Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH:19]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH3:23])=[O:9]
Reactant: CC(CCN)n1ccnc1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Product: Cc1ccc(N)c(C(=O)NCCC(C)n2ccnc2)c1

Procedure:
When 5-methylisatoic anhydride was reacted with 3-(1H-imidazol-1-yl)butanamine by the procedure of Example 11, the above compound, mp 128°-130° C., was obtained.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:6]([NH:8][C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].Cl[C:30]([F:42])([F:41])[C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:22]([O:21][C:19]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:17]([OH:18])[C:30]([F:41])([F:42])[C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=O)Cc1ccccc1
Reactant: O=C(CCc1ccccc1)C(F)(F)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Add titanium tetrachloride (0.019 g, 0.1 eq) to a suspension of activated zinc (0.196 g, 3mAtg) in anhydrous THF (3 mL) at 0° C. under nitrogen. Stir 30 minutes and add CBz(L)-Val-Phe-H (0.42 g, 1.1 mmol), 1-chloro-1,1-difluoro-2-oxo-4-phenylbutane (0.218 g, 1.1 mmol), in anhydrous THF (4 mL). Allow the reaction to warm to room temperature and stir for 12 hours. Add a saturated solution of ammonium chloride (2 mL). Extract two times with diethyl ether (4 mL) and wash the organic phase with brine and dry over anhydrous magnesium sulphate. Concentrate the organic phase under vacuum. Purify the crude residue by flash chromatography (silica gel, 3:7 ethyl acetate:cyclohexane) to provide the title alcohol (0.381 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH3:14])=[N:4][N:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:18][CH2:17]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:14])=[N:4][N:3]=[C:2]2[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:20][CH2:21]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(C)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(C)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-methylphthalazine with 4-amino-1-(naphthalen-2-yl-methyl)piperidine.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]2[CH2:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][C:6]2=[N:7][CH:8]=1.FC(F)(F)C(O)=O>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]2[CH2:11][NH:10][CH2:9][C:6]2=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cnc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 3-Trifluoromethyl-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine and trifluoroacetic acid. Yellow oil. MS (m/e): 189.4 ([M+H+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCCCCCCCCCCCO)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 52.2 %

Procedure:
25.0 g (188 mmol) of (4-hydroxyphenyl)acetonitrile and 56.6 g (225 mmol) of 11-bromoundecan-1-ol are dissolved in 250 mL of N,N-dimethylformamide. 51.8 g (375 mmol) of potassium carbonate and 6.0 g (36 mmol) of potassium iodide are added and the suspension was heated to 80° C. After 48 h, the reaction mixture is cooled to room temperature and poured to icy water. The precipitate is filtered off, purified on column chromatography (AcOET/Tol: 2/8) and dried overnight at 40° C. 29.8 g of {4-[(11-hydroxyundecyl)oxy]phenyl}acetonitrile are obtained as a slightly yellow solid (52% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[N+:9]([O-])([OH:11])=[O:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:9]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1cc[nH]n1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccn([N+](=O)[O-])n1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a stirred mixture of 3-nitro-1H-pyrazole (3.16 g, 27.9 mmol) in glacial acetic acid (20 mL) at 0° C. was added fuming nitric acid (2.6 mL, 58.69 mmol) dropwise, followed by acetic anhydride (6.6 mL, 69.87 mmol). The mixture was stirred and allowed to warm to rt over 3 h, then poured into ice water (50 mL) and stirred for 20 h. The mixture was extracted with EtOAc combined organic layers were dried over MgSO4, filtered and concentrated to dryness to afford 1,3-dinitro-1H-pyrazole (4.3 g, 97%). 1H NMR (300 MHz, DMSO-d6) δ 8.00 (br s, 1H), 6.44 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1.Br[C:37]1[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([C:37]4[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=4)=[CH:23][C:8]=3[N:9]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Reactant: Nc1cnc(Br)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cnc(N)cn3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 24.9 %

Procedure:
To a solution of (R)-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (0.34 mmol) in 1,4-dioxane and H2O (10:1, 5 mL) was added 5-bromopyrazin-2-amine (63.2 mg, 0.36 mmol), Cs2CO3 (197.3 mg, 0.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (21.9 mg, 0.03 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyrazin-2-amine (39 mg, 28%).
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]2[C@H:11]([S:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C@@H:10]([C@H:20]([OH:22])[CH3:21])[C:9]2=[O:23])=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:53].C(OCC)C>C(Cl)Cl.O1CCCC1>[OH:22][C@@H:20]([C@H:10]1[C:9](=[O:23])[N:8]2[C@@H:11]1[S:12][C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[C:7]2[C:5]([O-:6])=[O:4])[CH3:21].[K+:53]
Reactant: C=CCOC(=O)C1=C(c2cccnc2)S[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cccnc3)S[C@H]12
Reaction time: 0.25 h

Procedure:
(+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester (332.4 g) was dissolved in a mixture of methylene chloride (2.5 liters) and tetrahydrofuran (1.3 liters). To the solution were added triphenylphosphine (26.2 g) and tetrakis(tripheylphosphine)palladium (11.6 g), followed by further addition of the above solution of potassium 2-ethylhexanoate. The mixture was stirred for 15 minutes and ethyl ether was added dropwise thereto to deposit crystals. After stirring for 30 minutes, the crystals were corrected by filtration and washed with ethyl ether (2 liters). The crystals were dried under reduced pressure to obtain crude crystals of potassium (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: C([Mg]Cl)(C)C.CO[C:8](=[O:27])[C@@H:9]([N:16]([CH2:24][CH:25]=[CH2:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(=O)(O)[O-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CCOC(C)=O>[CH2:17]([N:16]1[CH2:24][CH:25]2[C@:8]([OH:27])([CH2:26]2)[C@@H:9]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN(Cc1ccccc1)[C@H](C(=O)OC)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[Mg]Cl
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a flame dried, 3 neck rbf equipped with an addition funnel was added THF (20 mL) and titanium(IV) isopropoxide (2.6 mL, 8.8 mmol) and the flask immersed in a −78° C. bath. To this mixture was added isopropylmagnesium chloride (2M/diethyl ether, 8.8 mL, 17.6 mmol) dropwise and stirring continued at −78° C. for 15 minutes. To the reaction flask was then added the starting material (S)-(allyl-benzyl-amino)-phenyl-acetic acid methyl ester (JACS, 19, 30, 1997, 6984) (˜40% pure, 2.0 g, 2.7 mmol dropwise in THF (7 mL total) and the reaction was allowed to stir at −78° C. for 2.5 hours, warmed to −10° C., stirred for an additional 3 hours, allowed to warm to room temperature gradually and stirred for 16 hours. The reaction was poured carefully into a saturated Rochelle's Salt solution, solid sodium bicarbonate was added until the pH=8, EtOAc was added and the mixture allowed to stir for 1 hour. The phases were separated and the aqueous extracted with ETOAc, the combined organics were washed with brine and dried over calcium sulfate, filtered and concentrated. The crude product was purified on a Biotage flash 40 system eluted with a gradient of Hexanes to 12% ETOAc/Hexanes to give the title compound as an oil. (0.57 g, 32% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH:11][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
2-Benzyloxy-5-chloro-4-nitroaniline (31.63 g, 0.0828 mmol) was dissolved in 300 mL of dry methylene chloride in a dry 250 mL round bottom and sealed with a septum. Triethylamine (13.2 mL, 0.0947 mol, 1.1 equiv) was then added. Benzoyl chloride (31.1 mL, 0.268 mol, 3 equiv) was then added to dry methylene chloride (100 mL) in a self-equalizing dropping funnel and covered with a drying tube. The benzoyl chloride solution was added dropwise to the round bottom. The reaction mixture was allowed to stir for 15 minutes after addition of the benzoyl chloride solution. The solution was then refluxed overnight under a drying tube. The solution was diluted with chloroform (100 mL) and washed with 5% sodium bicarbonate (100 mL) and water (100 mL). The organic layer was dried with anhydrous sodium sulfate, gravity filtered and concentrated on a rotovap. Ethyl ether (150 mL) was added to the solid forming a suspension which was then suction filtered to yield N-(2-benzyloxy-5-chloro-4-nitrophenyl)benzamide as a peach solid (31.63 g, 0.0828 mol, 85%). Mp 158-160° C.; TLC (chloroform) Rf=0.62; 500 MHz 1H-NMR (CDCl3) 8.89 (s, 1H), 8.74 (s br, 1H), 7.80 (d, 8.0, 2H), 7.68 (s, 1H), 7.58 (t, 8.0, 1H), 7.48 (t, 8.0, 2H), 7.44 (m, 5H), 5.25 (s, 2H); IR (nujol) 3416, 3378, 1670, 1586, 1529, 1517, 1499, 1335, 1259, 1194. EI-MS m/z (relative intensity) 382 (M+, 7). Accurate mass for C20H15N2O4Cl: calcd. 382.0720, obsd. 382.0712.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]C=1C=O.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[NH:1]1[C:3]2=[N+:4]([O-:21])[CH:5]=[CH:6][CH:7]=[C:8]2[CH:9]=[CH:10]1
Reactant: O=Cc1cnc2ccccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Yield: 67.6 %

Procedure:
A solution of 7-azaindole 22-1 (30.6 g, 259 mmol) in methylene chloride (300 mL) was treated with mCPBA (75.6 g, 285 mmol) at room temperature for 12 h. The reaction mixture was washed with saturated aqueous NaHCO3 (3×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel chromatography (100×250 mm silica, 10% to 50% EtOAc/hexanes) afforded 23.5 g of 1H-pyrrolo[2,3-b]pyridine 7-oxide as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:28][C:8]1[CH:9]=[C:10]([S:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=4)=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:27])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:29]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(Br)cc3)nc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(SCc2sc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of {4-[2-(4-Bromo-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (53 mg, 0.1076 mmol) in toluene:ethanol (1:1, 2.0 mL) is added palladium tetrakis triphenylphosphine (5.0 mg, 0.0053 mmol), 4-(trifluoromethyl)-phenyl boronic acid (22.5 mg, 0.1184 mmol), and a solution of sodium carbonate (0.216 mL, 1.0M in water, 0.216 mmol). The reaction is purged with nitrogen and heated to reflux. The reaction is monitored by HPLC, and upon completion is allowed to cool to room temperature. The reaction is diluted with EtOAc and then washed with 0.1N sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated. The product is purified by flash column chromatography. The pure ester compound is then diluted with THF and 1N sodium hydroxide is added. The reaction is allowed to stir at room temperature, and monitored by TLC. Upon completion, 1N hydrochloric acid is added to neutralize the solution. The reaction is diluted with EtOAc and then washed with water. The organic layer is dried over anhydrous sodium sulfate and concentrated to the pure acid, 50 mg or 94% yield. MS (ES): 530.7 (M++1), the structure is also confirmed by proton NMR.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: c1ccc(CNCCCCCCOCCCc2ccccn2)cc1
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Solvent: C1CCOC1
Product: O=C(CN(CCCCCCOCCCc1ccccn1)Cc1ccccc1)c1ccc(O)c(CO)c1
Yield: 67.8 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (2.45 g), N-[6-[3-(2-pyridinyl)propoxy]hexyl]benzenemethanamine (3.26 g) and DEA (2.6 g) in THF (25 ml) was left at room temperature for 48 h. The precipitate was removed by filtration, the solvent was evaporated and the residual red oil was purified by FCC eluting with System B (95:5:1→90:10:1) to give the title compound as a pale yellow oil (3.32 g), t.l.c. (System A 80:20:1) Rf 0.21.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[O:5].C>C(OCC)(=O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:2]([Cl:1])=[C:3]([CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[O:5]
Reactant: O=C(c1ccc(Cl)cc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2Cl)c1

Procedure:
7.5 g of 2,2',4'-trichloro-5-nitrobenzophenone in 100 ml of ethyl acetate are hydrogenated at atmospheric pressure and at ambient temperature in the presence of palladinized charcoal.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(NN2CCN(C)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NN2CCN(C)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of ethyl 2-[(4-methyl-1-piperazinyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.040 g, 0.30 mmol) in ethanol (2.0 mL), L-proline (0.020 g, 0.17 mmol) was added at ambient temperature. The mixture was refluxed for 1.5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.017 g, y. 14%).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:21]3(O)[CH2:24][CH2:23][CH2:22]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2(O)CCC2)c1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CCC2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)-benzonitrile (1.00 g, 2.96 mmol) in methylene chloride (30 mL) was added triethylsilane (2.4 mL, 14.80 mmol) followed by trifluoroacetic acid (2.3 mL, 29.60 mmol). The reaction mixture was stirred at 0° C. for 1.5 h and diluted with 1M aqueous sodium hydroxide solution (30 mL). The mixture was extracted with methylene chloride (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 5% to 10% gradient of ethyl acetate in hexanes to afford 4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzonitrile as colorless solid in quantitative yield (0.95 g): MS (ES+) m/z 322.2 (M+1);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]1([CH:16]=[CH:17][C:18](Cl)=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([CH:17]=[CH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(Cl)C=CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc2[nH]c(C=CC3CCCCC3)nc2c1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a solution of 4-bromo-benzene-1,2-diamine (3.0 g, 16.1 mmol) in anhydrous toluene (50 ml) was added a solution of 3-cyclohexyl-acryloyl chloride (as prepared in STEP B above, 32.5 mmol) in toluene (5 ml). The resulting solution was stirred at 40° C. for 6 h. To the resulting solution was added p-toluenesulfonic acid (3.0 g, 16 mmol) and heated to reflux for 18 h. The resulting solution was concentrated. The residue obtained was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The layers were separated. The organic layer was washed successively with saturated sodium bicarbonate, water, brine, then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed using a silica gel to yield 5-bromo-2-(2-cyclohexyl-vinyl)-1H-benzoimidazole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([NH:18][C@H:19]([CH2:35][OH:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl.CCCCCC>[C:11]([NH:18][C@H:19]([CH:35]=[O:36])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:26]=1)([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(OCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.76 g (37.5 mmol) of oxalyl chloride in 33.6 ml of methylene chloride are treated dropwise, at -60° C. and under a N2 atmosphere, with a solution of 3.5 ml (49 mmol) of DMSO in 60 ml of methylene chloride. After the mixture has been stirred for 15 min, 8.94 g (25 mmol) of (S)-N-Boc-(p-benzyloxyphenylalaninol) in 150 ml of methylene chloride are added, and this mixture is subsequently stirred for about 25 min. 14 ml (100 mmol) of triethylamine in 30 ml of methylene chloride are then added and the mixture is stirred for 30 min. 222 ml of a 20% of a KHSO4 solution and 187 ml of hexane are added, and the mixture is warmed to 0° C. The aqueous phase is separated off and extracted 2× with ethyl acetate. The organic phases are washed with saturated NaHCO3 solution and saline, dried with Na2SO4 and evaporated to give the title compound: TLC Rf (C)0.71; 1H-NMR (200 MHz, CDCl3): 1.44 (s, 9H), 3.06 (d, J=6 Hz, 2H), 4.39 (m, 1H), 5.03 (s +sb, H2C--O+HN), 6.86-6.98 and 7.03-7.15 (2m, each 2H), 7.30-7.48 (m, 5H), 9.62 (s, 1H).