Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Bromo-4,5-difluoro-2-nitro-benzene (24 g, 100 mmol) was carefully added dropwise to a solution of sodium methoxide (1.2 eq) in MeOH. After addition was complete, the reaction was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo and the residue diluted with water and extracted 2×250 mL with Et2O. The organic layers were combined, dried over MgSO4, filtered, and the solvent removed in vacuo leaving a yellow solid of 1-bromo-4-fluoro-5-methoxy-2-nitro-benzene: 1H NMR (300 MHz, CDCl3) 3.99 (s, 3H), 7.26 (m,1H) , 7.83 (d, 1H). MS(FD+): m/z 249, 251 (M+). Calculated for C7H5BrFNO3: C, 33.63; H, 2.02; N, 5.60; found: C, 33.79; H, 1.98; N, 5.62. 1-Bromo-4-fluoro-5-methoxy-2-nitro-benzene (20.5 g, 82 mmol) was hydrogenated over Pt on C (sulfided) at 60 psi (413 kPa) in THF (600 mL) for 4 hours. The reaction was filtered through celite to remove the catalyst. Removal of the solvent left a brown solid of 2-bromo-5-fluoro-4-methoxy-phenylamine which was taken on without further purification. 2-Bromo-5-fluoro-4-methoxy-phenylamine (18 g, 81.8 mmol) was dissolved in pyridine (200 mL) in a 500 mL round bottom flask equipped with a stir bar, septum, pressure equalizing dropping funnel, and nitrogen line with bubbler. The solution was cooled in an ice bath and ethyl chloroformate (1.5 eq.,122.7 mmol) was added dropwise from the dropping funnel. After addition was complete, the reaction was allowed to stir overnight gradually warming to room temperature. The pyridine was removed leaving a brown residue. This residue was taken up in Et2O/water and transferred to a separatory funnel. The water was extracted with Et2O (2×300 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated in vacuo to obtain a 23.62 g (99%) of a brown solid: 1H NMR (300 MHz, CDCl3, 1.33 (t, 3H), 3.85 (s, 3H), 4.23 (q, 2H), 7.09 (d, 1H), 7.97 (bd, 1H); MS(FD+): m/z 291, 293 (M+).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:11]2[CH:12]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (5 drops) is added to a solution of 4,4-diphenyl-cyclohex-2-en-1-one (155 g) and N-butoxymethyl-N-trimethylsilylmethyl-benzylamine (202 cc) in dry dichloromethane (1,000 cc) and the reaction mixture is refluxed for 45 minutes. N-Butoxymethyl-N-trimethylsilylmethyl-benzylamine (50 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for a further 45 minutes under reflux before adding further N-butoxymethyl-N-trimethylsilylmethyl-benzylamine (25 cc) and trifluoroacetic acid (3 drops). The reaction mixture is stirred under reflux for 45 minutes and then treated with potassium carbonate (50 g) and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in isopropyl ether (200 cc) and the solution is cooled at 0° C. for 1 hour. The crystals are drained, washed with isopropyl ether (2 * 15 cc) and dried to give (3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone (193 g) in the form of white crystals melting at 132° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C:42](=[N:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)=[O:40])([CH3:37])[CH3:36]>>[CH3:60][C:57]([O:56][C:54]([NH:53][C:42](=[N:41][C:39]([O:38][C:35]([CH3:37])([CH3:36])[CH3:34])=[O:40])[NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:20]2[CH2:21][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:23][C@@H:19]2[C:5]2[NH:6][C:7]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=3)=[C:3]([Cl:2])[N:4]=2)=[O:49])=[CH:46][CH:45]=1)=[O:55])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@H]3C[C@@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)nc2Cl)cc1

Procedure:
The compound prepared in Example 67 was treated with the compound prepared in Example 10 following the procedure described in Example 8 to give the title compound as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([Cl:19])=[N:17][CH:18]=1>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([NH:20][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[F:1])[C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
To a solution of 2,4-difluorobenzoyl chloride (0.33 g, 1.591 mmol) in CHCl3 (15.9 ml) were slowly added TEA (0.443 ml, 3.18 mmol) and 5-bromo-2-chloropyridin-3-amine (0.337 g, 1.91 mmol) at 0° C. The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was quenched with saturated aq. NaHCO3, and extracted with DCM (2×50 mL). The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=30:1) to give N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide (0.185 g, 34%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 6.93-7.26 (2H, m), 8.21-8.27 (2H, m), 9.08-9.12 (1H, m), 9.16-9.16 (1H, m).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH-].[Na+].CS(C)=[O:17].Cl>O>[Cl:8][C:7]1[C:2](=[O:17])[NH:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc(C(F)(F)F)cc1Cl

Procedure:
[B] 4 g of 2,3-dichloro-5-trifluoromethylpyridine was added to an aqueous solution of 2.4 g of sodium hydroxide dissolved in 12.5 ml of water, and 12.5 ml of dimethyl sulfoxide was further added thereto. The solution was reacted at 110° C. for 1 hour while stirring. After completion of the reaction, the reaction product was allowed to cool and made acidic with concentrated hydrochloric acid to obtain a precipitate. The thus obtained precipitate was collected by filtration to obtain 2.5 g of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH3:33])[S:31][CH:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH3:33])[S:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2csc(C)n2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4csc(C)n4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methylthiazol-4-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(2-methylthiazol-4-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a off white solid (0.039 g, 10% yield). MS: m/z 528.2 [M+H]+.
Reaction SMILES: C([N:8]([CH2:16][C@H:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH:33]3[CH3:37])=[CH:24][CH:23]=2)[C:20](=[O:38])[CH2:19][CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:16][C@H:17]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH:33]3[CH3:37])=[CH:26][CH:27]=2)[C:20](=[O:38])[CH2:19][CH2:18]1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Palladium hydroxide on charcoal is added to a solution of (5S)-5-[(dibenzylamino)methyl]-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 112 (0.377 g, 0.74 mmol, 1 eq) in methanol (10 ml). The mixture is shaken overnight at room temperature under hydrogen atmosphere (45 psi). The mixture is filtered over celite and concentrated under vacuum. The residue is taken up in a mixture of methanol (10 ml) and 4 drops of aqueous 5 N hydrochloric acid. Palladium hydroxide on charcoal is added and the mixture is shaken again overnight at room temperature under hydrogen atmosphere (45 psi). The mixture is filtered over celite and concentrated under vacuum to give 0.245 g of (5S)-5-(aminomethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 113 as a yellow oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[S:13]1[C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:16]=2[CH:15]=[CH:14]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:20]2[CH2:21][CH2:22][C:16]3[CH:15]=[CH:14][S:13][C:17]=3[CH2:18][CH2:19]2)[N:7]=1
Reactant: c1cc2c(s1)CCNCC2
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCc3ccsc3CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
According to the method described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was treated with 5,6,7,8-tetrahydro-4H-thieno-[2,3-d]azepine [J. Heterocycl. Chem. (1985), 22(4), 1011-16] in N,N-dimethylformamide in the presence of N-ethyl-di-isopropylamine at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M−H]−=305.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.42 g, 5.08 mmol), 4-fluorobenzenethiol (0.663 ml, 6.10 mmol) and K2CO3 (1.054 g, 7.62 mmol) in ACN (12.71 mL) was stirred at 85° C. overnight. The reaction mixture was filtered by suction and the solvent removed gave tert-butyl 4-((4-fluorophenyl)thio)piperidine-1-carboxylate (1.5 g, 95%) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Si]([O:32][CH2:33][CH2:34][CH:35]=O)(C(C)(C)C)(C)C.C[N+](C)(C)C.C1COCC1>>[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][CH:20]([NH:23][CH2:35][CH2:34][CH2:33][OH:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: CC1(C)CCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: C[N+](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCc2cc(-c3csc(N4CCC(NCCCO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The preparation is carried out starting from 1-[4-(1,1-dimethylindan-5-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 3-(tert-butyldimethylsilanyloxy)propionaldehyde. The protecting group is cleaved off by means of a 1M tetramethylammonium/THF solution: The reaction mixture was stirred at room temperature overnight and subsequently evaporated to dryness. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
Prepared using General Procedure 3. To a solution of crude (S)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile (0.11 g, 0.22 mmol) in anhydrous THF (3 mL) was added 1.0 M solution of TBAF (1.0 mL) in THF. The reaction mixture was stirred at room temperature for 2 h. The solvent was concentrated under vacuum and the reside purified by a silica gel chromatography to afford 35 mg (41%) of (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 70 as white solid. LCMS-ESI (m/z): calcd for: C22H20N2O2S: 376.4; found 377.1 [M+H]+, tR=3.66 min. 1H NMR (400 MHz, CDCl3) δ 8.14-7.89 (m, 2H), 7.82-7.62 (m, 1H), 7.35 (dd, J=7.5, 2.6 Hz, 2H), 7.22 (dd, J=15.0, 7.5 Hz, 1H), 7.02-6.77 (m, 1H), 5.36-5.08 (m, 1H), 4.65 (hept, J=6.0 Hz, 1H), 3.10 (ddd, J=16.1, 8.5, 4.6 Hz, 1H), 2.93-2.80 (m, 1H), 2.68-2.54 (m, 1H), 2.44 (dddd, J=11.7, 8.3, 7.0, 4.7 Hz, 1H), 2.01-1.77 (m, 1H), 1.41-1.29 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 164.98, 161.11, 146.82, 141.23, 140.87, 137.98, 132.11, 131.99, 128.40, 128.03, 127.91, 126.67, 124.62, 116.13, 113.98, 103.76, 76.43, 72.55, 35.89, 30.78, 22.01. Chiral HPLC: (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile was eluted using 15% IPA in hexanes: 100% ee; tR=24.19 min.
Reaction SMILES: [N-]=[C:2]=[O:3].[C:4]1([CH3:11])[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=1>>[C:2]([OH:3])(=[O:3])[CH2:10][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:4][CH2:11][CH2:10][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:4]([CH3:11])[CH3:2]
Reactant: [N-]=C=O
Reactant: Cc1ccccc1C
Product: CC(C)CCCCCCCCCCCCCCC(=O)O
Temperature: 28 °C

Procedure:
Then 200 ml. xylene was added and 100 g n-C18 -isocyanate (0.339 mole) was dispersed in the mixture with stirring. The temperature was about 45° C. and the mixture was allowed to cool to about 28° C. The mixture containing a little floc was filtered and solvent removed by "Rotavapor". The solid was dissolved in cyclohexane, filtered and again recovered by solvent evaporation. It was again washed with cyclohexane to give a white, waxy solid. Nitrogen content was 8.6 wt. %.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:33][CH:34]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(OC(CC)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of ethyl 3-{4-[1-(4′-trifluoromethylbiphenyl-4-yl)propoxy]benzoylamino}propionate (Isomer 2) (90 mg, 0.185 mmol) in THF (1.85 mL) is treated with 5 N NaOH (0.186 mL) and shaken at RT overnight. The reaction is neutralized with 1 N HCl (0.93 mL), and extracted into dichloromethane (3×). The combined organic layers are dried and concentrated, giving the title compound (79 mg). MS (ES): 472.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37]>O>[CH3:17][C:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A suspension of the product of Example 34C (0.049 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.095 mL, 0.095 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.051 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1 H) 0.69 (m, 6 H) 0.80 (m, 1 H) 1.29 (m, 1 H) 1.38 (m, 3H) 1.72 (m, 1 H) 2.14 (m, 1 H) 2.90 (m, 3 H) 7.34 (m, 6 H) 8.05 (m, 1 H) 15.42 (m, 1 H). MS (ESI−) m/z 516 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[C:10]([CH3:19])=[N:9]2)=[CH:5][CH:4]=1.Cl.CC[OH:25]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:17]=[C:16]([OH:25])[S:15][CH:14]=3)[C:10]([CH3:19])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1ccc(Cn2cc(C(=O)CSC#N)c(C)n2)cc1
Agent: Cl
Product: COc1ccc(Cn2cc(-c3csc(O)n3)c(C)n2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
According to Scheme 2, Step 4: To a solution of 1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone (6.57 mmol, 1.98 g) in EtOH was added HCl concentrated (1 mL) and the reaction mixture was stirred under reflux for 8 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was diluted with water. The aqueous phase was basified with NaOH and was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was evaporated. The crude residue was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 95:4.5:0.5) as eluent to yield 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-ol (3.42 mmol, 1.03 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:28]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(F)c3)c2)CC1
Reaction time: 0.08 h
Yield: 109.8 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (50 mg, 0.130 mmol) in tetrahydrofuran (1 mL) was allowed to stand for 5 min. 3-fluorobenzoyl chloride (28 μL, 0.229 mmol) and tetrahydrofuran (1 mL) were added to the reaction mixture. The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and allowed to stand for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43 mg (>100%) of the title compound.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccccn2)cc1Cl
Reaction time: 18 h
Yield: 23.9 %

Procedure:
In THF (50 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol), pyridine-2-ylmethylamine (69 mg, 0.64 mmol) and triethylamine (0.2 mL). The solution was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was then added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated and the obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyridin-2-ylmethyl)pyrimidine-5-formamide (60 mg, 24% yield).