Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][NH:12][C:11]3=O)=[N:5][N:4]=1.P(Cl)(Cl)([Cl:23])=O>C(N(CC)CC)C>[Cl:23][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]3[O:7][C:3]([C:2]([F:20])([F:19])[F:1])=[N:4][N:5]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=c1[nH]cnc2ccc(-c3nnc(C(F)(F)F)o3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1

Procedure:
6-(5-Trifluoromethyl-1,3,4-oxadiazol-2-yl)quinazol in-4-one (0.79 g) was treated with phosphorus oxychloride (18 ml) and triethylamine (8 ml) at reflux under N2 for 2 hours. The mixture was concentrated in vacuo and the residue azeotroped with toluene. This was then taken up in ethyl acetate and washed with 5% sodium bicarbonate and saturated brine, dried over magnesium sulphate and concentrated in vacuo to give the title compound (0.76 g) as an orange solid; δH CDCl3 9.17(1H, s), 9.05 (1H, d), 8.69(1H, dd), 8.30(1H, d).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:17][C:8]3[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=3[Cl:6])=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 2-chloro-4-trifluoromethyl phenol (0.29 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.61 g of desired compound (melting point: 113.0°-114.0° C.).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH3:3].C([CH:13]([C:17](Cl)=[O:18])[C:14](Cl)=[O:15])C.C(=O)([O-])[O-].[K+].[K+].[CH3:26][CH2:27][O:28]CC>O>[CH2:27]([O:28][C:17]([CH2:13][C:14]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:15])=[O:18])[CH3:26]
Reactant: CCOCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCCNCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCN(CC(=O)OCC)C(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7.16 g (49.4 mM) of ethyl N-(n-propyl)glycinate and 6.4 ml (50 mM) of ethyl malonyl chloride were added simultaneously to an ice-cold solution of 6.9 g (50 mM) of potassium carbonate in 15 ml water overlaid with 50 ml ether. The cooling bath was removed and the reaction warmed to ambient temperature stirring for 1.5 hours. The aqueous phase was acidified to pH 4 with concentrated HCl and the layers separated. The aqueous phase was extracted with 15 ml ether and the combined ether layer washed with brine and dried over anhydrous Na2SO4 then concentrated to yield 11.8 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: BrCc1ccccc1Br
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2Br)oc1C
Yield: 41.3 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (1.00 g, 10.4 mmol), commercial 2-bromobenzylbromide (2.60 g, 10.4 mmol) and 1.6M n-BuLi/hexanes (4.16 mL, 10.4 mmol) in THF. Purification on Biotage KP-Sil eluting with 100% pet. ether gave 1.14 g (41%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ 1.84 (s, 3 H), 2.11 (s, 3 H), 3.96 (s, 2 H), 5.81 (s, 1 H), 7.19 (dt, 1 H), 7.26-7.37 (m, 2 H), 7.60 (dd, 1 H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[CH2:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([NH2:41])[CH2:36]1)[CH3:34].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].C(Cl)(Cl)Cl>C1COCC1.CO>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:41][CH:37]4[CH2:38][CH2:39][CH2:40][N:35]([CH2:33][CH3:34])[CH2:36]4)=[O:29])=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:31][CH:32]=1
Reactant: CCN1CCCC(N)C1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN1CCCC(NC(=O)c2ccc(-c3cccc(COc4ccc(Cn5oc(=O)[nH]c5=O)cc4)c3)c(C)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
3′-({4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10.8 mg) was dissolved in a THF-methanol [1 ml, 4:1 (v/v)] mixed solution, and the solution was added to 1-ethylpiperidine-3-amine (5.8 mg). DMT-MM (12 mg) was added, followed by overnight stirring at room temperature. Thereafter, chloroform was added to the reaction liquid, and the organic layer was washed with water. The organic layer was concentrated, and the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm)) to obtain 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-N-(1-ethylpiperidin-3-yl)-2-methylbiphenyl-4-carboxamide (3.4 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]=O.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][NH:14][CH3:13]
Reactant: O=Cc1oc2ccccc2c1Cl
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1oc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 3-chlorobenzofuran-2-carboxaldehyde (1.62 g, 8.9 mmol) in methanol (50 mL) is added N-methylamine (33% solution in ethanol, 1.11 g, 35.9 mmol) and stirred overnight at room temperature. The mixture is concentrated in vacuo, re-solvated in methanol (50 mL) and cooled in an ice bath. Sodium borohydride (407 mg, 10.8 mmol) is added in portions and the mixture stirred at room temperature for 4 h. The mixture is concentrated in vacuo, re-solvated in 1.3M sodium hydroxide solution, stirred for 20 min, extracted with ethyl acetate, dried with sodium sulfate and concentrated. Purification by column chromatography (silica, CH2Cl2/MeOH, 9/1) gave title compound (1.43 g, 82%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.55-7.63 (m, 2H), 7.33-7.42 (m, 2H), 3.93 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C1OCCOC1>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:16])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1)=[O:20]
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Yield: 53 %

Procedure:
Prepared from 2-amino-6(5H)-phenanthridinone 3 and chloroacetyl chloride according to General Procedure A. P-dioxane was used as solvent and 1.1 equivalent of sodium hydroxide as base. A white precipitation was formed after stirring the mixture for 2 ours. Purification of the precipitation by crystallization in dioxane gave a white solid (53% yield), mp 300-303° C. 1H-NMR (400 MHz, DMSO-d6), 11.71 (s, 1H), 10.45 (s, 1H), 8.63 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.46 (m, 2H), 7.34 (d, J=8.8 Hz, 1H), 4.30 (s, 2H). Anal. (C15H11ClN2O2), C H N.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[CH2:49]([NH-:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:49]([NH-:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH-]Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 88 mg of Z-Phe-His-OH, 65 mg of H-Leu-Val-benzyl amide, 31 mg of Hobt and 54 mg of DCCI, the title compound is obtained after flash chromatography (100 g of silica gel 60, 40-63 μm, system B3). Rf (B2)=0.60, Rf(S10)=0.68.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)C1C=CC=CC=1.[F:34][C:35]([F:47])([F:46])[O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][N:28]1[C:24]([C:10]2[CH:11]=[C:12]([C:40]3[CH:39]=[CH:38][C:37]([O:36][C:35]([F:34])([F:46])[F:47])=[CH:42][CH:41]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:25][N:26]=[N:27]1
Reactant: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2ccc(OC(F)(F)F)cc2)c(O)cc1O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the mixture of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (200 μmol), and 4-(trifluoromethoxy)phenyl boronic acid (2 eq.) was added palladium tetrakistriphenylphosphine (45 mg), followed by toluene (1.2 ml), ethanol (1.2 ml) and saturated NaHCO3 solution (1.2 ml). The resulting mixture was stirred at 80° C. for 12 hours. The product was extracted with ethyl acetate (3×2000 μL), and the combined organic layers were washed with aqueous NaCl (2 ml), and dried. To the residue was added palladium on alumina (100 μL), followed by MeOH (2 ml). Triethyl silane (0.5 ml) was added to the reaction, and the resulting mixture was stirred at room temperature for 70 hours. Hexane (2 ml) was added to the reaction mixture and the top 4.5 ml of the solution was filtered through Baker filter cartridges and then dried in a genevac. The residue was purified by reverse phase HPLC to provide 5-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-4′-trifluoromethoxy-biphenyl-2,4-diol. LCMS: 411 [M+H].
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC>[OH:11][CH:4]([CH:13]1[CH2:14][CH2:15][CH2:16][C:12]1=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: CCCCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of heptanal (114 g) and cyclopentanone (152 g) was added dropwise thereto under stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and separated. Then, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a product (202 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 154 g of 2-(1-hydroxyheptyl)cyclopentanone (boiling point: 112-114° C./666 Pa; GC purity: 92%). The remaining 8% was 2-heptylidenecyclopentanone which is a dehydration product.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[C:53]([Cl:62])[C:52]=2[Cl:63])[CH2:48][CH2:47]1>>[CH:46]1([N:49]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[C:53]([Cl:62])[C:52]=2[Cl:63])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:31][CH:32]=2)[CH2:9][NH:8][CH2:15]3)=[O:25])[CH2:48][CH2:47]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Reactant: COCCCc1cc(Cl)c(Cl)c(CNC2CC2)c1
Product: COCCCc1cc(Cl)c(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and cyclopropyl-[2,3-dichloro-5-(3-methoxy-propyl)-benzyl]-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 733.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:13]1[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCCC2)CS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCCC2)N1CC(C)C

Procedure:
1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.
Reaction SMILES: C1(NS(=O)(=O)O)CCCCC1.[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[NH:21])[CH2:13][CH2:14][CH3:15].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[N:21][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)=[O:31])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCCC1=N
Reactant: O=C=Nc1cccc(Cl)c1
Agent: O=S(=O)(O)NC1CCCCC1
Product: CCCCN1CCCC1=NC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The cyclohexylsulfamic acid salt of 1-n-butyl-2-iminopyrrolidine (15.97 g.; 0.05 mole) is converted to free base (7.01 g.; 0.05 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 7.68 g. (0.05 mole) of m-chlorophenylisocyanate is added. The reaction mixture is stirred at room temperature for 21/2 hours and then taken to dryness in vacuo leaving a solid residue, 1-(1-n-butyl-2-pyrrolidylidene)-3-(m-chlorophenyl)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 94°-96° C.
Reaction SMILES: [OH-].[Na+].Cl.[C:4](N)(=[NH:6])[CH3:5].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][CH2:17][C:18]([NH:20][NH2:21])=O>CO.ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][CH2:17][C:18]1[N:6]=[C:4]([CH3:5])[NH:21][N:20]=1
Reactant: Cc1cccc(C)c1NCC(=O)NN
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(CNc2c(C)cccc2C)n[nH]1
Yield: 79.3 %

Procedure:
To a stirred solution of 8.8 g (0.022 mol) sodium hydroxide in 500 ml methanol was added 20 g (0.22 mol) acetamidine hydrochloride. After stirring for an additional 1/4 hour, 37.7 g (0.2 mol) alpha-(2,6-dimethylphenylamino)acethydrazide was added. The reaction mixture was heated under reflux for about 18 hours, cooled and filtered. The filtrate was evaporated under a reduced pressure to give a solid residue. The residue was diluted with dichloromethane, filtered, dried over magnesium sulfate and evaporated under reduced pressure to give a solid residue, which was triturated with ethyl ether/petroleum ether and dried to give 34.3 g of the product, m.p. 125°-126° C. The product is tabulated in Table I as Compound No. 2-A.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:15]2[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:24])([F:22])[F:23])[C:17](=[O:18])[N:13]([CH2:12][C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[C:34]([F:45])([F:44])[F:33])[CH:11]=[CH:10][C:5]=3[C:6]([O:8][CH3:9])=[O:7])[N:14]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O

Procedure:
Analogously to the preparation of Example 122, 265 mg (0.50 mmol) of the compound from Example 104A were reacted with 149 mg (0.74 mmol) of 2-(trifluoromethyl)phenylboronic acid. This gave 113 mg (38% of theory) of the target compound of a purity of 100% and 101 mg (28% of theory) of a purity of 81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a suspension of 10 g (46.66 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (100 ml) was added, at room temperature, 11.97 g (70 mmol.) of benzyl bromide. The mixture was stirred for 16 hours at 120° C. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a column chromatography (ethyl acetate/hexane 30%) to give the object compound as a pale yellow oily product. The yield was 13.56 g (95%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C([O-])([O-])=O.[K+].[K+].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[C:40]([O:44][C:45]([NH:47][C@@H:48]([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@@H:49]([OH:76])[CH2:50][CH:51]([NH:65]C(=O)OCC1C=CC=CC=1)[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=2)=[CH:55][CH:54]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(OCC)(=O)C>[CH2:77]([C@H:48]([NH:47][C:45](=[O:46])[O:44][C:40]([CH3:42])([CH3:41])[CH3:43])[C@@H:49]([OH:76])[CH2:50][CH:51]([NH:65][C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=2)=[CH:55][CH:54]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CC(Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)NC(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid (Degussa, 8.74 g, 46.18 mmol, 1.1 equivalents), K2CO3 (11.60 g, 83.96 mmol, 2equivalents), DEPBT (15.08 g, 50.38 mmol, 1.2 equivalents) in ethyl acetate (400 mL) was stirred at room temperature under N2 for 1 hour, treated with the product of Example 111-11 (20 g, 41.98 mmol) and stirred at room temperature under N2 for 24 hrs. The reaction mixture was washed with H2O (200 mL), 10% NaHCO3 (200 mL), and H2O (2×200 mL). The organic layer was concentrated, and the residue charged with ethyl acetate (30 mL), heated to 70° C. for 1 hr, added heptanes (120 mL) dropwise, stirred at 70° C. for 30 minutes, cooled to room temperature overnight. The slurry was filtered and washed with 100 mL of 1:1 heptane/ethyl acetate, and dried in 50° C. vacuum oven overnight to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH:26]1[CH2:28][O:27]1>C(#N)C.CCOC(C)=O>[CH3:13][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[O:1][CH2:25][CH:26]1[CH2:28][O:27]1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: ClCC1CO1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC1CO1
Yield: 5 %

Procedure:
A solution of methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate, K2CO3 (20 mmol, 2.68 g) and 2-(chloromethyl)oxirane (22 mmol, 2.03 g) in acetonitrile (60 ml) was stirred at reflux temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1.8% HCl/aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na2SO4 and concentrated at reduced pressure. The residue was purified on C18-column (H2O:CH3CN, 0.1M NH4OAc buffer, gradient 10% to 95% CH3CN) to give the subtitle compound (244 mg, 5% yield, two steps).