Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[N:2]1.[OH-].[K+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[N:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1n[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=O)c2ccccc21
Reaction time: 1 h

Procedure:
The synthesis was performed with reference to the known literature (Tetrahedron, Vol. 63, p. 419, 2007). A solution of 1H-indazole-3-carboxaldehyde (0.888 g, 6.08 mmol) in methylene chloride (8 mL) was added with 50% aqueous potassium hydroxide (6 mL) and tetrabutylammonium bromide (0.0196 g, 0.0608 mmol), and the mixture was cooled on ice. The reaction mixture was added dropwise with 2-(trimethylsilyl)ethoxymethyl chloride (1.18 mL, 6.67 mmol), and the mixture was stirred for 1 hour under ice cooling, and then at room temperature overnight. The reaction mixture was added with water (30 mL), and the mixture was extracted three times with methylene chloride. The organic layer was dried over magnesium sulfate, and concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxaldehyde.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=1.C(N)CN>CCOCC>[S:10]1[CH:11]=[CH:12][C:8]2[CH:7]=[CH:6][C:5]([C:2]#[N:3])=[CH:13][C:9]1=2
Reactant: N#C[Cu]
Reactant: Brc1ccc2ccsc2c1
Solvent: CCOCC
Solvent: NCCN
Product: N#Cc1ccc2ccsc2c1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
Heat copper(I) cyanide (0.84 g, 9.4 mmol) and 6-bromobenzo[b]thiophene (prepared as described in WO 01/23381) (1.0 g, 4.7 mmol) at 160° C. for 13 h. Cool the mixture to 0° C., add 33% aqueous ethylenediamine (20 mL) and dilute with ether. Wash the organic mixture with brine, dry over Na2SO4 and evaporate. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:3) to give the desired intermediate (0.58 g, 78%). GC-MS m/z: 159 (M+).
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[Na].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][SH:33]>CO>[CH3:36][O:35][C:31]([CH2:32][S:33][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:34]
Reactant: COC(=O)CS
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CO
Product: COC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1.93 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol is added a solution of 0.64 g of methyl thioglycolate sodium salt with stirring under ice-cooling. After 1 hour, the solvent is distilled off and the residue is dissolved in ethyl acetate. The solution is washed with water, then the solvent is distilled off, and the residue is purified by silica gel column-chromatography (methylene chloride: ethyl acetate=11:1) to give 1.38 g of (3R,4R)-4-methoxycarbonylmethylthio-3-tritylamino-2-oxoazetidine (A) and 0.92 g of the corresponding (3R,4S)-isomer (B)
Reaction SMILES: O.[ClH:2].C(N(CC)CC[O:8]C1C=CC(C(N2CC(=CC3C=CC=CC=3)C(=O)C(=CC3C=CC=CC=3)C2)=O)=CC=1)C.[CH2:40]([N:42]([CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([C:54](N2CC(=CC3C=CC=CC=3)C(=O)C(=CC3C=CC=CC=3)C2)=[O:55])=[CH:50][CH:49]=1)[CH2:43][CH3:44])[CH3:41].Cl.[S:78]1[CH:82]=[CH:81][CH:80]=[C:79]1[CH:83]=[C:84]1[C:89](=[O:90])[C:88](=[CH:91][C:92]2[S:93][CH:94]=[CH:95][CH:96]=2)[CH2:87][NH:86][CH2:85]1>>[ClH:2].[OH2:8].[ClH:2].[CH2:43]([N:42]([CH2:40][CH3:41])[CH2:45][CH2:46][O:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]([N:86]2[CH2:85][C:84](=[CH:83][C:79]3[S:78][CH:82]=[CH:81][CH:80]=3)[C:89](=[O:90])[C:88](=[CH:91][C:92]3[S:93][CH:94]=[CH:95][CH:96]=3)[CH2:87]2)=[O:55])=[CH:52][CH:53]=1)[CH3:44]
Reactant: CCN(CC)CCOc1ccc(C(=O)N2CC(=Cc3ccccc3)C(=O)C(=Cc3ccccc3)C2)cc1
Reactant: O=C1C(=Cc2cccs2)CNCC1=Cc1cccs1
Agent: Cl
Solvent: O
Product: CCN(CC)CCOc1ccc(C(=O)N2CC(=Cc3cccs3)C(=O)C(=Cc3cccs3)C2)cc1

Procedure:
Following the above procedure described for compound 4a, the reaction of 3,5-bis(thiophen-2-ylmethylene)-piperidin-4-one with V. HCl (X=CO, T=OH, Y=O, o=2, Z=N(C2H5)2) (0.015 mol) afforded 9a, m.p. 193-194° in 82% yield. δ (CDCl3): 1.44-1.47 (t, 6H, 2×CH3), 3.17-3.31 (m, 4H, 2×NCH2), 3.56 (br s, 2H, NCH2), 4.53 (t, 2H, OCH2), 4.93 (br s, 4H, 2×NCH2), 6.75-6.77 (d, 2H, C2—H &C6—H), 7.18-7.19 (t, 2H, 2×C3′—H), 7.38-7.40 (d, 4H, C3—H, C5—H & 2×C4′—H), 7.66-7.67 (d, 2H, C2′—H), 12.67 (s, 1H, NH). Found C, 59.90%; H, 5.76%; N, 4.81%. C28H31ClN2O3S2.H2O requires C, 59.92%; H, 5.56%; N, 4.99%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cn1c(C(=O)O)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 96.7 %

Procedure:
To a suspension of methyl 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.00 g, 10.5 mmol) in 1,4-dioxane (50 ml) was added an aqueous solution (20 ml) of lithium hydroxide monohydrate (1.32 g, 31.5 mmol). The obtained mixture was refluxed under heating for 24 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained, crystals were recrystallized from tetrahydrofuran-n-hexane to give 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (4.69 g, 96.7%) as crystals.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:26])[CH2:19][C:20](=[O:25])[C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:26])[CH2:19][C:20](=[O:25])[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
There was dissolved in 15 ml of tetrahydrofuran and 3.75 ml of 2 N sodium hydroxide 1.09 g (3 mMol) of the ester product prepared in Step B above; and the reaction mixture was stirred overnight at room temperature, whereupon a solid precipitated. Then, 4 ml of 2 N hydrochloric acid was added, and the mixture was stirred well. The tetrahydrofuran layer was then separated, and the aqueous layer was extracted twice with 20 ml of diethyl ether. The combined organic layers were dried and evaporated. The oily residue solidified on standing. The material was crystallized from carbon tetrachloride, whereupon a yellow solid was obtained (370 mg), m.p. 133°-140° C. The material was crystallized again from carbon tetrachloride, m.p. 142°-144° C. Analysis:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=O)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[C:29]1(B(O)O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]2[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=2)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:20])[CH3:21])=[O:4]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.2 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (0.20 g, 0.515 mmol) was dissolved in dichloromethane (1.0 mL) and HCl (4M dioxane, 1 mL) was added. The resultant suspension was stirred at room temperature for 60 minutes, after which all volatiles were removed in vacuo. The crude material was combined with phenyl boronic acid (188 mg, 1.545 mmol) and DCM (15 mL) was added. Triethylamine (1.2 mL, 8.89 mmol) was added, followed by copper(II) acetate and molecular sieves 4 Å. The reaction was stirred at room temperature. After 24 hrs, the reaction was quenched with aqueous ammonium hydroxide solution (10%) and the organic layer was isolated. The organic layer was washed with aqueous HCl solution (0.5 M), brine, and was dried over sodium sulfate. Filtration and evaporation gave crude material. Purification via flash chromatography on silica gel (eluent: EtOAc/hexanes) yielded the desired product 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1-phenyl-imidazolidine-4-carboxylic acid methyl ester (51.0 mg, 0.14 mmol): LCMS-ESI+: calc'd for C18H25N3O5: 363.4 (M+). Found: 364.4 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=2)=[O:15])=[C:5]([OH:9])[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(O)c1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: CCc1ccc(C(=O)c2cccc(F)c2)c(O)c1
Temperature: 105 °C

Procedure:
This compound was prepared from 3-ethylphenol (12.2 g), 3-fluorobenzoyl chloride (17.5 g) and aluminium chloride (26.7 g) in 1,1,2,2-tetrachloroethane (75 ml) using the same conditions as in Example 2, but heating under reflux, not at 105° C. The product was purified by chromatography on a silica column m.p. between 0° and 20° C. ηo22 1.5962. The same product was obtained using the method of Example 4.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@:7]([CH2:21][O:22][SiH3])(C(C)(C)C)[C:6]1(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:7]([CH2:21][OH:22])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)[C@@](CO[SiH3])(C(C)(C)C)C1(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
To a stirred mixture of (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenyl silyloxy methypyrrolidine (23.3 g, 46.9 mmol) and acetic acid (6.0 ml, 104.8 mmol) in THF (470 ml) was added TBAF (93.8 ml, 93.8 mmol) at 0° C. After 24 h stirring, the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAC and aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, which were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (4/1)], to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 8%) as a colorless oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.63 (m, 1H), 1.81 (m, 1H), 2.07 (s, 3H), 2.34 (m, 1H), 3.42 (dd, J=12.7, 0.9 Hz, 1H), 3.62–3.85 (m, 31H), 4.48 (br, 1H), 5.20 (br, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(5-methylthiophene-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 9, step a) (0.32 g) in DCM (3 mL) was treated with trifluoroacetic acid (1.0 g). After 2 h, the reaction mixture was evaporated in vacuo and azeotroped twice with toluene to yield the subtitled compound which was used directly. Yield 0.32 g.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClC(Cl)C(C1C(=O)N(C)C(=O)N(C)C1=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:22]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]([CH:8]2[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]2=[O:7])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: CN(C)c1ccncc1
Agent: CN1C(=O)C(C(=O)C(Cl)Cl)C(=O)N(C)C1=O
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C(c2ccccc2)c2ccccc2)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), diphenylacetic acid (10.19 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7:26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from EtOH giving 5-diphenylacetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 9 (6.70 g, 59%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10](F)[C:9]=1[CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C1C[O:34]CC1>>[CH2:1]([C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:34])[C:9]=1[CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(OCCc3c(Cc4ccccc4)ccnc3F)ccnc2c1
Reactant: C1CCOC1
Agent: Cl
Product: COc1ccc2c(OCCc3c(Cc4ccccc4)cc[nH]c3=O)ccnc2c1
Temperature: 70 °C

Procedure:
An NMR tube was charged with 4-(2-(4-benzyl-2-fluoropyridin-3-yl)ethoxy)-7-methoxyquinoline (0.0061 g, 0.016 mmol), 0.5 mL THF and 0.2 mL 35% HCl. The tube was heated to 70° C. for 40 h, and cooled. The solvent was removed under a stream of nitrogen, and the residue was diluted to 0.6 mL with MeOH, and treated with Si-carbonate (0.022 g, 0.016 mmol). The solution was filtered and concentrated in vacuo. A sample was scouted for prep purification using a 2.1×50 mm Xterra MS C18 column with a 3.5 μm particle size (PN 186000400); A=11 mM NH4HCO3 in water, pH adjusted to 8.5 with concentrated NH4OH; B=Acetonitrile; gradient: initial@1 mL/min, 10% B; 0→5 min@1 mL/min, linear gradient to 100% B; 5→6.9 min@1 mL/min, isocratic at 100% B; 6.9→6.95 min@1 mL/min, linear gradient to 110% B, 8 min end. A major peak was observed at 3.07. The sample was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 25% B; 5.0→35 min@20 mL/min, linear gradient to 55% B; 35→45@20 mL/min, isocratic at 55% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 25% B; 60 min end). A=11 mM NH4HCO3 in water, pH adjusted to 8.5 with concentrated NH4OH; B=Acetonitrile. A band that eluted from 20.9-21.9 minutes was isolated. The solvent was removed in vacuo to afford 4-benzyl-3-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1 H)-one. 1H NMR (400 MHz, CDCl3) δ ppm 3.28 (t, J=6.75 Hz, 2 H) 3.93 (s, 3 H) 4.07 (s, 2 H) 4.36 (t, J=6.65 Hz, 2 H) 6.09 (d, J=6.75 Hz, 1 H) 6.66 (d, J=5.38 Hz, 1 H) 7.08 (dd, J=9.15, 2.49 Hz, 1 H) 7.13-7.17 (m, 2 H) 7.19-7.25 (m, 2 H) 7.26-7.32 (m, 2 H) 7.34 (d, J=2.54 Hz, 1 H) 8.03 (d, J=9.19 Hz, 1 H) 8.62 (d, J=5.18 Hz, 1 H) 11.96 (br. s., 1H). 13C NMR (101 MHz, CDCl3) δ ppm 26.72 (s, 1 C) 38.97 (s, 1 C) 55.43 (s, 1 C) 66.50 (s, 1 C) 99.65 (s, 1 C) 107.20 (s, 1 C) 109.62 (s, 1 C) 116.02 (s, 1 C) 118.12 (s, 1 C) 123.11 (s, 1 C) 126.28 (s, 1 C) 126.79 (s, 1 C) 128.73 (s, 2 C) 128.81 (s, 2 C) 131.53 (s, 1 C) 138.24 (s, 1 C) 151.17 (s, 1 C) 151.82 (s, 1 C) 152.21 (s, 1 C) 160.85 (s, 1 C) 161.60 (s, 1 C) 164.55 (s, 1 C). MS (ESI pos. ion) m/z (MH+): 387.2, calcd for C24H22N2O3+H+=387.2.
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:13].[K+].[K+].S(=O)(=O)(O)O>O>[F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])[C:3]([OH:13])=[O:4]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)C(F)(F)C(F)C(F)(F)F
Temperature: 100 °C
Yield: 91.8 %

Procedure:
First, 9.1 g (50 mmol) of 2,2,3,4,4,4-hexafluorobutan-1-ol was dissolved in 40 ml of water, to which 14.7 g (50 mmol) of potassium dichromate and 17 ml of concentrated sulfuric acid, and the mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 9.0 g of 2,2,3,4,4,4-hexafluorobutyric acid.
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[C@@H:29]([OH:41])[C@@H:30]([NH2:40])[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>ClCCl.C(OCC)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[C@@H:29]([OH:41])[C@@H:30]([NH:40][C:1](=[O:3])[CH3:2])[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Add 1-acetylimidazole (0.035 g, 0.315 mmol) and triethylamine (0.04 mL, 0.286 mmol) to solution of 2-(R)-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-piperidine-1-carboxylic acid tert-butyl ester (0.106 mg, 0.286 mmol) in dichloromethane (10 mL) and stir 18 h at room temperature. Dilute with ethyl acetate and wash with 1 N hydrochloric acid (3×), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with dichloromethane and ethyl acetate) to give the title compound as a white solid (0.089 g, 76%).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH2:25][CH2:24]2)=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][N:31]([C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[C:2]([NH:1][CH3:4])=[O:3])[CH2:27][CH2:28]2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Yield: 59 %

Procedure:
A mixture of 1.1 parts of isocyanatomethane, 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[2-thiazolylamino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (59%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-methyl-N-(2-thiazolyl)urea; mp. 171.9° C. (compound 103).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][C:28](=[O:30])[NH:29][C:22]=23)=[CH:18][CH:17]=1>C1COCC1>[O:30]=[C:28]1[NH:27][C:23]2=[N:24][CH:25]=[CH:26][C:21]([O:20][C:19]3[CH:31]=[CH:32][C:16]([NH:15][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:14])([F:12])[F:13])[CH:4]=4)=[S:10])=[CH:17][CH:18]=3)=[C:22]2[NH:29]1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c2nccc(Oc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)c2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
A mixture of 4-chloro-3-trifluoromethylphenyl-isothiocyanate (20 μL, 0.12 mmol) and 7-(4-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (29 mg, 0.12 mmol) in anhydrous THF (2 mL) was stirred at room temperature for 3 days. The solvent was evaporated and the solid residue was washed with DCM to afford the title compound (47 mg, 82%). 1H-NMR (δ, ppm, DMSO-d6): 6.40 (d, 1H, HPy,6, J=5.8 Hz), 7.15 (d, 2H, Harom,Ph,3+5, J=8.70 Hz), 7.54 (d, 2H, Harom,Ph,2+6, J=8.75 Hz), 7.67 (d, 1H, HPy,6, J=8.55 Hz), 7.80 (broad s, 2H, Harom′), 8.08 (s, 1H, Harom′), 10.03 (s, 1H, NHthiourea,1), 10.10 (s, 1H, NHthiourea,3), 11.18 (s, 1H, NHPy3), 11.36 (s, 1H, NHPy2).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:8]2[CH2:12][C@H:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Br:23][CH2:24][CH2:25][CH2:26]Br>O1CCCC1>[Br:23][CH2:24][CH2:25][CH2:26][C@@:11]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12][C@H:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:9]=[CH:10]1
Reactant: Cc1ccc(C)n1C1C=C[C@@H](C(=O)OCc2ccccc2)C1
Reactant: BrCCCBr
Solvent: C1CCOC1
Product: Cc1ccc(C)n1[C@@H]1C=C[C@](CCCBr)(C(=O)OCc2ccccc2)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of Example 48A (21.94 g, 74.4 mmol) in tetrahydrofuran (200 ml) was added dropwise lithium hexamethyl bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 119 mL) at −50° C. The reaction mixture was stirred for 1 hour at the same temperature. 1,3-dibromopropane (150 g, 744 mmol) was added dropwise over 1 hour. The reaction mixture was allowed to warm to −20° C. and stirred at the same temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was quenched with an aqueous ammonium chloride solution (6%, 600 mL), and extracted with ethyl acetate. The organic fraction was washed with aqueous ammonium chloride (6%), brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:1) to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[I:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CI
Reactant: Ic1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(I)ncnc21

Procedure:
206 mg (0.84 mmol) of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 1 mL DMF. 37 mg (0.92 mmol) of 60% sodium hydride was added followed by 58 μL (0.92 mmol) of iodomethane. The reaction was quenched by adding 10 mL of water, the solid filtered off, washed with 10 mL of water, then 10 mL of hexanes and dried. Yield: 142 mg of a tan powder, 90% pure.