Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([CH2:31][NH2:32])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:32][CH3:31])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
To a solution (5 mL) of 1-[(4-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg) in tetrahydrofuran was added benzylmethylamine (88 mg), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (329 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), 10% palladium carbon (50% water-containing product, 180 mg) and formic acid (0.027 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a colorless oil (yield 55 mg, 33%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH3:3].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:18]([NH2:22])([CH2:20][CH3:21])[CH3:19]>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][CH:6]([NH:22][CH:18]([CH2:20][CH3:21])[CH3:19])[CH3:7])[CH3:3]
Reactant: CCC(C)N
Reactant: CC(=O)CC(=O)C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)NC(C)CC(=O)C(C)(C)C
Yield: 69.9 %

Procedure:
To a solution of 5.00 g (35.16 mmol) 2,2-dimethyl-3,5-hexanedione in 20 mL of toluene loaded with 10.00 g of sodium sulfate was added 5.14 g (70.32 mmol) sec-butylamine. The mixture was refluxed 3 days. 4.90 g of light yellow oil was obtained after work-up. The isolated yield was 71%. 1H NMR (500 MHz, C6D6): δ=11.52 (s, 1H), 5.18 (s, 1H), 2.95 (m, 1H), 1.51 (s, 3H), 1.31 (s, 9H), 1.14 (s, 2H), 0.80 (d, 3H), 0.67 (t, 3H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([OH:17])[CH:8]=2)=[O:3].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O.O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([O:17][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH:8]=2)=[O:3]
Reactant: NC(=O)Nc1[nH]c2cc(O)ccc2c1C(N)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1C(N)=O
Reaction time: 0.08 h
Yield: 61.4 %

Procedure:
Under ice-cooling, 2-aminocarbonylamino-6-hydroxyindole-3-carboxamide (Compound No.2-1, 1.3 g, 5.5 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added dropwise to a suspension of 60% sodium hydride (450 mg, 11 mmol) in anhydrous N,N-dimethylformamide (15 mL) over a period of 5 minutes and the mixture was stirred for 5 minutes. Moreover 4-fluoronitrobenzene (640 μL, 6.0 mmol) was added thereto, and the mixture was stirred for 15 minutes at room temperature and stirred overnight at 60° C. After cooling, the reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained solid was filtered off and washed with a mixed solvent of chloroform-diethyl ether solution (1:2, 60 mL). The solid was dried at 40° C. for 1 hour under reduced pressure to give the title compound (1.2 g) as a brown solid (59%).
Reaction SMILES: O[C:2]1([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23][CH2:22]3)[O:7][CH2:6][C@@H:5]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:4]2[CH2:3]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>>[CH2:6]1[C@@H:5]2[CH2:8][NH:9][CH2:10][CH2:11][N:4]2[CH2:3][C@@H:2]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23][CH2:22]3)[O:7]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(O)(c3ccc4c(c3)CCOC4=O)OC[C@@H]2C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCc2cc([C@@H]3CN4CCNC[C@H]4CO3)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
tert-Butyl(9aS)-3-hydroxy-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.84 g, 4.55 mmol) was diluted with TFA (18 mL, 234 mmol) and cooled to 0° C. Some off gassing was apparent and after a few minutes a homogenous solution had been formed. Approximately 5 minutes post-TFA addition, Et3SiH (5.09 mL, 31.8 mmol) was added and the reaction mixture allowed to slowly warm to RT (allowed to warm naturally in the ice bath) where it was stirred for 18 h. The trans:cis diastereomeric ratio appeared to be ˜95:5. The reaction vessel was transferred to a rotary evaporator and concentrated in vacuo to a two phase liquid. This crude material was diluted with CH2Cl2 washed with NaHCO3, aq then water. The separately kept aqueous layers were subsequently extracted once with the same portion of CH2Cl2, the combined organics dried with MgSO4, filtered and concentrated in vacuo. The crude residue was dried under house vacuum then the mixture was further purified by flash chromatography (2% MeOH 2% Et3N in CH2Cl2) to afford the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[C:5]([CH3:25])[N:4]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[CH2:44]([O:46][C:47](=[O:57])[C@H:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[NH2:49])[CH3:45]>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:57])[C@H:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[NH:49][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:6]3[C:7]([NH2:9])=[N:8][C:3]([NH2:2])=[N:4][C:5]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)[CH3:45]
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.8 %

Procedure:
A mixture of 4.27 g (0.01137 mole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid hydrochloride, 6.12 g (0.0375 mole) of diethyl phosphorocyanidate and 7.0 ml (0.050 mole) of triethylamine in 300 ml of previously dried dimethylformamide was stirred at room temperature for five hours and then at 80° C. for five minutes. The solution was cooled to room temperature, and a solution of 3.00 g (0.0125 mole) of L-glutamic acid diethyl ester hydrochloride and 1.74 ml (0.0125 mole) of triethylamine was added. The resulting mixture was stirred for two hours at room temperature. The solvent was removed under high vacuum at 40° C. and the gummy residue partitioned between 500 ml of dichloromethane and 500 ml of 5% sodium bicarbonate solution. The organic layer was separated, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. The dried solution was concentrated in vacuo to give a yellow solid. Recrystallization from acetonitrile gave 3.9 g of the product as a tan solid, mp 224° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29][C@@H:28]1[CH3:33])[CH3:26]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCNC[C@@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87-1.19 (m, 6H) 2.42 (s, 3H) 2.47 (br. s., 1H) 2.52-2.59 (m, 1H) 2.62-2.76 (m, 1H) 2.77-2.98 (m, 2H) 3.06 (d, J=10.61 Hz, 1H) 3.35 (br. s., 1H) 3.46-3.75 (m, 1H) 4.05 (br. s., 1H) 7.60 (dd, J=7.96, 1.64 Hz, 1H) 7.66 (d, J=1.26 Hz, 1H) 7.90 (d, J=8.34 Hz, 1H) 8.01 (dd, J=8.72, 2.15 Hz, 1H) 8.06 (s, 1H) 8.43 (d, J=8.59 Hz, 1H) 8.51 (d, J=1.77 Hz, 1H) 11.83-12.92 (m, 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[NH2:24][C@H:25]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:36][CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].Cl.CO>CN(C)C=O>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:11]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:38][CH:39]=1)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
6.46 g (20 mmoles) of Z-D-Asp(OBut)-OH are subjected to a condensation reaction with 7.73 g (20 mmoles) of H-Val-Tyr(But)-OMe.HCl in 50 ml of dimethylformamide analogously to Examples 38 A. Yield 11.2 g (85%), melting point 90°-92°, [α]D27 =-3.5° (c=1, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>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>[CH3:10][S:9][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:18]=2)[N:5]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nc(N)cc(-c2cccc(C(F)(F)F)c2)n1
Yield: 60.7 %

Procedure:
To a stirred solution of 4-amino-6-chloro-2-methylthiopyrimidine (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, 3-(trifluoromethyl)phenylboronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours. Ethyl acetate (150 mL) was added and the mixture washed with water (2×100 mL). Organic layer was separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g)
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]1=[O:39])[CH2:20]2.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][N:2]1[C:6]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=2)[CH2:28][N:29]2[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]2=[O:39])[CH2:20]3)=[CH:5][CH:4]=[N:3]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)ccc2C1=O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.557 g, 2.68 mmol), bis(tri-t-butylphosphine)palladium (0.114 g, 0.223 mmol), 2-[(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (1.10 g, 2.23 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.69 mmol) in 1,4-dioxane (12 mL, 150 mmol) and water (0.60 mL, 33 mmol) was stirred under microwave at 110° C. for 15 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (30-100%) to give 0.72 g (61% yield) of the desired product. LCMS found: 495.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[C:46]([F:49])([F:48])[F:47]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=2[C:46]([F:48])([F:47])[F:49])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ncccc12
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (12.8 g, 62.8 mmol) in dry DMF (400 ml) under an inert atmosphere of Argon is added dropwise, BEMP (18.1 ml, 62.8 mmol) over two minutes. After stirring at 10° C. for 40 minutes, the resulting solution is treated dropwise with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (23.8 g, 75.4 mmol) and allowed to warm to room temperature while stirring overnight. The reaction is concentrated in vacuo with toluene azeotroping and the resulting oil is partitioned between water (400 ml) and DCM (500 ml) and extracted with DCM (500 ml). The organic portions are combined and washed with water (2×200 ml). The resulting suspension is filtered and concentrated in vacuo with toluene azeotroping. The crude is purified by chromatography on silica eluting with iso-hexane/acetone (16:4) to yield the titled product. (MH+ 441)
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: O=Cc1ccc2ccccc2n1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 365.02 g/mol.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.CN(P(N(C)C)(N(C)C)=O)C.[CH2:35](Br)[CH:36]=[CH2:37]>C1COCC1>[CH2:37]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:19]1=[O:23])[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1CCc2cc(OC)ccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of LiHMDS (1.04 g, 6.24 mmol), in THF (40 mL) cooled at −78° C. is added slowly a solution of 6-methoxy-1-tetralone (1.0 g, 5.67 mmol) in anhydrous THF (40 mL). After the addition is complete, the solution is stirred at −78° C. for 30 minutes, then HMPA (1.97 mL, 11.3 mmol) is slowly added and the mixture is stirred for other 5 minutes followed by the addition of a solution of allyl bromide (0.74 mL, 8.5 mmol) in anhydrous THF (5 mL). The mixture is left to warm slowly to room temperature (2-3 h) and quenched at 0° C. with aqueous 1N HCl (20 mL), then extracted with diethylether. The organic phase is dried over MgSO4 and concentrated to dryness. The residue is purified by column chromatography on SiO2 (Petroleum Ether/EtOAc=95:5) to afford the title compound 53 as a colorless oil (Yield 0.56 g, 45%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16](OC)=[O:17])[C:10]=2[CH:9]=[CH:8]1>C1COCC1>[OH:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][NH:7]2
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a mixture of lithium aluminum hydride (1.3 g, 34 mmol) in THF (200 mL), methyl 4-indole carboxylate (3.0 g, 17 mmol) in THF (100 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h and then quenched with ethyl acetate. The mixture was treated with water (1.3 mL), 15% NaOH (1.3 mL) and water (3.9 mL), and then filtered. The filtrate was concentrated in vacuo to afford the crude 4-(hydroxymethyl)-indole (2.5 g, 99%): 1H NMR (500 MHz, CDCl3) δ8.29 (br s, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.16-7.22 (m, 2H), 7.12 (d, J=7.0 Hz, 1H), 6.67 (t, J=1.0 Hz, 1H), 4.98 (d, J=4.2 Hz, 2H); CI MS m/z=147 [C9H9NO+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:47])([F:46])[C:4]([F:45])([F:44])[C:5]([F:43])([F:42])[C:6]([F:41])([F:40])[C:7]([F:39])([F:38])[C:8]([F:37])([F:36])[C:9]([F:35])([F:34])[C:10]([F:33])([F:32])[CH2:11][O:12][C:13]1([F:31])[C:26]([F:27])=[C:25]([F:28])[C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[C:15]([F:29])[CH:14]1[F:30].[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1Cl)([O-:50])=[O:49]>CN1C(=O)CCC1>[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1[O:1][CH2:2][C:3]([F:46])([F:47])[C:4]([F:44])([F:45])[C:5]([F:42])([F:43])[C:6]([F:40])([F:41])[C:7]([F:38])([F:39])[C:8]([F:36])([F:37])[C:9]([F:34])([F:35])[C:10]([F:32])([F:33])[CH2:11][O:12][C:13]1([F:31])[C:14]([F:30])=[C:15]([F:29])[C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[C:25]([F:28])[CH:26]1[F:27])([O-:50])=[O:49]
Reactant: O=C(C1=C(F)C(F)C(F)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)C(F)=C1F)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: O=C(C1=C(F)C(F)C(F)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(F)=C1F)c1ccccc1

Procedure:
A solution of 4-(10-Hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecyloxy)-2,3,4,5,6-pentafluorobenzophenone(7.14 g), 2,4-dinitrochlorobenzene (2.42 g) potassium carbonate (2.76 g) and NMP (15 mL) is heated to 75-80° C. for 24 hrs. The solution is further processed as described in example 2 to give 4-[10-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecyloxy]-2,3,4,5,6-pentafluorobenzophenone.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10].C(N(CC)CC)C.S=[C:19]1[CH2:23][S:22][C:21](=[O:24])[NH:20]1>C(O)C>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:19]2[CH2:23][S:22][C:21](=[O:24])[N:20]=2)[C:4]1=[O:10]
Reactant: CN1CCCC(N)C1=O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCCC(NC2=NC(=O)SC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing 3-amino-1-methylpiperidin-2-one hydrochloride obtained in C) and triethylamine (3 mL) in ethanol (15 mL) was added 4-thioxothiazolidin-2-one (666 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (220 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 135 °C
Yield: 56 %

Procedure:
To a stirred solution of 22.5 g (0.092 mole) of 4-(3-chloropropoxy)benzoic acid ethyl ester in 150 mL of dimethylformamide was added 17.6 g (0.093 mole) of potassium phthalimide (98%, Aldrich) and the mixture was heated (135° C.) under a nitrogen atmosphere for 8 hr. The solvent was evaporated under reduced pressure to leave a semi-solid residue. The residue was triturated with 100 mL of water and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl alcohol to yield 18.2 g (55%) of title compound as an off-white solid, mp 106°-108° C.