08 h
Yield: 204.1 %

Procedure:
(S)-1,2,3,5,6,7,8,8a-octahydroindolizin-5,7-dione (117 mg (0.76 mmol), prepared as described in 3)) was dissolved in ethanol (1.2 ml). To the solution was added pyrrolidine (128 μl, 1.53 mmol), and the resulting mixture was allowed to stand at room temperature for 5 minutes. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure to remove solvents and any excess of pyrrolidine, to give the title compound (160 mg) as a light yellow powder (yield quantitative).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13](=[O:18])[C:12]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[N:11]1.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(O)=O>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13](=[O:18])[C:12]([C:19]2[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=[CH:21][CH:20]=2)=[N:11]1
Reactant: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)C=CN(C)C)c1=O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: COc1cn(-c2ccccc2OC(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A solution of 1-[2-(difluoromethoxy)phenyl]-3-[3-(dimethylamino)prop-2-enoyl]-5-methoxypyridazin-4(1H)-one (0.50 g, 1.369 mmol) and phenylhydrazine (0.269 mL, 2.74 mmol) in AcOH (5 mL) was refluxed for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M HCl aqueous solution, saturated NaHCO3 aqueous solution, and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (7/3-0/10) to give the title compound (0.38 g, 68% yield) as an off-white amorphous solid: NMR (300 MHz, CDCl3): δ ppm 3.88 (3H, s), 6.37 (1H, t, J=72.3 Hz), 6.57 (1H, dd, J=8.1, 1.7 Hz), 7.09-7.16 (1H, m), 7.22-7.25 (2H, m), 7.34-7.42 (6H, m), 7.76-7.78 (2H, m). LC-MS (ESI) m/z 411 [M+H]+. Anal. Calcd. for C21H16F2N4O3: C, 61.15; H, 4.07; N, 13.79. Found: C, 61.23; H, 4.11; N, 13.71.