Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:33]([NH:40][C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: -5 °C
Yield: 95.9 %

Procedure:
Into a 500 mL round bottomed flask equipped with a magnetic stirrer was added N-(tert-butoxycarbonyl)-L-isoleucine (22.53 g, 97.39 mmol, 1.0 eq) and THF (300 mL). The solution was stirred until homogeneous, cooled to -5° C., and treated with N-ethylmorpholine (14.23 mL, 12.88 g, 112.0 mmol, 1.15 eq). The solution was stirred at -5° C. for 20 min, and isobutyl chloroformate (13.24 mL, 13.90 g, 102 mmol, 1.05 eq) was added dropwise over 10 min. After stirring at -5° C. for 30 min, benzylamine (12.24 mL, 12.0 g, 112.0 mmol, 1.15 eq) was added dropwise over 10 min. After the addition was complete, the flask was removed from the cold bath and the solution was stirred at 22° C. for 2.5 hrs. The solution was concentrated to a residue, and partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was extracted with ethyl ether (2×100 mL) and discarded. The organic extracts were combined, washed with 1N HCl (5×50 mL), 1N NaOH (3×50 mL), satd. aq NaCl (50 mL), and dried (MgSO4). The solution was concentrated in vacuo to provide 29.93 g (96%) of N-(tert-butoxycarbonyl)-L-Isoleucine benzylamide as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[C:4]2=[C:9](S(C)(=O)=O)[S:10][C:11]([C:12]3[CH:16]=[CH:15][NH:14][N:13]=3)=[C:3]12.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>CC(N(C)C)=O>[CH:21]1([NH:26][C:9]2[S:10][C:11]([C:12]3[CH:16]=[CH:15][NH:14][N:13]=3)=[C:3]3[CH:2]([CH3:1])[CH2:7][NH:6][C:5](=[O:8])[C:4]=23)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: CC1CNC(=O)c2c(S(C)(=O)=O)sc(-c3cc[nH]n3)c21
Solvent: CC(=O)N(C)C
Product: CC1CNC(=O)c2c(NC3CCCC3)sc(-c3cc[nH]n3)c21

Procedure:
To a sealed tube, the 7-methyl-3-(methylsulfonyl)-1-(1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one from Step 6 (30 mg, 0.096 mmol) was added and dissolved in DMA (193 μl), treated with cyclopentylamine (189 μl, 1.927 mmol) and subjected to microwave conditions: 160° C., 8 hrs, normal absorption. The reaction mixture was diluted with CH2Cl2 and washed with water, dried by filtering through a hydrophobic frit and evaporated to give solid residue. This was purified via reverse phase HPLC (5-95% CH3CN/H2O/0.025% TFA) to give afford the title compound: 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 2H), 7.66 (d, J=2.4 Hz, 1H), 6.43 (d/=2.3 Hz, 1H), 3.75 (m, 1H), 3.63 (dd, J=12.5, 4.4 Hz, 1H), 3.35 (m, 1H), 3.27 (d, J=12.4 Hz, 1H), 2.18 (s, 1H), 2.10 (m, 2H), 1.78 (m, 2H), 1.65 (m, 3H), 1.31 (d, J=7.1 Hz, 3H). LRMS (M+H)+=317.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[O:8][N:7]=1)=[O:5])C.O.[Li+].[OH-]>CO>[O:8]1[C:9]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)C1=NOC2(CCOCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NOC2(CCOCC2)C1
Yield: 96 %

Procedure:
A solution of 1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester (3.00 g, 1.41 mmol, as prepared in the previous step) in MeOH (60 mL) and water (20 mL) was treated with LiOH (649 mg, 1.55 mmol) at rt for 2.5 h. MeOH was removed in vacuo. The resulting aqueous solution was acidified with 1 N aq HCl and extracted three times with EtOAc (100 mL, 100 mL, 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.50 g, 96%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 3.86-3.95 (m, 2H), 3.74 (dt, J=11.8, 4.7 Hz, 2H), 3.01 (s, 2H), 1.91-1.99 (m, 2H), 1.80-1.89 (m, 2H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:29][N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH3:28])[CH2:23]1>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:29][N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=3[N:6]=2)[C@H:24]([CH3:28])[CH2:23]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: CC(=O)N(C)Cc1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Solvent: CCO
Product: CC(=O)N(C)Cc1cnc(N2CCN(c3nc4cc(C(F)(F)F)ccc4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (88 mg, 0.4 mmol, Example 1c) and N-[5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-ylmethyl]-N-methyl-acetamide from step (b) above (148 mg, 0.5 mmol) in ethanol (2 mL) reacted under the conditions Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 481 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([F:8])[CH:7]=1.O.[NH2:11][NH2:12]>C(O)CC>[NH:11]([C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)[NH2:12]
Reactant: Fc1cc(Cl)cnc1F
Reactant: NN
Solvent: O
Solvent: CCCO
Product: NNc1ncc(Cl)cc1F

Procedure:
7.5 g of the compound obtained in Step 3 and 9.57 ml of hydrazine monohydrate were added to 50 ml of n-propanol, the resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The resulting residue was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 7.26 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCC=C3
Temperature: -20 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-8-hydroxy-4H-azocino[3,2,1-hi]indole-2-carboxylate (0.70 g, 2.27 mmol), triethylamine (0.61 g, 6.00 mmol) and tetrahydrofuran (30 ml) was cooled to -20° C. with stirring, and methanesulfonyl chloride (0.31 g, 2.73 mmol) was added dropwise. After completion of the dropwise addition, the reaction temperature was raised to room temperature and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with an aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.63 g of ethyl 5,6-dihydro-11-chloro-4H-azocino[3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][CH:23]=[C:22]([N:4]2[C:5]3[C:6](=[N:7][C:8]([C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]#[N:14])=[CH:9][CH:10]=3)[N:2]([CH3:1])[C:3]2=[O:19])[CH:21]=1
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(-c2cccc(-c3ccccc3)c2)c2ccc(-c3ccccc3C#N)nc21
Reaction time: 96 h

Procedure:
To a solution of 4-1 (13 mg, 0.052 mmol) in DCM (0.25 mL) was added copper (II) acetate, biphenyl-3-ylboronic acid (30 mg, 0.16 mmol) and triethylamine (0.022 mL, 16 mg, 0.16 mmol) at room temperature. After 4 days, the crude mixture was diluted in DCM (4 mL), filtered, concentrated and purified via reverse phase chromatography (1-100% Acetonitrile, 0.1% TFA in H2O) and the desired fractions were concentrated to give 76-1. MS (M+H)+: observed=403.0, calculated=403.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.C1COCC1.[Li]CCCC>C1(C)C=CC=CC=1>[CH3:19][C:17]1[CH:18]=[C:2]([B:24]([OH:25])[OH:23])[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(B(O)O)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 121.2 %

Procedure:
2-(3-Bromo-5-methylphenoxy)-5-(trifluoromethyl)pyridine (2 g, 0.006 mol) and triisopropylborate (1.66 mL, 0.0072 mol) were dissolved in toluene (40 mL) and THF (20 mL) and cooled to −78° C. n-BuLi (5.38 mL, 0.006 mol) was added while maintaining the reaction at −70° C. The reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20-0° C. and the reaction was quenched with 2NHCl. The reaction mixture was warmed to RT, concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.16 g).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[F:3][CH:4]([F:7])[CH2:5][O:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccc1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Under N2, 60% NaH (10.2 g, 254.27 mmol) and 40 mL DMF were added into a 500 mL reaction flask and cooled to 0° C. 2,2-difluoroethanol 12a (23 g, 280.3 mmol) was dissolved in 40 mL DMF and then dropwise added into the mixture within 4 hours at 0° C. The reaction mixture was then warmed to room temperature. After 30 minutes, a solution of bromobenzene (39.92 g, 254.25 mmol) in DMF (40 mL) and CuBr (0.35 g, 2.43 mmol) were added in turn before the reaction mixture was warmed and stirred for 16 hours at 160° C. Thereafter, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with n-hexane. 5% hydrochloric acid (160 mL) was added to the filtrate before the resulting residue was extracted with n-hexane (160 mL×3). The organic extract was washed with saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2,2-difluoroethoxybenzene 12c (32.97 g, yellow liquid), yield: 82.0%.
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[N:12][CH:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][N:10]=[CH:11][N:12]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: NCc1ccncn1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccncn1
Yield: 65 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyrimidin-4-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 65% yield: mp 188-191° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 7.33 (d, J=4.9 Hz, 1H), 6.89-6.87 (m, 1H), 4.69 (d, J=5.0 Hz, 2H), 4.16-4.11 (m, 2H), 3.74-3.69 (m, 2H), 3.20 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.00-0.91 (m, 1H), 0.61-0.55 (m, 2H), 0.28-0.23 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.0, 162.8, 158.5, 157.9, 156.9, 155.2, 153.2, 119.1, 117.1, 48.6, 44.1, 42.2, 42.1, 17.3, 8.9, 3.5; MS (ES+) m/z 373.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[CH:15][CH:14]=[C:13]([O:25]CC2C=CC=CC=2)[C:12]=1[O:33][CH3:34])[CH3:2].Cl.[H][H]>CCOCC.C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([OH:25])[C:12]=1[O:33][CH3:34])[CH3:2]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OCc2ccccc2)ccc(OCc2ccccc2)c1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCN1CCC[C@H]1CNC(=O)c1c(O)ccc(O)c1OC
Yield: 113.2 %

Procedure:
A mixture of (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3,6-dibenzyloxy-2-methoxybenzamide (130 mg, 0.27 mmol), 5% Pd/C (50 mg), 0.5 ml 4 M HCl in ether and 5 ml ethanol was shaken in a hydrogen atmosphere for 1 h. Filtration and evaporation of the solvent gave 90 mg pure title compound as an oily hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH:18]1([C@H:24]([NH2:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>CN1CCCC1=O>[CH:18]1([C@H:24]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2ccccc2)c2ccccc12)C1CCCCC1
Yield: 75.5 %

Procedure:
To 400 ml of N-methylpyrrolidone, 144.4 g (0.6 mol) of 1-chloro-4-phenylphthalazine and 230 g (1.8 mol) of (R)-(-)-1-cyclohexylethylamine were added, and the mixture was heated to 120° to 130° C. for 6 hours with stirring. After completion of the reaction, the mixture was cooled and added with 4.0 l of 5% aqueous NaOH solution, and then extracted with chloroform. The organic layer was dried over MgSO4, concentrated and purified by silica gel column chromatography (eluent; ethyl acetate/hexane/chloroform=1:3:1). After recrystallization from ether/chloroform, 150.2 g of (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine was obtained. m.p. 164.0°-167.0° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCC1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CCC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclobutylamine; ESI-MS [M+H]+: 496.2
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C([NH+](CC)CC)C.[N:32]1([CH2:41][C:42]([O-:44])=O)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[CH:33]1.CN1CCOCC1.[CH2:52]([NH2:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>C(#N)C>[N:32]1([CH2:41][C:42]([NH:59][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:44])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[CH:33]1
Reactant: CCCCCCCN
Reactant: O=C([O-])Cn1cnc2ccccc21
Agent: CC[NH+](CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCCCCCNC(=O)Cn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
O-(7-Azabenzotriazol1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol) was added under stirring to a solution of 1H-benzoimidazol-1-ylacetic acid triethylammonium salt (55.5 mg, 0.2 mmol) and N-methyl morpholine (66 μL, 0.6 mmol) in acetonitrile (1 mL). After 5 min 1-heptylamine (30 μL, 0.2 mmol) was added and mixture was stirred at ambient temperature for 3 h. The solvent was evaporated, the residue was dissolved in ethyl acetate (15 mL) and extracted with saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried over anhydrous Na2SO4 and concentrated. Purification of the crude product was performed by preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M NH4OAc/CH3CN). Product-containing fractions were pooled and lyophilised affording the title compound (43.7 mg, 80%). Calculated for C16H23N3O m/z: 273.18, found 274.03 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (m, 3H), 1.26 (m, 8 H), 1.41 (m, 2H), 3.07 (m, 2H), 4.88 (s, 2H), 7.20 (m, 2H), 7.42 (m, 1H), 7.64 (m, 1H), 8.14 (s, 1H), 8.27 (t, J=5.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[CH2:20]([NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. n-butylamine are added dropwise. After the addition is completed, the heating is continued for 10 minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 4-butylamino-6-chloro -2methyl-5nitropyridine-3-carboxylic acid, ethyl ester is crystallized with 300 ml. of methanol, yield 110 g. (70%); m.p. 33°-35° (methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[NH2:26][CH2:27][C:28]([NH2:30])=[O:29].C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: NCC(N)=O
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Intermediate (27) (0.00423 mol), 2-amino-acetamide (0.00431 mol), 1,4-dioxane (20 ml) and N,N-diisopropylethylamine (0.00862 mol) were combined and stirred at RT for 16 hours under argon. The reaction mixture was quenched with H2O and filtered. The residue was washed with H2O, filtered and recrystallized from ACN (200 ml). The precipitate was filtered off and dried, yielding 0.75 g (41.4%) of [N-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]]aminoacetamide (compound 14).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[Cl:23]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[Cl:23]
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Reactant: Clc1cccc(Br)c1Cl
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1c1cccc(Cl)c1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromo-2,3-dichlorobenzene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]2[CH2:23][CH2:22][Si:21](C3C=CC=CC=3)([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C@H:18]3[CH2:19][CH2:20][Si@H:21]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: FCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CBr)CC2)CC1
Reactant: Oc1ccc(F)c(F)c1
Product: FCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(F)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 3,4-difluorophenol and 4-(trans-4-bromomethylcyclohexyl)-1-phenyl-1-(4-fluorobutyl)-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: [N+:1]([C:4]1[C:8]([N:9]=[N:10][C:11]2[C:12]([N+:16]([O-:18])=[O:17])=[N:13][O:14][N:15]=2)=[N:7][O:6][N:5]=1)([O-:3])=[O:2].C(O)(=O)C>CO.[Zn]>[N+:1]([C:4]1[C:8]([NH:9][NH:10][C:11]2[C:12]([N+:16]([O-:18])=[O:17])=[N:13][O:14][N:15]=2)=[N:7][O:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1nonc1N=Nc1nonc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1nonc1NNc1nonc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a suspension of 3,3′-dinitro-4,4′-azofurazan (1.42 g, 6.0 mmol) and Zn (0.78 g, 12 mmol) in 10 ml of methanol at room temperature, was added dropwise glacial acetic acid (0.8 ml, 12 mmol). A vigorous reaction took place, and after the greenish reaction mixture was stirred at room temperature for 2 hours. The slurry was filtered through a bed of celite and the filtrate was concentrated on a rotary evaporator and passed through a bed of silica gel using CH2Cl2/EtOAc. Removal of solvent gave 1.46 g (100% yield, one spot by TLC) of 3,3′-dinitro-4,4′-hydrazofurazan, a pale yellow solid, 1H NMR(DMSO-d6); δ9.98 (s) ppm. Recrystallization from chloroform/acetone gave 1.26 g of 3,3′-dinitro-4,4′-hydrazofurazan, mp 171-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH3:14][C:13]1[N:1]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=2)[C:16]([CH3:15])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(N)nc(C)c1Br
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.76 g (13.75 mmol) of 2-amino-5-bromo-4,6-dimethylpyridine (13) in 25 mL of toluene were added 2.02 mL (17.18 mmol) of 2,5-hexadienone followed by 130 mg (0.68 mmol) of p-toluene sulfonic acid. The reaction mixture was stirred at reflux overnight under argon atmosphere. The reaction mixture was poured into 150 mL of water and then extracted with a portion of 200 mL of ethyl acetate. The organic solution was washed with a portion of 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5:1 gave the expected product as an orange oil: yield 2.37 g (62%). 1H-NMR (CDCl3) δ 6.93 (s, 1H), 5.88 (s, 2H), 2.70 (s, 3H), 2.47 (s, 3H), 2.12 (s, 6H); 13C-NMR (CDCl3) δ 157.35, 149.32, 128.42, 122.49, 121.22, 25.58, 23.41, 13.10.