Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH:38]([NH2:40])[CH3:39])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH:38]([CH3:39])[CH2:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CC(N)Cc1ccc(F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(F)cc1)N1CCC2(CCN(S(=O)(=O)c3ccccc3Cl)CC2)C1=O

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Fluoro-phenyl)-1-methyl-ethylamine. MS (ESI): 465.3 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].N1([C:12](N2C=CN=C2)=[O:13])C=CN=C1.CCN(C(C)C)C(C)C.Cl.[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[N:33]=[CH:32][N:31]=1>C1COCC1>[CH2:2]([CH:3]([O:6][C:12]([N:42]1[CH2:43][CH2:44][CH:39]([O:38][C:34]2[C:35]([O:36][CH3:37])=[C:30]([Cl:29])[N:31]=[CH:32][N:33]=2)[CH2:40][CH2:41]1)=[O:13])[CH2:4][CH3:5])[CH3:1]
Reactant: COc1c(Cl)ncnc1OC1CCNCC1
Reactant: CCC(O)CC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)OC(=O)N1CCC(Oc2ncnc(Cl)c2OC)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
Pentan-3-ol (0.88 g, 9.99 mmol) and di-imidazol-1-yl-methanone (1.39, 8.57 mmol) were added to THF (10 mL) and stirred at 50° C. for one hour. DIPEA (1.38 g, 10.7 mmol) and 4-chloro-5-methoxy-6-(piperidin-4-yloxy)-pyrimidine HCl (2.00 g, 7.14 mmol) were added, the vessel sealed and heated by microwave at 150° C. for one hour. Upon cooling the reaction mixture was partitioned between water and Ethyl Acetate, the organic phase washed with brine and dried with Sodium Sulfate. The crude material was purified by column chromatograph (silica gel) with 10-30% EtOAc/Hexanes to yield 1.0 grams (39%) of the desired product, as a white solid. 1HNMR (CDCl3, 400 MHz) δ 0.91 (t, J=7.83 Hz, 6H), 1.55-1.63 (m, 4H), 1.78-1.88 (m, 2H), 1.99-2.08 (m, 2H), 3.39-3.46 (m, 2H), 3.78-3.85 (m, 2H), 3.92 (s, 3H), 4.67 (m, 1H), 5.36-5.43 (m, 1H), 8.26 (s, 1H). Exact mass calculated for C16H24ClN3O4: 357.15. found: 358.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[N:18]([O:20]CCC(C)C)=O.[ClH:26]>>[Cl:26][C:2]([CH3:17])([CH3:1])[CH:3]([N:18]=[O:20])[CH2:4][CH2:5][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11]
Reactant: CC(C)CCON=O
Reactant: CC(C)=CCCN1C(=O)c2ccccc2C1=O
Reactant: Cl
Product: CC(C)(Cl)C(CCN1C(=O)c2ccccc2C1=O)N=O

Procedure:
To a cooled (0-5° C.) solution of 4-methyl-1-(phthalimido)-3-pentene (5.0 g, 0.022 mol) and isoamyl nitrite (13.0 g, 15 mL, 0.11 mol) was added concentrated hydrochloric acid (4.0 mL, 0.04 mol) with stirring. The reaction mixture was maintained below 5° C. during the addition and stirred at 5° C. for an additional 2 h. The solid formed was filtered and washed with cold ether:ethanol (3:1, 150 mL) and dried. Yield: 4.72 g (72.8%). It was crystallized from acetonitrile. mp 140-141° C. MS: (M+H)+ =296.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]([C:6]1[O:7][C:8](Br)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27].C1(NC2CCCCC2)CCCCC1>>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]([C:6]1[O:7][C:8]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C#CCCCCOCCCCCCBr
Reactant: CCN(CC)C(=O)c1ccc(Br)o1
Agent: C1CCC(NC2CCCCC2)CC1
Product: CCN(CC)C(=O)c1ccc(C#CCCCCOCCCCCCBr)o1
Yield: 73.2 %

Procedure:
N,N-diethyl-5-bromo-2-furancarboxamide (1.5 g) was treated with 6-[(6-bromohexyl)oxy]-1-hexyne (1.59 g) and N,N-dicyclohexylamine (2.10 g) according to the method of Intermediate 9 except that the reaction mixture was refluxed under nitrogen for 3 h and FCC eluting with hexane followed by hexane:ether (4:1→1:1) gave the title compound as an orange oil (1.90 g), t.l.c. (hexane:ether 1:1) Rf 0.15.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[NH2:38][C:13]1[C:12]2[N:11]=[C:10]([CH2:22][CH2:23][CH3:24])[N:9]([CH2:8][CH2:7][CH2:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:25])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCNC(=O)CCCn1c(CCC)nc2c(N)nc3ccccc3c21

Procedure:
N-Propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (5.6 g, 15 mmol) was treated with mCPBA (8.5 g, 38 mmol), concentrated ammonium hydroxide (100 mL), and p-toluenesulfonyl chloride (4.9 g, 26 mmol) according to the method described in Part F of Example 1. The crude product was dissolved in hot toluene (25 mL) and dichloromethane. A precipitate slowly formed, was isolated by filtration, and was washed with toluene (15 mL). The solid was recrystallized twice from 4:1 methanol:water (25 mL), and the crystals were heated at reflux in chloroform in the presence of charcoal (1 g). The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The residue was recrystallized twice from methanol:water and twice from toluene (15 mL) and dried overnight in a vacuum even to provide 0.74 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylbutanamide as a grey solid, mp 161-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:33])=[CH:27][CH:26]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)cc1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 4-Chlorophenyl isocyanate (0.03 mL, 0.26 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 29 (54 mg, 57% yield) as a yellow solid. LC-MS (M+H=362, obsd.=362).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:20])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[S:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=2)[CH:30]=1.C(N(CC)CC)C>C(O)CCC>[C:41]([C:38]1[S:37][C:36]([NH:35][C:31]2[N:32]=[CH:33][N:34]=[C:13]([N:10]3[CH2:9][CH2:8][CH:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[O:20])[CH2:12][CH2:11]3)[CH:30]=2)=[N:40][CH:39]=1)#[N:42]
Reactant: CC(C)NC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)NC(=O)CC1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
46-2 (0.21 g, 0.73 mmol) was treated with neat trifluoroacetic acid for 20 minutes and then the trifluoroacetic acid was evaporated off. This residue and 35-1 (0.17 g, 0.73 mmol) and triethylamine (0.37 g, 3.67 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 46-3. Hi-Res MS: calc: 386.1758 found: 386.1754. 1H-NMR (CD3OD): 8.36(s, 1H); 7.99(s, 1H); 6.14(s, 1H); 4.40(d, 2H); 3.98(m, 1H); 2.94(t, 2H); 2.10(complex, 3H); 1.77(d, 2H); 1.22(m, 2H); 1.13(d, 6H).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:16]([O:15][C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 20, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109°-110°C. (0.37 mm).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(O)C>[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:23][NH:24][CH3:25])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(C)nc2)c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (86 mg) in ethanol (2 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) at room temperature. The mixture was stirred for 2 hr, and concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (2 mL) and added to a solution (2 mL) of fumaric acid (11.3 mg) in ethanol, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 14 mg, 18%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:21])[NH:7]1.C([O:25][C:26](=[O:45])[CH2:27][CH:28]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1)[CH:29]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1)C.Cl>[OH-].[Na+]>[O:34]=[C:31]1[NH:30][CH:29]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=2)[CH2:27][C:26]([OH:45])=[O:25])[CH2:33][CH2:32]1.[O:21]=[C:8]1[NH:7][CH:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:2])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[CH2:9]1
Reactant: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)C1CCC(=O)N1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(c1ccc(C(F)(F)F)cc1)C1CCC(=O)N1
Product: O=C(O)CCC1NC(=O)CC1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 93.4 g of 5-oxo-3-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-β-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid ethyl ester in aqueous sodium hydroxide solution (1 N, 370 ml) is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 370 ml) is added and the solution is concentrated under reduced pressure to give 5-oxo-β-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid and 5-oxo-3-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])=[N+:9]=[N-:10].[NH4+:18]>CCCCC.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:10][N:9]=[N:8][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N:16][NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:18]=1
Reactant: [NH4+]
Reactant: [N-]=[N+]=NCCCCN=[N+]=[N-]
Reactant: Brc1ccccn1
Solvent: CCCCC
Solvent: CCCCCC
Product: c1ccc(NN=NCCCCN=NNc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.95 g (25 mmoles) of 2-bromopyridine in 20 ml of dry pentane was added dropwise to 10 ml. of 2.5M butylithium in hexane at -78° C. To the resulting yellow slurry was added dropwise with stirring 1.75 g (12.5 mmoles) of 1,4-diazidobutane in 10 ml. of pentane. Stirring was continued for 2 hr. at -78° and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was treated with 60 ml. of ammonium buffer which caused a precipitate to appear after the reaction was cooled to -78° C. The solid was filtered off. It was poorly soluble in common solvents such as halomethanes, acetone, methanol and water. It was sparingly soluble in dimethylsulfoxide. The yield was 2.3 g., m.p. 133-136. Spectroscopic data were consistent with the structure.
Reaction SMILES: I[C:2]([I:5])([CH3:4])C.[C:6](=O)([O-])[O-].[K+].[K+].[Si:12]([O:19][C@@H:20]1[N:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:25]2[CH:33]=[C:34]([OH:39])[C:35]([O:37][CH3:38])=[CH:36][C:24]=2[C:23](=[O:40])[N:22]2[CH:41]=[C:42](/[CH:44]=[CH:45]/[CH3:46])[CH2:43][C@@H:21]12)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CC(C)=O>[Si:12]([O:19][C@@H:20]1[N:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:25]2[CH:33]=[C:34]([O:39][CH2:6][CH2:4][CH2:2][I:5])[C:35]([O:37][CH3:38])=[CH:36][C:24]=2[C:23](=[O:40])[N:22]2[CH:41]=[C:42](/[CH:44]=[CH:45]/[CH3:46])[CH2:43][C@@H:21]12)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: CC(C)(I)I
Reactant: C=CCOC(=O)N1c2cc(O)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)N1c2cc(OCCCI)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 553.4 %

Procedure:
Diiodopropane (0.295 g, 1.00 mmol, 5.0 eq) and potassium carbonate (0.028 g, 0.20 mmol, 1.0 eq) were added to a solution of the phenol 12 (0.100 g, 0.020 mmol, 1.0 eq) in dry acetone (5 mL). The reaction mixture was heated at 60° C. for 6 hours when LC/MS showed complete reaction. The reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography (silica gel, 75/25 v/v n-hexane/EtOAc to 50/50 v/v n-hexane/EtOAc) to afford the product as a colourless oil (0.074 g, 56%). LC/MS (3.853 min (ES+)), m/z: 669.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 6.90 (s, 1H), 6.68 (s, 1H), 6.24 (d, 1H, J=15.3 Hz), 5.87 (d, 1H, J=8.9 Hz), 5.78 (m, 1H), 5.53 (m, 1H), 5.12 (m, 2H), 4.65 (m, 2H), 4.41 (m, 1H), 4.11 (m, 1H), 3.93 (s, 3H), 3.81 (m, 1H), 3.40 (t, 2H, J=6.7 Hz), 3.05 (dd, 1H, J=16.3, 10.1 Hz), 2.57 (m, 1H), 2.34 (m, 2H), 1.84 (d, 3H, J=6.6 Hz), 0.92 (s, 9H), 0.28 (s, 3H), 0.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(Cl)([Cl:15])=O.[NH2:17]/[C:18](=[N:24]\[OH:25])/[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([Cl:15])=[O:12].[NH2:17]/[C:18](=[N:24]\[O:25][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C(N)=N/O
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(N)=N/OC(=O)Cc1cc(F)ccc1F
Product: O=C(Cl)Cc1cc(F)ccc1F
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
2-(2,5-difluorophenyl)acetyl chloride was prepared by heating overnight a suspension of 2,5-difluorophenylacetic acid (0.865 g; 3.67 mmol) and thionyl chloride (1.34 mL; 18.15 mmol) in chloroform (30 mL) at 80° C. After evaporation of the solvent and the excess of the thionyl chloride under reduced pressure, the residue was dissolved in dried dichloromethane (10 mL). This solution was added to a suspension of (Z)-ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.67 mmol) and N,N-diisopropylethylamine (1.03 mL; 5.87 mmol) in dry dichloromethane (20 mL) cooled at −10° C. and stirred for 10 minutes. The mixture was stirred at room temperature for 23 h and poured into a mixture of ice/water. The white precipitate is filtered off and washed with dichloromethane and dried under reduced pressure to afford 0.469 g (45%) of (Z)-ethyl 2-amino-2-(2-(2,5-difluorophenyl)acetoxyimino)acetate as a white solid.
Reaction SMILES: ClC1C=CC=CC=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])NC1SC(SCC(C)(C)C(O)=O)=CN=1.BrC[CH:38]1[CH2:40][CH2:39]1.C([O:43][C:44](=[O:53])[CH2:45][S:46][C:47]1[S:51][C:50]([NH2:52])=[N:49][CH:48]=1)C>>[CH:38]1([CH:6]([O:5][CH3:4])[CH2:7][N:8]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:9](=[O:24])[NH:52][C:50]2[S:51][C:47]([S:46][CH2:45][C:44]([OH:43])=[O:53])=[CH:48][N:49]=2)[CH2:40][CH2:39]1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: BrCC1CC1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: COC(CN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1)C1CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using bromomethyl -cyclopropane and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8])[CH3:2].[CH2:21](OC(C1NC2C(C=1)=CC([N+]([O-])=O)=CC=2)=O)C.C(NCCN)CC>>[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH3:21]
Reactant: CCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCCNCCN
Product: CCCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 85 %

Procedure:
A similar procedure as described for preparation of 77 from 5-nitro-2-indolecarboxylic acid ethyl ester (0.8 g, 3.41 mmol) and N-propylethylenediamine (2 ml) gave a brown solid (0.84 g, 85%). ESI MS: 291.13 (M+H+). 1H NMR (DMSO-d6) δ 8.68 (d, 1H), 8.04 (d, 1H), 7.55 (d, 1H), 7.37 (s, 1H), 3.35 (m, 3H), 2.68 (q, 2H), 2.49 9 (q, 2H), 1.40 (tt, 2H), 0.84 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:42]([CH2:41][CH2:40][O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH:43]([CH3:44])[CH3:45])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(3-chlorophenyl)cyclo-pentyl)methyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (502) was synthesized from 5-(benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (501) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (245).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1C1=CC=CCC1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) was added dioxane (0.18 M) and p-TSA (1.1 equiv.). The solution was heated to 100° C. for 4 h. Cooled to room temperature, worked up with sat. NaHCO3 and ethyl acetate, the organic phase was dried with Na2SO4 and concentrated. The crude was purified via silica gel column chromatography eluting with 100% DCM to give 4-(cyclohexa-1,3-dienyl)-3-nitropyridine as a yellow oil (27% yield). LCMS (m/z): 203.1 (MH+), LC Rt=3.53 min, 1H-NMR (CDCl3): 9.02 (s, 1H), 8.70 (d, J=5.3, 1H), 7.30 (d, J=5.3, 1H), 6.15-6.17 (m, 1H), 6.02-6.11 (m, 2H), 2.35-2.38 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6]([NH2:11])=[CH:7][C:8]=1[O:9][CH3:10].[F:13][C:14]([F:21])([F:20])[CH:15]([OH:19])[C:16](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:12][C:16]([CH:15]([OH:19])[C:14]([F:21])([F:20])[F:13])=[N:11][C:6]=2[CH:7]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: COc1cc(N)c(N)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1OC
Temperature: 108 °C

Procedure:
4,5-Dimethoxy-benzene-1,2-diamine (2.02 g; 12.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (2.67 g; 18.5 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (40 mL) and with ethyl acetate (40 mL), then sodium bicarbonate (3.84 g; 46.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude dark orange solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a bright orange solid.