Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC)=O.[Cl:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1>C(#N)C.C(O)(C)(C)C>[Cl:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=3[Cl:1])[CH2:35][CH2:34]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(C=Cc1ccc(Cl)cc1Cl)N1CCN(Cc2ccc(Cl)cc2)CC1
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
In a mixture of acetonitrile and tert-butanol (5: 1, v/v, 20 ml) are dissolved 2,4-dichlorocinnamic acid (4.3 g, 19.8 mmole) and triethylamine (3 ml, 21.5 mmole), and the mixture is cooled with an ice water bath. To the mixture is added dropwise a solution of ethyl chloroformate (2 ml, 21.0 mmole) in a mixture of acetonitrile and tert-butanol (5:1, v/v, 5 ml) over a period of 3 minutes. After the addition, the mixture is stirred for 5 minutes, and then to the mixture is added an aqueous solution (15 ml) of N-(4-chlorobenzyl)piperazine (4.2 g, 20 mmole) (which is prepared by the process as disclosed in Yoshiaki Ikeda et al., Yakugaku Zasshi, Vol. 89, 669-676, 1969), and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure until about half volume, and thereto is added water (20 ml), and then extracted with benzene (30 ml) twice. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness. The resulting residue is recrystallized from methanol to give 1-(4-chlorobenzyl)-4-(2,4-dichlorocinnamoyl)piperazine (5.3 g, 65 %) as yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](=[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:11][OH:12])([CH3:9])[CH3:8].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:12][CH2:11][C:10](=[C:7]([CH3:9])[CH3:8])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CC(C)=CCC(CO)=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC(=O)OCC(CC=C(C)C)=C(C)C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
In a nitrogen atmosphere, 64.0 g of butyryl chloride was added dropwise to a mixture of 94.1 g of 2-isopropylidene-5-methyl-4-hexenol (3) having a purity of 81.1% and an α,β-isomer purity of 98.1%, 50 g of pyridine and 500 ml of acetonitrile over 55 minutes which was stirred under cooling with ice. The reaction mixture was stirred for 2 hours under cooling with ice. To the reaction mixture was added an aqueous solution of saturated sodium bicarbonate, followed by extraction with diethyl ether. The diethyl ether solution was subjected to work-up including washing, drying and concentration to obtain 131.22 g of the crude product. The crude product was purified by distillation under reduced pressure to obtain, as the intended product, 23.54 g of a fraction having a purity of 92.8% and an α,β-isomer purity of 97.0% and 82.05 g of a fraction having a purity of 92.2% and an α,β-isomer purity of 98.3%. The yield of fractions including the other fractions was 95%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([CH2:11][C:12]4[CH:28]=[CH:27][C:15]5[N:16]=[C:17]([NH:19][C@@H:20]6[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]6[OH:26])[S:18][C:14]=5[CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH:30]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(-c5cccnc5)cnc43)cc2s1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (80 mg, 0.175 mmol) from Example 29, pyridine-3-ylboronic acid (43 mg, 0.350 mmol), 2M aq Na2CO3 (400 μL, 0.40 mmol), and anhydrous DME (1.5 mL) was degassed under argon for 15 min. Bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.0171 mmol) was added and the reaction vessel was sealed and the mixture was heated at 100° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (25 mg, 31%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (br s, 1H), 8.66-8.77 (m, 2H), 8.60 (br s, 1H), 8.46 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.69 (s, 1H), 7.52 (dd, J=4.7, 7.7 Hz, 1H), 7.21-7.34 (m, 2H), 5.53 (s, 2H), 4.77 (br s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.11-1.34 (m, 4H). LCMS (ESI) m/z 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:23][NH:24][CH3:25].C(O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16]([N:24]([CH3:25])[CH3:23])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: CNC
Reactant: Clc1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2
Solvent: CO
Solvent: CCO
Product: CN(C)c1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2

Procedure:
This compound was obtained in an analogous manner to that given in Example 10a from 15 grams of 6-(o-chloro-phenyl)-8-chloro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine and 55 grams of dimethylamine in 500 ml. of ethanol by heating for 5 hours at 120° C. M.P. 240°-242° C. (from methanol); Yield 8.5 grams.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[C@H:27]([CH2:25][CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cn1
Yield: 61.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2 g) described in Preparation Example 23 and (R)-4-ethyloxazolidin-2-one (300 mg) described in Preparation Example 26, the title compound (710 mg) was obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1.Cl.C(OCC)C>ClCCl.O1CCOCC1>[F:23][C:6]1[CH:5]=[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:24][OH:25])[CH:9]=[N:8][C:7]=1[N:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C[C@@H](O)CO)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: OC[C@H](O)Cc1cnc(N2CCNCC2)c(F)c1
Yield: 114.3 %

Procedure:
A solution of 13 (1.40 g, 3.94 mmol) in dichloromethane (10 mL) was stirred with 4 mol/L HCl in dioxane (25 mL) in a closed vessel overnight at room temperature. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitated was collected by filtration and washed several times with ethyl ether to afford 1.15 g (yield 100%) of 14 as a pale yellow foam (HCl salt). The identity of compound 14 was confirmed by LC/MS and was used directly for the next step. LC/MS (M+1) 256.
Reaction SMILES: [CH:1]([C@@H:4]1[NH:9][C:8](=O)[CH2:7][NH:6][C:5]1=O)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([C@H:4]1[CH2:5][NH:6][CH2:7][CH2:8][NH:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1NC(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1CNCCN1
Temperature: 25 °C

Procedure:
To a solution of (S)-3-isopropylpiperazine-2,5-dione (100 mg, 0.6 mmol) in anhydrous THF was added lithium aluminum hydride 1M in THF (1.2 ml, 1.2 mmol). The reaction refluxed for 1 hr, cooled to room temperature, quenched with H2O, filtered, then concentrated under vacuum to yield (S)-2-isopropylpiperazine. This material was combined with 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (85.5 mg, 0.5 mmol) in triethylamine (1 ml) and isopropanol (2 ml). The reaction was heated in a microwave at 180° C. for 30 min, concentrated under vacuum, dissolved in EtOAc, washed with H2O, and concentrated under vacuum to afford (S)-4-(3-isopropylpiperazin-1-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine, carried on without further purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>>[NH:17]([C:1](=[O:3])[CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CC(=O)Nc2ccccc2)cs1)C(=O)O

Procedure:
The title yellow resin (2.9 g) was obtained using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and aniline as starting materials and by an operation similar to that of Example 461-5. A part of the resin was cleaved with trifluoroacetic acid and the structure was confirmed.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:23]([CH2:29][O:30][Si](C(C)(C)C)(C)C)[O:22][C@H:7]([O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[N:38]=[N+:39]=[N-:40])(=[O:3])[CH3:2]>C1COCC1>[C:1]([O:4][C@H:5]1[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:23]([CH2:29][OH:30])[O:22][C@H:7]([O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[N:38]=[N+:39]=[N-:40])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](N=[N+]=[N-])[C@@H](OCCNC(=O)OCc2ccccc2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](N=[N+]=[N-])[C@@H](OCCNC(=O)OCc2ccccc2)O[C@H](CO)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of compound 24 (575 mg, 0.99 mmol) in THF (5 mL), TREAT-HF (0.81 mL, 4.97 mmol) was added. The mixture was stirred under argon at rt overnight. Concentration and chromatography (2:1→0:1 toluene-EtOAc) gave 25 (448 mg, 0.96 μmmol, 97%); [α]D+60° (c 1.0, CHCl3); 13C NMR δ 20.7, 20.8 (CH3CO), 40.7 (HOCH2CH2NH), 61.4, 61.6, 66.4, 67.0, 67.5, 70.9, 71.0 (C-2-6, PhCH2O, OCH2CH2N), 98.2 (C-1), 128.3, 128.3, 128.7, 136.5 (aromatic C), 156.5 (NHCOOBn), 170.1, 170.5 (CH3CO); 1H NMR δ 2.04 (s, 3H), 2.1 (s, 3H), 3.32-3.46 (m, 2H), 3.54-3.60 (m, 2H), 3.62-3.78 (m, 3H), 4.02-4.04 (m, 1H), 5.06-5.18 (m, 3H), 5.22-5.28 (m, 1H), 5.36-5.40 (m, 1H), 7.28-7.38 (m, 5H); HRMS calcd for C20H26N4NaO9 [M+Na]+ 489.1597, found 489.1574.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([C:22]4[S:26][C:25]5[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:24]=5[CH:23]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:32])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:33]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([C:22]4[S:26][C:25]5[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:24]=5[CH:23]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:32])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:34]=[N-:35]
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2c(Cl)ccnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccnc2cc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Temperature: 65 °C
Yield: 101 %

Procedure:
1-(4-Chloroquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one (0.52 g, 1.03 mmol) is dissolved in DMF (15 mL), treated with sodium azide (0.52 g, 8.0 mmol), tetrabutyl ammonium chloride (0.1 g, 0.36 mmol) and heated to 65° C. overnight. The reaction mixture is cooled, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried (sodium sulfate) and concentrated to give the title compound (0.5 g, 1.04 mmol). 1H NMR (CD3OD, 300 MHz) δ9.0 (d, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.6 (d, 1H), 7.5 (d, 1H), 6.9 (s, 1H), 4.85 (s, 2H), 4.0 (s, 2H), 3.5-3.7 (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:42])[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:3])=[N:34][CH:33]=1)[CH3:42]
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 5 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 553.1 [M+H]+; tR=3.43 min (System 1); TLC: Rf=0.06 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].O>ClCCl>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Under a nitrogen atmosphere, 1-amino-2-methylpropan-2-ol (25.5 g, 0.28 mol) was added over a period of 30 minutes to a solution of 4-chloro-3-nitro[1,5]naphthyridine (54.5 g, 0.26 mol) in dichloromethane (1 L). A water bath was used to control the exotherm and maintain the temperature of the reaction at or below 27° C. The reaction mixture was stirred at ambient temperature overnight. The resulting precipitate (crop 1) was isolated by filtration. The filtrate was concentrated under reduced pressure to provide crop 2. The two crops were slurried separately with de-ionized water for 2 hours and then isolated by filtration. Crop 1: 40.53 g of 2-methyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-2-ol as a yellow solid. Crop 2: tan solid. Crop 2 was dissolved in dichloromethane and loaded onto an alumina column. The column was eluted first with 1% methanol in dichloromethane and then with acetone. The combined eluents were concentrated under reduced pressure. The residue was recrystallized from ethanol (10 mL/g) to provide 6.95 g of 2-methyl-1-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-2-ol.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C@@H:14]1[C@@H:19]([CH2:20][O:21]C(=O)C2C=CC=CC=2)[CH2:18][CH2:17][C@H:16]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][CH:33]=[N:34][C:35]=3[NH2:39])[CH2:15]1)(=O)C1C=CC=CC=1.Cl>CO>[OH:12][CH2:13][C@@H:14]1[C@@H:19]([CH2:20][OH:21])[CH2:18][CH2:17][C@H:16]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][CH:33]=[N:34][C:35]=3[NH2:39])[CH2:15]1
Reactant: Nc1ncnc2c1ncn2[C@H]1CC[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@H]1CC[C@H](CO)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Sodium methoxide (2.7 mg, 0.55 mole) was added to a solution of 9-[(1S,3S,4S)-3,4-bis(benzoyloxymethyl)cyclohexyl]-adenine (25 mg, 0.05 mole) in anhydrous methanol (2 ml) under cooling with ice. After stirring the mixture at room temperature overnight, the reaction mixture was neutralized with dilute hydrochloric acid and the solvent was distilled off under reduced pressure. Then, ethyl ether and water were added to the residue, the ethyl ether layer was removed, and the water was distilled off. Then, the residue was purified by Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1S,3S,4S)-3,4-bis(hydroxymethyl)-cyclohexyl]-adenine (9.4 mg, Yield 66.2%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[C:35]([O-:38])(O)=O.[Na+].CN(C=O)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:35]=[O:38])=[CH:14][CH:13]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Temperature: 80 °C
Yield: 163.6 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide (prepared as for Example 31) (2 g, 3.4 mmol), 4-formylboronic acid (0.612 g, 4.08 mmol), NaHCO3 (10.2 ml, 1M aq. solution, 10.2 mmol), PdCl2(PPh3)2 (119 mg, 0.17 mmol) and DMF (50 ml) were combined. The mixture was then degassed by bubbling N2 through it for 5 minutes before being heated at 80° C. for 1 hour. The mixture was then evaporated in vacuo and partitioned between EtOAc (3×50 ml) and water (50 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give a crude oil. This was dissolved in EtOAc and passed through a plug of SiO2, washing through with EtOAc. The filtrate was evaporated in vacuo and the resulting oil triturated with Et2O to afford 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1.577 g, 82%) as a pale coloured solid, LC/MS: RT=2.908 min. 567.3 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=O)C.Cl>[OH-].[K+].CO>[CH:17](/[C@H:14]1[CH2:13][CH2:12][C@H:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[CH2:16][CH2:15]1)=[CH:18]\[CH2:19][CH2:20][CH3:21]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(OC(C)=O)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
385 mg of p-[trans-4-(1E-pentenyl)cyclohexyl]phenyl acetate were dissolved in 100 ml of a 1N solution of potassium hydroxide in methanol while gassing with argon and the mixture was stirred at room temperature for 30 minutes. Subsequently, the reaction mixture was poured into 80 ml of 1N hydrochloric acid and extracted three times with 60 ml of diethyl ether each time. The organic phases were washed twice with 60 ml of water each time, dried over magnesium sulphate and concentrated. There were obtained 328 mg (100%) of p-[trans-4-(1E-pentenyl)cyclohexyl]phenol as colourless crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15](I)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(COC)OC.C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH:29]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(C(=O)O)CC3)cc12
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a suspension of Example 61A (300 mg, 0.813 mmol) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (342 mg, 1.219 mmol) in 10 mL dimethoxyethane/ethanol/water (7:2:3) was added sodium carbonate (345 mg, 3.25 mmol) and dichlorobis(triphenylphosphine) palladium(II) (17.09 mg, 0.024 mmol). The reaction was stirred at 90° C. for 12 hours, then cooled, and extracted with ethyl acetate. The combined organic fractions were washed with saturated sodium bicarbonate (2×), water, and brine, dried over magnesium sulfate and concentrated. The crude material was triturated with ethyl acetate, and the solid was collected by filtration. The solid was dissolved in 15 mL dioxane, treated with 6 M sodium hydroxide (1.355 ml, 8.13 mmol) and stirred at 90° C. for 12 hours. Most of the solvent was removed, and the residue was diluted with 30 mL water. The aqueous mixture was extracted with ethyl acetate (2×), and the organic fractions were discarded. The aqueous layer was made neutral (˜pH 7) with 1 M HCl. The solid was collected by filtration and dried under high-vacuum to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.16 (s, 1H) 8.75 (s, 1H) 7.28-7.39 (m, 2H) 7.15-7.26 (m, 1H) 6.60 (s, 1H) 6.24 (s, 1H) 3.69-3.85 (m, 3H) 2.26-2.47 (m, 4H) 1.93-2.10 (m, 1H) 1.54-1.77 (m, 1H) MS (ESI+) m/z 368.2 (M+H)+.