Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH2:14].CCOC(C)=O>C1COCC1>[CH3:13][NH:14][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
4-Nitrobenzoyl chloride (7.00 g, 38 mmol, 1 eq) was dissolved in 50 ml of THF and added to a 2.0 M solution of methylamine in THF (41.5 ml, 83 mmol, 2.2 eq.) at 0° C. Worked up after 3 hours by adding EtOAc and rinsing 3× with 1N NaOH, 1× with brine. The organic layer was dried over MgSO4, then stripped to obtain 2.25 g of off-white solids as product. NMR (300 MHz, DMSO-d6) δ 8.80 (m, 1H), 8.33 (d, 2H, J=7 Hz), 8.06 (d, 2H, J=7 Hz). 2.86 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:29]([OH:31])=O)[CH2:13][C:14]1[N:18]=[CH:17][N:16](C(OCC2C=CC=CC=2)=O)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:29]([N:41]1[CH2:42][CH2:43][N:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:39][CH2:40]1)=[O:31])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1cn(C(=O)OCc2ccccc2)cn1)C(=O)O)OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCN(c2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
7.13 g of N,N'-dibenzyloxycarbonyl histidine, 3.00 g of 4-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were dissolved in 100 ml of tetrahydrofuran, and to the mixture was added 3.84 g of DCC (dicyclohexylcarbodiimide), and the whole was stirred a& a room temperature for three hours. An insoluble matter was filtered off, the filtrate was concentrated under a reduced pressure, and to the concentrate was added 200 ml of ethyl acetate to reform crystals, which were then filtered off. The filtrate was sequentially washed with 20% potassium carbonate aqueous solution and saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting residue was dissolved in 60 ml of methanol, and after an addition of a 10% ammonium-methanol solution and stirring at a room temperature for 30 minutes, the solution was concentrated under a reduced pressure to obtain a residue, which was then subjected to silica gel chromatography and eluted with chloroform/methanol (50:1 to 10:1) to obtain 6.61 g of the title compound in a colorless amorphous form.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(Cl)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (75 mg, 88%), MS (ISP) m/z=343.4 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C(#N)C>[O:10]=[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]=1)[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CCCCCn1cc(C(=O)Cc2ccccc2O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCn1cc(C(=O)Cc2ccccc2OCC(=O)OC(C)(C)C)c2ccccc21
Yield: 95.9 %

Procedure:
2-(2-hydroxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone (O-desmethyl JWH-250) 5 (840 mg, 2.61 mmol) was dissolved in acetonitrile (20 ml) followed by the addition of potassium carbonate (1.08 g, 7.83 mmol) and t-butyl bromoacetate (0.76 g, 3.91 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Biotage Isolera 4, SNAP-25 g, 0%-10% ethyl acetate in hexane) to give 1.09 g (96%) of t-butyl 2-(2-(2-oxo-2-(1-pentyl-1H-indol-3-yl)ethyl)phenoxy)acetate (O-desmethyl JWH-250 t-Butyl 2-CME) 6.
Reaction SMILES: [CH3:1][N:2](N=O)[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[Cl:11][C:12]1[CH:13]=C([CH:16]=[C:17]([Cl:20])[C:18]=1[Cl:19])N.[OH-].[Na+]>C(O)C>[N+:6]([NH:5][C:3]([NH:2][C:1]1[CH:13]=[C:12]([Cl:11])[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=1)=[NH:4])([O-:8])=[O:7]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(Nc1cc(Cl)c(Cl)c(Cl)c1)N[N+](=O)[O-]
Temperature: 40 °C
Yield: 25.1 %

Procedure:
To a slurry of N-methyl-N-nitroso-N'-nitroguanidine 3.3 g (0.0225 mol) in 200 ml of a 50% aqueous ethanol mixture is added 5.0 g (0.025 mol) of 3,4,5-trichloroaniline. This mixture is heated to 40° C. for 72 hours and then treated with one equivalent of NaOH to decompose excess N-methyl-N-nitroso-N'-nitroguanidine. The mixture is then filtered and acidified with concentrated HCl to give 1.6 g of a yellow solid which, when recrystallized, gives 1.4 g of the desired product. The melting point of the product is 209.5° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCCCC2)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.42 g, 44.38 mmol), K2CO3 (13.5 g) and acetonitrile was added N-(2-chloroethyl)piperidine hydrochloride (9.8 g). The reaction mixture was refluxed overnight, cooled to room temperature and filtered. The filtrate was stripped to give an oil which was partitioned between CHCl3 (350 ml) and 1M NaOH (200 ml). The organic layer was separated, washed with 1M NaOH (2×200 ml), treated with DARCO®, then MgSO4, filtered, and stripped to afford, as a dark oily liquid, 6.28 g of 3-[2-(1-piperdinyl)ethoxy]benzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:17])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 56 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.50 mmol) in DMF (20 mL) cooled on an ice-bath was added sodium hydride (120 mg, 3.00 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 10 min. Methyl iodide (233 μL, 532 mg, 3.75 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated in vacuo affording 4-Methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester as a yellow oil (300 mg, 56%). 1H NMR (CDCl3, 300 MHz): δ 4.08 (s, 2H); 3.65 (t, J=5.4 Hz, 2H); 3.35 (t, J=5.4 Hz, 2H); 3.00 (s, 3H); 1.47 (s, 9H).
Reaction SMILES: S([O:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24](O)=[C:23]([CH3:29])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:11][CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]2)=[C:23]([CH3:29])[CH:22]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OC[C@@H]1CCCN(C)C1
Temperature: 25 °C

Procedure:
Alternatively, a solution of (R)-3-tosyloxymethyl-1 -methylpiperidine (100 mg, 0.35 mmol), 4-bromo-2,6-dimethylphenol (75 mg, 0.37 mmol), and cesium carbonate (240 mg, 0.74 mmol) in dimethylformamide (4 mL) was heated to 65° C. under a nitrogen atmosphere for 1.5 hours. The solution was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was removed and the aqueous phase extracted once more with ethyl acetate (30 mL). The combined acetate layers were dried over magnesium sulfate and concentrated to afford the (R)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine as a clear oil. This material was identical to that prepared in Example 2E when analyzed by chiral HPLC (Chiralpak AD, 97:3:0.1 hexane/2-propanol/diethylamine).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[O:5]=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])O>>[O:4]([CH:1]([CH3:3])[CH3:2])[CH:15]1[O:16][C@H:7]([CH2:6][OH:5])[C@@H:9]([OH:10])[C@H:11]([OH:12])[C@H:13]1[OH:14]
Reactant: CC(C)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The title compound was prepared in quantitative yield by the procedure described in example 10 using isopropanol (2000 ml, 26 mol) and glucose (500 g, 2.78 mol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]3([CH3:17])[CH2:16][CH2:15]3)=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.CCN(CC)CC.Cl[C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]3([CH3:17])[CH2:15][CH2:16]3)=[O:12])=[CH:9][N:10]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CC1(NC(=O)c2c[nH]c3ncc(Br)nc23)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(NC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Br)nc23)CC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-N-(1-methylcyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (600 mg, 2.1 mmol) in 20 mL of dry THF was added Et3N (0.42 mL, 4.2 mmol) and reaction mixture stirred for 5 mins, then (chloromethanetriyl)tribenzene (540 mg, 2.53 mmol) was added and reaction mixture stirred for 10 mins. Then, the reaction was heated to 60° C. and stirring continued for 3 hrs. The reaction was quenched with brine (10 mL), product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give 2-bromo-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (400 mg, 37%) as yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 8.01 (s, 1H), 7.31-7.26 (m, 15H), 1.51 (s, 3H), 1.25 (s, 2H), 0.90-0.74 (m, 2H). LCMS: (M+H)+=537/539.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]2[CH:12]=[CH:11][NH:10][C:8]=2[N:9]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]2[CH:12]=[CH:11][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:8]=2[N:9]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a suspension of NaH (119 mg, 60% in oil, 2.98 mmol) in DMF (5 mL) was added 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) at 0° C. The resulting mixture was stirred for 30 min before 2-(trimethylsilyl)ethoxymethyl chloride (0.42 mL, 1.1 eq) was added. The mixture was then warmed up to room temperature and stirred for 1 hr. Water was added to quench the reaction. Extraction with CH2Cl2 followed by drying combined organic layers, evaporation, and chromatography on silica gel (20% EtOAc in heptane as eluent) gave the desired product in 84% yield (570 mg).
Reaction SMILES: [CH3:1][Li].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]1[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O>C(OCC)C.[Cu]I>[CH2:12]([CH:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3]1)[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccccc3O2)cc1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: CCC1Cc2ccccc2O1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methyl lithium (1.6M in diethyl ether, 313 mL, 500 mmol) was added to a solution of copper (I) iodide (47.6 g, 250 mmol) in diethyl ether (750 mL) at −70° C. The solution was then allowed to warm to −10° C. and was stirred for 30 minutes. The mixture was then added to a solution of 2,3-dihydro-1-benzofuran-2-ylmethyl4-methylbenzenesulfonate (preparation 97) (15.2 g, 50 mmol) in diethyl ether (500 mL) and the reaction mixture was stirred at −40° C. for 1 hour and at room temperature for 2 hours. The mixture was then cooled to −70° C. and quenched with 10% ammonium chloride solution (750 mL) and 2M hydrochloric acid (50 mL), diluted with 0.88 ammonia (100 mL) and then stirred for 18 hours. The reaction mixture was extracted with diethyl ether (3×500 mL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown oil in 98% yield, 7.25 g.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Na+].Cl[C:27]([F:32])([F:31])C([O-])=O>CN(C=O)C.O>[F:31][CH:27]([F:32])[O:18][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]([OH:17])[CH:14]=1
Reactant: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
To a solution of 2-[[(2,3-difluorophenyl)methyl]thio]-4,6-pyrimidinediol (3 g) in DMF (30 mL), cesium carbonate (4.3 g) and chlorodifluoro-acetic acid sodium salt (1.9 g) was added. The resulting mixture was heated at 100° C. for 2 h. The reaction mixture was cooled then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a white solid. Yield: 0.4 g
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:12][C:11]#[CH:10])[C:6](=[O:9])[O:7][CH3:8]
Reactant: CONC(=O)OC
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(OC)C(=O)OC
Yield: 58.7 %

Procedure:
0.43 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 1.0 g of methyl N-methoxycarbamate and 1.36 g of propargyl bromide were added to the suspension in this order while being cooled with ice. The mixture was heat-refluxed for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.8 g of methyl N-methoxy-N-propargylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([N+:27]([O-])=O)=[CH:22][C:21]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1.[H][H]>[Pd].CCO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1

Procedure:
6-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-3-nitro-5-phenylpyridin-2-amine (4-3; 0.244 g, 0.470 mmol) and 300 mg 10% palladium on carbon was stirred in 10 ml EtOH. Hydrogenate under 1 atm of hydrogen for 1 h. The reaction was filtered through celite, washed with EtOH and concentrated to afford a yellow oil (4-4). 1H NMR (CDCl3) δ 7.70 (d, 1H, J=7.6 Hz), 7.62 (m, 1H), 7.36-7.20 (m, 9H), 7.10 (m, 2H), 7.03 (s, 1H), 4.22 (m, 1H), 3.67 (s, 2H), 2.61 (s overlapping with m, 5H), 2.27 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31]([OH:33])=O)[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([N:42]1[CH2:47][CH2:46][NH:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([N:42]1[CH2:47][CH2:46][N:45]([C:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]=23)=[O:33])[C:44]([CH3:49])([CH3:48])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Reactant: CC1(C)CN(Cc2ccccc2)CCN1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(Cc4ccccc4)CC3(C)C)c12
Yield: 97.4 %

Procedure:
In analogy to Example 1 step (d) 300 mg 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was reacted with 160 mg 1-benzyl-3,3-dimethyl-piperazine to obtain 410 mg (94%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[C:14]1([C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of glutaryl chloride (10 mmol, 1.3 mL) dissolved in anhydrous dichloromethane (20 mL) is introduced into a 100 mL two-necked round-bottomed flask under an inert atmosphere. Aluminum chloride (30 mmol, 4.00 g) is added to the mixture, which immediately turns orange-yellow. A solution of benzene (20 mmol, 1.8 mL) dissolved in anhydrous dichloromethane (10 mL) is added dropwise at room temperature. The solution becomes bright red. The mixture is then refluxed for 24 hours, and turns brown-black. The mixture is then cooled to room temperature and poured into a crystallizing basin containing 20 mL of 10% acidified water, with stirring. A black solid forms, and is filtered off on a Büchner funnel. The yellow organic phase is then extracted with ethyl acetate, dried over MgSO4, filtered, concentrated on a rotary evaporator and recrystallized from 20 mL of methanol. The product obtained is a white solid in a mass of 680 mg. The reaction yield is 27%.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][CH:16]=[O:17])[C:4]([NH:6][C:7]1[S:8][C:9]([O:12][CH3:13])=[N:10][N:11]=1)=[O:5])[CH3:2].Cl>O>[CH3:13][O:12][C:9]1[S:8][C:7]([N:6]2[CH:16]([OH:17])[CH2:15][CH2:14][N:3]([CH2:1][CH3:2])[C:4]2=[O:5])=[N:11][N:10]=1
Reactant: CCN(CCC=O)C(=O)Nc1nnc(OC)s1
Agent: Cl
Solvent: O
Product: CCN1CCC(O)N(c2nnc(OC)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([NH:36][C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])=[N:28][N:27]=2)=[CH:18][CH:17]=1.N12CCN(CC1)CC2>CN(C)C=O>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[C:23]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([NH:36][C@@H:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH3:38])=[N:28][N:27]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(N[C@H](C)c4ccccc4)c4ccccc34)c2c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COc1ccc2ccc(P(c3ccccc3)c3ccccc3)c(-c3nnc(N[C@H](C)c4ccccc4)c4ccccc34)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of NiCl2(dppe) (0.22 g, 0.42 mmol) in N,N-dimethylformamide (10 ml) was treated with diphenylphosphine (1.5 ml, 8.4 mmol) at 23° C. The resulting dark red solution was stirred at 120° C. for 30 min. Then a solution of trifluoromethanesulfonic acid 7-methoxy-1-[4-((R)-1-phenyl-ethylamino)-phthalazin-1-yl]-naphthalen-2-yl ester (2.3 g, 4.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 1.9 g, 17 mmol) in N,N-dimethylformamide (13 ml) was added via a syringe, the flask was washed with N,N-dimethylformamide (2 ml). The resulting green solution was stirred at 120° C. for 17 hrs. The mixture was concentrated under reduced pressure (20 mbar, 70° C. bath temperature). The residue was purified by flash chromatography on silica gel (toluene→toluene/EtOAc 5:1) to give 1.5 g (2.5 mmol) of the title compound as an off-white solid as a 1.7:1 (1st diastereomer: 2nd diastereomer) mixture of diastereomers.