Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:24][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c([N+](=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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 79.9 %

Procedure:
To a solution of methyl 4-bromo-3-nitrobenzoate (Chess, 3 g, 11.53 mmol) in toluene (100 mL) and water (100 mL) was added o-tolylboronic acid (1.88 g, 13.84 mmol) followed by potassium carbonate (7.972 g, 57.68 mmol), tetrakis(triphenylphosphine)palladium(0) (0.668 g, 0.577 mmol). The reaction mixture was refluxed at 120° C. for 14 h. After the completion of reaction, it was cooled to RT and organic layer was separated and evaporated under reduced pressure. The crude compound was passed through silica pad (60-120 mesh) using hexane as eluent to give the title compound as a white solid (2.5 g, 79%). 1H NMR: (DMSO-d6, 400 MHz) δ 8.52 (s, 1H), 8.29-8.26 (m, 1H), 7.63-7.61 (m, 1H), 7.34-7.33 (m, 2H), 7.23 (m, 1H), 7.13 (m, 1H), 3.94 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[CH3:7][N:8]([O:17][CH3:18])[C:9]([C:11](N(C)OC)=[O:12])=[O:10]>Cl>[CH3:7][N:8]([O:17][CH3:18])[C:9](=[O:10])[C:11](=[O:12])[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: CON(C)C(=O)C(=O)N(C)OC
Agent: Cl
Product: CON(C)C(=O)C(=O)CC1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
The finely divided Mg was treated with 22.5 mL (0.20 mol) of bromomethylcyclobutane maintaining the internal temperature at <5° C. The resulting mixture was stirred cold for 1 h, then was treated with 26.40 g (0.15 mol) of N,N′-dimethyl-N,N′-dimethoxy oxamide (from Step A) in portions as a solid. The resulting mixture was stirred at 0° C. for 16 h. The reaction was poured onto a mixture of 100 mL conc. HCl and 500 g of ice under N2 atmosphere. The quenched mixture was extracted with 1.5 L of EtOAc. The extract was washed with 500 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 500 g of silica gel using 3:1 v/v hexanes/EtOAc as the eluant afforded 22.3 g (80%) of the title compound: 1H NMR (500 MHz) δ 1.66-1.76 (m, 2H), 1.82-1.98 (m, 2H), 2.12-2.22 (m, 2H), 2.74-2.84 (3H), 3.20 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 0 %

Procedure:
To a solution of 4-phenoxyphenol (1.0 g, 5.4 mmol) in N,N-dimethylformamide (20 mL) were added 4-fluorobenzaldehyde (0.67 g, 5.4 mmol) and potassium carbonate (0.75 g, 5.4 mmol), and the mixture was stirred at 100° C. for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to give the title compound (1.4 μg, yield 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3]C(Cl)=O.[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCN(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C. The product is tabulated in Table C as Compound No. C-2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]([O:15]CC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+].CS(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: O=C(O)C1CC1COCc1ccccc1

Procedure:
A solution of 0.23 mol of the compound obtained in Step 1 in 500 ml of ethanol, 230 ml of 1N sodium hydroxide solution and 5 ml of dimethyl sulphoxide is heated at reflux for 2 hours and is then concentrated. The residue is taken up in a mixture of water/ether. After conventional treatment, the combined organic phases are concentrated. Chromatography of the residue over silica gel (dichloromethane/tetrahydrofuran: 97/3) allows a cis/trans mixture of the products obtained to be isolated, some of the fractions of which have a preponderance of the cis isomer and some a preponderance of the trans isomer.
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=[CH2:2]
Reactant: [Li]CCCC
Reactant: Cc1c(C2CCCCC2)csc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Product: C=Cc1scc(C2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (4.983 g, 13.96 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (8.7 ml, 13.96 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-3-methyl-4-cyclohexylthiophene dimer (2.7 g, 6.98 mmol) in a minimum of ether was added. The solution was stirred overnight. The reaction mixture was then diluted with ether and washed with water and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by column chromatography using hexane as the eluant to afford 2-vinyl-3-methyl-4-cyclohexylthiophene dimer 1.32 g (50% yield) as a white solid. 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.90 (dd, 1H), 5.52 (d, 1H), 1.15 (d, 1H), 2.22 (s, 1H), 2.19 (s, 1H), 2.11 (s, 1H), 2.10 (s, 1H), 2.09 (s, 1H), 2.08 (s, 1H). 13C NMR (CDCl3) δ 147.93, 146.37, 137.41, 136.09, 134.78, 129.97, 128.44, 127.57, 118.61, 112.7, 40.07, 38.86, 33.74, 31.37, 27.19, 26.91, 26.30, 26.12, 13.61, 13.33.
Reaction SMILES: NC(N)=[S:3].S(=O)(=O)(O)O.Br[C:11]1[S:12][C:13]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:23]=[CH:24][C:25]=3[O:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31]C[CH2:29]3)[CH:17]=[CH:16][C:14]=2[N:15]=1.[OH-].[Na+]>C(#N)C.O>[CH:28]1([CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:21][C:20]=2[C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11](=[S:3])[S:12][C:13]=3[CH:19]=2)[CH2:33][CH2:32][CH2:31][CH2:29]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCc1ccc(OCC2CCCC2)c(-c2ccc3[nH]c(=S)sc3c2)c1
Temperature: 90 °C
Reaction time: 20 h
Yield: 55.3 %

Procedure:
A solution obtained beforehand by adding thiourea (52 mg, WAKO) to 1 M sulfuric acid (5 ml) and mixing them was added with a solution of Intermediate 76 (101 mg) in acetonitrile (5 ml), and stirred at 90° C. for 20 hours. The reaction mixture was poured into water (20 ml), neutralized by addition of 1 N aqueous sodium hydroxide under ice cooling, and then extracted with ethyl acetate (80 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, methylene chloride:ethanol=30:1) to obtain the title compound (Compound No. V-91, 46 mg).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=O)[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:11](=[O:13])[CH:6]3[CH:5]([C:4]4([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:7]3[CH:8]=[CH:9]4)[C:14]2=[O:15])=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C1C(=O)N(c3ccc(O)cc3)C(=O)C12
Reaction time: 1 h

Procedure:
408 g of a mixture of isomers of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are heated with 238.26 g of 4-aminophenol to 200° C., the pressure is reduced to 2.7 Pa and the mixture is kept for 1 hour under these conditions. This gives 535 g of a red solid resin (87.7% of theory) having a glass transition temperature of 58° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20](O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([O:10][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=Cc1ccc(O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C=O)c(O)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
In 40 ml of tetrahydrofuran were dissolved 1.38 g of 2,4-dihydroxybenzaldehyde, 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphone. The thus prepared solution was mixed with 1.91 g of diethyl azodicarboxylate and stirred at room temperature for 1 hour. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography, thereby obtaining 1.2 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-2-hydroxybenzaldehyde in a viscous and oily form.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][CH:26]=4)=[N:21]3)[N:15]2[CH2:18][CH3:19])=[C:11]([NH2:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=4)=[N:21]3)[N:15]2[CH2:18][CH3:19])=[C:11]([NH2:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(-c2ccn(-c3nc4c(N)nc(NCc5ccccc5)nc4n3CC)n2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(-c2ccn(-c3nc4c(N)nc(NCc5ccccc5)nc4n3CC)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N2 benzyl-8-[3-(4-vinylphenyl)pyrazol-1-yl]-9-ethyl-9H-purine-2,6-diamine, a compound of Formula I (25 mg, 0.05 mmoles), was dissolved in methanol (2 mL), and to this solution was added 20% w/w Pd/C. The reaction mixture was stirred at room temperature under hydrogen at 1 atmosphere. After 2 hours, the reaction mixture was filtered over celite, solvent evaporated under reduced pressure, and the residue obtained was purified by preparative TLC (eluting with 1:1 EtOAc:Hexanes) to give N2 benzyl-8-[3-(4-ethylphenyl)pyrazol-1-yl]-9-ethyl-9H-purine-2,6-diamine as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[O:23])=[N:19]2)=[CH:14][C:13]=1[Br:24])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH:25]O>C(O)=O>[Br:24][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[C:9]([P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])([F:10])[F:11])[N:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=[CH:16]2
Reactant: OO
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C=O)ccc2cc1Br
Solvent: O=CO
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As described in the literature (Synthesis, 1993, 295), to the product of step 4 (105 mg, 0.25 mmol) in 1 ml formic acid was added 30% hydrogen peroxide (0.13 mL, 1 mmol) dropwise and the mixture was stirred overnight at rt. The solvent was evaporated and absolute ethanol was added. This was repeated 3 times and after evaporation of the remaining ethanol yielded the title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:38])[CH2:36]Cl)[CH2:30][CH2:29]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:36][C:35]([NH:34][CH:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:39]=[CH:40][C:41]([Cl:42])=[C:24]([Cl:23])[CH:25]=4)[CH2:33][CH2:32]3)=[O:38])[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(CCl)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=[N+]([O-])c1cc(-c2csc(S)n2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CSc1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
4-(4-Chloro-3-nitrophenyl)-2-mercaptothiazole (0.5 g) was dissolved in dimethylformamide (20 mL), and potassium carbonate (0.7 g) was added to the solution. Then, N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]chloroacetamide (0.6 g) was added, and the mixture was stirred at room temperature for 3 hrs. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give the title compound (0.7 g) as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=[O:5])C.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[C:15]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:16][O:17][C:18]=3[CH2:19][OH:20])=[CH:8][N:7]=2)=[O:5])[CH2:30][CH2:31]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 10 %

Procedure:
As described for example 29e, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (9 mg, 10%), which was obtained as a colourless gum. MS: m/e=428.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[N:62]=[C:63]=[O:64]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([NH:62][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as starting materials in 51% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.41 (m, 2H), 9.02 (s, 1H), 8.25 (m, 4H), 7.65 (s, 1H), 7.30 (m, 2H), 7.05 (m, 4H), 4.09 (m, 2H), 2.98 (m, 4H), 2.83 (m, 2H), 2.32 (m, 2H), 2.02 (m, 1H), 1.75 (m, 2H), 1.21 (m, 2H). LCMS for C31H31ClFN8O2 (M+H)+: m/z=601.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCc1ccccn1
Reactant: BrCCCCCBr
Product: BrCCCCCOCCc1ccccn1

Procedure:
From 2-pyridineethanol (5.0 g) and 1,5-dibromopentane (16.6 ml), with a reaction time of 4 h. FCC eluting with hexane-diethyl ether (1:0→1:1) gave the title compound as a colourless oil (6.15 g), t.l.c. (ether-hexane 1:1) Rf 0.19.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[C:38]([CH3:39])=[C:37]2[C:32]([CH:33]=[C:34]([NH2:40])[CH:35]=[CH:36]2)=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:40][C:34]2[CH:35]=[CH:36][C:37]3[C:32]([CH:33]=2)=[N:31][N:30]([CH3:29])[C:38]=3[CH3:39])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Cc1c2ccc(N)cc2nn1C
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CC4)CCN(C(=O)OC(C)(C)C)CC5)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a suspension of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (659.8 mg, 1.59 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (580.6 mg, 2.94 mmol) in n-BuOH (6 mL) was added DIPEA (755.5 mg, 5.79 mmol). The reaction mixture was stirred at 150° C. under microwave radiation for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a yellow solid (169.7 mg, 19.8%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:12][CH2:11][C@H:10]([CH3:9])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCC[C@@H](C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCBr
Temperature: 25 °C
Yield: 87.3 %

Procedure:
5.65 g (31.8 mmol) of N-bromosuccinimide are added portionwise while stirring to a solution of 5 g (31.6 mmol) of (R)-3,7-dimethyl-1-octanol and 9.05 g (34.5 mmol) of triphenylphosphine in 20 ml of methylene chloride. The temperature is held below 25° by occasional cooling of the reaction vessel. After 30-minutes stirring at room temperature, the solvent is removed on the rotary evaporator. The residue is washed out several times with n-hexane, then filtered and again rinsed with n-hexane. The combined n-hexane phases are concentrated on the rotary evaporator and the crude product is chromatographed on 200 g of silicagel with n-hexane. Distillation in the bulb-tube at 105°/15 Torr gives 6.1 g (87%) of (R)-1-bromo-3,7-dimethyloctane; [α]D20 =-5.0 (c=0.82, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([O:37][C:38](=[O:43])[CH2:39]C(O)=O)([CH3:36])([CH3:35])[CH3:34].[O-]CC.[Mg+2].[O-]CC>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][C:6](=[O:8])[CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:43]
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-succinic acid 1-methyl ester (3.0 g, 10.67 mmol) and tetrahydrofuran (50 mL). To this mixture was added carbonyldiimidazole (1.90 g, 11.74 mmol) and the resulting mixture was stirred at 25° C. for 6 h. In a separate round bottom flask was placed malonic acid mono t-butyl ester (1.98 g, 11.74 mmol), tetrahydrofuran (30 mL) and magnesium ethoxide (685 mg, 5.87 mmol) and the resulting mixture stirred at 25° C. for 1 h and then concentrated in vacuo. The residue was taken up in tetrahydrofuran (15 mL) and added to the flask containing the succinic acid and carbonyldiimidazole mixture and stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and partitioned between diethyl ether (200 mL) and a 0.5N aqueous hydrochloric acid solution (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (150 mL), dried over sodium sulfate and concentrated. Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-t-butyl ester 1-methyl ester (3.04 g, 75%) as a pale yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([CH:17]1[CH2:20][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>[N+](C1C=CC=CC=1)([O-])=O>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:17]2[CH2:20][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]2)=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C1CC(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CC(Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of concentrated nitric acid (0.5 mL) and concentrated sulphuric acid (0.8 mL) was added slowly with stirring to an ice-cooled solution of ethyl 3-benzylcyclobutanecarboxylate (German Patent DE 2626287) (876 mmol, 4.02 mmol) in nitrobenzene (2 mL). The reaction mixture was warmed to ambient temperature and stirred for 1.5 h then poured onto ice/water. DCM (5 mL) was added and the mixture was stirred before passing through a phase separation cartridge. Solvent was removed by evaporation to give the title compound that was used directly in the next step.