Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)c1nc(CCl)cs1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1csc(C(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-thiazole (1.90 g) and triethyl phosphite (3.49 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-isopropyl-1,3-thiazol-4-yl)methyl]phosphonate as a pale-yellow oil (2.48 g, yield 83%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH:9]([N:11]3[CH2:16][CH2:15][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:17](O)=[O:18])[CH2:13][CH2:12]3)[NH:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])([CH3:29])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:26]([C:30]1[CH:31]=[C:32]([NH:33][C:17]([C:14]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13][CH2:12][N:11]([C:9]3[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=[CH:7][N:8]=3)[CH2:16][CH2:15]2)=[O:18])[CH:34]=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: Cc1c[nH]c2c1C(N1CCC(C(=O)O)(c3ccccc3)CC1)NC=N2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(C(C)(C)C)c4)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-phenylpiperidine-4-carboxylic acid from step B (33 mg, 0.1 mmol) in DMF (2 mL) was added 3-tert-butylaniline (15 mg, 1.0 mmol), BOP (50 mg, 0.11 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was stirred at room temperature for 20 hours, and the amide product was isolated by prep HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)=[O:14])C#N>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)=[O:14]
Reactant: COc1ccc(C(C#N)C(=O)c2ccnc(C)c2)c(Cl)c1
Agent: Br
Product: Cc1cc(C(=O)Cc2ccc(O)cc2Cl)ccn1

Procedure:
2-(2-Chloro-4-methoxy-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propionitrile (1.2 g, 4.0 mmol) was suspended in aqueous HBr (48%, 12 mL) and heated to reflux overnight. Upon cooling, the precipitated yellow solid was filtered and dried. The product (420 mg, 40%) was used in the next step without further purification. 1H NMR (300MHz, DMSO-D6) □ 8.84 (1H, d), 8.09 (1H, s), 7.97 (1H, d), 7.19 (1H, d), 6.85 (1H, d), 6.73 (1H, dd), 4.49 (2H, s), 2.69 (3H, s); MS (m/e)=262.0 [MH+].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1)=[N:4]O>[OH-].[NH4+].CO.[Ni]>[F:19][C:2]([F:1])([F:18])[CH:3]([NH2:4])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: ON=C(c1cccc(N2CCOCC2)c1)C(F)(F)F
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Reaction time: 16 h
Yield: 100 %

Procedure:
A suspension of 2,2,2-trifluoro-1-(3-morpholin-4-yl-phenyl)-ethanone oxime (1.37 g) and Ra—Ni (1 mL) in a mixture of 3 ml of 30% ammonium hydroxide and 15 mL of MeOH was hydrogenated at 60 psi for 16 hours. The crude reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound as an oil (1.3 g).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc([C@@H]2C[C@H]2NCC2CCNCC2)cc1
Yield: 58.9 %

Procedure:
To the solution of 1,1-dimethylethyl 4-({[trans-2-phenylcyclopropyl]amino}methyl)-1-piperidinecarboxylate (Example 1) (50 mg, 0.151 mmol) in 1,4-dioxane (1 mL) was added 1 M HCl (1 ml, 32.9 mmol) and the reaction mixture was heated to reflux for 10 minutes. The reaction mixture was then evaporated. [trans-2-phenylcyclopropyl](4-piperidinylmethyl)amine (25 mg, 0.089 mmol, 58.8% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.45 (m, 2H), 7.16-7.29 (m, 3H), 3.47 (d, J=13.39 Hz, 2H), 3.22 (d, J=7.07 Hz, 2H), 2.96-3.14 (m, 3H), 2.63 (ddd, J=3.66, 6.63, 10.42 Hz, 1H), 2.04-2.26 (m, 3H), 1.49-1.70 (m, 3H), 1.35-1.46 (m, 1H); LC-MS Rt=0.39 min; MS (ESI): 231.2 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC(N(C)C)=O.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:20][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCOc1ccc(C(=O)O)o1
Reaction time: 42 h

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 75.4 g (0.471 mole) of decanol and 1000 ml of dried dimethyl acetamide is stirred at room temperature after which 15.0 g (0.628 mole) of sodium hydride is added. The mixture is refluxed with stirring for 42 hours after which the mixture is poured into a water-ice mixture, acidified with acetic acid and extracted with ether. The ether layer is washed several times with water and salt water, then dried over sodium sulfate, filtered and evaporated on a steam bath replacing the ether with hexane and allowing the mixture to crystallize. The solid obtained is recrystallized from methanol to give 5-decyloxy-2-furoic acid, M.P. 124°-126° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:13]1[C:21]2[C:16](=[C:17]([N:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)([CH3:12])([CH3:11])[CH3:10].[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.Cl>C1COCC1>[C:9]([N:13]1[C:21]2[C:16](=[C:17]([N:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[B:31]([OH:36])[OH:32])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)N(c1cccc2c1ccn2C(C)(C)C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N(c1cccc2c1cc(B(O)O)n2C(C)(C)C)C(C)(C)C
Reaction time: 1 h

Procedure:
A THF solution of lithium diisopropylamide prepared above was added in an ice bath dropwise to a THF (5 mL) solution of 1-(tert-butyl)-4-(di-tert-butyl)aminoindole (300 mg, 0.694 mmol) and triisopropyl borate (157 mg, 0.832 mmol) which was separately prepared. After the reaction solution was stirred in an ice bath for 1 hour, the solution was adjusted to pH3 with adding a 1M HCl solution. The resulting solution was extracted with ethyl acetate (15 mL×2), and the combined solution was dried over anhydrous magnesium sulfate to afford the crude product 53 of 1-(tert-butyl)-4-(ditert-butyl)amino-2-indoleboronic acid. The crude product was used for the next reaction without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[CH2:13][CH2:14][O:15][C:16](=[O:17])[C@H:10]2[CH2:9]1)[C:2]1C=CC=CC=1.Br.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C(O)C.C(Cl)(Cl)Cl>[CH2:14]([O:15][C:16]([CH:10]1[CH:11]2[CH2:12][N:8]([CH2:1][CH2:2]2)[CH2:9]1)=[O:17])[CH3:13]
Reactant: O=C1OCC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: Br
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C1CN2CCC1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 56.4 %

Procedure:
(±) cis-2-benzyl-hexahydropyrano[3,4-c]pyrrole-4(1H)-one (D20) (180 g, 0.78 mole) in ethanol (400 ml) was stirred and cooled to 0° C. and hydrogen bromide gas introduced at such a rate that the temperature did not rise above 20° C. until the solution was saturated. The reaction was allowed to stand at room temperature for 6 h. The reaction was then poured into a well stirred mixture of chloroform (2 L) and saturated aqueous potassium carbonate solution (1.5 L) which was cooled by the addition of solid carbon dioxide. The organic layer was separated and the aqueous layer extracted with chloroform (4×1 L). The combined organic extracts were dried (Na2SO4) concentrated in vacuo to a gum. The gum was then stirred with ether (3×750ml) to remove any unreacted starting material and the ether insoluble gum dissolved in ethanol (1 L). Palladium on charcoal 10% (20 g) was then added and the mixture stirred under an atmosphere of hydrogen at 50° C. for 6 h when the uptake of hydrogen was complete. The reaction was then filtered through Kieselguhr and concentrated in vacuo to a gum. This was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum. Distillation in vacuo afforded the title compound (D21, 75 g, 0.44 mole, 56%) as an oil b.p. 90°-95° C.0.5mmHg
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].Br[CH2:16][C:17]([CH3:34])=[CH:18][CH2:19][C:20]1[C:28]([OH:29])=[C:27]2[C:23]([CH2:24][O:25][C:26]2=[O:30])=[C:22]([CH3:31])[C:21]=1[O:32][CH3:33].[Cl-].[NH4+].Cl>C1COCC1.[Cu]I>[CH2:9]([O:8][P:7]([CH2:6][CH2:16][C:17]([CH3:34])=[CH:18][CH2:19][C:20]1[C:28]([OH:29])=[C:27]2[C:23](=[C:22]([CH3:31])[C:21]=1[O:32][CH3:33])[CH2:24][O:25][C:26]2=[O:30])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:10]
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Reactant: CCOP(C)(=O)OCC
Agent: [Cu]I
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)OCC
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6 M in hexanes, 1 mL) was added to an equal volume of THF at −20° C. A solution of diethyl methylphosphonate (220 mg, 1.45 mmol) in THF (1 mL) was then added dropwise and the solution was stirred for 30 minutes. After cooling at −60° C., the solution was transferred via a cannula to a vial containing copper(I) iodide (276 mg, 1.45 mmol), and the resulting mixture was stirred for 1 h at −30° C. A solution of 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one 158B (50 mg, 0.15 mmol) in THF (1 mL) was added and the mixture was allowed to warm to 0° C. for 2 h before saturated aqueous ammonium chloride was added. The reaction mixture was acidified with 2 N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was chromatographed on silica gel (40% to 100% ethyl acetate/hexanes), affording [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonic acid diethyl ester 158C as an oil (27 mg, contaminated with the starting diethyl methylphosphonate); 1H NMR (300 MHz, CDCl3) δ 1.32 (m, 6H), 1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J=7.2 Hz, 1H), 7.65 (s, 1H) ppm.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=3)[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3cccc(Cl)c3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 3-chlorophenyl isocyanate to give the title compound as a colorless solid. MS: 552.7 ([M+H]+)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])(=O)=O.B1(C=C)OB([CH:58]=[CH2:59])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:58]([C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])=[CH2:59]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(-c2cc3cc(CN4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 82 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (46.0 mg, 0.0611 mmol) was dissolved in dimethoxyethane (2.8 mL), and the solution was treated with 2,4,6-trivinylcyclotriboroxane-pyridine complex (32 mg, 0.13 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (4.4 mg, 0.0054 mmol), potassium carbonate (46 mg, 0.34 mmol) and water (0.024 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 4-vinyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (31.6 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[C:13]([C:20](O)=[O:21])=[N:14][N:15]([CH:17]3[CH2:19][CH2:18]3)[CH:16]=2)[CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:12]3[C:13](=[N:14][N:15]([CH:17]4[CH2:18][CH2:19]4)[CH:16]=3)[C:20]2=[O:21])[CH:3]=1
Reactant: Cn1cc(NC(c2ccc(Cl)cc2)c2cn(C3CC3)nc2C(=O)O)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: Cn1cc(N2C(=O)c3nn(C4CC4)cc3C2c2ccc(Cl)cc2)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-1H-pyrazole-3-carboxylic acid (Step 37.5). tR: 4.08 min (HPLC 1); tR: 0.92 min (LC-MS 2); ESI-MS: 415 [M+H]+ (LC-MS 2); Rf=0.22 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.05 (m, 2H) 1.09-1.15 (m, 2H) 3.43 (s, 3H) 3.84-3.94 (m, 1H) 6.17 (s, 1H) 7.20-7.26 (m, 2H) 7.33-7.38 (m, 2H) 7.87-7.95 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](=[O:36])[NH:15][C:16]1[CH:17]=[C:18]2[C:34](=[O:35])[NH:33][N:32]=[CH:31][C:20]3=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][C:23]([CH:24]=1)=[C:19]23)=O)(C)(C)C.Cl.O1CCOCC1>>[O:35]=[C:34]1[C:18]2[C:19]3[C:20](=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][C:23]=3[CH:24]=[C:16]([NH:15][C:14]([C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[O:36])[CH:17]=2)[CH:31]=[N:32][NH:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@@H]4CCCCN4)cc1c23

Procedure:
Preparation of the title compound from Intermediate 137(a) (0.16 g, 0.33 mmol) and 4M HCl in dioxane (1.6 mL, 6.6 mmol) was carried out analogously to Example 91. Isolation, also in an analogous manner, included a further trituration with CH2Cl2/diethyl ether and afforded the title compound (0.132 g) as an orange/yellow powder in 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH2:17]([C:20]1[N:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[C:22]([CH:29]=O)[CH:21]=1)[CH2:18][CH3:19]>>[C:25]([N:24]1[C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][C:22]([CH2:29][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:23]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Product: CCCc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1C(C)(C)C
Yield: 76.7 %

Procedure:
Compound 62 was prepared using the same method as Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]3[O:26][C:16]4=[N:17][C:18](=[O:25])[CH:19]=[C:20]([CH2:21][S:22][CH2:23][CH3:24])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1([O-])OO1.[OH2:33].[OH2:34].O.O.[Na+].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O>[CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][C@H:13]3[O:26][C:16]4=[N:17][C:18](=[O:25])[CH:19]=[C:20]([CH2:21][S:22]([CH2:23][CH3:24])(=[O:34])=[O:33])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O
Reactant: CCSCc1cc(=O)nc2n1CC(COc1ccc(C3CCCCC3)cc1)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCS(=O)(=O)Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-(4-cyclohexyl-phenoxymethyl)-5-ethylsulfanylmethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.3 g, 0.75 mmol) in HOAc (20 mL) was added sodium perborate tetrahydrate (0.3 g, 1.95 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with sodium hydroxide (2N) to pH˜7 and further to pH˜10 with aqueous sodium carbonate. The mixture was extracted with EtOAc three times. The organic phase was washed with brine and dried (Na2SO4). Silica gel chromatography (MeOH/CH2Cl2) provided 0.254 g of the title compound. [α]D25 +5.45 (c 0.5, CHCl3).
Reaction SMILES: Cl.C([O:4]C(=O)[C@H](CC1C=CC=CC=1)N)C.[CH:16]([N:19]=[C:20]=[N:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>O>[CH:16]([NH:19][C:20](=[O:4])[NH:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)NC(=O)NC(C)C
Reaction time: 20 h

Procedure:
Then 11.5 g (50 mM) of Phenylalanine Ethyl Ester hydrochloride and 7.75 mL (45 mM) of diisopropylcarbodiimide were added. Then 8.6 mL (50 mM) of diisopropylethylamine was added via the dropping funnel for 10 min. The reaction mixture was kept for 20 hours at a room temperature, then 10 mL of H2O was added, a precipitate of diisopropylurea formed was filtered off, a resulted solution was analyzed by HPLC. According analysis, the reaction was completed at 50%.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([OH:5])=[O:4].[CH3:26]O.S(=O)(=O)(O)O>O>[F:1][C:2]([F:25])([C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12])[C:3]([O:5][CH3:26])=[O:4]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 89 %

Procedure:
A 2-1, four-necked, round-bottomed flask equipped with stirrer, addition funnel, thermometer and reflux condenser, is charged with 828 g (2 mol) of dried perfluorooctanoic acid, 160 g (5 mol) of methanol. The mixture is stirred and 50 ml concentrated sulfuric acid is added dropwise. Then the mixture is heated to reflux for 4 hr. At the end of the reflux period the mixture is cooled to room temperature and poured into 2 l cold water. After separation of the phases, the lower organic phase is washed with water till pH neutral and dried over CaCl2. Distillation of the crude gives 762 g (89%) of methyl perfluorooctanoate, bp 160° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:15][CH:16]1[CH2:33][N:21]2[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:32]=[C:20]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>ClCCl>[Si:8]([O:15][CH:16]1[CH2:33][N:21]2[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:32]=[C:20]2[CH2:19][NH:18][CH2:17]1)([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1Cc2nc3cnc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC1CNCc2nc3cnc4ccccc4c3n2C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Trifluoroacetic acid (500 mL of a 10% solution in dichloromethane) was added to tert-butyl 11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (9.23 g, 19.7 mmol), and the reaction was stirred at ambient temperature for 75 minutes. The solvent was removed under reduced pressure, and the residue was shaken with triethylamine (300 mL) and dichloromethane. The solution was concentrated under reduced pressure, and the product was dried under high vacuum for two hours to provide 11-{[tert-butyl(dimethyl)silyl]oxy}-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline, which was used in the next step without removing the triethylamine trifluoroacetate salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: COC(=O)CCCc1ccccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.9 %

Procedure:
To 3-bromo-4-chloro-benzoyl chloride (1.09 g, 4.3 mmol) in DCM (30 mL) cooled with an ice bath, was added 4-(2-amino-phenyl)-butyric acid methyl ester (0.85 g, 4.4 mmol), followed by addition of diisopropylethylamine (1 mL, 5.6 mmol) slowly. Upon the completion of the addition, ice bath was removed and the mixture was stirred at room temperature for 12 hrs. The mixture was further diluted with DCM, washed with saturated NaHCO3, 1N HCl, brine and dried over Na2SO4 and concentrated to yield 4-[2-(3-bromo-4-chloro-benzoylamino)-phenyl]-butyric acid methyl ester (1.8 g). MS [M+H]+: 411.7; tR=2.45 min. (method 1)