Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl[C:27]1[N:28]=[N:29]C(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)=CC=1.C(NN)=O>C(O)CCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:27]=[N:28][N:29]=3)[N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F
Reactant: O=c1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Agent: NNC=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(-c2ccc3nncn3n2)cc1C(F)(F)F

Procedure:
A mixture of 7.0 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone and 80 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The solvent is removed and ice water added to the residue. Filtration gives 7.2 g. of 3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine as tan crystals, m.p. 129°-135° C. Recrystallization from dichloromethane-hexane gives cream colored crystals, m.p. 151°-155° C. The preceding compound is reacted with formylhydrazine in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: [OH:1][C:2]([CH3:29])([CH3:28])[CH:3]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[OH:1][C:2]([CH3:28])([CH3:29])[CH:3]([C:22]1[CH:23]=[N+:24]([O-:38])[CH:25]=[CH:26][CH:27]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]=1
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(C)(C)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc[n+]([O-])c1)C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
Compound 1 (89.6 mg, 0.215 mmol) obtained in Example 1 was dissolved in dichloromethane (5.0 mL). To the solution was added 65% meta-chloroperbenzoic acid (85.7 mg, 0.323 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give Compound 2 (47.7 mg, 51% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]1.F[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:27])=[N:19][N:20]=2)[CH:17]=1.[CH3:28]N(C=O)C>>[CH3:27][C@H:22]1[CH2:23][CH2:24][CH2:25][C@@H:26]([CH3:28])[N:21]1[C:18]1[N:16]2[CH:17]=[C:12]([O:10][CH:7]3[CH2:8][CH2:9][CH:4]([NH2:3])[CH2:5][CH2:6]3)[CH:13]=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(N)CC3)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Sodium hydride (60% in mineral oil, 0.26 g, 6.39 mmol) was added to a stirred solution of trans-4-amino cyclohexanol (0.397 g, 3.45 mmol) in anhydrous DMF (10 mL) at RT under an argon atmosphere. The reaction mixture was stirred at RT for 30 min, then Intermediate 2d (0.50 g, 2.13 mmol) in anhydrous DMF (4 mL) was added and stirred at 60° C. for 10 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and water (1:1) and extracted with EtOAc and then DCM. The combined organic extracts were concentrated in vacuo and the resultant residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to afford the title compound (0.193 g, 27%) as an orange residue. LCMS (Method 3): Rt 2.00 min, m/z 330 [MH+].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[ClH:1].[CH3:21][O:20][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:10]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19]
Reactant: C1CNCCN1
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Solvent: Cc1ccccc1
Product: COc1cc(NCCCCCCN2CCNCC2)c2nccc(C)c2c1
Product: Cl

Procedure:
A solution of 6.2 g (0.02 mole) of crude N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine in 75 ml of toluene was added dropwise to a stirred, hot suspension of 25 g (0.29 mole) of piperazine in 25 ml of toluene. The mixture was distilled until the internal temperature rose to 130°, allowed to cool, and taken up in a mixture of water and dichloromethane. The organic layer was separated, washed again, dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. The residual brown oil was chromatographed over 200 g of silica gel first with ethyl acetate and then with 500 ml each of the following solutions of methanol in ethyl acetate: 4%, 8%, 12% 16%, 20% and 25%. The eluant which appeared to contain only the product, Rf (silica--25 methanol:75 ethyl acetate:1 triethylamine)=0.05 was concentrated to dryness in vacuo. The residue was triturated with ether and filtered to remove 1 g of the bis product, mp 126°-128°, and concentrated again. The residue was dissolved in hot 2-propanol, filtered to remove haze and treated with a saturated solution of hydrogen chloride in 2-propanol. The resulting precipitate was collected, dried overnight at 60° in vacuo and allowed to air-equilibrate to afford 5.8 (60% ) of the title compound, mp 245°-247° (dec) with prior sintering at 125°. The NMR spectrum confirmed the presence of 2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1=CC(C)C(C)=C1c1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(C)C(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 88.7 %

Procedure:
An experiment was performed in the same manner as in Example 49 using 0.534 g (2.68 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)phenylamine, 0.325 g (3.22 mmol) of triethylamine, and 0.388 g (3.22 mmol) of pivaloyl chloride. The reaction product was purified using a column chromatography with a hexane/ethylacetate (v/v, 5:1) solvent. The purified product was dried in vacuum to remove the solvent therein, thereby obtaining while solid (0.674 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([OH:31])=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([O:31][CH2:5][CH2:6][N:7]7[CH2:12][CH2:36][O:39][CH2:9][CH2:8]7)=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCN5CCOCC5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 100 °C
Yield: 21.2 %

Procedure:
A mixture of 4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide (50 mg, 0.104 mmol), 4-(2-chloroethyl)morpholine, HCl (67.4 mg, 0.362 mmol), and cesium carbonate (202 mg, 0.621 mmol) in DMF (6 mL) was heated at 100° C. for 3 hr. The mixture was diluted with ethyl acetate (100 mL) and filtered through CELITE®. The filtrate was washed with water (2×30 mL) and brine (30 mL), and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the purified product (7.1 mg, 0.011 mmol, 10.9% yield) as a pale yellow sold. LCMS (M+H)+=596.29. 1H NMR (500 z, DMSO-d6) δ: 11.72 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.82-7.78 (m, 3H), 7.72 (d, J=6.9 Hz, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (s, 1H), 7.22 (br. S, 1H), 6.79 (br. S, 1H), 5.10 (d, J=17.6 Hz, 1H), 5.00 (d, J=17.6 Hz, 1H), 4.23 (m, 2H), 3.81-3.53 (m, 8H), 2.81 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61][N:39]3[C:38](=[O:42])[CH:37]=[C:36]([O:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][N:32]=4)[CH:41]=[N:40]3)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccc(Cl)cn4)cc3=O)cc2C1

Procedure:
7-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 15b from 1.20 g (5.05 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 18b) and 2.62 g (6.06 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][C@H:18]1[C@@H:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:22][CH2:21][NH:20][CH2:19]1>O.CCOCC>[CH2:1]([O:8][C:9]([N:20]1[CH2:21][CH2:22][C@H:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C@H:18]([CH3:17])[CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNCC[C@@H]1Nc1ccccc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a rapidly stirred mixture of benzylchloroformate (0.39 ml, 2.76 mmol) and sodium bicarbonate (284 mg, 3.6 mmol) in water (4 ml) and ether (4 ml) is added cis-3-methyl-4-(2-fluoro-phenylamino)-piperidine (500 mg, 2.4 mmol) as a solution in ether (2 ml). The mixture is stirred for one hour at ambient temperature, the layers are separated, and the organics washed with 2N NaOH (2×) and brine (1×). The organics are dried over sodium sulfate and concentrated to give cis-1-benzyloxycarbonyl-3-methyl-4-(2-fluorophenylamino)-piperidine as an oil: 740 mg; 90%.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].CI.[C:19](OCC)(=O)C>O1CCCC1.CN(C)C=O>[O:3]=[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[N:6]([CH3:19])[S:7]([CH3:10])(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccccc1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: CC(=O)c1ccccc1N(C)S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
2'-Acetylmethanesulfonanilide (1.0 g, 4.7 mmol) in 10 ml tetrahydrofuran is reacted with 0.23 g (4.8 mmol) of 50% sodium hydride dispersion in mineral oil at 5° C. for 15 min. Methyl iodide (1.5 g, 10.56 mmol) in 10 ml of dimethylformamide is added over 15 min at 0°-10° C. and stirred in cold for 15 min. Dimethylformamide (10 ml) is added, and the reaction is stirred for 2 days at room temperature. The reaction is taken up into ethyl acetate, the organic layer washed with water, sodium carbonate solution, water, and saturated sodium chloride successively. The dried organic layer is evaporated and the product crystallized from ether-pet. ether; m.p. 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#N)=[O:11].[CH2:20]([OH:22])C>>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:14]([C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[C:10]([O:22][CH3:20])=[O:11])=[N:1][C:2]=2[CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccccc1C=O
Reactant: Cc1ccc(O)c(N)c1
Product: COC(=O)c1ccccc1-c1nc2cc(C)ccc2o1
Reaction time: 20 h

Procedure:
A solution of 2-amino-p-cresol (9.8 g) and 2-formylbenzonitrile (10.5 g) in ethanol (160 ml) was allowed to stand for 20 hours. The precipitated solid was filtered off and washed with ethanol (30 ml) to give 2-hydroxy-5-methyl-N-(2-cyanobenzylidene)aniline (C) (3.1 g), m.p. 135°-138° C.; NMR: 2.35(s, 3H), 6.95(d, 1H), 7.1(dd, 1H), 7.2(s & br s, 2H), 7.55(dt, 1H), 7.7(dt, 1H), 7.8(dd, 1H) 8.1(dd, 1H), 8.9(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1(/[CH:14]=[C:15](\B2OC(C)(C)C(C)(C)O2)/[CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10]1.[F-].[Cs+]>C1COCC1.C1(P([Pd-4](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)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:15](=[CH:14]\[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)/[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(/C(=C\C2CCCC2)CO)OC1(C)C
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC/C(=C/C1CCCC1)c1ccc(Br)cc1
Temperature: 60 °C
Yield: 39.7 %

Procedure:
According to the procedure described for example 26b the use of 4-bromo-1-iodo-benzene (1.42 g, 5.0 mmol), (E)-3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.01 g, 4.00 mmol), caesium fluoride (2.28 g, 15.0 mmol) and tetrakis(triphenylphosphino)palladium(0) (577 mg, 500 μmol) in 120 mL THF with heating to 60° C. for 16 h gives a brown oil. Purify the crude product by column chromatography, eluting with a gradient from 100:0 to 60:40 hexanes:ethyl acetate to obtain (E)-2-(4-bromo-phenyl)-3-cyclopentyl-prop-2-en-1-ol (446 mg) as a yellow oil. MS (m/e): 263 {[(79Br)M−H2O]+H}, 265 {[(81Br)M−H2O]+H}.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH3:8][C:9]1([CH3:22])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[O:10]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:15][C:13]1([CH3:14])[C:9]([CH3:22])([CH3:8])[O:10][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:6]([NH2:5])=[O:7])[CH2:20][CH:21]=2)[O:12]1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(C2=CCN(C(N)=O)CC2)OC1(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyl isocyanate (0.2205 mL, 1.629 mmol) was added to a room temperature solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (200.0 mg, 0.8145 mmol) and DIPEA (0.5675 mL, 3.258 mmol) in DCM (10 mL). The mixture was stirred for 3 hours, after which, it was partioned between DCM and sat. NaHCO3. The organic layer was concentrated in vacuo to afford the title compound as a tan solid. MS (ES+): m/z 253.07 (100) [MH+]; HPLC: tR=2.61 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[CH3:11][Si:12]([CH2:15][Mg]Cl)([CH3:14])[CH3:13]>CCOCC>[C:2]1([CH:1]([OH:8])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To benzaldehyde (2.17 g, 20.4 mmol) in 20 mL of ether, 1 M (trimethylsilyl)methyl magnesium chloride solution in ether (28.6 mL) was added at 0° C. After two hours of stirring at 0° C., a saturated NH4Cl solution was added and the mixture was extracted with ether (3×). The combined organic extract was dried (Na2SO4), filtered, and concentrated to give the title product (4.12 g).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30]C(=O)C)=[N:22][C:21]2=3)[C@@H:6]1[NH:34]C(=O)C(F)(F)F)(=O)C.CCN(CC)CC.CO>O>[NH2:34][C@@H:6]1[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([CH2:15][OH:16])[O:8][C@H:7]1[N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2
Reactant: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2NC(=O)C(F)(F)F)c(=O)[nH]1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 14.56 g (25.35 mmol) of N-[9-[3,4,6-tris-O-acetyl-2-deoxy-2-[(trifluoroacetyl)amino]-β-D-glucopyranosyl]-6,9-dihydro-6-oxo 1H-purin-2-yl]-acetamide was added a solution composed of 45 mL of Et3N, 225 mL of CH3OH, and 180 mL of H2O. This solution was stirred at room temperature for 12 hours. At this time, the solution was concentrated to dryness in vacuo. The residue was recrystallized from H2O yielding a white powder (7.2 g, 69%). To 7.08 g of this white powder was added 140 mL of 30% (wt/vol) NH4OH, and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was then concentrated to dryness in vacuo. To the residue was added H2O and the mixture was frozen and lyophilized to a white powder yielding 9-(2-amino-2-deoxy-β-D-glucopyranosyl)guanine quantitatively. FAB-MS: m/z 313 for (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 25 °C

Procedure:
3,5-Dibromopyridine (30.0 g) was added to a stirred solution of sodium methoxide (prepared from 11.6 g of sodium) in methanol (120 ml) and heated to reflux for 70 hours under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, poured into water (1 l), extracted with diethyl ether (three times) and the extracts combined, washed with water (four times) and dried (magnesium sulphate). The solvent was evaporated under reduced pressure to give 3-bromo-5-methoxypyridine as a colourless liquid, 19.3 g, which slowly crystallised on storing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.BrC1C=CC(C(C2C=CC(S(C)(=O)=O)=CC=2)=O)=CC=1.[BH4-].[Na+]>C(O)(=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)N=C(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: CS(=O)(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CC(C)C)NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution of a 1:1 mixture of methyl N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methylene}leucinate and (4-bromophenyl)[4-(methylsulfonyl)phenyl]methanone from step 1 (185 mg, ˜0.2 mmol) in acetic acid/methanol (1:3, 4 mL) was added sodium borohydride (˜400 mg) by portions every 30 min over 2 days (addition was stopped during the night) using a solid addition funnel. The reaction mixture was partitioned between EtOAc and water, the organic layer was dried over Na2SO4 and concentrated. The resulting mixture was purified by chromatography using EtOAc and hexane as eluant. Methyl N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}-L-leucinate was obtained as a colorless gum and (4-bromophenyl)[4-(methylsulfonyl)phenyl]methanol was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[C:24]([C:26]1[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=1)#[N:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:31]([C:28]2[NH:29][CH:30]=[C:26]([C:24]#[N:25])[CH:27]=2)=[O:32])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CN1CC(c2ccc(N)c(C3=CCCCCC3)c2)CN(C)C1=O
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCCC3)c2)CN(C)C1=O
Yield: 14 %

Procedure:
A mixture of 5-(4-amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one (as prepared in Example 9, step (a), 21 mg, 0.067 mmol), 4-cyanopyrrolecarboxylic acid (Canadian J. Chem. 59: 2673 (1981)). (24.6 mg, 0.180 mmol), EDCI (19.4 mg, 0.101 mmol), HOBt (9.2 mg, 0.068 mmol), DIEA (35 μL, 0.20 mmol) in DCM (0.5 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue was purified RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA/H2O over 20 min on a C18 column to obtain the title compound (4.2 mg, 14%): 1H-NMR (CD3OD; 400 MHz): δ 7.58 (d, 1H, J=1.5 Hz), 7.44 (d, 1H, J=8.2 Hz), 7.15-7.24 (m, 3H), 5.93 (t, 1H, J=6.5 Hz), 3.38-3.61 (m, 5H), 2.96 (m, 6H), 2.48 (m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.45-1.23 (m, 4H); Mass spectrum (ESI, m/z): Calcd. for C25H29N5O2, 432.2 (M+H), found 432.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][N:17]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:18]1=[O:25].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH2:23][C:21]3[CH:20]=[CH:19][C:18](=[O:25])[N:17]([CH3:16])[CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(=O)n(C)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)n(C)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.