Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16]C(C#N)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH2:18]([OH:21])[CH2:19]O.[OH-:22].[K+].Cl>O>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:19]([C:18]([OH:21])=[O:22])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: OCCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1

Procedure:
Into a 2 l three-neck flask were added compound (F) (25 g, 0.109 mol) obtained in the fifth step and ethylene glycol (722 ml) and further an aqueous solution obtained by dissolving KOH (18.8 g, 0.335 mol) in water (26 ml), followed by refluxing the mixture for 12 hours while heating on a mantle heater. After cooling, the reaction mixture was acidified by adding 6N-HCl (200 ml) to form crystals, which were filtered off and dried, followed by dissolving the crystals in ethanol (200 ml) and recrystallizing to obtain 4-(trans-4'-methyloxymethylcyclohexyl)benzoic acid (G) (18.8 g). This had a melting point (C-N point) of 132.7° C. and a clearing point (N-I point) of 234.6° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:16](=[O:19])[NH:17][N:18]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[CH:9]=2.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[F:15][C:10]1[CH:9]=[C:8]2[C:13]([N:14]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:6]3[N:7]2[C:16](=[O:19])[NH:17][N:18]=3)=[CH:12][CH:11]=1
Reactant: Clc1ncccn1
Reactant: NCCNc1nc2ccc(F)cc2n2c(=O)[nH]nc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]nc2c(NCCNc3ncccn3)nc3ccc(F)cc3n12
Reaction time: 18 h

Procedure:
A mixture of 50 mg of 4-(2-amino-ethylamino)-8-fluoro-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one 13.5 mg of 2-chloropyrimidine, and 76 mg of diisopropylethylamine in DMSO (0.5 mL) was heated for 18 hrs. An additional 13.5 mg of 2-chloropyrimidine was added and heating was continued for another 18 hrs. The reaction was diluted with EtOAc, washed with water, and dried over sodium sulfate prior to concentration. The residue was separated by silica gel chromatography, and the isolated residue was recrystallized from MeOH to give the title compound. MS (M−H)−=339.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:32]=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][C:25](=[O:29])[C:24]2=[O:30])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:36]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:37]([O:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:32]=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH:36]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:37]([O:39][CH:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:38])[C:25](=[O:29])[C:24]2=[O:30])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCCN2CCNC(=O)C2=O)cc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCCN2CCN(C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 0.2 g of 1-[4-(4-benzyloxycarbonylamidinophenoxy)butyl]-2,3-dioxopiperazine, followed by adding thereto 20 mg of sodium hydride (60%, oil), and the resulting mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and 0.17 g of diphenyl-methyl α-bromophenylacetate was added thereto. After stirring at the same temperature for 2 hours, the reaction mixture was added to a mixed solvent of 20 ml of ethyl acetate and 20 ml of water. The organic layer as separated, washed with water and then a saturated aqueous sodium chloride solution, and then 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; chloroform: methanol=20:1) to obtain 0.29 g of diphenylmethyl α-[4-[4-(4-benzyloxycarbonylamidino-phenoxy) butyl]-2,3-dioxopiperazin-1-yl]-α-phenylacetate as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1.CCN(CC)CC.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>C(Cl)Cl>[CH:40]([NH:37][C:38]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1)=[O:39])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25° C. solution of N-[4-(piperidin-4-yl sulfamoyl)-naphthalen-1-yl]-benzamide (C-1) in CH2Cl2 was added Et3N followed by 2-isocyanato-propane. The reaction mixture was stirred at 25° C. overnight. Aqueous work-up followed by purification using reverse phase HPLC provided the title compound. 1H NMR (300 MHz, MeOD) δ 8.74 (d, 1H), 8.29 (d, 1H), 8.17 (d, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.81 (d, 1H), 7.63 (m, 5H), 3.75 (m, 3H), 3.21 (m, 1H), 2.68 (t, 2H), 1.51 (m, 2H), 1.26 (m, 2H), 1.05 (d, 6H); LC/MS (M+H)+ m/z 495.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:14](CO)[N:15]=1)[CH3:10].C(O)C>O1CCOCC1>[CH2:9]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:14]([Cl:1])[N:15]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1nc(CO)c(CO)[nH]1
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 0.18 h

Procedure:
1.76 Grams (13.2 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 2.06 g (13.2 mmol) of an ethyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane maintained at room temperature with stirring over a period of about 11 minutes. The mixture was then stirred at the same temperature for three hours and for another 30 minutes at a temperature of 50° C. After the reaction, the solvent was distilled off under reduced pressure and the resulting yellowish oily product was subjected to the column chromatography (silica gel-acetone), and the obtained effluent was evaporated to dryness under reduced pressure. By using acetonitrile, the resulting solid product was recrystallized three times to obtain a colorless crystalline 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.82 g (yield, 39.0%). The TLC and spectra of this compound were the same as the properties exhibited by the above-mentioned 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[O:5])[CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](=O)[CH2:10]Cl>O>[Cl:7][CH2:8][C:9]1[N:6]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[O:5][CH:10]=1
Reactant: NC(=O)C1CC1
Reactant: O=C(CCl)CCl
Solvent: O
Product: ClCc1coc(C2CC2)n1
Temperature: 110 °C
Yield: 43.2 %

Procedure:
A mixture of cyclopropanecarboxylic acid amide (5.0 g, 58.74 mmol) and 1,3-dichloro-propan-2-one (14.92 g, 117.49 mmol) was heated at 110° C. for 4 h. The mixture was cooled to room temperature and water (75 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to get crude residue. After purification via column chromatography (100-200 silica gel, elution with 2% EtOAc in hexane), 4 g of 4-chloromethyl-2-cyclopropyl-oxazole was obtained as a dark brown liquid, 158.0 (M+H)+. But it contained impurities. This compound was used for the next step as such.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[C:26]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:30][CH:29]=1)#[N:27].C(N(C(C)C)CC)(C)C>C(#N)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:34][C:35](=[O:36])[NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)=[O:33])=[CH:37][CH:38]=1)#[N:27]
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
In a similar manner to Example 1, starting material step (a), the p-toluenesulphonate salt of ethyl 4-aminophenoxyacetate (12.9 g, preparation described by Coutts, I. G. C. et al (1985), J. Chem. Soc. Perkin I, 1829), 4-cyanobenzoyl isocyanate (5.9 g), acetonitrile (400 ml total) and diisopropylethylamine (6.5 ml) were reacted to give, after stirring at ambient temperature for 1.5 hours, a solid, which was crystallised from acetonitrile/ethanol to give ethyl 4-[3-(4-cyanobenzoyl)ureido]phenoxyacetate (10.16 g) as an off-white solid: m.p. 200°-203° C.; NMR Spectrum (DMSO-d6) 1.22 (3H, t), 4.17 (2H, q), 4.75 (2H, s), 6.93 (2H, d), 7.49 (2H, d), 8.02 (2H, d), 8.13 (2H, d), 10.49 (1H, br s), 11.17 (1H, br s); Mass Spectrum m/Z 368 (M+H)+.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]3([CH:49]([F:51])[F:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][C:43]3([CH:49]([F:50])[F:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)F)CCCCC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(C(F)F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)-methoxy)-2-fluorobenzoic acid, and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a yellow oil (0.085 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ11.64 (s, 1H), 7.17-7.10 (m, 2H), 6.04 (t, J=56.4 Hz, 1H), 4.14 (s, 2H), 4.05 (t, J=7.7 Hz, 4H), 2.22-2.08 (m, 2H), 2.06-1.98 (m, 1H), 1.74-1.65 (m, 2H), 1.59-1.44 (m, 7H), 1.32-1.21 (m, 1H), 0.92-0.85 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z 461.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.O>[CH3:9][C:10]([OH:11])([CH3:13])[CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-nitro-1H-pyrazole (10.0 g, 88.43 mmol), 2,2-dimethyl-oxirane (15.7 mL, 176.9 mmol), potassium carbonate (18.2 g, 132 mmol) and DMF (100 mL) was stirred at 100° C. for 1 h, then stirred ON at rt. The mixture was then diluted with ethyl acetate and water, the organic layer was separated, dried over Na2SO4, and filtered. The resulting mixture was concentrated under reduced pressure to yield the crude product that was purified (50% EtOAc/heptane) to yield the product 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol as a waxy solid (4.88 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:9][CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.NC[C@@H:23]([NH:32][C:33](=[O:39])OCCCC)[CH2:24][C@H:25]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27][CH2:26]1.[NH2:40][CH2:41][C@@H](N(C)C(=O)OC(C)(C)C)C[C@H]1CCCOC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:9][CH2:10][N:11]([CH3:12])[C:33](=[O:39])[NH:32][CH2:23][C@H:24]([CH2:25][C@H:31]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26]2)[NH:40][CH3:41])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Reactant: CCCCOC(=O)N[C@H](CN)C[C@H]1CCCCOC1
Product: CN[C@H](CNC(=O)N(C)CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1)C[C@H]1CCCOC1

Procedure:
The following compounds were prepared following procedures analogous to those described in Example 21 using (R)-methyl 2-(1-(3-chlorophenyl)-3-(methylamino)propoxy)ethylcarbamate and ten-butyl (S)-1-amino-3-((R)-oxepan-3-yl)propan-2-ylcarbamate and tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate in Step 1. LC-MS (3 min) tR=1.2 m/z=500. 1H NMR (CD3OD) d 7.35-7.23 (m, 4H), 4.28 (dd, J=8.4, 4.4 Hz, 1H), 3.86-3.81 (m, 2H), 3.62 (s, 3H), 3.54 (br d, J=14.4 Hz, 1H), 3.50-3.23 (m, 10H), 3.14 (dd, J=11.2, 9.6 Hz, 1H), 2.90 (s, 3H), 2.74 (s, 3H), 1.95-1.43 (m, 8H), 1.26 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH3:13])=[C:4]([CH:3]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1c(COc2ccc([N+](=O)[O-])cc2)cc(Br)cc1C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1c(COc2ccc(N)cc2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.5 %

Procedure:
step 3 To a solution of 116 (0.19 g, 0.49 mmol) in MeOH-water (1:1, 20 mL) was added NH4Cl (0.26 g, 4.9 mmol) and iron powder (0.14 g, 2.5 mmol). The resulting mixture was heated at reflux and stirred for 1 h. After cooling to RT, the mixture was filtered through a pad of diatomaceous earth which was washed with MeOH. The filtrate was concentrated under reduced pressure and the resulting aqueous fraction was extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.24 g (64%) of 4-(5-bromo-3-tert-butyl-2-methoxybenzyloxy)phenylamine (118) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[OH:8][NH2:9].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5](=[NH:6])[NH:9][OH:8]
Reactant: NO
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CC(=N)NO
Reaction time: 2 h

Procedure:
2-Cyano-acetic acid methyl ester (990 mg, 10 mmol) was dissolved in THF (30 mL). Hydroxy amine (690 mg, HCl salt, 10 mmol) was added thereto, and the mixture was stirred for 2 h at 80°. After completion of the reaction, 1N HCl was added. The reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was used in the next reaction without further purification.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 60 mg (0.56 mmol, 1.5 eq.) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 104 mg (59% of theory)
Reaction SMILES: Cl.[CH3:2][C@@:3]1([OH:8])[CH2:7][O:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:5]4[CH2:4][C@:3]([CH3:2])([OH:8])[CH2:7][O:6]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Reactant: C[C@]1(O)CNOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@](C)(O)CO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
Following the same procedure in Example 3, Step A, using (4S)-4-methylisoxazolidin-4-ol hydrochoride (36.8 mg, 0.264 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (83.2 mg, 0.253 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (114.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature,and quenched by adding H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 74.9mg (56%) of a white solid. [a]D: −14.1° (c 0.17,EtOH). 1H NMR (400 MHz, CD3OD): δ 0.85 (t, J=7.52 Hz, 3H), 1.27 (m, 5H), 1.50 (s, 3H), 1.66 (m, 3H), 1.69 (s, 6H), 1.79 (m, 2H), 2.04 (q, J=7.42 Hz, 2H), 2.13 (m, 1H), 3.82 (d, J=11.33 Hz, 1H), 3.89 (d, J=8.40 Hz, 1H), 3.97 (m, 2H), 4.50 (d, J=7.62 Hz, 2H), 7.99.(m, 2H), 8.18 (s, 1H). MS (ESI) (M+H)+=414.2. Anal. Calcd for C24H35N3O3+1.30 TFA+2.00 H2O (597.83): C, 53.44; H, 6.79; N, 7.03. Found: C, 53.39; H, 6.64; N, 7.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3-chlorophenol: 1H-NMR (CDCl3) δ 7.92 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.8, 2.8 Hz), 7.25–6.80 (5H, m), 3.81 (3H, s).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2-c2ccccc2)cc1

Procedure:
113 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(2,4-dimethylphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]OS([O-])=O.[K+].OS([O-])(=O)=O.[K+].[OH2:37]>CN(C)C(=O)C>[CH2:1]([S:8]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][N:10]=1)(=[O:25])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: c1ccc(CSc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Cc1ccccc1)c1nnc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-Benzylthio-4-phenylphthalazine (98 mg; 0.3 mmol from Example 1B) in N,N-dimethylacetamide (13 ml) is cooled in an ice bath. Oxone® (2KHSO5.KHSO4.K2SO4) (670 mg; 1.1 mmol) is added, followed by the stepwise addition of water (1.4 ml). The mixture is stirred at room temperature for 2 days, is poured into ice water, is stirred 10 minutes and is filtered to give the title compound as a solid (53 mg) (R1=phenyl, R2=phenyl, A=benzene, Y1=CH2, m=0, n=1, p=0, q=2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5](I)=[CH:6][CH:7]=1.[C:14]([Cu])#[N:15].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(I)ccc1Cl
Reactant: N#C[Cu]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(C#N)ccc1Cl
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-chloro-6-iodopicolinate (1.6 g, 5.38 mmol) in pyridine (40 mL) was added CuCN (480 mg, 5.36 mmol). The reaction mass was heated at 80° C. for 6 h. Then water was added to the reaction mass and it was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=8.1 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]1[CH:8]=[C:7]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14]CC)=[O:13])[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:5]=1.O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]1[CH:8]=[C:7]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([OH:14])=[O:13])[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:5]=1
Reactant: CCOC(=O)c1cccnc1Nc1cc(CC(C)(C)C)nn1-c1ccccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nc(CC(C)(C)C)cc1Nc1ncccc1C(=O)O
Temperature: 40 °C
Yield: 96.8 %

Procedure:
To a solution of ethyl 2-{[3-(2,2-dimethylpropyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}nicotinate (266 mg, 0.68 mmol) (step 1) in a mixture of ethanol (1 mL) and THF (1 mL) was added lithium hydroxide monohydrate (284 mg, 6.8 mmol) in water (2 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid solution, and was concentrated to dryness. The crude product was redissolved in methanol and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 240 mg (97%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.39 (s, 1H), 8.43 (dd, 1H), 8.14 (dd, 1H), 7.25-7.42 (m, 4H), 6.81-6.86 (m, 2H), 2.57 (s, 2H), 2.05 (s, 3H), 1.00 (s, 9H); ES-MS m/z 365.3 (MH+); HPLC RT (min) 3.67.