Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]([CH2:8]Cl)=[N:6][CH:7]=1.[C:22]([N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28][C:27]1=[O:35])([CH3:25])([CH3:24])[CH3:23].[Li]>C1COCC1>[C:22]([N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH:28]([CH2:8][C:5]2[C:4]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[C:27]1=[O:35])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1C(=O)Cc2cccnc21
Reactant: CC(C)[Si](OCc1cc(Cl)cnc1CCl)(C(C)C)C(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cc(Cl)cnc1CC1C(=O)N(C(C)(C)C)c2ncccc21)(C(C)C)C(C)C
Reaction time: 0.67 h

Procedure:
A solution of 65 (23.84 g, 60.7 mmol) and 54 (17.32 g, 91 mmol) in THF (200 ml) was degassed by vacuum/flush N2 below 5° C. To the solution was added lithium amoxide solution in heptanes (27.4 mL, 40%, 85 mmol) maintaining below 7° C. The reaction was aged below 5° C. for 40 min, then quenched with saturated aqueous NH4Cl (10 mL), diluted with hexane (120 mL). The organic layer was separated, washed with saturated aqueous NH4Cl (100 mL) and water (150 mL), concentrated and purified by silica gel column (0 to 5% AcOEt/hexane) to obtain 69, which was used in the next reaction without further purification. HRMS m/z calcd. for C28H41C1N3O2Si 502.2651 (M+H). found 502.2641
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:27][N:26]([CH3:28])[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[N:19][CH:20]=1)=[O:25]
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)c2cc(C)oc2c1
Temperature: 90 °C
Yield: 82.3 %

Procedure:
The flask was charged with ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 6.07 g, 27.6 mmol), 5-chloro-N,N-dimethylpyrazine-2-carboxamide (SM-1: 5.06 g, 27.3 mmol), cesium carbonate (9.78 g, 30 mmol). The solids were dissolved in dimethylformamide (60 mL). The reaction was heated to 90° C. for 3 hours. After the reaction was cooled down to ambient temperature, dimethylformamide was removed in vacuo. The crude reaction mixture was partitioned between ethyl acetate (100 ml) and water (30 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (silica gel, 30 to 80% gradient of ethyl acetate in heptane) to give desired ethyl 4-(5-(dimethylcarbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-1d) as a light brown solid (8.3 g, 95%).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].Cl>ClCCl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:19](=[O:20])[CH2:18][Cl:17])=[CH:3]1
Reactant: O=C(Cl)CCl
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Into a 250 ml round bottom flask containing the bicyclo[3.2.1]octane-2,4-dione (10 g, 72 mmol) is added dry dichloromethane (100 ml) and pyridine (6.28 g, 87 mmol). To the stirred mixture is added dropwise over a period of 15 minutes the chloroacetyl chloride (9.82 g, 72 mmol) diluted in dichloromethane (100 ml). The reaction mixture is therefore stirred for 2 hours at room temperature. The reaction mixture is therefore poured into 100 ml of aqueous 2N HCl and extracted with ethyl acetate (2×100 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an orange oil. The crude product is distilled under reduced pressure to give chloro-acetic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester (13.4 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[O:26][C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CS(C)=O.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]3[CH:31]=[CH:30][C:22]4[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[O:26][C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 57.5 %

Procedure:
To a solution of 7-[4-(4-butyl-phenylethynyl)-benzylamino]-2,2-dimethyl-benzo[1,3]-dioxin-4-one (1.16 g, 2.64 mmol) in DMSO (32 mL) was added sodium hydride (159 mg, 3.96 mmol, 55-65% in oil) and the resulting mixture was stirred 2 min at rt, then 1-bromohexane (559 μl, 3.96 mmol) was added. The red solution was stirred at rt for 2 hrs. The reaction mixture was poured in EtOAc (70 mL) and washed with an aqueous solution of HCl (2×30 mL, 0.1N) and water (6×30 mL). The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude mixture was purified by flash chromatography on silicagel (c-Hex/EtOAc (6/1)) to give 795 mg (56%) of the title compound as a yellow oil. HPLC, Rt: 6.4 min (purity: 98.3%). M+(ESI): 524.5. 1H NMR (CDCl3) δ: 7.71 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.13 (m, 4H), 6.36 (m, 1H), 6.04 (m, 1H), 4.58 (s, 2H), 3.40 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.76-1.48 (m, 8H), 1.42-1.20 (m, 10H), 0.95-0.82 (m, 6H).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38](=[NH:55])[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]2>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:55]=[C:38]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CCOC(=O)CCc1cc2cc(C(=N)NO)ccc2[nH]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 10 min. ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (193 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 6 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from ethanol to afford ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D33) (95 mg) as a light pink solid. MS (ES): C24H24ClN3O4 requires 453; found 454.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:21][C@:20]3([CH3:34])[C@@H:22]([CH3:33])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:32])([CH3:31])[C@@H:27]([OH:30])[CH2:28][CH2:29][C@@:19]34[O:18][C:11]=2[C:12]2[CH2:13][NH:14][CH2:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)(Cl)Cl>[C:41]([N:14]1[CH2:13][C:12]2[C:11]3[O:18][C@@:19]45[CH2:29][CH2:28][C@H:27]([OH:30])[C:26]([CH3:32])([CH3:31])[C@@H:25]4[CH2:24][CH2:23][C@H:22]([CH3:33])[C@@:20]5([CH3:34])[CH2:21][C:10]=3[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][C:16]=2[CH2:15]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1Cc2cc(OCc3ccccc3)c3c(c2C1)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of Compound (33a) (47 mg, 0.10 mmol) in 5.0 ml of chloroform was added a sodium carbonate aqueous solution (prepared from 14 mg (0.10 mmol) of sodium carbonate and 5.0 ml of water). Under ice-cooling, to the mixture was added 8 μl (0.12 mmol) of acetyl chloride dissolved in 0.3 ml of chloroform in a single portion with vigorous stirring. After the reaction mixture was stirred for 30 min and warmed up to room temperature, it was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate) to give 47 mg (92%) of Compound (33b).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[C:12]([O:16][C:17]([N:19]1[CH2:51][CH2:50][C:21]2([CH2:49][N:24]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]([C:32]4[C:33](=O)[O:34][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]3[CH2:22]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:51][CH2:50][C:21]2([CH2:49][N:24]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]([C:32]4[C:33](=[O:34])[NH:3][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]3[CH2:22]2)[CH2:20]1)=[O:18])([CH3:14])([CH3:13])[CH3:15]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CC3(CCN(C(=O)OC(C)(C)C)C3)C4)C(=O)OC2=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC3(CCN(C(=O)OC(C)(C)C)C3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 72 h

Procedure:
A mixture of 0.59 ml of 1,1,1,3,3,3-hexamethyldisilazane and 45 mg of methanol was added to a solution of 150 mg of 3-[1-(tert.butoxy-carbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione in 10 ml of DMF and stirred for 72 hours. The solvent was removed by evaporation and the residue was treated with 10 ml of methanol. After evaporation, the residue was subjected to chromatography on silica gel using dichloromethane/ethyl acetate (4:1) for the elution. There were obtained 120 mg of 3-[1-(tert.butoxycarbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 232°-235° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CN(C)c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)c1ccc(COc2cccc(C=O)c2)cc1
Temperature: 25 °C

Procedure:
Mix 4-(dimethylamino)benzyl alcohol (3.35 g. 22 mmol), 3-hydroxybenzaldehyde (2.69 g, 22 mmol), triphenylphosphine (5.8 g, 22 mmol) and diethylazadicarboxylate (3.83 g, 22 mmol) in tetrahydrofuran (25 mL). Stir at room temperature under anhydrous atmosphere until the reaction is done. Concentrate the solution in vacuo and dilute with a small quantity of ethyl ether. Filter any precipitate and concentrate the filtrat in vacuo. Purify by silica gel chromatography to give 3-(4-(dimethylamino)-benzyloxy) benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC.O>CN(C=O)C>[O:8]=[C:7]1[C@@H:6]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][O:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A mixture of (S)-3-(2-amino-phenoxy)-2-tert-butoxycarbonylamino-propionic acid (3.8 g, 12.8 mmol, 1 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 2.46 g, 12.8 mmol, 1 eq) in DMF (56.4 mL) was stirred for 1 h 45 min. The reaction was poured into H2O (250 mL) and extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated to give the title compound (3.1 g, 87%) as a tan solid which was used without purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH2:10])(C)(C)C.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[NH2:10][CH2:9][CH2:8][NH:7][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Br:21])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NCCNS(=O)(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (208 mg, 1.3 mmol) in CH2Cl2 (20 mL) was added DIEA (300 μL, 1.72 mmol) at 0° C., followed by the addition of 2-bromo-benzenesulfonyl chloride (383 mg, 1.5 mmol). After it was stirred at 0° C. for 1 h and at the room temperature for another 16 h, the reaction mixture was evaporated thoroughly. The residue was diluted with 20% TFA in CH2Cl2 (10 mL), stirred for 3 h at the room temperature, and evaporated. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1) afforded the title compound (313 mg, 86%). 1H NMR (DMSO-d6) δ 2.86 (t, J=8 Hz, 2H), 3.04 (t, J=8 Hz, 2H), 7.55-7.65 (2H), 7.89 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H); ESI-MS m/z 279.1 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([C:16]3([C:19]4[CH:29]=[CH:28][C:22]5[O:23][C:24]([F:27])([F:26])[O:25][C:21]=5[CH:20]=4)[CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:9][C:8]=2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].CO>[CH:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([C:16]3([C:19]4[CH:29]=[CH:28][C:22]5[O:23][C:24]([F:27])([F:26])[O:25][C:21]=5[CH:20]=4)[CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:9][C:8]=2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1C1=CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1C1CCCCC1
Reaction time: 16 h

Procedure:
N-(6-Cyclohexenyl-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (82.4 mg, 0.200 mmol) was added to a flask containing 20 mg of 10% palladium on carbon under an atmosphere of argon. Methanol (5 mL) was added and then the reaction atmosphere was replaced with an atmosphere of hydrogen. The mixture was stirred vigorously for 16 hours. The atmosphere was then replaced with argon. The mixture was filtered, evaporated to dryness, and then purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-cyclohexyl-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 414.2. found; 415.1 (M+1)+ Retention time 1.78 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=1)=[O:7]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: COc1cc(OC)cc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)c1
Yield: 3.4 %

Procedure:
In a manner similar to that described in Example 3, 3,5-dimethoxy-benzoyl chloride (0.068 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.003 g of 4-[4-(3,5-dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+358.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[CH3:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[F:25][C:23]([F:26])([CH3:24])[CH2:22][O:21][C:17]1[N:16]=[CH:15][C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])=[CH:19][C:18]=1[CH3:20]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(C)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(C)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (93 mg, brown solid) from 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-73, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[N:8]=1)([CH3:3])[CH3:2].[NH2:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]1[S:50][CH:49]=[N:48][CH:47]=1)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([NH:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]2[S:50][CH:49]=[N:48][CH:47]=2)=[O:43])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[N:8]=1)([CH3:2])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)O)C(C)C)cs1
Product: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U, but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl) methyl)amino)carbonyl)-L-valine with N-((2-(2-isopropyl-4-thiazolyl)ethoxy) carbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl) methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl) amino)-1,6-diphenyl-3-hydroxyhexane provided, after purification by silica gel chromatography using 99:1 CHCl3 :CH3OH, 50 mg (30%) of the desired compound (Rf 0.3, 95:5 CHCl3 :CH3OH) as a solid, mp 159°-160° C. Mass spectrum: (M+H)+ =722 HRMS. Exact mass calcd for C37H47N5O6S2 : 722.3046. Found: 722.3036.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH3:21])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:23].[Na+]>CO>[NH2:23][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: [BH3-]C#N
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (3.5 g, 45.45 mmol) was added to the stirred solution of 1-benzyl-3,3-dimethyl-4-piperidone (2.0 g, 9.2 mmol), in methanol (20 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.58 g, 9.2 mmol) was added. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,3-dimethyl piperidine. Yield 1.6 g (77%), C14H22N2, m/z 219 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D2O exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1F.NC1C(F)=CC([OH:21])=CC=1F>>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([OH:21])=[C:2]([F:1])[CH:7]=1
Reactant: Nc1c(F)cc(O)cc1F
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Product: Nc1cc(F)c(O)cc1F
Yield: 72.3 %

Procedure:
This compound was prepared from 1,2,4-trifluoro-5-nitrobenzene (5.0 g, 28 mmol) in the manner described for 4-amino-3,5-difluorophenol, affording 3.0 g (72.3%) of 4-amino-2,5-difluorophenol. 1H-NMR (DMSO-d6) δ 9.04 (s, 1H), 6.67 to 6.46 (m, 2H), 4.64 (s, 2H); MS GC-MS M+=146.1, RT=1.04 min.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)O1
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
AlCl3 (128.8 g, 0.97 mol) was added by portions within 20 min to a suspension of succinic anhydride (44.3 g, 0.44 mol) and bromobenzene (100 ml, 0.99 mol) in DCM (500 ml) while the reaction flask was cooled in a water bath. After 1 h 30 min at RT, the reaction mixture was refluxed for 2 h. After cooling, the reaction medium was slowly poured into a mixture of ice (1.5 l) and concentrated HCl (100 ml). The precipitate was washed twice with water, with isopropanol, and finally with pentane. After drying 4-(4-bromophenyl)-4-oxobutyric acid was obtained as an off-white solid (86.4 g, mp=148° C.). 1H NMR (CDCl3): 7.85 (2H, d, J=8.5 Hz), 7.62 (2H, d, J=8.5 Hz), 3.28 (2H, t, J=6.5 Hz), 2.82 (2H, t, J=6.5 Hz).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][C:12](=[O:16])C(O)=O.[OH2:17].OO>CO>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][C:12]([OH:16])=[O:17]
Reactant: O
Reactant: O=C(O)C(=O)Cc1c(I)cccc1[N+](=O)[O-]
Agent: OO
Solvent: CO
Product: O=C(O)Cc1c(I)cccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
3-(2-Iodo-6-nitro-phenyl)-2-oxo-propionic acid 74c (2.086 g, 6.2 mmol) was dissolved in 6 ml of methanol under stirring, and added with 20 ml of water and 7 ml of hydrogen peroxide to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered, extracted with ethyl acetate (20 ml×2). The combined organic extracts were concentrated under reduced pressure, combined with the above filter cake, and dried to obtain the title compound (2-iodo-6-nitro-phenyl)-acetic acid 74d (1.77 g, yield 70%) as a brown solid.