Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1.C(OC(C)C)(C)C>O1CCCC1.CN(C)C=O.Cl.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:39][CH2:40]4)=[O:37])[N:34]=3)[N:31]=2)[CH:41]=[CH:42][C:43]=1[CH3:44])=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (560 mg, 2.97 mmol) in tetrahydrofuran (15 mL) were added oxalyl chloride (320 μL, 3.71 mmol) and N,N-dimethylformamide (2 drops), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in N-methylpyrrolidone (15 mL). N-[6-(3-Amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (800 mg, 2.47 mmol) was added to the mixture, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give a colorless oil. The oil was dissolved ethyl acetate, and diisopropyl ether was added to allow precipitation to give the title compound (220 mg, 18%) as a white solid.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [I-]
Solvent: CO
Product: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
4-(3-methoxy-4-nitrophenyl)-1-propylpyridinium iodide (10 g, 25 mmol) was dissolved in methanol (200 mL). As the mixture was cooled to −10° C. the starting material started to precipitated out of the solution. Sodium borohydride (4.61 g, 11.3 mmol) was added in ˜500 mg portions. Effervescence was observed during the addition as dissolution of the solids in the reaction was observed. The reaction was stirred for 2 h at −10° C. when analysis by TLC revealed completion of the reaction. Saturated aqueous ammonium chloride was added and the reaction warmed to room temperature. The mixture was extracted with Ethyl acetate, the organic layers were dried (Mg2SO4), filtered, and concentrated in vacuo to provide 4-(3-methoxy-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (6.7 g, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.4 Hz, 3 H), 1.50 (dt, J=7.3, 7.3 Hz, 2 H), 2.37 (t, J=7.2 Hz, 2 H), 2.53 (m, 2 H), 2.63 (m, 2 H), 3.11 (br s, 2H), 3.96 (s, 3 H), 6.43 (t, J=3.5 Hz, 1 H), 7.16 (dd, J=8.4, 1.5 Hz, 1 H), 7.29 (d, J=1.3 Hz, 1 H), 7.86 (d, J=8.6 Hz, 1 H). ESIMS (M+H)+=277.
Reaction SMILES: [CH:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([C:11]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([C:23](=O)[C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH2:32][CH3:33])[CH3:31])=[CH:26][CH:25]=3)=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=O)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:17]2[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([CH2:9][C:8]3[CH:35]=[CH:36][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:6][CH:7]=3)=[CH:19][C:18]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1)([CH2:32][CH3:33])[CH3:31]
Reactant: [H][H]
Reactant: CCC(C)c1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(C(C)CC)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(Cc2cc(C(=O)O)c(Cc3ccc(C(C)CC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 120 grams of 2,5-bis(4-sec-butylbenzoyl)terephthalic acid, 1.5 L of tetrahydrofuran, and 9.65 grams of 10% palladium on carbon (as a catalyst) was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a solid. The solid was triturated with 10% ethyl acetate in heptane, collected and dried to give 2,5-bis(4-sec-butylbenzyl)terephthalic acid.
Reaction SMILES: C([NH:4][C:5]1[N:10]([OH:11])[C:9](=[NH:12])[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[N:10]([OH:11])[C:9](=[NH:12])[N:8]=[C:7]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:6]=1
Reactant: CC(=O)Nc1cc(N2CCCCC2)nc(=N)n1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=c1nc(N2CCCCC2)cc(N)n1O

Procedure:
0 5 g (2 mmoles) of 6-acetamido-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine prepared as described in Example 6 is dissolved in a mixture containing 10 ml of ethanol and 4 ml of 1N sodium hydroxide solution, the mixture is refluxed for 30 minutes, then evaporated under reduced pressure. After taking up the residue in 10 ml of water, the crystals are filtered, washed with water and dried to give the aimed compound in a yield of 0.35 g (85%), which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7](=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]>C1COCC1>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:7](=[O:16])[CH3:1]
Reactant: CON(C)C(=O)Cc1ccccc1C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)Cc1ccccc1C
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of CeCl3 (114.4 g, 0.45 mol) in THF (4 L) was degassed for 1 h and heated to 45-50° C. for 5 h. When the solution was cooled to −10˜−5° C., MeMgCl (193.2 g, 2.6 mol) in THF was added and the mixture was stirred for 1 h at −10˜−5° C. After amide 34 (256 g, 1.3 mol) was charged into the reaction mixture at −10˜−5° C., the mixture was stirred for 5 h at 10-20° C. After the reaction was complete monitored by LCMS, the mixture was quenched by 1M HCl, and then partitioned with water and EtOAc. The organic phase was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give 35 (157 g, 80% yield). 1H NMR (CDCl3, 400 MHz): δ 7.1-6.91 (d, 4H), 3.55 (s, 3H), 2.25 (s, 3H), 2.05 (s, 3H); MS (ESI) m/e [M+H]+: 149.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:15]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2-chloro-aniline (49 mg, 0.39 mmol). The title compound was obtained as a solid (42 mg, 28% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.53 (1H, s), 8.99 (2H, s), 8.61 (1H, s), 7.55 (1H, m), 7.47 (1H, m), 7.38 (2H, m), 7.32 (1H, m). MS m/z: 458.07, 460.05 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].O1CCCC1>[O:19]1[CH2:18][CH2:17][CH:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CCOCC3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCN(C3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
To a mixture of 1-(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (1.5 g), ethanol (13 mL), and tetrahydrofuran (13 mL) was added 10% palladium-supported carbon (53% wet product) (150 mg), followed by stirring at room temperature for 2 hours under a hydrogen gas atmosphere (3 atm). The reactant was filtered through celite and then the solvent was evaporated under reduced pressure to obtain 4-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]aniline (1.45 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][OH:16])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.ClCCl.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(OCC)C>[CH2:1]([N:4]([CH2:14][CH2:15][O:16][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C=CCN(CCO)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCN(CCOC(=O)C(=C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-allyl-N-(2-hydroxyethyl)-4-nitrobenzenamine (2.22 g, 0.01 mol), triethylamine (1.2 ml) and dichloromethane (20 ml) is added methacryloyl chloride (1.14 g, 11 mmol) with stirring at room temperature. After 3 hours, an additional amount of triethylamine (0.6 ml) and methacryloyl chloride (0.5 g) is added and stirring continued for 3 hours. The mixture is diluted with ethyl ether (100 ml) and washed with water two times, washed with brine, and dried over sodium sulfate. The mixture is concentrated and chromatographed on silica with hexane-ethyl acetate to provide N-allyl-N-(2-methacryloyloxyethy1)-4-nitrobenzenamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:11][N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNCCC(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCN(C)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), N-methylisoamylamine (101 mg, 1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness to yield 220 mg. ES-MS calcd for C11H17N3O2 (m/e) 223.28, obsd 224.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CC1CCNCC1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(c2ncnc(C)c2C#Cc2ccc(N)nc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 2.0 g (8.17 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 1.90 g (9.81 mmol) piperidin-4-yl-acetic acid methyl ester using 3.50 mL (20.4 mmoL) DIPEA in 50 mL ACN. The reaction mixture is stirred for 1 h at 80° C. The solvent is removed under reduced pressure. The residue is taken up in DCM/MeOH and filtered over silica. After removal of the solvent and extractive work up 2.9 g (96%) of the desired product is obtained. The product is used without further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.CCN(C(C)C)C(C)C.[CH3:27][CH:28]([N:30]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[N:31]1)[CH3:29].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:35]([C:34]2[N:30]([CH:28]([CH3:29])[CH3:27])[N:31]=[CH:32][CH:33]=2)=[O:36])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Reactant: CC(C)n1nccc1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nccc1C(=O)Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
6-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (2.25 g, 7.59 mmol) was dissolved in DCM (40 ml) and DIPEA (2.85 ml, 16.34 mmol) was added. 1-(1-methylethyl)-1H-pyrazole-5-carbonyl chloride (1.41 g, 8.17 mmol) in DCM (10 ml) was added and the mixture left to stir at room temperature overnight. Water (50 ml) was added and the mixture vigorously stirred. The DCM layer was passed through a hydrophobic frit and evaporated to dryness. The material was combined with that obtained from a previous smaller scale reaction carried out in an identical manner but starting with 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (0.2 g, 0.675 mmol). The combined crude materials were purified by chromatography on silica using a 50 g cartridge and eluting progressively with DCM, then 1-4% methanol in DCM. Product containing fractions were combined and evaporated to dryness to afford the title compound (2.8 g).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: C1CCNC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and pyrrolidine are converted to the named compound
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[Cl-].Cl[C:13](=[N+:15]([CH3:17])[CH3:16])Cl>C(Cl)Cl>[CH3:13][N:15]([CH3:17])[C:16]1[O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)c1nc2cc(C#N)ccc2o1

Procedure:
A mixture of 3-Amino-4-hydroxybenzonitrile (2 g, 14.9 mmol) and dichloromethylenedimethylammonium chloride (phosgene iminium chloride, 2.42 g, 14.9 mmol) in 50 mL of dry CH2Cl2 was refluxed for 6 h. After cooling the solution was extracted with EtOAc, washed with NaHCO3, brine and dried (MgSO4). The residue was crystallized in MeOH yielding 2.51 g (90%) of the title compound as a white solid. M.p.: 198-200° C., 1H NMR (CD3OD) δ 7.61 (d, 1H, J=2.8 Hz, H-4), 7.36-7.32 (m, 2H, H-6, H-7), 3.28 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 164.4 (C-2), 152.2 (C-7a), 145.0 (C-3a), 125.4 (C-6), 120.0 (CN), 119.9 (C-4), 109.8 (C-7), 108.0 (C-5), 38.2 (CH3).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[N:39]O)[NH2:38]>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:38]=1
Reactant: NC(=NO)c1ccccc1Cl
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccccc4Cl)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 45.8 mg (0.269 mmol) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 72.4 mg (55% of theory).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1.[I:12]I>C(Cl)Cl>[I:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][CH:4]2[OH:11]
Reactant: OC1CCOc2ccccc21
Reactant: II
Solvent: ClCCl
Product: OC1CCOc2ccc(I)cc21
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of chroman-4-ol (19.6 g, 131 mmol) in CH2Cl2 (500 mL), at rt., was added HgO (29.7 g, 137 mmol) and I2 (34.8 g, 137 mmol) under N2. After stirring for 48 h. the mixture was filtered through a plug of silica gel and the plug washed plug with 30% EtOAc/Hexanes. The filtrate was washed with 15% Na2S2O3 and the organic layer was dried over Na2CO3; filtered and concentrated in vacuo, yielding 6-iodochroman-4-ol as an off-white solid (32.44 g, 90% crude yield). Recrystallization was performed by dissolving product in hot dichloromethane (250 mL) and slowly adding petroleum ether (250 mL). Overall yield 25.9 g, 72% yield. Anal. Calcd for C9H9IO2; C, 39.16, H, 3.29; found C, 39.26, H, 3.27.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:20]([NH:19][CH2:18][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:28])(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccccc1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (50 mg, 0.21 mmol) in CH2Cl3 (1 mL) was treated with hippuric acid (38 mg, 0.21 mmol), EDCI (48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (38 μL, 0.27 mmol). The reaction mixture was stirred for 16 h at 25° C., diluted with 1 mL of CH2Cl2, washed with 2 N aqueous NaOH solution (2×0.75 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 6 to 8% CH3OH/CH3Cl2 gradient elution) afforded 4-{(N-benzoylglycyl)amino}methyl-1-(4-chlorobenzyl)piperidine (compound No. 458) which was treated with TFA to give a TFA salt (105 mg, 97%): The purity was determined by RPLC/MS (85%); ESI/MS m/e 400 (M++H, C22H26ClN3O2).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:16](COCC[Si](C)(C)C)[C:15]2[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[S:12][C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[C:9]=2[N:8]=1.C(=O)([O-])O.[Na+]>CO.Cl.O>[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[NH:16][C:15]2[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[S:12][C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[C:9]=2[N:8]=1
Reactant: CN(C)CCOCc1nc2c(n1COCC[Si](C)(C)C)-c1ccccc1Sc1ccccc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CCOCc1nc2c([nH]1)-c1ccccc1Sc1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-amine (0.32 mmole) in methanol (7.0 ml), 0.5 M hydrochloric acid in methanol (3.2 ml) was slowly added. The reaction mixture was heated under reflux for 3 hours, then it was cooled to room temperature, neutralized with a saturated aqueous solution of sodium hydrogencarbonate, diluted with water and extracted with dichloromethane. The organic extract was washed with an aqueous sodium chloride solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure. After purification by chromatography on a silica gel column, dimethyl-[2-(1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine in the form of an oily product was isolated;
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1>CN1CCCC1=O>[CH3:13][C:14]1[N:18]=[CH:17][N:16]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[N:15]=1
Reactant: Cc1nc[nH]n1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Solvent: CN1CCCC1=O
Product: Cc1ncn(-c2nccc3[nH]c(=O)ccc23)n1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A stirred mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 20 g of 3-methyl-1H-1,2,4-triazole and 75 ml of N-methylpyrrolidinone was heated in an oil bath at 170°-180° C. for 18 hours and then cooled to room temperature whereupon a tan solid crystallized out. The mixture was diluted by adding 125 ml of water and the separated solid was collected, washed with water, air-dried and combined with another 1.2 g sample of the same material obtained in another run starting with 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were recrystallized from dimethylformamide and dried in an oven at 95°-100° C. for three days to yield 6.1 g of 5-(3-methyl-1H-1,2,4-triazole-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:26])[C:12]([C:18]1[CH:19]=[CH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1)([OH:17])[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:26])[C:12]([C:18]1[CH:19]=[CH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1)([OH:17])[C:13]([F:16])([F:14])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1Cl
Agent: BrB(Br)Br
Product: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 183, 5-[2-(2,3-dichloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 208) was reacted with BBr3 to give the title compound as a light yellow foam. MS (m/e, ISP neg. ion)=393.8 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C2CCCCO2)=[O:20])[C:12](=[O:34])[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:30])=[O:31])[C:19]([NH:21][OH:22])=[O:20])[C:12](=[O:34])[CH:11]=1
Reactant: COc1ccc(-c2ccn(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)c(=O)c2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)c(F)c1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
(2R)-4-[4-(2-Fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (34.7 mg, 69.9 mmol) and pyridinium p-toluenesulfonic acid (8.8 mg, 34.9 mmol) were dissolved in ethanol (277.6 uL) and immersed in a 75° C. oil bath. The reaction was stirred at this temperature for 1 hour and allowed to cool. Water (600 uL) was added to the solution and the reaction was stirred overnight. A solid was collected via filtration and dried under vacuum to afford the title compound as an off-white powder (22 mg, 76.33%). LCMS m/z 413.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.11-2.22 (m, 1H) 2.37-2.47 (m, 1H) 3.10 (s, 3H) 3.68-3.79 (m, 1H) 3.82 (s, 3H) 4.05-4.16 (m, 1H) 6.44-6.50 (m, 1H) 6.54 (s, 1H) 6.89 (dd, J=8.68, 2.44 Hz, 1H) 6.97 (dd, J=13.37, 2.44 Hz, 1H) 7.54 (dd, J=8.98, 8.98 Hz, 1H) 7.71 (d, J=7.02 Hz, 1H) 11.14 (br. s., 1H).