Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[N:18]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH:26]C(=O)OC(C)(C)C)[CH:16]=[N:15][C:14]=3[C:34]#[N:35])[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1>C(O)(C(F)(F)F)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:34]#[N:35])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH2:26])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-n3nccn3)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.574 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (123 mg, 0.574 mmol) and DIEA (0.150 mL, 0.862 mmol) in NMP (3 mL) was stirred at room temperature for 20 h. HOAc (0.3 mL) was added. Then, water was added to induce precipitation. The precipitate was collected, dried on vacuum to give tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (165 mg). A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (80 mg, 0.227 mmol), 3-(2H-1,2,3-triazol-2-yl)aniline (50 mg, 0.312 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated. The aqueous phase was extracted with EtOAc again. The combined organic phases were dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg). The crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg) was dissolved in TFA (4 mL). After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg).
Reaction SMILES: C(OC(C)C)(=O)CCC[CH2:5][C:6](C)([CH3:8])[CH3:7].[C:15](#[N:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:17][C:16]([CH3:19])([CH2:18][C:6]([CH3:8])([CH3:7])[CH3:5])[C:15]#[N:20]
Reactant: CC(C)OC(=O)CCCCC(C)(C)C
Reactant: CC(C)(C)C#N
Product: CC(C)(C)CC(C)(C)C#N

Procedure:
isopropyl neononanoate; pivalonitrile; methyl 2,2,4,4-tetramethyl pentanoate (methyl neononanoate); and methyl 3,5,5 trimethyl hexanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([O:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cn1
Reactant: OCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cn1
Yield: 25.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 1.5 g (5.1 m mol) of 2-(5-chloropyridine-2-yl)-4,5-dichloropyridazinone and 0.73 g (5.1 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.34 g of powdery potassium hydroxide. Then, the procedures in Synthesis Example 2 were repeated to give 500 mg of the intended compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([Br:10])=[C:7]([Br:9])[N:8]=1.I[CH2:12][CH3:13]>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:12][CH3:13])[C:6]([Br:10])=[C:7]([Br:9])[N:8]=1
Reactant: CCI
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(Br)nc(Br)c1Br
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in anhydrous DMF (50 ml) is added a solution of 2,4,5-tribromoimidazole (15.09 g, 50 mmol) in DMF (30 ml) at rt. The resulting mixture is stirred at 50° C. for 1 hr, and then cooled to 0° C., followed by the dropwise addition of iodoethane (8.19 g, 52.5 mmol, 1.05 eq.). The mixture is stirred at rt for 1 hr, and then heated to 50° C. for an additional 8 hr. The reaction mixture is cooled to rt, and poured into ice-water (200 ml). The mixture is extracted with EtOAc (100 ml×3). The combined organic layers are washed with water, brine, dried over anhydrous sodium sulfate, filtered, and solvent evaporated at reduced pressure. The crude product is purified by flash chromatography on silica gel to give the title product. LCMS 330 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.[I:18]I.[OH-].[K+].S(=O)(O)[O-].[Na+]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[I:18]
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ccc2c1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2,6-difluorophenyl)-1H-indole (1.06 g, 4.62 mmol) in DMF (10 mL) was added I2 (0.262 mL, 5.09 mmol) followed by KOH (0.317 mL, 11.56 mmol). The reaction was stirred at RT for 1 h, and then poured into ice/water mixture with sodium bisulfite. The mixture was extracted with DCM and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 355.0 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][N:16]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])=[CH:26][CH:25]=2)[C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][F:23])=[O:12])=[O:6].CC(C)([O-])C.[K+].Cl>C1COCC1>[F:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])=[CH:26][CH:25]=2)[N:15]=[N:14][C:13]=1[C:11]([NH:10][CH2:9][CH2:8][N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])=[O:12]
Reactant: O=C(NCCCl)NCCNC(=O)c1nnn(-c2ccc(C(=O)NCC(F)(F)F)cc2)c1CCCCCF
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)c1ccc(-n2nnc(C(=O)NCCN3CCNC3=O)c2CCCCCF)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of N-[2-({[(2-chloroethyl)amino]carbonyl}amino)ethyl]-5-(5-fluoropentyl)-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (0.06 g) obtained in Example 301 in THF (5.5 ml) was added potassium tert-butoxide (0.03 g), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile-water) and recrystallized from acetonitrile-water to give the title compound as a white powder (0.01 g, 14%).
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[OH:9])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:10]1[C:15](=[O:16])[N:14]([O:17][C:18](ON2C(=O)CCC2=O)=[O:19])[C:12](=[O:13])[CH2:11]1.C(N(CC)CC)C>C(#N)C>[CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:18]([O:17][N:14]1[C:15](=[O:16])[CH2:10][CH2:11][C:12]1=[O:13])=[O:19])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C=CCCC[C@@H]1C[C@H]1O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCCC[C@@H]1C[C@H]1OC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
To a solution of (1R,2R)-2-(pent-4-en-1-yl)cyclopropanol (see International Patent Application Publication No. WO 08/057209) (17.1 g) in acetonitrile (193 mL) was added N,N′-disuccinimidyl carbonate (49.3 g) then triethylamine (53.7 mL) The mixture was heated to 40° C. for 18 hours. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The solvent was removed in vacuo. The residue was purified by flash chromatography (ISCO, 10 to 70% ethyl acetate in hexanes) to give the desired product (18 g). 1H NMR (500 MHz, CDCl3): δ (ppm) 4.06-4.03 (m, 1H), 2.87 (s, 4H), 2.28-2.25 (m, 2H), 1.98-1.97 (m, 1H), 1.72-1.63 (m, 2H), 1.44-1.39 (m, 2H), 1.30-1.25 (m, 1H), 1.12-1.08 (m, 1H), 0.72-0.68 (m, 1H).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:7]1[C:8](=[C:15]([C:18]#[N:19])[C:16]#[N:17])[O:9][C:10]([CH3:14])([CH3:13])[C:11]=1[CH3:12])#[N:6].[C:20]([SiH2:24][O:25][C:26]([CH3:52])([CH3:51])[CH:27]1[CH2:32][O:31][C:30]2=[C:33]([CH:38]=[CH:39][C:40]3[CH:45]=[CH:44][C:43]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[CH:42][CH:41]=3)[S:34][C:35]([CH:36]=O)=[C:29]2[O:28]1)([CH3:23])([CH3:22])[CH3:21]>C(N(CC)CC)C>[C:20]([SiH2:24][O:25][C:26]([CH3:51])([CH3:52])[CH:27]1[CH2:32][O:31][C:30]2=[C:33]([CH:38]=[CH:39][C:40]3[CH:41]=[CH:42][C:43]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[CH:44][CH:45]=3)[S:34][C:35]([CH:36]=[CH:12][C:11]3[C:10]([CH3:13])([CH3:14])[O:9][C:8](=[C:15]([C:16]#[N:17])[C:18]#[N:19])[C:7]=3[C:5]#[N:6])=[C:29]2[O:28]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCN(CC)c1ccc(C=Cc2sc(C=O)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc(C=Cc2sc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
20 mL of anhydrous chloroform was added to 0.318 g (0.0016 mole) of 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile, and 0.640 g (0.00131 mole) of 5. Once in solution, 10 mg of triethylamine were added and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The compound was purified on a silica column with a hexane/ethyl acetate mobile phase.
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH3:15])[CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1.CO>[CH3:15][C:7]1[CH:6]=[C:5]([OH:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CC(=O)Oc1cc(C)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)c2c(c1)CCCC2
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixed solution of 3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate synthesized in Reference Example 173 (5.1 g, 25.1 mmol) in THF (120 mL) and methanol (30 mL) was added 12 N aqueous sodium hydroxide solution (2.5 mL) at room temperature, and the mixture was stirred for 30 minutes, and then concentrated under reduced pressure. Water and hydrochloric acid were added to the residue, and the mixture was acidified, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized with ethyl acetate-hexane to obtain 4.1 g (yield 99%) of the title compound. Melting point: 95-96° C. (hexane-ethyl acetate).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])(=[O:14])=[O:13])=[C:9]([CH3:26])[C:8]=2[CH:27]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])(=[O:14])=[O:13])=[C:9]([CH3:26])[C:8]=2[CH:27]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
1.7 M aq. KOH (5 mL) was added to a slurry of methyl 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (400 mg, 1.01 mmol) in MeOH (5 mL). The reaction mixture was stirred at 50° C. for 1.5 h. After removal of the MeOH under reduced pressure, the remaining aqueous solution was acidified to pH 3 by addition of ortho-phosphoric acid. The precipitate was collected, washed with water and dried giving the title compound as an off-white solid (363 mg, 91%). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.49 (s, 3 H) 7.32-7.39 (m, 2 H) 7.46 (dd, J=8.67, 2.08 Hz, 1 H) 7.75 (dt, J=7.32, 1.59 Hz, 1 H) 7.82-7.86 (m, 3 H). MS (ESI+) m/z 399 [M+NH4]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)Oc2ccccc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (0.050 g, 0.130 mmol), phenyl chloroformate (0.020 mL, 0.59 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.574 mmol) in CH2Cl2 (10 mL) was stirred at room temperature, then concentrated to dryness. The crude product was purified using preparative reverse-phase HPLC to provide 7-chloro-4-oxo-3-(phenoxycarbonylamino-methyl)-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester. MS calcd. for C25H20ClN2O5 [(M+H)+] 463.1, obsd. 462.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31]>C1COCC1>[OH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCC(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCCC(O)(c1ccccc1)c1ccccc1

Procedure:
Batch size: 3.2 g (21.6 mmol) 3-(3-pyridyl)-acrylic acid, 3.85 g (23.8 mmol) CDI and 4.2 g (25.9 mmol) 6-hydroxy-6,6-diphenyl-hexylamine in 60 ml abs. THF.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(O)C.[N+]([NH:31][C:32](N)=[O:33])([O-])=O>O>[NH2:31][C:32]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:33]
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
A mixture of 4.89 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, 50 ml of 95% ethanol and 2.1 g of nitrourea was refluxed at 70° C. until the evolution of gas had ceased. After refluxing for an additional 30 minutes, the mixture was cooled, treated with 200 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 3.5 g (64.81%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 155°-160° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[OH:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:28]5[CH2:29][CH:26]([OH:25])[CH2:27]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: OC1CNC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC(O)C3)cc1OCC2
Yield: 14 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 3-hydroxyazetidine hydrochloride with added DIPEA (2.2 eq.), were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from IMS to give 370 as pale green crystals (16 mg, 14%). LCMS: RT=2.26 min, [M+H]+ 368. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.90 (1H, d, J=0.63 Hz), 7.84 (1H, s), 5.95-5.94 (1H, m), 5.91 (1H, s), 5.70 (1H, d, J=6.40 Hz), 4.59 (1H, s), 4.55-4.47 (4H, m), 4.18 (2H, t, J=7.66 Hz), 3.70 (2H, dd, J=8.85, 4.66 Hz), 1.48 (6H, d, J=6.60 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][S:43]([C:46]1[CH:58]=[CH:57][C:49](CN2C=CC(N)=N2)=[CH:48][CH:47]=1)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]3[CH:57]=[CH:58][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CS(=O)(=O)c1ccc(Cn2ccc(N)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (166 μL, 0.33 mmol) at 0+ C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (46 μL, 0.39 mmol) was added to the solution at 0° C. After 1 h, 1-(4-methanesulfonyl-benzyl)-1H-pyrazol-3-ylamine (0.30 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methanesulfonyl-benzyl)-1H-pyrazol-3-yl]-propionamide (150 mg, 88%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O5S2 [M+] 563.13, found 564.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.21 (m, 2H, CH2), 1.34-1.88 (m, 8H, 4×CH2), 2.09-2.29 (m, 1H, CH), 2.98 (s, 3 H, SO2CH3), 3.22 (s, 3H, SO2CH3), 3.56 (t, J=7.5 Hz, 1H, CH), 5.24 (AB, Jgem=15.9 Hz, 2H, NCH2), 6.76 (d, J=2.3 Hz, 1H, Ar), 7.14 (d, Jo=8.3 Hz, 2H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.44 (d, J=2.3 Hz, 1H, Ar), 7.53 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (d, Jo=8.3 Hz, 2H, Ar), 7.91 (d, Jo=8.2 Hz, 1H, Ar), 8.34 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1>>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: CC(=O)Nc1ccc(N)cn1
Product: CC(=O)Nc1ccc(NC2CCN([C@H](C)CCN)CC2)cn1

Procedure:
Using general procedure A with N-(5-amino-pyridin-2-yl)-acetamide (Bae, Jong Woo; et al., Tetrahedron Lett., 41, 2, 2000, 175-178) (1.00 g, 6.62 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.16 g, 6.95 mmol) and then using general procedure J afforded N-{5-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-pyridin-2-yl}-acetamide as a white solid (1.05 g, 52% over 2 steps).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-])=O.[OH-].[Na+]>Cl.O>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c(N)cccc1N
Yield: 60.2 %

Procedure:
2,6-Dinitrobenzonitrile (10.0 grams) is added in portions to a stirred solution of stannous chloride (82.5 grams) in concentrated HCl (230 ml.) at room temperature. Stirring is continued at room temperature for two and one-half hours, then the reaction mixture is cooled to 0° and made strongly basic with 50% NaOH. The reaction mixture is diluted with water (1 l.) and extracted four times with methylenechloride (200 ml.). The combined extracts are washed once with water (200 ml.), dried over sodium sulfate, then taken to dryness under reduced pressure. Recrystallization of the crude solid (4.6 grams) from benzene-Skellysolve "B" gives the product (4.15 grams) melting at 91°-92°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[N:30][CH:31]=1.O>CN(C)C=O>[N+:32]([C:29]1[N:30]=[CH:31][C:26]([O:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To a solution of benzyl (4-hydroxyphenyl)carbamate (1.44 g, 5.91 mmol) in N,N-dimethylformamide (10 mL) were added cesium carbonate (2.41 g, 7.39 mmol) and 5-bromo-2-nitropyridine (1.0 g, 4.93 mmol), and the mixture was stirred at room temperature for 16 hr. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran (=2/1, 120 mL). The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (NH silica gel, hexane/ethyl acetate=3/1→1/3) to give the title compound (1.01 g, 56%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)cnc1OC
Reactant: COCC(=O)Cl
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)COC)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester and methoxyacetyl chloride were reacted as described in Example 5, Step 4 to provide [5-(2-{[N-ethyl-N-(2-methoxy-acetyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.