Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=O)C>C(O)C.[OH-].[Na+].O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([C:11]2[C:10]3[CH:9]=[C:8]4[NH:4][CH2:5][CH2:6][C:7]4=[CH:15][C:14]=3[NH:13][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CC(=O)N1CCc2cc3[nH]cc(C4CCN(C)CC4)c3cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCC(c2c[nH]c3cc4c(cc23)NCC4)CC1
Yield: 61.4 %

Procedure:
To a stirred suspension of 1-acetyl-7-(1-methylpiperidin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (D5, 0.55 g, 1.85 mmole) in ethanol (10 ml) and 10% sodium hydroxide solution (10 ml) was added sodium hydroxide pellets (0.50 g) and the resultant mixture was heated at reflux under argon for 18 hours. The mixture was cooled, diluted with water (75 ml) and extracted with dichloromethane (5×30 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was triturated with diethyl ether and the solid filtered off and dried in vacuo to afford the title compound as an off-white powder (0.29 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O>CO>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(CO)n1
Yield: 6126.9 %

Procedure:
6-Methylpyridine-2-carboxaldehyde (0.44 mmole) in 50 ml methanol was reduced with 20.6 mmole sodium borohydride at 0°-5° C. After reduction was complete, the mixture was neutralized (pH 7.5) with 2N sulfuric acid, filtered, the filtrate concentrated and partitioned between chloroform and water. Evaporation of solvent from the organic layer gave 3.32 g of red-black oil which was used in the next step.
Reaction SMILES: [CH:1]([Si:4]1([CH:22]([CH3:24])[CH3:23])[O:11][C@H:10]2[C@@H:12]([OH:15])[CH:13]=[CH:14][C@@H:9]2[CH2:8][O:7][Si:6]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5]1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[CH:22]([Si:4]1([CH:1]([CH3:3])[CH3:2])[O:11][C@H:10]2[CH:12]([OH:15])[C@@H:13]3[O:33][C@@H:14]3[C@@H:9]2[CH2:8][O:7][Si:6]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[O:5]1)([CH3:24])[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C=C[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@H]2[C@H]3O[C@H]3C(O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a stirred solution of compound 11 (13.7 g, 36.8 mmol) in dichloromethane (300 mL), m-CPBA (15.9 g, 92.0 mmol) was added portion wise at room temperature. The mixture was stirred at room temperature for 16 h, quenched with a saturated NaHCO3 solution and extracted with DCM (200 mL×2). The combined organic layer was washed with brine (100 mL×2) and dried over Na2SO4. The solvent was removed under reduced pressure and residue was purified by silica gel column chromatography (3% EtOAc/Hexane) to give epoxide 12 (12.2 g, 85%) as an oil. [α]24D +18.25° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.00-1.11 (m, 28H), 2.30 (in, 1H,), 3.05 (s, 1H), 3.37 (s, 1H), 3.56 (d, J=2.5 Hz, 1H), 3.99-4.05 (m, 2H), 4.19 (d, J=5.0 Hz, 1H), 4.26 (dd, J=3.0, 11.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6, 13.1, 13.3, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 48.2, 55.5, 58.4, 64.7, 70.7, 75.0; HR-MS Calcd. For (C18H36O5Si2+H)+ 389.2101. found 389.2171.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][NH:10][C:4]=2[CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[O:24].CC(C)([O-])C.[K+]>C1COCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:5]3[CH:6]=[N:7][C:2]([NH:25][C:23]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[O:24])=[CH:3][C:4]=3[NH:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: COCCNC(N)=O
Reactant: Fc1ccc(-c2n[nH]c3cc(Cl)ncc23)cc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1CCOC1
Product: COCCNC(=O)Nc1cc2[nH]nc(-c3ccc(F)cc3)c2cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
6-Chloro-3-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine (433 mg, 1.748 mmol), 1-(2-methoxyethyl)urea (313 mg, 2.65 mmol) and chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (97 mg, 0.121 mmol) were taken up in THF (10.5 mL) in a 20 mL microwave vial. 1 M potassium t-butoxide in THF (5.25 mL, 5.25 mmol) was added and the vial was evacuated and back-filled with N2 (x3). The reaction mixture was stirred at 60° C. for 18 hours. Room temperature was attained and the mixture filtered through Celite, eluting with MeOH. The filtrate was concentrated in vacuo and the residue purified by MPLC (0-10% MeOH-EtOAc). The product was then triturated in EtOH to give 1-(3-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(2-methoxyethyl)urea (237 mg, 0.720 mmol, 41.2% yield). MS ESI calc'd. for C16H17FN5O2 [M+H]+ 330, found 330. 1H NMR (600 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.15 (s, 1H), 9.04 (s, 1H), 8.07-8.04 (m, 2H), 7.72 (s, 1H), 7.35-7.31 (m, 3H), 3.39 (t, J=5.5 Hz, 2H), 3.32-3.29 (m, 2H), 3.27 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:21]=[C:22]([O:24]CC3C=CC=CC=3)[CH:23]=2)[C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])[C:3]1=[O:32]>C1COCC1.CO.[Pd]>[OH:24][C:22]1[CH:21]=[C:10]([CH:9]=[C:8]([O:7][C@H:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:32])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reaction time: 16 h
Yield: 109.5 %

Procedure:
A solution of 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)-5-phenylmethoxy-benzamide (Intermediate 19) (449 mg, 1.04 mmol) in THF (10 mL) and methanol (10 mL) containing 10% palladium on carbon (catalytic) was stirred under an atmosphere of hydrogen for 16 hours. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure to afford product (390 mg, 100%). 1HNMR δ (300 MHz, CDCl3) 2.07-2.22 (m, 1H), 2.54 (s, 3H), 2.57-2.70 (m, 1H), 2.97 (s, 3H), 3.38-3.58 (m, 3H), 4.99 (t, 1H), 6.71 (s, 1H), 6.87 (s, 1H), 6.97 (s, 1H), 8.15 (s, 1H), 8.66 (s, 1H), 9.49 (s, 1H); m/z 343 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:33]=[C:32]([C:30]([OH:34])([CH3:31])[CH3:29])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CC(C)(C)O
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(-n2cc(C(C)(C)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and 2-methyl-but-3-yn-2-ol (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 70:30 as the eluent to afford the title compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([CH:12]=1)[C:9](O)=[O:10].[NH4+].O[N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([CH:12]=1)[C:9]([NH2:26])=[O:10])=[O:2]
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 35 h
Yield: 73 %

Procedure:
A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid (0.40 g, 1.23 mmol) obtained in Step 4 in DMF (5.00 mL) was added with 1-hydroxybenzotriazole ammonium salt (0.30 g, 1.97 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g, 1.84 mmol), followed by stirring at room temperature for 35 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the residue was added with hydrochloric acid (3 mol/L, 3.00 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution (50 mL) and was extracted with ethyl acetate (50 mL×3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 5-formyl-2-(2-morpholinoethoxy)benzamide (0.25 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])(C([O-])=O)[C:6]([O:8]CC)=[O:7].[Cl-].[Li+].Cl>CS(C)=O.O>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccccc1F)(Cc1ccccc1F)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)C(Cc1ccccc1F)Cc1ccccc1F
Yield: 41.7 %

Procedure:
In 15 ml of dry dimethoxyethane was dissolved 5.2 g of ethyl malonate, and to the solution was added 3.8 g of a 50% sodium hydride (dispersion in an oil) with stirring under ice-cooling. To the mixture was added a solution of 20 ml of dry dimethoxyethane containing 12.3 g of 2-fluorobenzyl bromide. The mixture was stirred for 1 hour at room temperature, and then heated under reflux for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was acidified by an addition of diluted hydrochloric acid. The acidic mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (eluent: benzene) to obtain 8.6 g of ethyl bis(2-fluorobenzyl)malonate as a colorless oil. In a mixture of 20 ml of dimethyl sulfoxide and 1 ml of water was dissolved 8.6 g of ethyl bis(2-fluorobenzyl)malonate, and to the solution was added 4.4 g of lithium chloride. The mixture was heated at 190°-200° C. for 10 hours. After cooling, the reaction mixture was acidified by an addition of diluted hydrochloric acid. The acidic mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. In 50 ml of methanol was dissolved the residue, and to the solution was added 30 ml of a 2N-aqueous sodium hydroxide solution. The mixture was heated under reflux for 1 hour, and the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water, and the solution was extracted with diethyl ether. The aqueous layer was acidified by an addition of hydrochloric acid, and the acidic mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=15/1) to obtain 2.85 g of bis(2-fluorobenzyl)acetic acid as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[NH2:16][C:17]1[NH:18][C:19]2[C:24]([C:25](=[O:27])[N:26]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:1][C:2]1([CH3:15])[CH:3]=[C:4]([NH:16][C:17]2[NH:18][C:19]3[C:24]([C:25](=[O:27])[N:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11]1
Reactant: Nc1nc(=O)c2ccccc2[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)C=C(Nc2nc(=O)c3ccccc3[nH]2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using 2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-amino-1H-quinazolin-4-one as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: Br[Si:2]([CH3:5])([CH3:4])[CH3:3].C([O:9][P:10]([CH2:16][CH:17]1[CH2:19][CH2:18]1)(=[O:15])[O:11]C(C)C)(C)C>>[CH3:3][Si:2]([O:9][P:10]([CH2:16][CH:17]1[CH2:19][CH2:18]1)(=[O:15])[O:11][Si:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Br
Reactant: CC(C)OP(=O)(CC1CC1)OC(C)C
Product: C[Si](C)(C)OP(=O)(CC1CC1)O[Si](C)(C)C
Temperature: 5 °C

Procedure:
Bromotrimethylsilane (43 mL, 0.326 mol) was added dropwise to cyclopropylmethyl-phosphonic acid diisopropyl ester (18.00 g, 81.8 mmol) stirred in a reaction flask chilled to 5° C. The resulting solution was allowed to warm to ambient temperature, stirred for three hours, and then concentrated by rotary evaporation yielding crude cyclopropylmethyl-phosphonic acid bis(trimethylsilyl) ester which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O)=[O:5])[CH3:2].[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 9 (2.81 g, 7.74 mmol) in TFA (30 ml) was added dropwise Et3SiH (7.42 ml, 46.44 mmol) at 0° C. Stirring was continued at 0° C. for 2 hours. Then, the solvent was evaporated, and the residue was purified by chromatography, CombiFlash silica gel column, hexane/CH2Cl2, CH2Cl2 from 0% to 50%, to give compound 10 as a clear oil (mixture of cis and trans diastereomers, 2.63 g, 97%). 1H NMR (CDCl3) δ 1.18-1.34 (m, 3H), 1.88 (dd, J=25.2 Hz, 12.4 Hz) and 2.14-2.19 (m, total 1H), 2.25-2.33 (m) and 2.43-2.55 (m, total 1H), 2.67-2.74 (m) and 2.82-2.92 (m, total 1H), 3.00-3.18 (m, 2H), 4.08-4.29 (m, 3H), 6.72-7.42 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[CH:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH2:12][CH2:11]1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 50 g of ethyl 4-hydroxybenzoate in 500 ml of toluene is hydrogenated at 2.5 bar and 110° C. in the presence of palladium on activated carbon. The reaction mixture is filtered and freed from water by azeotropic distillation. It is then treated with 10 g of pyridine sulfone and stirred at 50° C. for 1 hour. After filtration with basic alumina and removal of the solvent, 49.6 g (97% yield) of ethyl cyclohexan-4-onecarboxylate having a purity of 94.1% (GC) remain.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[C:20]=3[CH3:28])=[N:15]2)=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:27][C:21]1[C:20]([CH3:28])=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[CH3:29])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)[nH]n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cc(C(C)O)n[nH]3)n2)ccc(C#N)c1Cl
Yield: 99.9 %

Procedure:
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1H-pyrazole-5-carboxamide (0.04 g, 0.097 mmol) as prepared in the previous Example was added in ethanol (5 ml). Solid sodium borohydride (0.018 g, 0.487 mmol) was added to the mixture and it was refluxed for 15 min under nitrogen. To the cooled solution a portion of 10 ml of saturated ammonium chloride was added and the mixture was extracted several times with DCM. The organic extracts were combined and washed with water, dried with Na2SO4, filtered and evaporated to dryness affording 0.040 g of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (m, 3H), 1.51 (m, 3H), 2.49 (d, 3H), 3.72 (m, 1H), 4.29 (m, 1H), 4.41 (m, 1H), 4.61 (m, 1H), 4.99 (m, 1H), 6.42 (d, 1H), 6.56 (s, 1H), 7.43-7.50 (m, 3H), 7.53 (d, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[Cl:20][C:21]1[CH:27]=[CH:26][C:24](N)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1>[Cu](F)F.N1C=CC=CC=1>[N+:28]([C:23]1[CH:22]=[C:21]([Cl:20])[CH:27]=[CH:26][C:24]=1[O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11])([O-:30])=[O:29]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CC(O)CC(C)(C)N1Oc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 52.1 %

Procedure:
The procedure of Example 1 is repeated using 4.31 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 7.73 g (75 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) flouride, 70 mL of pyridine and 5.61 g (32.5 mmol) of 4-chloro-2-nitroaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (70:30/heptane:ethyl acetate) to give 4.28 g of the title compound in 84.8% yield as a light yellow solid melting at 124-125.5° C. The structure is confirmed by 1Hnmr and elemental analysis.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[Br:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@H:10]4[CH2:21][C@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of (1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.00 g, 2.87 mmol) in methanol (5 mL) and THF (5.00 mL) was added a 2.0 M aqueous solution of sodium hydroxide (2.87 mL, 5.74 mmol). The reaction was stirred at 23° C. for 2 h. The organic solvents were removed by distillation. The remaining aqueous solution was diluted with water (20 mL) then acidified to pH ˜2 by addition of 6 M aq. HCl. The resulting precipitate was collected by filtration, rinsed with water, then dried under vacuum to give the title compound (0.87 g) as a white solid. LCMS m/z=320.0 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)=[CH:26][C:25]=2[O:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:27]3[CH:28]=[CH:29][C:30]4[O:31][CH2:23][O:24][C:25]=4[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCOCc1ccc2c(c1)OCO2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOCc2ccc3c(c2)OCO3)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-((3,4-methylenedioxyphenyl)methoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-((3,4-methylenedioxyphenyl)methoxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29].CCOC(C)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:28]([N:27]([CH3:31])[CH3:26])=[O:29])=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)ONCCc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(CCNOC(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
N-t-butoxycarbonyloxy 2-(4-hydroxyphenyl)ethylamine (2.53 g, 10.7 mmol), Et3N (2.96 mL, 2 eq.), a catalytic amount of DMAP (131 mg) and dimethylcarbamyl chloride (2.0 mL, 2 eq.) are mixed in CH2Cl2 at 0° C. The resulting mixture is stirred overnight. EtOAc is added to dilute the reaction mixture and then is washed with 1N HCl, sat. Na2CO3 and brine. Solvent is removed under reduced pressure to give pure t-butoxycarbonyloxy 2-[4-(N,N-dimethylaminocarbonyloxy)phenyl]ethylamine as a colorless solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:36])([CH3:35])[C@@H:14]([O:27]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].Cl>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:35])([CH3:36])[C@@H:14]([OH:27])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)OC(C)C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of (methylethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (40c) (13.0 g, 24.4 mmol), 3.2 g of 10 wt.-% of palladium on activated carbon in 40 mL of methanol (MeOH), and 0.2 mL of one molar (1.0 M) hydrochloric acid (HCl) was stirred overnight under a hydrogen atmosphere. Upon the completion of reaction and following aqueous work-up, 10.0 g (93% yield) of the title compound (40) was obtained as a colorless, viscous oil. RT=12.46 min and 14.22 min. 1H NMR (400 MHz, DMSO-d6, both diastereomers): δ=0.89-0.91 (2s, 3H), 0.93-0.95 (2s, 3H), 1.21-1.24 (m, 6H), 1.45-1.47 (2d, J=5.2, 5.2 Hz, 3H), 1.78-1.83 (m, 5H), 3.10-3.15 (m, 2H), 3.30-3.33 (m, 2H), 3.89-3.93 (m, 2H), 4.05-4.08 (2d, J=9.2, 9.6 Hz, 1H), 4.73-4.82 (m, 1H), 5.78-5.85 (2d, J=6.0, 6.0 Hz, 1H), 6.65-6.71 (m, 1H), 7.89-7.92 (br. m, 1H) ppm. MS (ESI) m/z: 442.08 (M+H)+, 464.02 (M+Na)+. The analytical data was consistent with the proposed structure.