Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:52].Cl.[NH2:54][C@@H:55]([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:56]([OH:70])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=1>O1CCCC1.CO.O.O.[OH-].[Li+].C(OCC)(=O)C>[ClH:52].[ClH:52].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([NH:54][C@@H:55]([CH2:71][C:72]1[CH:73]=[C:74]([F:79])[CH:75]=[C:76]([F:78])[CH:77]=1)[C@H:56]([OH:70])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:67])([F:68])[F:69])[CH:61]=1)=[O:7]
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Reactant: CCCCN(C)Cc1cc(Br)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCN(C)Cc1cc(Br)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(F)(F)F)c2)c1
Reaction time: 16 h

Procedure:
Methyl 3-bromo-5-{[butyl(methyl)amino]methyl}benzoate prepared by the method in Example SP-190, Step 1 (200 mg, 0.64) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (60 mg, 1.3 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (445 μL, 2.6 mmol), HATU (304 mg, 0.8 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol dihydrochloride prepared by the method in Example S-2511 (315 mg, 0.7 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, and saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 656.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)#[N:33]
Reactant: N#Cc1ccccc1CBr
Reactant: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (2.79 g, 10.0 mmol) (prepared from 10,11-dihydrodebenz[b,f][1,4]oxazepine-11-one, Aldrich and piperazine, as in example 1) in DMF (25 mL) was added sodium hydride (0.56 g, 60% in oil, 14 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 10 minutes at room temperature for 20 minutes, and then treated with α-bromo-o-tolunitrile (2.35 g, 12.0 mmol, Aldrich). The resulting mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (25 mL). The mixture was separated and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate:hexane (1:2) as the eluent. The title compound was obtained as a white solid (2.34 g, 59%), m.p. 136°-138° C.; MS 395 (M+ +1).
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:40]=[C:39]([C:41]2[N:45]=C(C)O[N:42]=2)[CH:38]=[CH:37][C:21]=1[CH2:22][NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH3:33])=[C:27]([O:34][CH3:35])[CH:26]=1.[CH3:47][C:48]([CH3:50])=O.COC(OC)OC>ClCCCl.CO.[Ni]>[C:41]([C:39]1[CH:38]=[CH:37][C:21]([CH2:22][NH:23][C:24](=[O:36])[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH3:33])=[C:27]([O:34][CH3:35])[CH:26]=2)=[C:20]([NH:19][CH:48]([CH3:50])[CH3:47])[CH:40]=1)(=[NH:42])[NH2:45]
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: [Ni]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Solvent: ClCCCl
Product: COc1cc(C(=O)NCc2ccc(C(=N)N)cc2NC(C)C)cc(OC)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic acid (0.007 mL, 0.12 mmol) and sodium triacetoxyborohydride (42 mg, 0.20 mmol) were added to a suspension of compound 1g (50 mg, 0.13 mmol) and acetone (0.010 mL, 0.14 mmol) in DCE (0.5 mL). The reaction was stirred at rt for 16 h. Trimethylorthoformate (0.5 mL) was added, and the reaction was stirred at rt for 24 h. MeOH (1 mL) was added, and the reaction was stirred for 3 h. The reaction mixture was concentrated on a rotary evaporator and the residue was purified by preparative tlc (silica gel, 9:1 chloroform/methanol). This material was dissolved in a mixture of MeOH (3 mL) and TEA (0.040 mL, 0.29 mmol), and Raney nickel (washed with methanol) was added. The reaction mixture was hydrogenated overnight (50 psi), filtered, and concentrated on a rotary evaporator. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to give to give Example 11. ESI-MS m/e 385.4 (M+1).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]([O:8][C:9](OCC)(OCC)[CH2:10][CH2:11][CH3:12])[CH3:7]>>[CH2:6]([O:8][C:9](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:10][CH2:11][CH3:12])[CH3:7]
Reactant: N#CCC#N
Reactant: CCCC(OCC)(OCC)OCC
Product: CCCC(OCC)=C(C#N)C#N
Temperature: 25 °C

Procedure:
18.69 g (283 mmol) of malononitrile and 41.94 g (283 mmol) of triethylorthobutyrate are heated for 4 hours at 150° C. The reaction mixture is cooled to room temperature and, after the ethanol has been removed, distilled in vacuo. B.p.: 85° C. (3mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:20])[CH2:7]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc(C(F)(F)F)c1

Procedure:
Example 22 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-3-(trifluoromethyl)benzene (18.8 μl) to give the title compound (0.0112 g). LC-MS (System A): Rt 2.56 mins, Mass Spectrum m/z 462 [MH+].
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][C:21]=1[O:28]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2cc3c(cc2Nc2ccccc2)C(=O)NC3=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)c2cc(Nc3ccc(O)cc3O)c(Nc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 100 mg (0.26 mmol) of 4-anilino-5-(2,4-dimethoxy-anilino)-phthalimide in 8 ml of chloroform, a solution of 120 μl (1.24 mmol) boron tribromide is added dropwise at RT. The reaction mixture is stirred for 5 hours at RT, is then quenched with 5 ml of water and the phases are separated. The water phase is extracted three times with ethyl acetate. The organic phases are combined and washed twice with water, dried over magnesium sulfate and concentratedby evaporation. Excluding light, the evaporation residue is chromatographedwith ethylacetate/hexane 2:1 on a silica gel column (precoated with 0.1 g of sodium ascorbate per g silica gel) that is cooled with ice-water (double jacket), the product fractions are combined and concentrated by evaporation. Recrystallization from ethyl acetate/dichloromethane/hexane yields the title compound in the form of yellow crystals, m.p. 155°C. (decomp.), FAB-MS: 362 [M+ +H].
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].OS(O)(=O)=O.[CH3:17]O>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A 500-mL, three-necked, round bottom flask was eqipped with a teflon-coated stirring bar, soxlet extractor and condensor with drying tube at the top. The flask was charged with 10.0 g (66.6 mmol) of 4-formylbenzoic acid, about 320 mL of absolute CH3OH and 0.1 mL of concentrated H2SO4. The soxlet extractor was filled with 3 Å molecular sieve. After the solution was boiled for 48 hours, it was allowed to cool to room temperature and then was concentrated to a volume of about 50 mL, diluted with an equal amount of water, and extracted (ether 4×70 mL). The combined organic layers were washed with saturated NaHCO3 solution (5×50 mL), 0.1 NHCl (10×40 mL), H2O (2×50 mL), and saturated NaCl solution (2×50 mL). The resulting organic solution was finally dried (MgSO4, 2 h) and filtered and concentrated in vacuo. The white solid obtained was recrystallized (hexane) to give 6.3 grams (57.6%) of ester 33 mp 59.5°-60° C. [literature reports 59°-60° C.; see J. M. Landesberg, M. A. Slam, and M. Mandel J. Org. Chem., 46, 5025 (1981)]; IR (KBr) 1680-1740 cm-1 (C=O); 1H NMR (DCCl3) δ4.00 (s, 3H, OCH3), 7.80=8.32 (m, 4H, Ar-H), 10.10 (s, 1H, CHO); 13C NMR (DCCl3)ppm 52.6 [OCH3 ], Ar-C [129.6, 130.4, 135.2, 139.2], 166.0 [CO2CH3 ], 191.7 [CHO]; mass spectral data for C9H8O3 : m/e (M+): 164.0473. Found: 164.0472. ##STR19##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][CH2:34][NH2:35])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][CH2:34][NH:35][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@@H](CCN)C1
Solvent: CO
Solvent: CS(C)=O
Product: CCN1CC[C@@H](CCNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 130 °C
Yield: 46.8 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.2 g) and 2-((R)-1-ethylpyrrolidin-3-yl)ethylamine (Intermediate 203, 2.0 g) in DMSO (2 mL) was divided between two sealed vials and each was stirred and heated at 130° C. for 24 hours. After cooling, the combined mixture was diluted with methanol and then concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.125 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:18][NH2:19]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:19][CH3:18])[N:3]=1
Reactant: CN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Product: CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(methylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, methylamine hydrochloride, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[O:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: NC1CCOCC1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCOCC1
Temperature: 98 °C
Reaction time: 23 h
Yield: 90.6 %

Procedure:
A 3-neck flask (200 mL) was charged with 1-fluoro-2-nitro-4-trifluoromethylbenzene (1.59 g, 7.61 mmol), 4-aminotetrahydropyran (1.00 g, 9.89 mmol), and pyridine (16 mL), and this was stirred at 98° C. for 23 hours. The yellow oil produced was allowed to cool, distilled water (approx. 20 mL) was added with stirring, and the precipitated crystals were filtered off. These were washed with distilled water and dried with heating at reduced pressure to yield the title compound (2.00 g, 90.5% yield) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:16])[CH:10]=1)[CH3:8])=[CH2:5].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][C:2]([CH3:17])([CH3:1])[CH2:3][C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:22]([CH:21]=[CH2:20])(=[O:24])=[O:23])=[C:11]([I:16])[CH:10]=1)[CH3:8])=[CH2:5]
Reactant: C=C(CC(C)(C)C)NC(C)c1ccc(N)c(I)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1ccc(C(C)NC(=C)CC(C)(C)C)cc1I
Temperature: 0 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
4-{1-[1-(2,2-Dimethylpropyl)vinylamino]ethyl}-2-iodophenylamine (218.1 mg, 0.65 mmol) was dissolved in methylene chloride. The reaction mixture was cooled down to 0° C. 2-Chloroethane sulfonyl chloride (3 eq, 1.95 mmol, 203.64 μl) and Pyridine (3 eq, 1.95 mmol, 157.71 μl) were added into mixture. The reaction mixture was stirred for 48 hrs. After confirming the completion of the synthesis, a reaction solvent was removed in vacuo. A residue was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over NaSO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=3:1) to yield title compound (104.9 mg, 78%) as a brownish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:24]3[N:25]=[C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])[S:22][CH:23]=3)=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 4-chlorophenyl isocyanate and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 8.912 (s, 1H), 8.870 (s, 1H), 8.820-8.792 (d, 1H), 8.318 (s, 1H), 8.052-8.024 (d, J=8.4 Hz, 2H), 7.590-7.561 (d, J=8.7 Hz, 2H), 7.521-7.492 (d, J=8.7 Hz, 2H), 7.356-7.326 (d, J=9 Hz, 2H), 4.395-4.343 (t, J=7.8 Hz, 1H), 3.700 (s, 3H), 2.319-2.273 (m, 1H), 1.000-0.953 (t, J=6.9, 7.2 Hz, 6H); MS (ESI) m/z 485 (M−H), 487 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li]CCCC.[C:16]1([C:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:23]2[CH:27]=[C:26]([CH2:28][CH2:29][CH:30]=[O:31])[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.[Cl-].[NH4+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([CH:30]([OH:31])[CH2:29][CH2:28][C:26]3[N:25]=[CH:24][N:23]([C:22]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:27]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc2cc(F)ccc2s1
Temperature: -40 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of 5-fluorobenzo[b]thiophene (1.22 g) in THF (22 ml) was added n-BuLi (1.6 M solution in hexane, 5.0 ml) at −78° C., and the mixture was stirred for 1 hour. To this mixture was added a solution of 3-(1-triphenylmethyl-1H-imidazole-4-yl)propanal (2.93 g) in THF (10 ml), and the mixture was allowed to warm to −40° C. over 1 hour. The mixture was diluted with 10% aqueous ammonium chloride, warmed to room temperature, and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel using hexane-ethyl acetate (1:1) as an eluent to give the titled compound as colorless crystals (2.58 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCN(CC)CC>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccsc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(CN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccsc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115 %

Procedure:
To a solution of 0.13 g (0.48 mmol) of 1-benzyl-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine and 0.13 g (0.67 mmol) of 4-phenylpiperidine in 2 mL of dichloroethane and 0.1 mL of Et3N at rt was added 0.21 g (0.96 mmol) of sodium triacetoxyborohydride. After stirring for 3 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 1:3) to give 0.23 g of the title compound. 1H NMR CDCl3) δ7.21-7.44 (m, 11H), 7.07-7.13 (m, 2H), 3.74 (d, 1H, J=12.8 Hz), 3.67 (d, 1H, J=13.1 Hz). Mass Spectrum (CI) m/e=417 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2ccc(F)cc2)s1
Temperature: 85 °C
Yield: 3.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) in toluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronic acid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL), Pd(PPh3)4 (1.5 g, 1.3 mmol) under argon atmosphere. The resulting mixture was heated at 85° C. for 6 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (150 mL), and extracted with ethyl acetate (5×500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressures to obtain crude product. The crude product was purified by Combiflash® chromatography (Mobile phase: 10% ethyl acetate in hexane) to give 2-(4-fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 8.74 (s, 1H), 8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]+ 208.02. found 207.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]1[O:59][C:53]2([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[O:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:52]1[C:53]2([CH2:58][CH2:57][N:56]([C:15](=[O:17])[C@@H:14]([NH:13][C:11]([C:9]3[NH:8][C:5]4=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:55][CH2:54]2)[O:59][CH2:50][CH2:51]1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: C1CC2(CCN1)OCCO2
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: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC2(CC1)OCCO2)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (4 mL) was added HATU (50 mg, 0.13 mmol) and the reaction stirred for 10 min. 4-Piperidone ethylene ketal (19 mg, 0.13 mmol) was added, followed by DIPEA (23 μL, 0.13 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with 1M HCl solution (15 mL), sodium bicarbonate solution (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (9:1) as the eluent gave the title compound as a pale yellow powder. (ES+)=487.30 [M+H]+; RT=3.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6][OH:7].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([Si:23]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:26])[CH3:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzyl alcohol (2.15 g, 11.75 mmol) and imidazole (880 mg, 12.94 mmol) in dry dichloromethane (58 ml) at 0° C. was quickly added tert-butyldimethylchlorosilane in one portion and the mixture was stirred at for 1 hour. LC-MS analysis indicated complete conversion. The solution was washed with ice cold water (50 ml) dried over Na2SO4, adsorbed on silicagel and purified by HPLC with hexanes/ethyl acetate 20-30% gradient to give compound 5 as a light yellow solid (3.3 g, 94%). MS (EI+): 282 (M-Me); 240 (M-tBu); H-NMR (400 MHz, CD2Cl2): 7.85 (1H, d, J=8 Hz) 7.19 (1H, s) 6.98 (1H, dq, J=8 Hz, 0.4 Hz) 4.82 (2H, s) 3.99 (3H, s) 1.0 (9H, s) 0.17 (6H, s). C-NMR (400 MHz, CD2Cl2): 153.96, 150.05, 138.73, 126.32, 117.74, 111.26, 64.65, 57.06, 26.30, 18.90, −4.97.