Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=c1[nH]c2cccc(OCC(O)CNC3CCN(c4ccc(S(=O)(=O)NCc5ccccc5)cc4)CC3)c2[nH]1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a grey solid. 1H NMR (DMSO) δ 1.37 (m, 2H), 1.90 (m, 2H), 2.73 (m, 2H), 2.84(m, 2H), 2.99(m, 4H), 3.87(m, 3H), 4.03(m, 1H), 5.07(bs, 1H), 6.67 (m, 1H), 6.85(t, 1H, J=8.1 Hz), 7.07(d, 2H), J=9.0 Hz), 7.32 (m, 6H), 7.59 (d, 2H, J=8.7 Hz), 10.59 (bs, 1H), 10.72 (bs, 1H); MS (ES) m/z: 552.1 (MH+); HRMS for C28H33N5O5S: 552.2267 (MH+).
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](Cl)=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([NH2:1])=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Reaction time: 0.25 h

Procedure:
To 1000 ml. of cold, stirring NH4OH, 63 g. (0.26 mole) of 5-(p-chlorophenyl)-2-furoyl chloride is added portionwise. The resulting mixture is stirred at ice bath temperature for 15 minutes and then is stored at room temperature for 18 hours. The solid is filtered, is washed with water and is dried at 60° to yield 56 g. (97%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13](OC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H]1CCC=C[C@H]1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC[C@H]1CCC=C[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of 300 mg (1.38 mmol) of 1(R)-phenyl-2(S)-carbomethoxy-cyclohex-5-ene (from Step A) in 30 mL of CH2Cl2 at 0° C. was treated with 2.3 mL of 1.5 M diisobutylaluminum hydride solution in toluene. After stirring for 30 minutes the reaction was quenched with 50 mL of sat'd sodium potassium tartrate solution, diluted with 100 mL of ether and stirred at rt for 20 h. The layers were separated and the organic layer was washed with 75 mL of H2O , dried over MgSO4 and concentrated in vacuo. Flash chromatography on 100 g of silica gel using 5-25% v/v EtOAc/hexanes as the eluant afforded 185 mg (72%) of the title compound as an oil. 1H NMR (CDCl3, 500 MHz) δ 7.23-7.34 (m, 5H), 5.95-5.97 (m, 1H), 5.77-5.79 (m, 1H),3.66 (s, 1H), 3.23-3.32 (m, 2H), 2.14-2.25 (m, 3H),1.51-1.62 (m, 3H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([C:21](OC)=[O:22])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([C:21]([NH:26][NH2:27])=[O:22])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1nccnc1NC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nccnc1NC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of methyl 3-[(1-benzylpiperidin-4-yl)amino]pyrazine-2-carboxylate (3.0 g, 9.2 mmol) and hydrazine hydrate (6 mL) in ethanol (100 mL) was refluxed with stirring for 2 h. The reaction was cooled and concentrated to give the title compound (3.0 g). MS 327 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:2]=2[Cl:1])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: O=C(O)COc1ccc(-c2cccnc2)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3cccnc3)cc2Cl)cc1Cl

Procedure:
The product was prepared according to general working method I from (2-chloro-4-pyridin-3-yl-phenoxy)-acetic acid (136b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:22])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[N:18][CH:17]=2)[C:8](=[O:9])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCI
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Product: O=C(O)CCSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1

Procedure:
3-Cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 100 mg, 300 μmol) was reacted with 3-iodopropionic acid (60 mg, 300 mol), employing the procedure described in Step 1 of EXAMPLE 67, to furnish the title compound: RTA=3.61 min; m/z (ES+)=406.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([O:28][CH:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(OC(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazol (2.4 g), 2-iodopropane (5.4 8 g), and potassium carbonate (2.67 g) in N,N-dimethyl-formamide (10 ml) was stirred at 100° C. for 3 hrs.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C[Si](C)(C)N[Si](C)(C)C>O1CCOCC1>[N:16]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=C1N=C(N2CCCC2)CON1
Yield: 47 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 2.06 (0.029 mole) of pyrrolidine and 20 ml of hexamethyldisilazane in 40 ml of dry freshly distilled dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 0.8 g (47 percent) of 5-(1-pyrrolidinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH:9]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:12]([S:15]([N:17]=[CH:9][CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:16])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)S(N)=O
Reactant: CCOC(=O)C(C)CC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A yellow solution of ethyl 2-methyl-4-oxobutanoate (35.16 mmol) in DCM (72 ml) was treated with 2-methylpropane-2-sulfinamide (4.261 g; 35.16 mmol) and with anh. CuSO4 (11.223 g; 70.32 mmol). The resulting beige heterogeneous mixture was further stirred at rt, under nitrogen, for 24 h. The resulting heterogeneous mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained yellow filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate as a yellow oil. LC-MS (conditions B): tR=0.78 min.; [M+H]+: 248.38 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH:39]([CH3:43])[CH2:40][CH:41]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:41][CH2:40][CH:39]([CH3:43])[CH3:38])[CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCN1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
Dissolve (2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (167 mg, 0.33 mmol) in 1,2-dichloroethane (2.5 mL) and add 3-methylbutyraldehyde (0.042 mL, 0.41 mmol). After 5 min, add sodium triacetoxyborohydride (100 mg, 0.47 mmol) and stir for 1 h. Add saturated aqueous sodium bicarbonate solution (5 mL) and stir for 10 min. Add ethyl acetate and separate the layers. Extract the aqueous layer with ethyl acetate, combine the organic layers, wash the organic layer with saturated aqueous sodium chloridesolution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate) to give the title compound as a colorless oil (165 mg, 87%).
Reaction SMILES: [F:1][C:2]1([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>C(O)C.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1(F)CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)C1(F)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
A mixture of the compound (0.18 g) obtained in step 2 and 20% palladium hydroxide (0.02 g) in ethanol/ethyl acetate (2/1 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 4 hr. The reaction mixture was filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (0.084 g, 78%) as a gray powder.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:13]([CH3:17])([C:15]#[CH:16])C.[F-].[Cs+].Cl.[CH2:22](N(CC)C1C=CC=CC=1)C>>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]2[C:5]=1[O:12][C:13]([CH:15]([CH3:16])[CH3:22])=[CH:17]2
Reactant: C#CC(C)(C)Oc1cc(C=O)ccc1OC(F)F
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)c1cc2c(C=O)ccc(OC(F)F)c2o1

Procedure:
5.5 g of 4-difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy) benzaldehyde are heated to reflux with 7.2 g of cesium fluoride with nitrogen aeration for 12 h in 30 ml of N,N-diethylaniline. The mixture is stirred into 300 ml of 4 N hydrochloric acid after cooling, the resulting emulsion is extracted three times with 50 ml of ethyl acetate, and the organic extracts are combined, dried over ignited potassium carbonate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene. After the evaporation of the appropriate fractions, the title compound is obtained as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:22][OH:23])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[OH:23][CH2:22][C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(Br)cc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 44 %

Procedure:
The product of step E and sodium benzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 1:1 hexane/ethyl acetate) provided tert-butyl 6-(hydroxymethyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (33 mg, 44%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.99-7.93 (m, 2H), 7.88 (d, J=1.6 Hz, 1H), 7.58-7.46 (m, 3H), 4.99 (d, J=6.0 Hz, 2H), 4.56 (s, 2H), 3.82 (s, 2H), 2.87 (s, 2H), 2.13 (t, J=6.0 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH:13]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15](=[O:27])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH:13]2[CH2:17][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:15](=[O:27])[CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COc1ccc(CN2CC(N)CC2=O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CN2CC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2=O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene (9.2 g, 52.4 mmol), 4-amino-1-(4-methoxybenzyl)pyrrolidin-2-one (11.5 g, 52.4 mmol) and K2CO3 (14.5 g, 105 mmol) in 300 mL of anhydrous CH3CN was heated with stirring at 50° C. for 16 hours. The reaction mixture was filtered and the filter cake was dissolved with H2O (400 mL), and extracted with EtOAc (200 mL×4). The organic layers and the filtrate was combined and concentrated in vacuo to 50 mL. The precipitate was collected by filtration and washed with 10 mL of PE to afford 4-[(4-chloro-2-nitrophenyl)amino]-1-(4-methoxybenzyl)pyrrolidin-2-one as an orange solid (15.8 g, yield: 80.2%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:34](=[CH:35][CH:36]=1)[NH:33]C1CC(C(NC[C@@H]3OC4=C5C(=CC=C4OC3)N=C(C)C=C5)=O)CCC2=1>ClCCl>[F:23][C:24]1[CH:36]=[C:35]2[C:34](=[CH:26][CH:25]=1)[NH:33][C:8]1[CH2:7][CH2:6][CH:11]([CH:12]=[O:14])[CH2:10][C:9]2=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNC(=O)C1CCc2c([nH]c4ccc(F)cc24)C1)O3
Solvent: ClCCl
Product: O=CC1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Dess-Martin periodinane (7.37 g, 17.4 mmol) was added portion-wise to a stirred solution/suspension of alcohol II (2.64 g, 11.8 mmole) in dichloromethane (120 mL). The alcohol completely dissolved after the Dess-Martin reagent was added. The reaction mixture was stirred at ambient temperature for 30 min, and then quenched with ethanol. The reaction mixture was diluted with ether (860 mL) and washed twice with saturated aqueous sodium bicarbonate (550 mL) followed by 5% sodium thiosulfate pentahydrate. After washing with brine and drying (MgSO4), the solvent was evaporated to give a residue which was purified by chromatography on silica gel eluting with hexane/ethyl acetate (4:1). Compound V was obtained in 47% yield (1.2 g). mp: 96-98° C. MS: [M−H]− @m/z=216.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[I-].[CH3:20][N+]1C=CC=CC=1.[BH4-].[Na+]>>[C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH2:12][N:13]([CH3:20])[CH2:14][CH2:15][CH:16]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[n+]1ccccc1
Reactant: O=C(CCc1ccccc1)c1cccnc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CI
Product: CN1CCC=C(C(=O)CCc2ccccc2)C1

Procedure:
Employing the general methods of Examples 4 and 6 above, 10 g (47.3 mmol) of 3-phenyl-1-(3-pyridinyl)-1-propanone were first converted by the action of methyl iodide to the N-methylpyridinium iodide and then reduced by the action of sodium borohydride to produce 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone which was isolated as the hydrochloride salt (5.2 g, 58%), mp 195°-197° C.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:12][C:11](=C)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=[O:15].[K+].[K+]>C(Cl)Cl.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([NH:8][CH:9]1[CH2:12][C:11](=[O:15])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(=O)C1
Yield: 177.6 %

Procedure:
To a vigorously stirring solution of N-Boc-3-methylene-cyclobutanamine (9.8 g, 53.5 mmol) in DCM (160 mL) and H2O (160 mL) was added K2CO3 (3 g, 21.7 mmol), followed by NaIO4 (35 g, 163.5 mmol), tetrabutylammonium chloride (0.2 g, 0.72 mmol) and RuCl3 (0.6 g, 7.6 mmol). During the course of the reaction, the organic solution turned dark brown, the catalyst turned black, while the upper aqueous layer turned white. The reaction was monitored by TLC, and upon completion, the reaction mixture was filtered through a pad of celite. The filtrates were transferred to a separatory funnel, and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with 5% NaHCO3 (2×30 mL), brine (30 mL), dried over Na2SO4, filtered and evaporated to dryness to yield a crude, which was purified by flash chromatography (silica gel/hexanes:ethyl acetate 0-60%) to yield the desired N-Boc-3-amino-cyclobutanone (7.13 g, 38.53 mmol, 72% yield): NMR (250 MHz, CDCl3) δ 4.88 (bs, 1 H), 4.13-4.29 (m, 1 H), 3.23-3.41 (m, 2 H), 2.9-3.05 (m, 2 H), 1.39 (s, 9 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:13]([NH2:15])[CH3:14].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[Cl:2][C:3]1[C:8]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:13]([NH:15][C:45]([C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:24]3[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:34][CH:33]=1)[C:37]([CH3:49])=[C:38]2[CH3:48])=[O:46])[CH3:14]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cccc(C(F)(F)F)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 605 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH2:16]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:16]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:6](=[O:8])[C:5]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)CNCC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)CN(CC(C)C)C(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 64.8 %

Procedure:
To a slurry of 106.5 g of 2,6-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 133.2 g of diisobutylamine. Next 44.9 g of phosphorus oxychloride was added dropwise at such a rate to maintain the temperature below 40° C. The mixture was heated to 50° C. for 12 hrs and poured into 500 ml of aqueous 5% NaHCO3 solution with stirring. The organic layer was separated, washed with 500 ml water, and the toluene removed under reduced pressure. The remaining solid was recrystallized from hot ethanol to give 105.2 g of N,N-diisobutyl-2,6-dinitrobenzamide, a yellow solid, mp 97°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9]C)[CH:5]([Br:7])[CH3:6])C.[CH2:14]([C:16](CO)(CO)CC)O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[Br:7][CH:5]([C:4]12[O:3][CH2:1][C:13]([CH2:14][CH3:16])([CH2:9][O:8]1)[CH2:12][O:11]2)[CH3:6]
Reactant: CCOC(OCC)(OCC)C(C)Br
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCC12COC(C(C)Br)(OC1)OC2
Temperature: 140 °C
Yield: 63.7 %

Procedure:
25.5 g (0.1 moles) of the product obtained in step (a) above, 13.4 g (0.1 moles) of trimethylolpropane and 0.05 g of p-toluenesulfonic acid were placed in a flask fitted with a Dean & Stark condenser and the contents of the flask were heated at 140° C. for about 2 hours. The reaction was stopped when a theoretical amount of ethyl alcohol was evaporated off, after which the reaction solution was distilled under reduced pressure using a Vigreaux distillation column to yield 16 g (63%) of the desired product having a boiling point of 81°-83° C./0.1 mmHg.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.NC1C=CC([C:38]([NH2:40])=[O:39])=CN=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[N:6]=[CH:5][CH:4]=[CH:9][C:8]=2[C:38]([NH2:40])=[O:39])=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: NC(=O)c1ccc(N)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ncccc2C(N)=O)cc1

Procedure:
The product from Example 1, Part C (160 mg, 0.5 mmol) and 6-aminonicotinamide (103 mg, 0.75 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the aqueous phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (10 mg, 5%). 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2 Hz, 1H), 8.71 (br s, 1H), 8.22 (d, J=9 Hz, 1H), 8.13 (dd, J=9 Hz, 2 Hz, 1H), 7.20 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 5.05 (d, J=15 Hz, 1H), 4.63 (s, 1H), 4.13 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.94 (s, 2H), 1.95 (s, 3H), 1.83 (s, 3H). MS: m/z (MH+) 441.