Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].[C:17]1([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:17]1([S:23]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
N,N'-carbonyldiimidazole (14.45 g) was added to a solution of 10.00 g of 4-acetylamino-3-nitrobenzoic acid in 300 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, 14.03 g of benzenesulfonamide and 13.58 g of diazabicycloundecene were added thereto, and the mixture was stirred at 100° C. for 72 hours. The reaction mixture was separated with the addition of chloroform and water. The organic layer was then concentrated, and the resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) to give 12.67 g of N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[CH2:24]([Li])CCC.S(OC)(OC)(=O)=O>C1COCC1>[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH:6]([CH3:24])[CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CC1CC(c2ncc3nccc-3[nH]2)C(C)C(c2ccccc2)N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A suspension of 2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyridine (Example 35) (57 mg, 0.20 mmol) in THF (3 mL) was placed under a N2 atmosphere and cooled with a dry-ice bath to −78° C. n-Butyl lithium (Aldrich Chemical Company) (360 μL, 0.90 mmol, 4.5 equiv of a 2.5 M solution in hexanes) was added slowly. The reaction mixture was stirred at −78° C. for 1 h and allowed to warmed to 0° C. Dimethyl sulfate (Eastman Kodak Company) (73.8 mg, 0.60 mmol, 3.0) was added slowly at 0° C. The solution was allowed to warm to room temperature and stir overnight. The reaction was quenched by the addition of 10% NH4Cl (3 mL) and the THF was evaporated under reduced pressure. The solution was extracted with CHCl3 (3×50 mL), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-20%):hexanes (100-80%) to provide 20 mg (34%) of the title compound as a white solid [30 mg (53%) of recovered starting material was also obtained]. Mp: 131-132° C. 1H NMR (acetone-d6, 400 MHz): δ 7.68 (d, 2, J=7.0), 7.54 (t, 2, J=7.0), 7.47 (t, 1, J=7.0), 3.84 (s, 3), 3.40 (t, 4, J=4.9), 2.50 (s, 3), 1.78 (m, 4), 1.70 (m, 2). MS m/z: 307 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>CC(C)=O>[BrH:11].[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC(C)=O
Product: Br
Product: O=C(O)C(Sc1nc2ccccc2s1)c1ccccc1

Procedure:
A solution of 16.7 g (0.10 m) 2-mercaptobenzothiazole and 21.5 g (0.10 m) α-bromo-α-phenylacetic acid in acetone is heated to reflux for 5 hours and the solvent is then removed. The residual oil is triturated in acetone and 31 g of solid collected. The compound melts at 192°-4° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][CH2:10][O:11][C:12]([CH2:14][C:15]([C:17](OCC)=O)=O)=[O:13].P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:7][C:3]1[CH:2]=[C:1]2[C:6]([C:14]([C:12]([O:11][CH2:10][CH3:9])=[O:13])=[CH:15][C:17]([Cl:24])=[N:8]2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc2cc(N)ccc12
Reaction time: 1 h

Procedure:
To 25 g (231 mmol) of m-phenylenediamine was added 43 g (231 mmol) of diethyl oxaloacetate, followed by stirring at 160 degrees for 1 hour. After standing to cool, the crystals were washed with methanol. To a solution of the crystals (3.0 g, 13 mmol) in chloroform (30 ml) was added phosphorus oxychloride (3.6 ml), followed by heating under reflux for 1 hour. After standing to cool, the reaction mixture was poured onto ice water, basified with 1 N sodium hydroxide aqueous solution, and the resulting crystals were collected by filtration. The crystals were washed with tetrahydrofuran and the filtrate was evaporated, to give 4.85 g of the title compound.
Reaction SMILES: Cl.Cl.C1([C@H](N[C@H]2CCNC2)C)C2C(=CC=CC=2)C=CC=1.ON1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2N=N1.[CH2:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH3:32].C(=O)(O)[O-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:25]1([CH2:32][C:31]([N:33]2[CH2:36][CH2:37][CH2:35][CH2:34]2)=[O:39])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: On1nnc2ccccc21
Reactant: CCN(CC)CC
Reactant: O=C([O-])O
Agent: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To solution of 125.3 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in 5 ml of DMF were added 81.6 mg of (3-trifluoromethyl)phenylacetic acid, 84.3 mg of 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride, 67.3 mg of 1-hydroxybenzotriazole, and 153 μl of triethylamine, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture was stirred and the liquids were separated. The organic layer was washed with water and then dried, the solvent was evaporated, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=19:1) to obtain 145.7 mg of (S)-3-[(R)-(naphthalen-1-yl)ethylamino]-1 -3-trifluoromethyl)phenylacetylpyrrolidine (Example 5.017 in the following Table C).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12](B(O)O)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]2)(=O)=O.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]5)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: OB(O)c1cc2cc(C3CCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(C5CCCC5)ccc4o3)ccc2C1
Yield: 33.2 %

Procedure:
A mixture of 5-cyclopentylbenzofuran-2-ylboronic acid (78 mg, 0.34 mmol), tert-butyl 3-(6-(trifluoromethylsulfonyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (93 mg, 0.23 mmol), triethylamine (0.95 mL, 6.8 mmol) and bis(triphenylphosphine)palladium(II)chloride (16 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (34 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 2H), 7.40 (d, 2H), 7.15 (dd, 1H), 7.07 (d, 1H), 6.91 (s, 1H), 3.70 (s, 2H), 3.08 (m, 1H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.54 (dd, 2H), 2.11 (m, 2H), 1.84 (m, 2H), 1.68 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated: 445.26; Observed: 446.00 (M++1).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@:4]1([C:15]([OH:17])=[O:16])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[CH2:7][NH:6][CH2:5]1.CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[ClH:1].[NH2:3][C@:4]1([C:15]([OH:17])=[O:16])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[CH2:7][N:6]([C:33](=[O:34])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:5]1
Reactant: N[C@@]1(C(=O)O)CNC[C@@H]1CCCB(O)O
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@@]1(C(=O)O)CN(C(=O)Nc2ccc(F)cc2)C[C@@H]1CCCB(O)O
Reaction time: 1.5 h
Yield: 26.8 %

Procedure:
While under nitrogen, a stirred mixture of (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]pyrrolidine-3-carboxylic acid dihydrochloride (0.225 g, 0.623 mmol) in dry DMF (9 mL) was treated with Et3N (0.521 mL, 3.74 mmol) and 4-fluorophenyl isocyanate (92.1 uL, 0.810 mmol). After stirring for 1.5 h, the reaction mixture was diluted with water (5 mL) and acidified to pH˜1 with 3M aqueous HCl (5 mL). The aqueous phase was washed with methylene chloride (2×25 mL) and ethyl acetate (25 mL), concentrated and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[(4-fluorophenyl)carbamoyl]pyrrolidine-3-carboxylic acid hydrochloride (racemate) (65 mg, 27%) as a white amorphous solid. MS (ESI+) m/z 336 (M−H2O+H+), 318 (M−2H2O+H+) and MS (ESI−) m/z 334 (M−H2O+H+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=[O:17])(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=[O:17])(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1
Agent: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccccc3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) was synthesized according to the literature procedure of Gibson, K. H. et al. Bioorganic & Medicinal Chemistry Letters, 1997, 7(21), 2723–2728. To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.2 g, 5.13 mmol) in SOCl2 (30 mL) Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then aniline (0.47 mL, 5.13 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours, then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-7-methoxy-4-phenylamino-quinazoline as a white solid. (Yield 1.0 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([Cl:20])[N:3]=1.[C:21]([O-:24])([O-])=[O:22].[K+].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C>[Cl:20][C:4]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:8]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:7]([C:21]([OH:24])=[O:22])=[C:6]([CH3:19])[CH:5]=1.[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: C1COCCN1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C(=O)O)C(N2CCOCC2)N(Cc2cccc(F)c2)C(Cl)=C1
Product: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 17 %
Yield: 49 %

Procedure:
To a solution of 2.0 g (6.4 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2) in DMF (19 ml) were added 1.32 g (9.6 mmol) K2CO3 and 660 mg (7.7 mmol) morpholine and the RM was stirred at 90° C. for 16 h. Then the RM was poured into ice water (40 ml), followed by extraction with EtOAc (3×40 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 1.14 g (3.2 mmol, 49%) 6-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-2-morpholin-4-yl-pyridine-3-carboxylic acid and 400 mg (1.1 mmol, 17%) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[CH3:13][N:14]([CH2:19][C:20](O)=[O:21])[CH2:15][C:16](O)=[O:17].C1(C)C=CC=CC=1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([B:8]2[O:10][C:20](=[O:21])[CH2:19][N:14]([CH3:13])[CH2:15][C:16](=[O:17])[O:9]2)[CH:7]=1
Reactant: Cc1cc(Br)cc(B(O)O)c1F
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(B2OC(=O)CN(C)CC(=O)O2)c1F
Yield: 85.2 %

Procedure:
To a 50 mL round bottom flask equipped with a stir bar was added 5-bromo-2-fluoro-3-methylphenylboronic acid (1.0 g, 4.3 mmol), N-methyliminodiacetic acid (0.76 g, 5.2 mmol), toluene (8 mL) and DMSO (2 mL). The flask was fitted with a Dean-Stark trap and the Dean-Stark trap was fitted with a reflux condenser. The mixture was heated to reflux with azeotropic removal of water for 4.5 h. The solution was concentrated in vacuo. The residue was absorbed on Celite in vacuo from an acetone suspension and the resulting powder was subjected to Isco flash chromatography eluted with 0 to 70% acetonitrile in ether to give 2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (1.26 g, 86%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:17]=[C:16]([C:18]3[C:27]4[C:22](=[C:23]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH2:4][CH2:3]1.[I-].C[CH:40]=[N+:41]=[CH:42]C.[CH2:44](Cl)Cl>>[CH3:40][N:41]([CH2:42][NH:13][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([C:18]2[C:27]3[C:22](=[C:23]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)=[CH:17][C:9]=1[NH:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH3:44]
Reactant: CC=[N+]=CC
Reactant: NC(=O)c1ccc(-c2nccc3c(-c4cnc5ccccc5c4)cccc23)cc1NC1CCC(O)CC1
Reactant: ClCCl
Agent: [I-]
Product: CN(C)CNC(=O)c1ccc(-c2nccc3c(-c4cnc5ccccc5c4)cccc23)cc1NC1CCC(O)CC1
Yield: 95 %

Procedure:
A solution of compound (6) (0.050 g) and N,N-dimethylmethylene ammonium iodide (0.025 g) in methylene chloride (1 ml) was stirred overnight at room temperature. The reaction solution was partitioned between chloroform and water. The organic layer was neutralized with an aqueous sodium bicarbonate solution, then washed with brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (38) (0.053 g, 95%) as a pale yellow solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[C:15]([NH2:18])=[N:16][CH:17]=1>>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[C:15]([NH:18][CH:5]=[O:7])=[N:16][CH:17]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ncc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of acetic anhydride (49 mL, 0.5 mol) and formic acid (19 mL, 0.5 mol) was heated at 60° C. for 3 h. 5-Fluoro-3-nitropyridin-2-amine was added and the mixture was stirred at 60° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was stirred vigorously in diethyl ether (200 mL) for 30 minutes. The solid was collected by filtration to afford N-(5-fluoro-3-nitropyridin-2-yl)formamide (4.5 g, 96%) as an orange solid which did not require further purification. LCMS (ESI) m/z 186 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11]Cl)[C:6]=1[C:7]([F:10])([F:9])[F:8].[O-:22][CH2:23][CH3:24].[Na+].C(O)C>O1CCCC1.[O-]CC.[Na+].O>[Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11][O:22][CH2:23][CH3:24])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CC[O-]
Reactant: N#Cc1c(Cl)c(C(F)(F)F)n(CCl)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-chloro-1-(chloromethyl)-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (2.6 g, 0.0074 mol) in tetrahydrofuran is treated with sodium ethoxide as a 21% wt/wt solution in denatured ethanol (3.6 mL, 0.0096 mol), stirred at room temperature for 1 hour, treated with an additional 2-3 drops of the sodium ethoxide solution, heated at reflux temperature for 1 hour, cooled and poured in water. The resultant precipitate is filtered, dried and recrystallized from isopropanol to afford the title product as a white solid, 1.6 g (60% yield), mp 104.0°-104.5 C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:5][O:6][CH2:7][CH2:8]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:10]2[CH2:8][CH2:7][O:6][CH2:5][CH:4]2[C:3]([O:2][CH3:1])=[O:25])(=[O:13])=[O:12])=[CH:15][CH:16]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(COCCBr)C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulfonylamino)-propionic acid methyl ester (0.15 g, 0.35 mmol) dissolved in DMF (2 mL) and cooled in an ice bath was added potassium carbonate (0.16 g, 1.15 mmol) and the reaction was stirred at room temperature for 1 hour. After removing the solvent, the residue was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 0.09 g of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester as an oil. Yield 73.8%. Electrospray Mass Spec 354.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:15])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:18]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[F:15][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[C:18]2=[O:33])[CH2:3]1
Reactant: Oc1ccc(C2CCNCC2(F)F)cc1
Reactant: O=C1C(Br)CCN1Cc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(N2CCC(c3ccc(O)cc3)C(F)(F)C2)CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
A mixture of 4-(3,3-difluoropiperidin-4-yl)phenol (200 mg, 0.94 mmol, E-2a from step D), 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (604 mg, 1.9 mmol), triethylamine (0.65 mL, 4.7 mmol), and 2 mL of DMF was heated in a microwave reactor at 120° C. for 1 h. The cooled reaction mixture was partitioned between water and 30 mL of ethyl acetate, and the aqueous phase was again extracted with 30 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 150 mg of 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one (0.33 mmol, 35%, 2 diastereoisomers) which was purified and separated in step F. LCMS (method J) RT 0.8 min (60% AP), m/z 455.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:18]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCl)cc1
Yield: 90.4 %

Procedure:
20 g (103 millimoles) of β-(p-aminobenzoyl)-propionic acid and 12.9 g (114 millimoles) of chloroacetyl chloride, together with 200 ml of absolute toluene, are kept for 4 hours at 80° C. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 25.1 g (90% of theory) of β-(p-chloroacetylaminobenzoyl)-propionic acid are isolated as light brown crystals which, after recrystallization from acetone, melt at 184°-185° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:27][C:28](=[NH:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:37]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=3)[N:27]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
A solution of 4-isobutyl-benzoic acid (451 mg, 2.53 mmol) and 1,1′-carbonyldiimidazole (491 mg, 3.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. N-hydroxy-4-hydroxymethyl-benzamidine (420 mg, 2.53 mmol) was added to the reaction mixture, stirred at room temperature for 18 hours and diluted with ethyl acetate. The reaction mixture was washed with aqueous sodium hydroxide (0.25 N), water and brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was treated with a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.78 mL) and THF (6 mL) and stirred at room temperature for 12 hours. The reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by flash chromatography (silica, 1:9 to 2:3 EtOAc:hexanes) provided the title compound (193 mg, 29% yield) as a solid.