Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].C(O)(C(F)(F)F)=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([NH2:10])=[O:12])=[N:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(C#N)ccc1Br
Agent: O=S(=O)(O)O
Product: Cc1nc(C(N)=O)ccc1Br
Temperature: 40 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution of 5-bromo-6-methylpicolinonitrile (1.8 g, 9.14 mmol) in a mixture of TFA and sulfuric acid (30 mL, 4:1, VAT) was stirred at 40° C. for 16 h. The reaction mixture was poured into ice water. The resulting solid was filtered off and washed with water and dried to give the desired product as a white solid (1.0 g, 4.65 mmol, 54% yield). MS (ESI) m/z 217.1 [M+2]+.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([NH:41][CH2:42][C:43]2[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=2[CH3:49])=[O:20])=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(=O)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(=O)c3ccccc3)c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzoyl-2-methyl-1H-indole-3-carboxylic acid (125 mg, 0.45 mmol), 1-hydroxybenzotriozole (122 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (173 mg, 0.9 mmol), triethylamine (0.4 mL) in dichloromethane (20 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (137 mg, 0.9 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 1-benzoyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (50 mg, 53%). LRMS (M+H+) m/z: calcd 413.17. found 413. HPLC Purity (214 nm): 96%. 1H NMR (300 MHz, d6-DMSO): δ 11.57 (s, 1H), 8.13 (q, J=5.1 Hz, 1H), 7.74-7.70 (m, 4H), 7.60-7.58 (m, 2H), 7.20-7.00 (m, 3H), 5.88 (s, 1H), 4.32 (d, J=5.1 Hz, 2H), 2.37 (s, 3H), 2.267 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH:26]([CH:27]=[CH:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:25][CH2:24][CH:23]1[OH:36]>CC(C)=O.O.[Cr]>[O:36]=[C:23]1[CH2:24][CH2:25][CH:26]([CH:27]=[CH:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([OH:3])=[O:14]
Reactant: CC(C)=O
Reactant: CCCCCC(=O)C=CC1CCC(O)C1CCCCCCCO
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCC(=O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 1 h
Yield: 26 %

Procedure:
8N Jones' reagent (3.24 ml.; J. Chem. Soc., 1953, 461) was added to a stirred solution of 2-(7-hydroxyheptyl)-3-(3-oxo-1-octenyl)cyclopentanol (1.4 g., 0.0043 mole) in acetone (10 ml.) at 15°-25°C., at a rate such that the deep red coloration caused by the addition of one drop of reagent had changed to green before addition of the next drop. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts, and was then extracted three times with diethyl ether. The combined ether extracts were washed with 2N aqueous sulphuric acid and then added to 10% aqueous sodium carbonate (100 ml.) and stirred for 1 hour. The aqueous layer (containing the desired acid as the sodium salt) was separated and washed with diethyl ether. The solution was then covered with a layer of diethyl ether, cooled to below 20°C. and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid. The ether layer was separated and the aqueous layer was again extracted with diethyl ether. The combined extracts were dried over magnesium sulphate, and the other was removed in vacuo to give the crude acid (0.79 g.). This was purified by preparative thin layer chromatography on silica gel using a 65:15:1 mixture of benzene, dioxane and acetic acid as solvent. Evaporation gave pure 7-[2-oxo-5-(3-oxo-1-octeny)cyclopentyl]heptanoic acid (0.38 g., 26%), λmax 228 mμ, ε 11,600 (ethanol), νmax 1730 cm-1, 1700 cm-1, 1670 cm-1, 1625 cm-1 and 980 cm-1 (liquid film). N.M.R. (approximately 10% solution in deuterochloroform) 0.9 δ(triplet J=5c/s, terminal CH3), 1.2-2.0 δ(overlapping multiplets, cyclic and chain CH2), 2.0-2.8 δ (multiplet CH2C=O), 6.17 δ (doublet J=16c/s, CH=CHC=O) and 6.8 δ (doublet of doublets J=16c/s and ##EQU4##
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:19][C:4]=1[O:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:2].Cl.[CH2:31]([O:38][NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1C=CC=CC=1>C(O)C>[OH2:2].[CH2:31]([O:38][N:39]=[CH:1][C:3]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:19][C:4]=1[O:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C=NOCc1ccccc1
Product: O
Temperature: 65 °C
Yield: 22 %

Procedure:
A mixture of (RS)-4-[2-formyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (0.7 g), O-benzylhydroxylamine hydrochloride (0.48 g) and pyridine (1 mL) in ethanol (50 mL) is heated at 65° C. for 5 hours. The reaction mixture is evaporated. The residue is dissolved dichloromethane (80 mL), washed with 1 N hydrochloric acid, then with water, dried over magnesium sulphate and evaporated. The resulting oil is purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5 v/v). Fractions homogeneous in the required product are combined, evaporated and the solid residue triturated with pentane to give (RS)-4-[2-(benzyloxyiminomethyl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid hydrate (0.2 g) as a cream coloured solid, m.p. 35-37° C. [Elemental analysis:- C,69.2; H,5.60; N,2.58; S,6.26%. Calculated for C25H23NO8.0.3H2O: - C,69.2; H,5.72; N,2.69; S,6.16%]
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[CH3:8][N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][NH:12]2.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(Cl)Cl>[CH3:8][N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Cc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nsc(N2C[C@@H]3C[C@H]2CN3C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A solution of 1.04 g of 5-chloro-3-methyl-1,2,4-thiadiazole, prepared by the procedure of J. Goerdeler, Chim. Ber., 1957, 90, 182, in 2 ml of tetrahydrofuran is added over one hour to a solution of 0.825 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.77 g of potassium carbonate in 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, diluted with methylene chloride and the organic layer is washed with water. The methylene chloride solution is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride) to give 0.56 g of the desired product:
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2sc(-c3ccccc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccccc2)sc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methanol (286 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (183 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.4 mL) and 1,1′-(azodicarbonyl)dipiperidine (505 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methoxy]benzoate as an amorphous compound. The obtained methyl 4-[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methoxy]benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (251 mg, 62%) as a white crystal.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:19]=1[CH2:20][N:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:18]([F:17])[C:19]=1[CH2:20][N:21]([CH3:42])[C:22](=[O:23])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][CH:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:38][CH2:39]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CN(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Yield: 39.9 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.126 g, 0.51 mmol), 1-(2,6-Difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-1-methyl-urea (0.5 mmol), glacial acetic acid (0.028 g, 0.49 mmol) and sodium cyanoborohydride (0.031 g, 0.49 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.136 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][N:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:18]3[CH:19]=[C:14]([N:12]([CH3:13])[CH3:11])[CH:15]=[CH:16][CH:17]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 95 °C
Yield: 21.4 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.150 g, 0.455 mmol, 1 eq), 3-(N,N-dimethylamino)phenylboronic acid (0.113 g, 0.682 mmol, 1.5 eq), Cs2CO3 (0.296 g, 0.909 mmol, 2 eq) and Pd(PPh3)4 (0.032 g, 0.027 mmol, 0.06 eq) were dissolved in Dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 95° C. for 24 h. Additional amounts of 3-(N,N-dimethylamino)phenylboronic acid (1.5 eq) and Pd(PPh3)4 (0.06 eq) were added and the reaction mixture was heated at 95° C. for 3 days. The solvent was removed in vacuo, redissolved in DCM/water (150 mL) and extracted with DCM (2×80 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (20-70% EtOAc in cyclohexane) to afford the desired product (36 mg, 21%) as a yellow solid. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.73 min, [M+H]+ m/z 371.1.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:7]=1[CH2:8][N:9]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11][C@H:10]1[C:34](O)=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:3][CH2:2][CH2:1][NH:4][C:34]([C@H:10]1[N:9]([CH2:8][C:7]2[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:6]=2[F:5])[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11]1)=[O:35]
Reactant: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)O
Reactant: NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
ethane-1,2-diamine (18 mg, 0.290 mmol) was added to a stirred mixture of (2S,5R)-1-(2-fluoro-6-methoxybenzyl)-5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)-piperidine-2-carboxylic acid (50 mg, 0.097 mmol), N,N-DIISOPROPYLETHYL-AMINE (0.084 ml, 0.483 mmol), HATU (73.5 mg, 0.193 mmol) in dimethylformamide and the mixture was stirred at room temperature for Overnight. The reaction was rotovap to dryness and the residue was purified by column chromatography on silica gel Isolute Flash Si; 50 g prepacked, eluting with 5% MeOH/NH3(2M)CH2Cl2 to give the desired (48.1 mg, 0.085 mmol, 88% yield) as a white solid.
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[O:6]([C:13]1[N:14]=[CH:15][C:16]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]3[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[O:22][N:21]=2)=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a tetrahydrofuran (2 mL) solution of (2-phenoxy-pyridin-5-yl)-acetohydroximoyl chloride (100 mg, 0.381 mmol) described in Manufacturing Example 40-1-4 and 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (714, 0.51 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 50° C. Water was added to the reaction mixture at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (27 mg, 31%).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@@:13]([OH:24])([CH3:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C.[I-].[Na+]>C(#N)C.CN(C=O)C>[OH:24][C@:13]1([CH3:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][O:35][C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)[CH2:12]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc4ccc([N+](=O)[O-])cc4)CC[C@@H]32)C1
Yield: 51.3 %

Procedure:
A solution of 21-bromo-3α-hydroxy-3β-methyl-5α-pregnan-20-one (250 mg, 0.61 mmol), 4-nitrophenol (127 mg, 0.912 mmol), triethylamine (127 μL,0.912 mmol), and a small amount of sodium iodide in 2:1 acetonitrile DMF was stirred with heating to ~60° C. for 6 hours. The mixture was partitioned between EtOAc and 1:1 water:sat. aq. sodium bicarbonate. The organic layer was washed with 2N HCl, water and sat. aq. NaCl, dried with Na2SO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 20% acetone in hexane yielded 3α-hydroxy-3β-methyl-21-(4'-nitrophenoxy)-5α-pregnan-20-one (147 mg) as a solid; mp 169-172° C.; TLC Rf (hexane:acetone 4:1)=0.35.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:10])[C:7]#[C:8][CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:10][CH2:6][C:7]#[C:8][CH3:9])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC#CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
305 ml methanesulfonyl chloride was added dropwise to a solution of 138 g 2-butyn-1-ol and 683 ml triethylamine in 2.7 L methylene chloride under ice-cooling, and the mixture was stirred at 0° C. for 1 hour and 40 minutes. Ice was added to the reaction solution under ice-cooling, and this mixture was extracted with methylene chloride. The organic layer was successively washed with 1M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine, and the organic layer was dried over magnesium sulfate. This organic layer was filtered and then the solvent was evaporated, to give a dark brown oil (280 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][O:19][C:18]2=[C:22]([C:25](O)=[O:26])[S:23][CH:24]=[C:17]12>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:22]2[S:23][CH:24]=[C:17]3[C:18]=2[O:19][CH2:20][CH2:21][O:16]3)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1scc2c1OCCO2
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2scc3c2OCCO3)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 2,3-dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (acidic): tR=0.98 min; [M+H]+=381.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.CCN(CC)CC.[NH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C=O)C>[OH:45][CH2:44][CH2:43][CH2:42][NH:41][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: NCCCO
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCCO)cc2)nc2c1CN(C)C2
Temperature: 50 °C
Yield: 24.2 %

Procedure:
To a stirring solution of (S)-phenyl 4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenylcarbamate (intermediate 10) (50 mg, 0.12 mmol) in dry DMF, was added Et3N (51 μL, 0.36 mmol) and 3-aminopropan-1-ol (42 μL, 0.56 mmol). The reaction mixture was then heated at 50° C. for 2 hours. The solvent was then removed in vacuo and the crude residue was purified by prep. LCMS (high pH) affording the title compound as clear oil (12.5 mg, 0.029 mmol, 26%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:11]=2[C:12]2[N:16]=[C:15]([C:17]3C=CC=C(C)C=3C)[NH:14][C:13]=2[CH:25]=1)=[O:4].C[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[CH2:34](O)C.C(NCC)C>>[CH3:1][N:2]([CH3:26])[C:3]([C:5]1[C:6]2[CH2:7][CH2:8][C@H:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:10][C:11]=2[C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:34])[C:13]=2[CH:25]=1)=[O:4]
Reactant: Cc1cccc(-c2nc3c4c(c(C(=O)N(C)C)cc3[nH]2)CCCO4)c1C
Reactant: CCO
Reactant: CCCCCCC
Solvent: CCNCC
Product: Cc1nc2c3c(c(C(=O)N(C)C)cc2n1C)CC[C@H](c1ccccc1)O3

Procedure:
Resolution of racemic 2,3-dimethylphenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid dimethylamide (0.5 g, 1.4 mmol) was achieved by preparative chromatography using a 275×110 mm CHIRALPAK® AS-V 20 μm column. The mobile phase consisted of a n-heptan/ethanol/diethylamine mixture [95/5/0.1 (v/v/v)]. The separation was performed at room temperature with a flow rate of 1 ml/min. The products were detected at a wavelength of 225 nm. The separation afforded 0.19 g (39%; ee 99.8%) of the title compound ((8R)-enantiomer) as a white solid. m.p. 227°-228° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.[O-:10][CH2:11][CH3:12].[Na+].[CH2:14](O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:12][C:11](=[O:10])[NH:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC[O-]
Reactant: NNc1cccc(Cl)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCN(c2cccc(Cl)n2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20.1 g (140 mmol) of 6-chloro-2-pyridylhydrazine (synthesis: Chem. Ber. 103. (1970) 1960) are added dropwise at 15°-20° C. to a mixture of 12.4 g (182 mmol) of sodium ethoxide, 100 ml of ethanol and 100 ml of toluene. After stirring for 2 hours at 25° C., the reaction mixture is evaporated, the residue is taken up in water and extracted with MTBE. The aqueous phase is adjusted to a pH of 6.5 and cooled to 5° C. The precipitate formed is filtered off and dried under reduced pressure at 40° C.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Product: COC(=O)Cn1cc(I)c(=O)[nH]c1=O

Procedure:
Astoundingly, as can be seen from FIG. 2, it was the use of a modification of the Heck reaction (Heck, J. Am. Chem. Soc. 90 (1968), 5518), of all possible options, which led to the desired C—C linkage. 5-Iodouracil (5) was first of all alkylated with methyl bromoacetate to give methyl 5-iodouracil-1-acetate (6). The Heck reaction of 6 with Z-protected allylamine in the presence of Pd(OAc)2 and triphenylphosphine in absolute acetonitrile was carried out with the exclusion of air and at a superelevated temperature (bath temperature of 110° C.), and yielded the compound (7) together with a small portion of the oxidized byproduct (8). The methyl ester (7) was then hydrolyzed to give the free acid (9), which was reacted with methyl 2-Boc-aminoethylglycine (10) in analogy with the method of Dueholm et al., (J. Org. Chem. 59 (1994), 5767). The desired amino-modified thymine PNA building block (11) was obtained after the ester had been subjected to alkaline hydrolysis.