Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:21][N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)[CH2:20][CH2:19][CH2:18][C:12]2([O:16][C:15](=[O:17])[NH:14][CH2:13]2)[CH2:11]1)C1C=CC=CC=1.Br.[OH-].[Na+]>O1CCOCC1>[OH:8][CH2:9][C@:10]1([CH2:21][N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)[CH2:20][CH2:19][CH2:18][C@:12]2([O:16][C:15](=[O:17])[NH:14][CH2:13]2)[CH2:11]1
Reactant: N#Cc1ccc2ncn(CC3(COCc4ccccc4)CCCC4(CNC(=O)O4)C3)c2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc2ncn(C[C@@]3(CO)CCC[C@@]4(CNC(=O)O4)C3)c2c1
Temperature: 70 °C
Yield: 65.3 %

Procedure:
To a light orange suspension of 1-((7-((benzyloxy)methyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.120 g, 0.279 mmol) in 1,4-dioxane (2.157 mL) was added concentrated hydrobromic acid (0.631 mL, 5.57 mmol). The reaction mixture was heated at 70° C. for 17 h. The reaction was then cooled to RT. Next, 6N NaOH was added till the pH was adjusted to 13 and then the mixture extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The compound was loaded onto florisil and purified using silica gel chromatography: 1-5% methanol/dichloromethane (25 min), 4 g silica. The product eluted early from 2-10 minutes. Next, the compound was loaded onto florisil and purified using silica gel chromatography: 1-10% methanol/dichloromethane (30 min), 12 g silica. The product did not elute cleanly but did yield 1-{[(5S,7R)-7-(hydroxymethyl)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (70% pure, 62 mg, 46% yield). MS (m/z) 341.0 (M+H+).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:17]([CH3:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH:17]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:26])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Product: CC(C(=O)c1ccccc1)N1CCN(Cc2ccccc2)CC1
Yield: 142.9 %

Procedure:
A mixture of N-benzylpiperazine dihydrochloride (7 mmol) and 2-bromo-1-phenylpropan-1-one (8.4 mmol) was treated according to the general preparation 2 to obtain N1-benzyl-N4-(1-benzoylethyl) piperazine dihydrochloride (2.6 g, 5 mmol), which was reduced according to the general preparation 3 to obtain 1.28 g of the title compound, yield 67%, mp 244-246° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine and 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one, the title compound was prepared as a solid having a melting point of 243-244° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Br:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:53]=2)[NH:48][C:47]=1[C:63](O)=[O:64].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:53]=2)[NH:48][C:47]=1[C:63]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:64]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Br)c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
HATU (0.231 g, 0.608 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.126 g, 0.405 mmol), 3-bromo-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.144 g, 0.405 mmol) and diisopropylethylamine (0.106 mL, 0.608 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.086 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (br. s., 1H), 9.27 (br. s., 1H), 8.45 (br. s., 1H), 7.66-7.84 (m, 2H), 7.38-7.56 (m, 4H), 7.17-7.34 (m, 2H), 4.57 (d, 2H), 1.14-1.62 (m, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]([CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH:19]1[CH:20]=[CH:21][N:22]=[C:18]1[CH2:17][N:16]([CH2:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1)[CH2:23][C:24]1[NH:28][CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)c2ccccc12
Reaction time: 1 h
Yield: 104.2 %

Procedure:
The compound (675 mg) obtained in Example 36-3 was added with methanol (7.0 ml) and a 1 mol/l sodium hydroxide (7.0 ml), followed by stirring for 1 hour. After completion of the reaction, 1 mol/l hydrochloric acid (8.0 ml) was added to adjust the solution to pH 4. Then, the solvent was distilled off and the residue was washed with methanol, followed by drying. Consequently, the subject compound (677 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(CC)CC)C.BrC1[N:47]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[CH:45]=[CH:44][CH:43]=1>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:47]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[CH:45]=[CH:44][CH:43]=3)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: COC(=O)c1cccc(Br)n1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC)n3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.9 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (25 mg, 0.06 mmol) was dissolved in methanol (3 mL). A 4 N hydrochloric acid/ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for one hour. Following concentration under reduced pressure, the residue was dissolved in NMP (0.5 mL). Triethylamine (9.81 mg, 0.1 mmol) and methyl 6-bromo-pyridine-2-carboxylate (13.96 mg, 0.06 mmol) were added, and the mixture was stirred using a microwave irradiation reactor at 150° C. for 10 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. Sodium chloride was added to the aqueous layer, followed by reextraction with ethyl acetate four times. The organic layers were combined and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=40/1, 20/1, 10/1) to obtain 30.6 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([S:41]C)=[C:4]([C:9]2[C:10]([CH:24](O)[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:13]=[CH:12]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[S:41][CH:24]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:30]=1)[C:10]1[C:9]2=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([O:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15]2
Reactant: CSc1c(F)cc(F)cc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1SC3c1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Dissolve methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-phenyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-yl ester (7.4 g, 12 mmol) in dry methylene chloride (200 mL) and purge with nitrogen. Add triethylamine (8.3 mL, 60 mmol) followed by methanesulfonyl chloride (4.6 mL, 60 mmol). After 30 minutes, pour reaction into water and extract with methylene chloride. Wash organic layer with water, dry over sodium sulfate, filter and concentrate. Purify over silica gel, eluting with 0 to 3% methanol in methylene chloride, to yield 5.2 g (74%) of the title compound. LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=3.34 min (100%); mass spectrum (ion spray): m/z=582.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.C(=O)([O-])O.[Na+]>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 72.5 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 17.4 g (0.207 mol) of sodiumhydrogen carbonate were charged, and the mixture was reacted at 130° C. for 5 hours with vigorous stirring. Then the reaction mixture was separated by distillation to obtain 33.0 g of tetrafluorophthalic anhydride. The yield was 72.5%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[C:12]([CH3:29])([CH2:13][CH2:14][CH:15]([NH2:28])[CH2:16]3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([C:36]2([C:41](O)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:17]23[CH2:16][CH:15]([NH:28][C:41]([C:36]4([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:42])[CH2:14][CH2:13][C:12]2([CH3:29])[CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]3)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C23CCN(CCCc4ccccc4)CC2(C)CCC(N)C3)c1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C23CCN(CCCc4ccccc4)CC2(C)CCC(NC(=O)C2(c4ccccc4)CCCC2)C3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To compound 24 (71 mg, 0.180 mmol) dissolved in anhydrous THF (15 mL) was added 1-phenyl-1-cyclopentanecarboxylic acid (51 mg, 0.27 mmol), triethylamine (0.126 mL, 0.904 mmol), and BOP reagent (88 mg, 0.20 mmol), and the reaction mixture was allowed to stir at room temperature for 2 h. Reaction progress was monitored by TLC (30% CMA 80 in CH2Cl2). The reaction mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (25 mL) followed by water (25 mL). The aqueous layers were back extracted with EtOAc (2×20 mL). The combined organic layers were washed with 1 N NaOH (30 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude product. The crude product was purified by flash chromatography (25% CMA 80 in CH2Cl2) to afford 94 mg (92%): LCMS (ESI): m/z 565.6 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.17-7.36 [m, 13H], 6.71-6.73 [m, 1H], 4.92, [d, J=6 Hz, 1H], 4.19 [m, 1H], 3.79 [s, 3H], 2.74 [br, 1H], 2.62-2.64 [m, 2H], 2.33-2.45 [m, 5H], 2.10-2.31 [m, 2H], 1.98-2.09 [m, 3H], 1.61-1.84 [m, 10H], 1.46 [d, J=12 Hz, 1H], 1.20-1.33 [m, 2H], 1.15 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 176.1, 159.2, 148.9, 144.8, 142.8, 129.0, 128.9, 128.7, 128.6, 127.2, 127.1, 126.0, 121.9, 116.3, 110.7, 62.2, 59.6, 58.2, 55.5, 51.2, 46.2, 44.2, 37.8, 37.4, 37.2, 36.9, 36.6, 35.6, 33.9, 29.2, 28.1, 26.6, 24.4.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>C1COCC1>[C:19]([N:4]1[C:5]2[CH:10]=[C:9]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(c2)NCCO3)S1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)N(C(=O)c2ccccc2)CCO3)S1
Yield: 35 %

Procedure:
5-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione (example 96) (35 mg, 0.13 mmol) in 4 ml anhydrous THF were treated with benzoylchloride (156 uL, 10 eq.) in the presence of DIEA (2 eq.) for 3 h. Excess of benzoylchloride was hydrolysed, EtOAc was added and the organic phase was washed with NaHCO3 and brine. The crude was purified on silica gel using EtOAc/cyclohexane 3:7 as eluent affording 14 mg (35%) of the title compound.
Reaction SMILES: NC1C(C#N)=C(N2CCC(C3N(CCNCC4CC4)[CH:18]=[C:19]([C:21]4C=CC(F)=C(C)C=4)[N:20]=3)CC2)N=CN=1.C(N)(C)C.[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[N:54]([CH2:69][CH2:70]OS(C)(=O)=O)[CH:55]=[C:56]([C:58]4[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=4)[N:57]=3)[CH2:49][CH2:48]2)[C:42]=1[O:76][CH2:77][CH3:78].NC1N=CN=C(N2CCC(C3N(CCOS(C)(=O)=O)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)C=1C#N>>[CH2:77]([O:76][C:42]1[C:41]([NH2:40])=[N:46][CH:45]=[N:44][C:43]=1[N:47]1[CH2:52][CH2:51][CH:50]([C:53]2[N:54]([CH2:69][CH2:70][NH:20][CH:19]([CH3:21])[CH3:18])[CH:55]=[C:56]([C:58]3[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:67])([F:66])[F:68])[CH:59]=3)[N:57]=2)[CH2:49][CH2:48]1)[CH3:78]
Reactant: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCOS(C)(=O)=O)CC1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Agent: CS(=O)(=O)OCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Solvent: CC(C)N
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC(C)C)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isopropylamine and methanesulfonic acid 2-[2-[1-(6-amino-5-ethoxy-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethyl ester instead of cyclopropylmethylamine and methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]ethyl ester. LC-MS: (M+1=536, obsd.=536).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>Cl.[Rh]>[NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCOC(=O)CCc1ccc2ncccc2c1
Agent: [Rh]
Agent: Cl
Product: CCOC(=O)CCc1ccc2c(c1)CCCN2
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A stirred mixture of ethyl 3-(6-quinolinyl)propanoate (0.3 g, Reference Example 3) in hydrochloric acid (3 ml, 0.1N) and 5% rhodium in carbon powder (33 mg) was hydrogenated in a 22 cm3 stainless steel pressure reactor at a pressure of 50 bars of hydrogen. After stirring for 4 hours at 25° C. a further portion of 30 mg of 5% rhodium in carbon powder (33 mg) was added and the hydrogenation was continued under a pressure of 50 bars at 25° C. for 1 hour. The reaction mixture was filtered through a pad of celite and the filter pad was washed with hydrochloric acid (3 ml, 0.1N) then with ethyl acetate (25 ml). The combined filtrate and washings were combined and the aqueous phase was decanted from the organic phase. The aqueous phase was extracted twice with ethyl acetate (25 ml) and combined with the aforementioned organic phase. The combined solutions were dried over magnesium sulfate then evaporated under reduced pressure (2.0 kPa) at 40° C. to give the title compound (0.121 g) as a brown oil.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])[N:13]=[C:12]1[CH3:30])(C)(C)C>ClCCl>[NH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])[N:13]=[C:12]1[CH3:30]
Reactant: Cc1nc(NC(=O)Nc2cccc(C(F)(F)F)c2)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(NC(=O)Nc2cccc(C(F)(F)F)c2)cn1CCN
Reaction time: 2 h
Yield: 117.5 %

Procedure:
4 N HCl in dioxanes (3 mL) was added to a solution of compound 40.3 (0.11 g, 0.26 mmol) in dichloromethane (3 mL). The reaction mixture stirred for 2 hours and concentrated to provide 1-[1-(2-amino-ethyl)-2-methyl-1H-imidazol-4-yl]-3-(3-trifluoromethyl-phenyl)-urea (compound 40.4; 0.10 g, 100%) as a HCl salt. ES (+) MS m/e=328(M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>ClC1C=CC=CC=1>[Cl:12][C:3]1[C:2]([NH:1][C:16](=[O:17])[CH2:15][O:14][CH3:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(Cl)c(N)c1
Reactant: COCC(=O)Cl
Solvent: Clc1ccccc1
Product: COCC(=O)Nc1cc(C(=O)OC)cnc1Cl

Procedure:
A solution of 0.75 g (4.02 mMol) of methyl 5-amino-6-chloro-nicotinate and 0.43 g=0.35 ml (4.5 mMol) of methoxyacetylchloride in 20 ml of chlorobenzene was stirred for one hour at 110° C. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=100:1), evaporated down again in vacuo and then digested with petroleum ether.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][CH2:9][CH:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)C(COCc1ccccc1)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C(CO)CC1COC(C)(C)N1C(=O)OC(C)(C)C

Procedure:
A solution of 15.40 g of tert-butyl 4-(2-benzyloxymethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate in 450 ml of tetrahydrofuran is hydrogenated at room temperature in the presence of 3.07 g of 10% Pd/C over 2 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.28 (1:2 EtOAc-heptane). Rt=4.58 (gradient I).
Reaction SMILES: [C:1]([N:5]1[CH2:30][CH2:29][CH2:28][CH2:27][C:8]2[C:9]([Br:26])=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:31])([CH3:4])([CH3:3])[CH3:2].C(N1CCCCC2C(C3SC=CC=3)=C3C4C=C(N5C=C(C[C@@H](O)C[OH:59])N=N5)C(OC)=CC=4CCN3C=2C1=O)(C)(C)C.N1C=CN=C1.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.OS([O-])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O>ClCCl>[C:1]([N:5]1[CH2:30][CH2:29][CH2:28][CH2:27][C:8]2[C:9]([Br:26])=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])(=[O:59])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCS(=O)c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reactant: COc1cc2c(cc1-n1cc(C[C@@H](O)CO)nn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCS(=O)(=O)c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O

Procedure:
A solution of 350 mg of 23d, and 20g of Mn(III)TPPP(OAc) and 75 mg of imidazole in 20 ml of dichloromethane were treated with tetrabutylammonium oxone, according to a described procedure; D. Mohajer et al., Tetr. Letters, 45, 3811 (2004). This provide after work-up, and chromatographic purification on silicagel (using a gradient of CH2Cl2 and ethyl acetate as eluent) 160 mg of crystalline 23e (triturated with diisopropyl ether); Mp 227° C. Rf (CH2Cl2-ethyl acetate 1/1) 0.61. LC-MS-ESI: [M+1] 522.97 and 524.99. NMR (CDCl3) δ 1.28 (t, 3, ethyl), 3.38 (q, 2, ethyl), 1.58 (s, 9, tertC4H9), 4.00 (s, 3, OCH3), 8.89 and 6.89 (2×s, 2, Ar—H), 4.50 and 3.85 (2×m, 2, CH2), 3.80 and 3.50 (2×m, 2, CH2), 3.05 (m, 2, CH2), 2.70 (m, 2, CH2) 1.90-1.65 (2×m, 4, 2×CH2).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(#N)C.CCOCC>[CH3:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN(C)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of 16.7 g (100 mmol) of ethyl bromoacetate, 10.7 g (100 mmol) of N-methylaniline, and 12.9 g (100 mmol) of N,N-diisopropylethylamine in 100 mL of acetonitrile was allowed to stand for 24 hr. and then diluted with 200 ml of ether. The amine salt was filtered and the filtrate concentrated, dissolved in 150 ml of CH2Cl2, washed with water, filtered through a plug of sodium sulfate/silica and distilled: 15.5 g (80%), b.p. 132°/12 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18]/[C:19](=[N:37]\[OH:38])/[C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1

Procedure:
In analogy to example 151, step 3, 3-fluoro-4′-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=485.3 [M+H]+.