Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([Cl:29])[CH3:28]>>[Cl:29][CH:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: CC(Cl)CCCCBr
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Product: COc1ccc(C(C#N)(CCCCC(C)Cl)Sc2ccc(C)cc2)cc1OC
Yield: 82 %

Procedure:
The procedure of Example 15 is repeated using 3.8 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.66 g of 1-bromo-5-chlorohexane. This affords 4.35 g of the desired product as a colorless oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9](C)C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Br:12]CC(OC(C)(C)C)=O.C(OCC)C>C(#N)C>[Br:12][C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH2:8][NH2:9])=[O:5]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=C(C)C(=O)OCCN(C)C
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(Br)C(=O)OCCN

Procedure:
5 g 2-(Dimethylamino)ethyl methacrylate and 8.68 g tert-butyl bromoacetate were reacted in 20 ml acetonitrile for 24 h at 50° C. under N2 protection. Upon addition of 250 ml ethyl ether to the reaction mixture, the formed white crystals were isolated and dried. The resulting CB-tBu monomers were immediately stored in a desiccator at −20° C. (yield 96%). 1H NMR (D2O) δ (ppm): 1.44 (s, 9H, —OC(CH3)3), 1.87 (s, 3H, CH2═C(CH3)COO—), 3.31 (s, 6H, —CH2N(CH3)2CH2COO—), 3.98 (t, J=3 Hz, 2H, CH2═C(CH3)COOCH2CH2N(CH3)2CH2—), 4.28 (s, 2H, —CH2N(CH3)2CH2COO—), 4.60 (t, J=3 Hz, 2H, CH2═C(CH3)COOCH2CH2N(CH3)2CH2—), 5.73 and 6.10 (s, 2H, CH2═C(CH3)COO—).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[CH2:2]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=1[OH:3])[CH3:1]
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
2-Methyl-6-nitro-benzoxazole (12.25 g, 68.76 mmol) was dissolved in Tetrahydrofuran (500 mL) and Acetic acid (4.00 mL, 70.4 mmol) and was cooled at 0° C. Sodium tetrahydroborate (5.20 g, 138 mmol) was added over 10 min and the reaction was stirred at 0° C. for 30 min, then warmed to room temperature and stirred an additional 2.5 h. The undissolved borohydride was removed by filtration, and the filtrate conc. in vacuo to ˜100 mL. The filtrate was poured into water (800 mL) and neutralized with sodium bicarbonate powder. The aq. was extracted 3×200 mL DCM; the org. extract was washed with 100 mL water and 200 mL 1:1 brine:satd. sodium bicarbonate sol., then dried over sodium sulfate before being filtered through a ½″ h×2″ diameter plug of silica gel, washing with 500 mL 1:1 DCM:EtOAc. The filtrate was conc. to give 2-Ethylamino-5-nitro-phenol as a yellow solid (11.5 g, 92%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][NH:29]C(=O)OCC3C=CC=CC=3)[CH:23]=[CH:24][CH:25]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCNC(=O)OCc3ccccc3)c2)c1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCN)c2)c1
Temperature: 25 °C
Reaction time: 2.17 h

Procedure:
To a solution of benzyl 3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]propylcarbamate (71.1 mg, 134 μmol) in methanol (3 mL) was added 10% Pd/C (26 mg). The mixture was stirred magnetically under a H2 atmosphere (balloon) at room temperature for 130 min. H2 was replaced by N2, and the catalyst was removed by filtration over a cotton plug. The solution was evaporated and dried (30° C./oil pump vacuum) to yield 47.3 mg (89%) of a colorless film. MS (EI) m/z 397(M+, 4.3%), 341 (4.3%), 311 (17%), 242 (18%), 241 (25%), 198 (10%), 100 (12%), 70 (14%), 57 (100%), 56 (73%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][SH:11].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:9])([S:11][CH3:10])[CH3:8])[CH3:7]
Reactant: CS
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC

Procedure:
Ethyl 2-bromoisobutyrate (40.0 g, 0.205 mole), methanethiol (1.09 g, 0.0226 mole), potassium hydroxide (14.4 g, 0.226 mole,), ethyl alcohol (100 g), refluxed reaction mixture until peak for ethyl 2-bromoisobutyrate is no longer detectable by gas chromatography. Distill to purify.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([NH:4][C:5](=[O:33])[C:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:17][CH:16]=2)=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CNc2ccc(C(=Cc3ccc(F)cc3)C(=O)NC3CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NC1CC1)C(=Cc1ccc(F)cc1)c1ccc(NCc2ccc(C(=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution methyl 4-((4-(3-(cyclopropylamino)-1-(4-fluorophenyl)-3-oxoprop-1-en-2-yl)phenylamino)methyl)benzoate (0.42 g, 0.9 mmol) in methanol (10 mL), a solution of NaOH (0.075 g, 18 mmol) in water (0.5 mL) was added. The reaction mixture was refluxed for 1 hour at 70° C. The solvent was removed by evaporation and the remainder was poured to ice cold water. The aqueous layer was acidified to pH 3 with citric acid and allowed to stand at 4° C. for 30 minutes, the solid precipitated was filtered and dried under vacuum to give a pale yellow solid (0.22 g, 51% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([S:30][CH2:31][C:32]#[N:33])=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:35][CH2:36]Br.CN(C=O)C>C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([S:30][C:31]3([C:32]#[N:33])[CH2:36][CH2:35]3)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC#N)c2CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SC3(C#N)CC3)c2CC1
Temperature: 38 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
Add sodium bis(trimethylsilyl)amide (5.4 mL, 5.4 mmol, 1M solution in THF) at room temperature under nitrogen to a solution of 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 1.1 mmol) in anhydrous toluene (4 mL). Stir the solution for 10 min, then add quickly 1,2-dibromoethane (2.8 mL, 32.4 mmol) followed by anhydrous DMF (4 mL). An exothermic reaction was observed and the reaction temperature increased to 38° C. Stir the mixture for 15 min at ambient temperature, then quench with methanol (2 mL). Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (259 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]
Reactant: COC(=O)c1cc(OC)c(OCCCCCl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCCl)cc1N
Temperature: 40 °C
Yield: 100 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 2.02 g (6.29 mmol) of methyl 5-methoxy-4-(4-chlorobutoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-10, and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.2 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 2 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 1.81 g (isolated yield: 98.1%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(4-chlorobutoxy)anthranilate as a white crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])[C:5]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:18]C(=O)C(C)(C)C)=[O:9])=[N:6][CH:7]=1.C([O-])(O)=O.[Na+]>CC(O)=O.Cl>[NH2:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[C:8]([C:5]1[C:4]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: COc1cccc(NC(=O)C(C)(C)C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(N)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of N-{2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-3-methoxy-phenyl}-2,2-dimethyl-propionamide (105 mg, 0.17 mmol) in AcOH (6 mL) and 2 M aqueous HCl (1 mL) was heated at 60° C. for 4 days. The reaction mixture was neutralized with aqueous NaHCO3, extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure and the residue purified by HPLC to provide N-[2-(2-amino-6-methoxy-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide: MS m/z 520.0 (M+H)+.
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C@:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]2)([OH:32])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A 250 mL three-necked flask was charged with magnesium turnings (2.88 g, 0.12 mol) and a small crystal of iodine in THF (20 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (40 mL) was added dropwise to the above mixture. After heating under reflux for 1 h, most of the magnesium had been consumed and the reaction mixture cooled to rt. Another 250-mL, three-necked flask was charged with (R)-3-(3-chloro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 10 mmol) and THF (50 mL), which was evacuated and refilled with N2. The mixture was cooled in a dry ice-acetone bath and the Grignard reagent derived from 1-chloro-4-methoxybutane (20 mL) was added dropwise. After addition, the mixture was allowed to warm slowly to rt and stirred for 2 h. The mixture was quenched with satd aq NH4Cl (100 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (10:90 EA/PE) to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (3.0 g, 73%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.52-1.58 (m, 3H), 1.75 (m, 1H); 1.92 (m, 2H), 2.52 (m, 2H), 3.25 (s, 3H), 3.27 (m, 2H), 3.95 (m, 1H), 4.35 (m, 1H), 7.20-7.26 (m, 3H), 7.36 (m, 1H). MS (E/Z): 412 (M+H+).
Reaction SMILES: [OH-:1].[Na+].OO.CS(C)=O.[CH3:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:20]([F:38])=[CH:19][C:18]=2[C:39]#[N:40])[CH:13]=[N:14][CH:15]=1>O.C(O)C>[NH2:40][C:39]([C:18]1[CH:19]=[C:20]([F:38])[C:21]([NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[N:22][C:17]=1[NH:16][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([CH3:9])[CH:11]=1)=[O:1]
Reactant: [OH-]
Reactant: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(F)cc2C#N)c1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(F)cc2C(N)=O)c1
Temperature: 34 °C
Reaction time: 0.5 h

Procedure:
A 5N sodium hydroxide aqueous solution (1.18 ml) and 30% hydrogen peroxide solution (0.70 ml) were added to a solution of dimethyl sulfoxide (10 ml) and ethanol (10 ml) containing tert-butyl cis-2-(6-(5-methylpyridin-3-ylamino)-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (520 mg), followed by stirring at 34° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water was added. Solid matter was collected by filtration, dissolved in ethyl acetate and tetrahydrofuran, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was added to diisopropylether, solid matter was collected by filtration and washed with diisopropylether and hexane, and a light yellow solid of tert-butyl cis-2-(5-aminocarbonyl-3-fluoro-6-(5-methylpyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate (506 mg) was thus obtained.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2]>CO.N.[Ni]>[NH2:2][CH2:1][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1
Reactant: COc1ccc2c(c1)C(CC#N)CN(C(=O)OC(C)(C)C)C2
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc2c(c1)C(CCN)CN(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The compound obtained in Step I (6.3 g; 21 mmol) is dissolved in 150 ml of methanol saturated with NH3(g). The solution is poured into an autoclave and Raney nickel (600 mg) is added. The reaction mixture is then stirred at 60° C. and under a hydrogen pressure of 50 bars for 6 hours. After removal of the catalyst by filtration, the solution is evaporated under reduced pressure and the title compound is obtained in the form of a colourless oil.
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(Cl)c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (3-chloro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 347 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1([F:32])[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][C:24]=2[CH3:31])[CH2:19][CH2:18]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:26]3[CH:27]=[N:28][C:23]([N:20]4[CH2:19][CH2:18][C:17]([F:32])([F:16])[CH2:22][CH2:21]4)=[C:24]([CH3:31])[CH:25]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)cnc1N1CCC(F)(F)CC1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1N1CCC(F)(F)CC1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (228 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (212 mg, 0.76 mmol, Step-1 of Intermediate-1) and (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride (211 mg, 0.76 mmol, Amine-82) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[Br:20][C:21]1[C:22]([CH2:31]Br)=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24](OC)=[O:25]>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:23]2[C:22]=1[CH2:31][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:24]2=[O:25]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1C(=O)c2cccc(Br)c2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing methyl 2-((tert-butoxycarbonyl)amino)acetate (4.18 g, 22.09 mmol) in anhydrous DMF (50 ml) was added KOtBu (3.99 g, 35.6 mmol) then after 1 min at room temperature added methyl 3-bromo-2-(bromomethyl)benzoate (4.97 g, 16.14 mmol) as a solid in 1 portion. The reaction mixture was then capped (not under N2) & stirred at room temperature for 3 hours. Followed by LC/MS. The reaction mixture was quenched/diluted with sat'd NaHCO3, then suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-20% EtOAc/Hex; 220 g ISCO); desired fractions concentrated to yield 2-tert-butyl 3-methyl 8-bromo-4-oxo-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylate (24-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]3)=[O:24])=[C:16]2[N:15]=1.[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]3)=[O:24])=[C:16]2[N:15]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
(R)-ethyl 1-(5-(2-(2,5-di fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylate (49 mg, 0.10 mmol) was dissolved in 1:1 THF/MeOH (1.0 mL) and 1M LiOH (0.20 mL, 0.20 mmol) was added. The mixture was stirred at ambient temperature for 2 hours and the reaction mixture was concentrated. The residue was diluted in water and the mixture acidified with 2N HCl. The mixture was extracted with DCM and EtOAc. The combined organics were washed with brine, dried with MgSO4, filtered and concentrated. The residue was triturated with hexanes and the resulting white suspension was concentrated to afford the final product (43 mg, 92% yield) as a white solid. MS (apci) m/z=456.1 (M+H).
Reaction SMILES: [CH:1]([C@H:4]([NH2:7])[CH2:5]O)([CH3:3])[CH3:2].[Cl-].ClC[C@@H]([NH3+])C(C)C.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[S:28]>>[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]1[NH:7][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][S:28]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)[C@H]([NH3+])CCl
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CS1

Procedure:
(1S)-1-Isopropyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-isopropylethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-isopropylethylammonium chloride according to Method C1a to give (45)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:7]=[O:8])([O-:3])=[O:2].[CH2:22]([OH:26])[CH:23](O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:24][CH:23]1[CH2:22][O:26][CH:7]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:11]([N:12]([CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH3:18])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=2)[O:8]1
Reactant: CC(O)CO
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C2OCC(C)O2)cc1[N+](=O)[O-]

Procedure:
A mixture of 3.0 g. of 3,5-dinitro-4-(dipropylamino)benzaldehyde, 2.0 ml. of 1,2-propanediol, 75 ml. of benzene, and a small amount of p-toluenesulfonic acid was refluxed for about 4 hours, using a Dean-Stark trap to collect the evolved water. The reaction product mixture was cooled and extracted successively with saturated aqueous sodium bicarbonate solution, and brine, and then dried. The drying agent was filtered off and the benzene solution passed through an aluminum oxide column. The eluate was collected and evaporated. A total of 2.2 g. of 4-(4-methyl-1,3-dioxolan-2-yl)-2,6-dinitro-N,N-dipropylaniline was isolated as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccccc3F)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the (2-fluoro-phenyl)-piperazine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellow amorphous solid; MS: [M+H]+=334.