Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:18].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([F:18])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-proline, 24d, (215.3 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 170.3 mg of 25d as a colorless oil. FTIR (neat) 1850 cm−1.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[CH2:25]([N:27]=[C:28]=[S:29])[CH3:26]>C(OCC)C>[CH2:25]([NH:27][C:28]([C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1)=[S:29])[CH3:26]
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Reactant: CCN=C=S
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.03 h
Yield: 56.9 %

Procedure:
An amount (103 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in diethyl ether (0.3 ml); to the solution, 1.68 M n-butyllithium (0.18 ml) was added at 0° C. under a nitrogen atmosphere. After stirring the reaction mixture for 2 minutes, a diethyl ether solution (0.3 ml) of ethyl isothiocyanate (34 mg) was added and the mixture was stirred for 2.5 hours at 0° C. The reaction mixture was diluted with diethyl ether, washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=4/1) to give the titled compound (60 mg) as a pale yellow crystal.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH:23]=[O:24])[CH:30]=4)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 74.6 mg (0.50 mmol) of 3-formylphenylboronic acid are introduced into 1 ml of DMF. Addition of 0.75 ml of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf) is followed by heating to 80° C. After 18 h, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, mixed with a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane and again concentrated. Drying under high vacuum results in 92.4 mg (39.5% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7](=O)[C:6]=2[CH:14]=1.[NH2:15][CH2:16]C(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:16][NH:15][C:7](=[O:8])[C:6]=2[CH:14]=1
Reactant: Cn1c(=O)oc(=O)c2cc(F)ccc21
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2cc(F)ccc21
Temperature: 0 °C

Procedure:
As illustrated in the scheme above, a mixture of 6-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (1.00 g, 5.12 mmol) and glycine (0.385 g, 5.13 mmol) in glacial acetic acid (13 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Water was added to the residue, and the mixture was cooled to 0° C. NaHCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2Cl2 (4×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et2O to provide the title compound as a slightly yellow solid (0.560 g, 52%). 1H-NMR (DMSO-d6): δ 8.80 (br s, 1H), 7.49-7.38 (m, 3H), 3.76 (br d, 1H), 3.47 (br d, 1H), 3.26 (s, 3H). MS (ESI) (M+H)+=209.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[CH2:12]([NH:19][CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:12]([N:19]([C:6]1[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=[C:2]([Cl:1])[N:7]=1)[CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCNCc1ccccc1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCN(Cc1ccccc1)c1nc(Cl)nc2c1CCC2
Temperature: 27.5 °C
Yield: 99.3 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.4 g, 2.1 mmol), N-benzyl-ethylamine (0.35 mL, 2.3 mmol) and diisopropylethylamine (0.4 mL, 2.1 mmol) in anhydrous ethanol (5 mL) was heated at a temperature in the range of 20° C. to 90° C. for 18 hours. After cooling to about 20 to 35° C., the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a light pink liquid (0.60 g, 98% yield).
Reaction SMILES: [F:1][CH2:2][C:3]([O-])=O.[Na+].C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[Si:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:47]2[CH2:56][CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH:53]=3)[CH2:48]2)=[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[C:33]([F:46])[CH:32]=2)[CH:28]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.CN(C)C=O>[Si:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:47]2[CH2:56][CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60])[CH:53]=3)[CH2:48]2)=[C:27]([N:29]([CH2:3][CH2:2][F:1])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[C:33]([F:46])[CH:32]=2)[CH:28]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C([O-])CF
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCF)Cc1ccc(OCCN3CCCCC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To a solution of sodium fluoroacetate (420 mg) in dichloromethane (20 ml) were added dropwise N,N-dimethylformamide (1 drop) and oxalyl chloride (0.48 ml) on an ice bath, the solution was stirred for 20 minutes at room temperature, an aqueous solution of 1N sodium hydroxide was added thereto, the solution was stirred for 1 minute at room temperature, then a solution of {5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}[3-fluoro-4-(2-piperidin-1-yl-ethoxy)benzyl]amine (300 mg) in dichloromethane (5 ml) was added thereto followed by stirring at room temperature for 3 hours. The solution extracted with dichloromethane, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting residue according to an analogous synthetic method to Example 337 described below, the title compound (200 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[OH:4][CH2:3][C:2]([NH:1][C:16]([NH:15][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[S:17])([CH3:6])[CH3:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=S)NC(=O)c1ccccc1

Procedure:
Following the procedure in US2008/45579, 2008, 2-amino-2-methylpropan-1-ol was coupled with benzoylisothiocyanate to give N-(1-hydroxy-2-methylpropan-2-ylcarbamothioyl)benzamide which was then reacted with lithium hydroxide to give 1-(1-hydroxy-2-methylpropan-2-yl)thiourea. 1H NMR (400 MHz, DMSO) δ 7.09 (s, 2H), 5.01 (s, 1H), 3.44 (s, 2H), 1.30 (s, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([OH:26])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:37](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](=[O:26])[NH2:37])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(N)=O)CC1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxynitrobenzene (0.9 g) in dichloromethane (20 ml) were added isobutyl chloroformate (0.3 ml) and triethylamine (0.4 ml) in an ice bath and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia (0.2 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (0.9 g, yield 98%) as a pale yellow amorphous solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: Nc1ccccc1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 4-nitrophthalonitrile (0.6 g, 5.78 mmol), 2-aminophenol (1 g, 5.78 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in DMF (25 ml) was stirred at room temperature for 2 hours. The mixture was then poured into water. The precipitate was filtered off, washed with water and dried to give yellow crystals of 4-(2-aminophenoxy)phthalonitrile (yield: 1.32 g (97%)). Mp: 118-118.2° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].O>CCO.Cl>[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1
Reactant: O=c1cc(Cl)c([N+](=O)[O-])c[nH]1
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To the mixture of 4-chloro-5-nitropyridin-2(1H)-one (90.1 mg, 0.517 mmol) and 2-fluoro-4-iodoaniline (137.5 mg, 0.58 mmol) dissolved in EtOH (5 mL) was added 6 drops of HCl (37% wt in water). The reaction vessel was closed and heated at 90° C. for 48 hours. After cooling to room temperature, water was added, and the solution was stirred at room temperature for 20 min. The precipitate was filtered, washed with water, dried under vacuum and used for the next reaction without further purification. (87.3 mg, 45% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:34]([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([F:41])[CH:40]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:33]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc(F)cc1Nc1cncc(F)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a suspension of (S)-Boc-alaninamide (17.4 g, 92.5 mmol) in DCM (180 mL, dried over molecular sieves) was added triethyloxonium tetrafluoroborate (16.0 g, 84.1 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue taken up in absolute EtOH (200 mL) then 4-fluoro-N2-(5-fluoropyridin-3-yl)-benzene-1,2-diamine (6.20 g, 28.0 mmol) added. After stirring the reaction mixture at 60° C. for 2 h, the solvent was removed in vacuo and the resulting residue partitioned between DCM and an aqueous solution of NaHCO3. The layers were separated and the aqueous fraction extracted with DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (120 g Si—PCC, gradient 0-70% EtOAc in DCM) to afford the title compound as a green solid (10.1 g, 96%). LCMS (Method C): RT 3.23 min [M+H]+ 375.18.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:30]2[CH:34]=[C:33]([CH3:35])[S:32][CH:31]=2)O1>>[CH3:35][C:33]1[S:32][CH:31]=[C:30]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=2)[CH:34]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cs1
Yield: 69.4 %

Procedure:
tert-Butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridine-1(2H)-carboxylate (1.66 g, 5.00 mmol) and a crude product of 4,4,5,5,-tetramethyl-2-(5-methylthiophen-3-yl)-1,3,2-dioxaborolane (3.40 g) were used to obtain a crude product of the title compound (970 mg) by synthesis in a similar manner to Reference Synthesis Example 139.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C1C[O:24]CC1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:15]([OH:24])=[O:16])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Product: CC(C)C[C@H](N[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(=O)O

Procedure:
A stock solution of H5IO6/CrO3 was prepared by dissolving H5IO6 (68.4 g, 0.3 mol) and CrO3 (138 mg, 1.2 mol %) in CH3CN (684 mL) to give a 0.44 M solution. To a solution of H5IO6/CrO3 (16 mmol, 36 mL, 0.44 M in THF) at −5° C. (ice and salt bath) was added a solution of (2S)-2-{[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl]amino}-4-methylpentan-1-ol (1 g) in 3 mL THF dropwise. The internal temperature was monitored and reaction temperature was not allowed to rise above 0° C. The reaction was monitored by TLC until the reaction was complete (3-4 h). Na2HPO4 (80 mL) was added to the reaction mixture which was then extracted with EtOAc. The organic extract was washed with brine, NaHSO3 (120 mL) and brine again, dried over anhyd. MgSO4 and concentrated to an oil. The oil was redissolved in EtOAc and filtered through a short pad of silica gel, eluted with EtOAc and the filtrated was concentrated to give the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15](=[O:19])[NH:16]2)=[CH:12][C:11]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1Nc2cc(Br)ccc2C12CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cc(Br)c(Cl)cc2C12CCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
N-Chlorosuccinimide (500 mg, 3.75 mmol) was added to a solution of 6′-bromospiro[cyclopentane-1,3′-indolin]-2′-one (preparation 2, 0.20 g, 0.75 mmol) in chloroform (5 mL). The mixture was stirred and heated to reflux. After 6 hours, the mixture was cooled to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction and the mixture was extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (8:2 hexanes/ethyl acetate) gave the title compound (0.17 g, 75%) as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[C:23]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:22]=2[CH:21]=1>C1(C)C=CC=CC=1.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>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:26]1[CH:27]=[CH:28][C:29]2[C:30]3[C:22](=[CH:21][C:20]([C:6]4[S:7][CH:8]=[CH:9][CH:10]=4)=[CH:32][CH:31]=3)[C:23]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:24]=2[CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(-c3cccs3)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 3 h
Yield: 70 %

Procedure:
2-(tributylstannyl)thiophene (5.80 ml, 0.018 mol) was added under nitrogen directly to a single-necked round bottom flask equipped with a condenser and a magnetic stir bar that had been previously dried in an oven at 110° C. The 2,7-dibromo-9,9-di-n-decyl-9H-fluorene (5.26 g, 8.70 mmol) was weighed into a beaker and dissolved in toluene (14 ml) which had been freshly distilled and degassed with nitrogen. The resulting fluorene solution was pipetted into the round bottom flask and the beaker rinsed twice with 3 ml portions of degassed toluene. Pd(PPh3)4 (0.50 g, 0.43 mmol) and PdCl2 (PPh3)2 (0.31 g, 0.44 mmol) were added to the reaction flask and the solution refluxed until it turned black. The toluene was removed under reduced pressure and the residue dissolved in hexane. The hexane solution was stirred vigorously with a 100 ml of a 2% aqueous KF solution for 3 hours. The organic layer was separated, washed twice with an equal volume of water, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by column chromotography on silica gel using hexane as the eluent. The purified waxy solid compound (mp 59.9°-60.8° C.) was isolated in a 70% yield. Mass Spec. m/z 610 (M+), 469 (M--C10H21), Elemental Analysis: Calculated for C41H52S2 : C, 80.60, H, 8.91, S, 10.49. Found: C, 80.55, H, 8.97, S, 10.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[F:12].[CH3:13][CH2:14][N:15](C(C)C)C(C)C.[Si](OCCN)(C(C)(C)C)(C)C>C(#N)C>[CH2:14]([NH:15][C:5]1[CH:4]=[C:3]([F:12])[C:2]([F:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[CH3:13]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)(C)[Si](C)(C)OCCN
Solvent: CC#N
Product: CCNc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (0.5 g, 0.0028 mol) in acetonitrile (5 ml) was added DIPEA (0.98 ml, 0.0056 mol) and 2-(tert-butyldimethylsilyloxy)ethanamine (0.49 g, 0.0028 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 4 h. The reaction was concentrated and diluted with water (20 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product N-ethyl-4,5-difluoro-2-nitroaniline. (37 as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.37 (bs, 1H), 8.13-8.17 (dd, J=8.4, 8.4 Hz, 1H), 7.21-7.27 (dd, J=7.2, 7.2 Hz, 1H), 3.8-3.82 (t, J=5.2 Hz, 2H) 3.45-3.49 (m, 2H), 0.84 (s, 9H), 0.021 (s, 6H). MS (M+1=333).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([C:12]2([OH:16])[CH2:15][O:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:16][C:12]1([C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[CH2:15][O:14][CH2:13]1
Reactant: OC1(c2cccc(C3OCCO3)n2)COC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: O=Cc1cccc(C2(O)COC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-(6-(1,3-dioxolan-2-yl)pyridin-2-yl)oxetan-3-ol (67 mf, 0.30 mmol) and p-toluenesulphonic acid (14.8 mg, 0.26 mmol) in acetone (3.00 mL) was heated to 50° C. and stirred for 18 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure to afford the title compound. The material was used without further purification. MS (ES+) (M+H) 180.0; LCMS retention time: 1.57 minutes (Method L).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[F:20])[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-fluorobenzoic acid (29 mg, 0.21 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was dried to afford 87 mg (94%) of N-biphenyl-4-yl-3-[4-(2-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 446.18 (M+1)+ 93.2%, 1H NMR: (CDCl3): δ 9.7 (d, 1H), 7.6 (m, 6H), 7.44 (t, 4H), 7.34 (t, 1H), 7.22 (m, 1H), 7.14 (t, 1H), 3.86 (m, 6H), 3.54 (d, 2H), 3.4 (bs, 2H).