Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9]([NH:16]C(=O)[C@H]([C@H](CC)C)N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[CH2:33][C:34]([CH:36]1[CH2:41][CH:40]2[CH2:42][CH:38]([C:39]2([CH3:44])[CH3:43])[CH:37]1[CH3:45])=[O:35].C12CC(C1(C)C)CC(C(O)=O)C2C>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9].[CH3:45][CH:37]1[CH:36]([C:34](=[O:35])[CH2:33][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([C:10]2([CH:11]=[CH:12][CH:13]=[CH:14][CH2:15]2)[CH2:9][NH-:16])=[O:5])[CH2:41][CH:40]2[CH2:42][CH:38]1[C:39]2([CH3:43])[CH3:44]
Reactant: CC1C(C(=O)CCl)CC2CC1C2(C)C
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC1C(C(=O)O)CC2CC1C2(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1C(C(=O)CN2CCC[C@H]2C(=O)C2(C[NH-])C=CC=CC2)CC2CC1C2(C)C
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 68 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (153 mg, 0.48 mmol) and triethylamine (337 uL, 5.0 eq), in THF (2 mL), was treated with 205 mg (0.95 mmol) of 1-chloro-2-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-2-oxoethane (prepared from (-)-3-pinanecarboxylic acid using the procedure described in example 1) to provide 164 mg, (68%) of L-isoleucine, N-[1-[(2-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([NH:9]C(=O)C(F)(F)F)=[N:7][CH:8]=1)#N.C(O)=[O:18]>O.[Ni].[Al]>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([CH:1]=[O:18])=[C:4]([CH3:16])[CH:5]=1
Reactant: O=CO
Reactant: Cc1cc(NC(=O)C(F)(F)F)ncc1C#N
Agent: [Ni]
Agent: [Al]
Solvent: O
Product: Cc1cc(N)ncc1C=O

Procedure:
A solution of N-(5-cyano-4-methyl-2-pyridinyl)-2,2,2-trifluoroacetamide (D98) (0.050 g, 0.22 mmol) in formic acid (1.35 mL) was diluted with water (0.48 mL) and nickel/aluminium alloy (0.122 g) was added. The reaction mixture was heated at reflux under argon for 2 h then filtered while still hot, washing with further formic acid (3×5 mL). The filtrate and washings were concentrated, diluted with toluene (5 mL) and re-concentrated to give the crude title compound as a pale yellow solid (0.053 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 9.91 (1H, s), 8.34 (1H, s), 6.31 (1H, s), 5.49 (2H, br.s), 2.57 (3H, s). MS (ES): MH+ 137.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:30]1([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:28]=[CH:29][C:16]([CH2:15][N:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)[CH2:8][C:9]3[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=3)=[CH:17][CH:18]=2)[CH3:27])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCCCC1
Reactant: CN(CCCCN)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCNC1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
The compound (110.0 mg) obtained in Example 103-7 was dissolved in anhydrous methanol (4.4 ml). Then, the solution was added with cyclohexanone (0.058 ml) and sodium cyanoborohydride (52.8 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. Subsequently, the residue was added with a 1 mol/l sodium hydroxide aqueous solution (3.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (96.7 mg) of the subject compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.C([Li])(C)(C)C.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCOCC>[CH2:18]([C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1cnc2ccccc2c1
Reactant: CCCCCCI
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCCCc1nc2ccccc2cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of quinolin-3-ylamine in ether was added tert-butyl lithium at −78° C. and was stirred for 2 hours. To the reaction mixture was added the solution of 1-Iodo-hexane in ether and was allowed to warm up to RT. The reaction was continued for 1 day. The reaction was quenched with saturated ammonium chloride solution and extracted with chloroform. The product was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([Cl:29])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:29].[CH3:10][C:11]1[C:12]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(N2CCc3ccccc3C2C)nc(Cl)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)nc(C)c1C
Product: Cl
Yield: 72.7 %

Procedure:
After 2-methyl-4-fluoroaniline(0.7 ml, 6.3 mmol) was added to a mixture solution of 5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.85 g, 3.0 mmol) and dimethylformamide(10 ml), 0.9 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>O.CN(C=O)C>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNCCNc1ccc([N+](=O)[O-])cn1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To a suspension of resin-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine (3.0 g, 2.1 mmol) and DMF (30 mL) at 23° C. was added H2O (2 drops), K2CO3 (2.9 g, 21 mmol) and PhSH (2.2 mL, 21 mmol). The resulting mixture was shaken at 23° C. for 12 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound dimethyl[2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)ethyl]amine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:32][N:33]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([NH:33][CH3:32])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OC)nc1Cl
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)NC)s3)C[C@H]2OC)nc1Cl
Yield: 83.3 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid obtained in Example (11b) (40 mg, 0.09 mmol), methylamine hydrochloride (8 mg, 0.11 mmol), WSC hydrochloride (61 mg, 0.32 mmol), HOBT (22 mg, 0.16 mmol), diisopropylethylamine (0.020 mL, 0.12 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 32 mg of the title compound as a white solid (77%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:24]([O-:26])=[O:25])[NH:21][CH2:20][CH2:19][CH2:18][S:17][C:16]2([CH3:23])[CH3:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:24]([OH:26])=[O:25])[NH:21][CH2:20][CH2:19][CH2:18][S:17][C:16]2([CH3:22])[CH3:23])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)[O-])NCCCSC2(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)NCCCSC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-1,4-thiazepane-3-carboxylate (220 mg, 0.49 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1.5 mL) and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo. Traces of trifluoroacetic acid was removed by adding toluene (1 mL) and removing the solvent to obtain 170 mg (88%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 3H), 1.60 (s, 3H), 1.85 (m, 3H), 1.91 (m, 1H), 2.17 (m, 1H), 2.67 (m, 1H), 2.82 (m, 1H), 3.54 (m, 1H), 3.82 (m, 1H), 4.59 (s, 1H), 4.68 (m, 2H), 7.0 (d, 2H, J=8.7 Hz), 7.75 (d, 2H, J=8.7 Hz); HRMS (C18H23NO5S2)(M+); cald. 397.1018, found 397.0998.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:15][C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCC1CCCCC1=O
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCCC1

Procedure:
Treatment of 2-(3-carbethoxypropyl)cyclohexan-1-one (Example 14) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=2)=[CH:4][CH:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:18]([CH3:22])(=[O:20])=[O:17])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1nccc(-c2ccc(Cl)cc2)n1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 4-(4-chlorophenyl)-2-(methylthio)pyrimidine (3 g, 12.71 mmol), in methanol (125 mL) and water (125 mL) under nitrogen at 4° C. was treated with oxone™ (23.44 g, 38.13 mmol), stirred and allowed to warm up to room temperature for 18 h. The reaction mixture was diluted with water (220 mL), extracted with CHCl3 (250 mL), dried (Na2SO4) and the solvent removed in vacuo to afford the title compound as a yellow solid (3.36 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([O:36][C:37]([F:40])([F:39])[F:38])[CH:29]=1)=O)(=[O:22])[CH3:21].C[Si]([N:45]=[N+:46]=[N-:47])(C)C>C1COCC1>[C:20]([O:23][CH2:24][C:25]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([O:36][C:37]([F:40])([F:39])[F:38])[CH:29]=2)[N:47]=[N:46][N:45]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(OC(F)(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(OC(F)(F)F)c1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
Triphenylphosphine (17.29 g, 65.7 mmol) and diisopropylazodicorboxylate (13.3 g, 65.7 mmol) were added to a solution of 2-({4-cyano-3-[(trifluoromethyl)oxy]phenyl}amino)-2-oxoethyl acetate (Intermediate 52, 8.0 g, 26.5 mmol) in THF (160 mL) at 0° C. and the mixture was stirred for 30 min. Trimethylsilyl azide (7.60 g, 66.0 mmol) was added dropwise at room temperature and the mixture was heated to reflux for 4 hr. THF was removed under reduced pressure and the residue was diluted with EtOAc and washed with ice-cooled water. The extracted organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20% EtOAc/pet ether to give the title compound (7.0 g).
Reaction SMILES: [C:1]([C:3](=[CH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N+:30]([O-:32])=[O:31])[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=O)#[N:2].[CH3:33][NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([N:34]([CH3:33])[C:7](=[O:9])[CH2:6][CH2:5][CH:4]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:3]([C:1]#[N:2])=[CH:16][C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:18]=2[N+:30]([O-:32])=[O:31])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CNC1CCCCC1
Reactant: N#CC(=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(CCC(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C(=O)CCC(C(C#N)=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCOCC1)C1CCCCC1

Procedure:
A solution of 5-cyano-6-(2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid (0.87 g, 2 mmol), N-methylcyclohexylamine (0.26 mL, 2 mmol), HBTU (1.13 g, 3 mmol), DIPEA (1.2 mL, 7 mmol) in DMF (20 mL) was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture. The solution was washed with saturated aqueous NaHCO3 solution. The organic phase was separated and dried with MgSO4, and filtered. The solvent was removed in vacuo to yield the title compound as an oil.
Reaction SMILES: OC(C(F)(F)F)=O.Cl[C:9]1[CH:10]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[C:29](=[O:41])[N:30]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:21][CH:20]=2)[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[N:14]=1.[H][H]>C(N(CC)CC)C.[Pd].CCO>[F:40][C:37]1[CH:38]=[CH:39][C:34]([N:30]2[CH2:31][CH2:32][CH2:33][CH:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:11]4[C:12]5[N:13]([CH:15]=[CH:16][N:17]=5)[N:14]=[CH:9][CH:10]=4)=[CH:24][CH:23]=3)=[O:27])[C:29]2=[O:41])=[CH:35][CH:36]=1
Reactant: O=C(Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Nc2ccnn3ccnc23)cc1)C1CCCN(c2ccc(F)cc2)C1=O
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a suspension of N-(4-((6-chloroimidazo[1,2-b]pyridazin-8-yl)amino)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide TFA salt (0.013 g, 0.027 mmol) from Example XXI(i) and EtOH (4 mL) in a 500 ml PARR bottle was added 10% Pd/C (20 mg) and 2 drops of triethylamine. The PARR bottle was then charged with Hydrogen gas at 55 psi and allow to shake at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC to furnish 0.008 g of the title compound as a TFA salt. LC/MS, m/e 445 (M+1). HPLC Rt, 1.81 mm. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 mm, hold at 100% B 1 mm, flow rate 4 mL/min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[C:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:39]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])([O-:41])=[O:40]>CC(C)=O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[C:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][CH:50]=[C:42]([N+:39]([O-:41])=[O:40])[CH:43]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1Oc1ccc(-c2nnnn2Cc2ccccc2)c(-c2nnnn2Cc2ccccc2)c1
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1Oc1ccc(-c2nnnn2Cc2ccccc2)c(-c2nnnn2Cc2ccccc2)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
2-[3,4-Bis-(1-benzyl-1H-tetrazol-5-yl)phenoxy]phenylamine (37 mg, 0.07 mmol) and TEA (19 mg, 0.18 mmol) were mixed in acetone (10 ml), and 3-nitrobenzoyl chloride (15 mg, 0.08 mmol) was added. The reaction mixture was stirred for 120 hours at room temperature. The reaction mixture was evaporated in vacuo to an oil. The oil was purified on a silica column with methylene chloride/methanol (39:1) as eluent. The title compound was isolated as yellow oil (yield: 30 mg (62%). 1H-NMR (CDCl3 in ppm): 5.6 (4H,2xs); 7.0 (1H,d,d); 7.15 (1H,d,d); 7.2 (1H,d,d); 7.25-7.4 (11H,m); 7.6 (1H,d,d); 7.73 (1H,d); 7.9 (1H,d); 8.1 (1H,d,d); 8.35 (1H,d,d); 8.45 (1H,broad s); 8.55 (1H,d,d); 8.7 (1H,d,d).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH:19]=O)[CH:13]=1.S(=O)(=O)(O)O.C([BH3-])#N.[Na+]>O1CCCC1.O>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:13]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(C=O)c1
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)nc(CNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
p-Nitroaniline (0.51 g, 3.7 mmol) was added to a solution of 4,6-dimethyl-pyridine-2-carbaldehyde (0.5 g, 3.7 mmol) in tetrahydrofuran (20 mL) at 0° C., followed by sulfuric acid and water (1 mL:1 mL). After stirring at 0° C. for 30 min. sodium cyanoborohydride (0.47 g, 7.4 mmol) was added portionwise at 0° C. The mixture stirred at room temperature for 1 h then concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase was washed with sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by column chromatography on silica gel (60-120 mesh) using 18% ethyl acetate/hexane as eluent to afford (4,6-dimethyl-pyridin-2-ylmethyl)-(4-nitro-phenyl)-amine (0.35 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:23])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:5].[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([N:29]=[C:30]=[O:31])=[O:28]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([NH:29][C:30]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([Cl:23])[CH:6]=1)=[O:31])=[O:28]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Temperature: 60 °C

Procedure:
To a solution containing 1.55 grams (0.004 moles) of 3,5-dichloro-4-(2-phenylphenylmethoxy) aniline prepared in Part B and 5 milliliters of toluene, which solution was heated to a temperature of 60° C. and placed under an atmosphere of nitrogen, was added 0.98 grams (0.005 moles) of 2-chlorobenzoyl isocyanate. The resulting mixture was maintained at a temperature of 60° C. for a period of 0.5-1.0 hours. After cooling to ambient temperature, the reaction mixture was diluted with 1 milliliter of toluene. This mixture was then filtered to give a solid material. The solid material was washed once with toluene, once with a toluene-hexane mixture (1:1 volume ratio) and finally once with hexane and then dried overnight in a vacuum oven at 50° C. This afforded a white powder material having a melting point of 188.5° C.-192.0° C. Elemental analysis of the white powder indicated the following:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]([NH:13][NH2:14])=[O:12].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]([CH3:44])([C:28]2[N:32]([CH3:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:42])[F:41])=[N:30][N:29]=2)[CH3:27])=[C:20]([CH:24]=1)[C:21]([OH:23])=O.O>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]([CH3:27])([C:28]2[N:32]([CH3:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:43])[F:42])=[N:30][N:29]=2)[CH3:44])=[C:20]([CH:24]=1)[C:21]([NH:14][NH:13][CH:11]=[O:12])=[O:23]
Reactant: NNC=O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NNC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
WSC•monohydrochloride (130 mg), HOBt (110 mg) and formic hydrazide (60 mg) were sequentially added to a solution of 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (300 mg) in DMF (6 ml), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution, water and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain 5-chloro-N′-formyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (230 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([CH:23]=1)[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.FC(F)(F)C1C=CC=C[C:29]=1[O:30]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:29]([N:20]2[CH2:21][CH2:22][CH:17]([O:16][C:15]3[CH:23]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=3[CH3:24])[CH2:18][CH2:19]2)=[O:30])=[CH:7][CH:6]=[N:5]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Cn1nccc(N)c1=O
Reactant: Cc1ccc(F)cc1OC1CCNCC1
Agent: Cl
Product: Cc1ccc(F)cc1OC1CCN(C(=O)Nc2ccnn(C)c2=O)CC1
Yield: 46 %

Procedure:
Compound 68 is prepared from intermediate 4c and from 4-(5-fluoro-2-methyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 46%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[NH:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22])(=O)=O.Cl.[CH:27]([O:30][NH2:31])([CH3:29])[CH3:28]>C(O)(C)C>[CH2:19]([C:18]1[N:31]([O:30][CH:27]([CH3:29])[CH3:28])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=O)Nc1cnc2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)ON
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1nc2cnc3cccnc3c2n1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 3-(pentanoylamino)[1,5]naphthyridin-4-yl trifluoromethanesulfonate (2.7 g, 7.2 mmol), O-isopropylhydroxylamine hydrochloride (1.1 g, 9.9 mmol), and isopropanol (50 mL) was heated at reflux for six hours, allowed to cool to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was stirred with dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL) for 15 minutes. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product (2.3 g) was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent) to provide 0.40 g of 2-butyl-1-isopropoxy-1H-imidazo[4,5-c][1,5]naphthyridine as an oil.